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NCCN Prostate Cancer Guidelines 2026

Q: Analyze how clinical trial findings inform the recommended guidelines for the use of enzalutamide in prostate cancer treatment.

Clinical trial findings play a key role in shaping the guidelines for using enzalutamide in treating prostate cancer. Trials such as the ARCHES and ARANOTE studies demonstrated significant benefits in progression-free survival (PFS) and overall survival (OS) when enzalutamide was added to androgen deprivation therapy (ADT) in metastatic castration-sensitive prostate cancer (mCSPC). These trials also highlighted enzalutamide's efficacy in delaying disease progression and reducing mortality risk, thus supporting its recommendation as a category 1 treatment option for mCSPC. The data from these studies inform guidelines by providing robust evidence of enzalutamide's effectiveness and its role as a preferred strategy in contemporary prostate cancer management, especially for patients with mCSPC .

Q: How does the use of abiraterone in combination with other treatments impact outcomes in metastatic castration-resistant prostate cancer (mCRPC)?

Abiraterone, when used in combination with other treatments such as prednisone, significantly impacts outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Clinical trials demonstrated that abiraterone improved overall survival and progression-free survival, with a noted decline in PSA levels and prolonged time to radiographic progression. Additionally, when combined with olaparib in patients with BRCA mutations, the combination therapy demonstrated improved outcomes such as enhanced median overall survival and progression-free survival, particularly in BRCA mutation-positive patients. Abiraterone's combination with olaparib has been included in the NCCN Guidelines for mCRPC in patients with BRCA mutations, highlighting its role in tailored treatment regimens aimed at optimizing patient outcomes .

Q: What are the key considerations for the incorporation of androgen receptor pathway inhibitors (ARPIs) in prostate cancer treatment strategies?

When incorporating androgen receptor pathway inhibitors (ARPIs) into prostate cancer treatment strategies, several key considerations must be addressed. One important aspect is understanding the tumor's androgen dependence and the presence of certain genetic mutations, such as those affecting the DNA repair pathway, which might influence the response to ARPIs. Clinical trials have shown benefits of using enzalutamide for patients with metastatic castration-sensitive prostate cancer (mCSPC), improving progression-free survival and overall survival. Understanding patient-specific factors such as previous therapies, volume of metastatic disease, and overall health status are crucial for determining if ARPIs should be used alone or in combination with other therapies. The choice of ARPI may also depend on the side effect profile and patient preferences .

Q: Discuss the role of shared decision-making in the management of prostate cancer patients considering active surveillance as a treatment option.

Shared decision-making is a pivotal component in managing prostate cancer patients who are considering active surveillance. This approach involves a thorough discussion between the patient and healthcare provider about the potential risks and benefits of active surveillance compared to immediate intervention. This includes consideration of the patient's life expectancy, general health condition, specific disease characteristics, and personal preferences. The data illustrate that patients with a low percentage of Gleason pattern 4 cancer and low PSA density may be better candidates for active surveillance. By including the patient in the decision-making process, a more personalized and satisfactory treatment plan can be achieved, thus improving adherence to active surveillance protocols and potentially enhancing quality of life .

Q: What are the implications of genetic testing in the management of prostate cancer, particularly in relation to treatment personalization and prognosis?

Genetic testing has significant implications in the management of prostate cancer, offering insights into treatment personalization and prognosis. Identifying germline mutations such as BRCA1 and BRCA2, or microsatellite instability, helps to stratify patients according to risk and potentially guide tailored treatment strategies, including the use of PARP inhibitors like olaparib in those with DNA repair deficiencies. Genetic profiling informs prognosis by revealing adverse prognostic indicators or predicting responses to specific therapies. Consequently, integrating genetic testing into treatment plans allows for more personalized care, potentially improving outcomes and guiding long-term management decisions .

Q: What are the factors influencing the choice between active surveillance and other treatment options for patients with favorable intermediate-risk prostate cancer?

The decision to choose active surveillance over other treatments for patients with favorable intermediate-risk prostate cancer involves several factors. These include the patient’s life expectancy, general health, disease characteristics such as tumor volume and PSA density, potential side effects of treatment, and patient preference. Heterogeneity within the low-risk group requires consideration of factors like high PSA density or a number of positive cores, which could influence the probability of grade reclassification. For Grade group 2 intermediate-risk cases, the risks of metastasis under active surveillance or observation are high, demanding careful individualized assessment of the risks versus benefits, highlighting the need for shared decision-making. Furthermore, early intervention may be appropriate based on these assessments .

Q: What are the limitations of active surveillance for low-risk prostate cancer, and how do they impact long-term patient outcomes?

The limitations of active surveillance for low-risk prostate cancer include the potential for the disease to progress to a regional or metastatic stage. Although this risk remains very low, estimated at less than 1% at 10 years and about 5% at 15 years, it underscores the importance of careful monitoring and patient selection. Additionally, current evidence with more than 10 years of follow-up is predominantly limited to low-risk patients with low-volume and low PSA density cancers. The data suggest that while many patients may avoid treatment for a significant period, the majority eventually receive treatment within 15 years post-diagnosis. These limitations suggest that while active surveillance is effective in delaying treatment, ongoing assessment is required to ensure timely intervention if disease progression occurs .

Q: In what situations is imaging deemed unnecessary during active surveillance for prostate cancer, and what factors might alter this approach?

During active surveillance for prostate cancer, metastatic staging evaluations (such as PSMA PET, bone scan, CT scan, or whole-body MRI) are generally not recommended unless the patient develops unfavorable intermediate or higher-risk disease, or exhibits symptoms that cannot be explained by other causes. This approach is designed to prevent unnecessary interventions and maintain patient quality of life. However, factors such as an increase in PSA levels or clinical findings indicative of disease progression might necessitate earlier imaging to assess changes in disease status .

Q: Evaluate the impact of long-term follow-up on understanding the safety and efficacy of active surveillance for intermediate-risk prostate cancer.

Long-term follow-up is crucial in understanding the safety and efficacy of active surveillance for intermediate-risk prostate cancer. Extended follow-up from studies such as those in the Toronto and Canary PASS cohorts indicates varying outcomes based on initial risk categorization. For example, metastasis-free survival rates over 15 years demonstrate the potential for disease progression, particularly in patients with a higher Gleason score or PSA. While initial survival rates are favorable, with 94% to 100% survival in cohorts including intermediate-risk patients, extended follow-up reveals a high rate of late metastasis, especially in cases of Gleason 4+3 disease. This highlights the need for close monitoring and possibly transitioning to treatment when progression markers are evident, ensuring timely intervention and maintaining the efficacy of surveillance strategies .

Q: How does anxiety in prostate cancer patients affect their management under active surveillance, and what role does provider education play in addressing this?

Anxiety in prostate cancer patients undergoing active surveillance is often cited as a reason for transitioning to active treatment. However, studies show that patient anxiety is closely linked to the level of education provided by the healthcare provider regarding the safety and effectiveness of active surveillance. By providing patients with comprehensive information about the safety of active surveillance, healthcare providers can help alleviate anxiety and support sound decision-making regarding surveillance versus treatment. This indicates the critical influence of patient education in maintaining adherence to surveillance protocols and reducing premature cessation of surveillance due to anxiety .

The NCCN Guidelines for Prostate Cancer (Version 4.2026) emphasize the importance of clinical trials and provide updated recommendations for diagnosis, risk stratification, and treatment of prostate cancer. Key updates include modifications to androgen deprivation therapy and imaging principles, as well as changes in terminology to enhance patient sensitivity. The guidelines serve as a consensus on accepted treatment approaches, urging clinicians to apply independent medical judgment in patient care.

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NCCN Prostate Cancer Guidelines 2026

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Prostate Cancer
Version 4.2026 — December 4, 2025

NCCN recognizes the importance of clinical trials and encourages participation when applicable and available.
Trials should be designed to maximize inclusiveness and broad representative enrollment.

NCCN Guidelines for Patients® available at [Link]/patients

Version 4.2026, 12/04/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Lim Tze Ying Benjamin on 12/14/2025 6:04:38 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 4.2026 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Daniel E. Spratt, MD/Chair § Xin Gao, MD † Tyler Robin, MD, PhD §

Case Comprehensive Cancer Center/University Dana-Farber/Brigham and Women's University of Colorado Cancer Center
Hospitals Seidman Cancer Center and Cleveland Cancer Center | Mass General Cancer Center Stan Rosenfeld ¥
Clinic Taussig Cancer Institute University of California San Francisco
Shilpa Gupta, MD †
*Sandy Srinivas, MD/Vice-Chair † w Case Comprehensive Cancer Center/University Patient Services Committee Chair
Stanford Cancer Institute Hospitals Seidman Cancer Center and Cleveland Kristen R. Scarpato, MD, MPH w
Nabil Adra, MD, MSc † Clinic Taussig Cancer Institute Vanderbilt-Ingram Cancer Center
Indiana University Melvin and Bren Joseph E. Ippolito, MD, PhD ∩ Ahmad Shabsigh, MD w
Simon Comprehensive Cancer Center Siteman Cancer Center at Barnes- The Ohio State University Comprehensive
Bilawal Ahmed, MD † Jewish Hospital and Washington Cancer Center - James Cancer Hospital
The University of Tennessee Health Science Center University School of Medicine and Solove Research Institute
Yi An, MD § R. Jeffrey Karnes, MD w Russell Szmulewitz, MD ‡ †
Yale Cancer Center/Smilow Cancer Hospital Mayo Clinic Comprehensive Cancer Center The UChicago Medicine
Rhonda Bitting, MD † Amar U. Kishan, MD § Comprehensive Cancer Center
Duke Cancer Institute UCLA Jonsson Comprehensive Cancer Center Benjamin A. Teply, MD †
Brian Chapin, MD w Michael R. Kuettel, MD, MBA, PhD § Fred & Pamela Buffett Cancer Center
The University of Texas Roswell Park Comprehensive Cancer Center Jonathan Tward, MD, PhD §
MD Anderson Cancer Center Joshua M. Lang, MD, MS † Huntsman Cancer Institute
University of Wisconsin Carbone Cancer Center at the University of Utah
Heather H. Cheng, MD, PhD †
Fred Hutchinson Cancer Center Daniel Lee, MD, MS w Richard Valicenti, MD §
Abramson Cancer Center at UC Davis Comprehensive Cancer Center
Steve Y. Cho, MD φ
The University of Pennsylvania David VanderWeele, MD, PhD †
University of Wisconsin Carbone Cancer Center
Tamara Lotan, MD ≠ Robert H. Lurie Comprehensive Cancer
Anthony Victor D’Amico, MD, PhD § Center of Northwestern University
Johns Hopkins Kimmel Cancer Center
Dana-Farber/Brigham and Women’s
Cancer Center | Mass Andrew McDonald, MD, MS § Jessica Karen Wong, MD §
General Cancer Center O'Neal Comprehensive Cancer Center at UAB Fox Chase Cancer Center
Neil Desai, MD, MHS § *Todd Morgan, MD w NCCN
UT Southwestern Simmons University of Michigan Rogel Cancer Center Deborah Freedman-Cass, PhD
Comprehensive Cancer Center Rodrigo Pessoa, MD, PhD w Emily Kovach
*Tanya Dorff, MD † Moffitt Cancer Center
City of Hope National Cancer Center Soroush Rais-Bahrami, MD, MBA w ∩ Diagnostic/ § Radiotherapy/Radiation
James A. Eastham, MD w O'Neal Comprehensive Cancer Center at UAB Interventional radiology oncology
w Urology
Memorial Sloan Kettering Cancer Center Mack Roach, III, MD § ‡ Hematology/Hematology
oncology ¶ Surgery/Surgical
*Thomas A. Farrington, BSEE ¥ UCSF Helen Diller Family † Medical oncology oncology
Prostate Health Education Network (PHEN) Comprehensive Cancer Center * Discussion Section
φ Nuclear medicine
≠ Pathology Writing Committee
NCCN Guidelines Panel Disclosures ¥ Patient advocate

NCCN Guidelines Version 4.2026 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

NCCN Prostate Cancer Panel Members Principles of Life Expectancy Estimation (PROS-A)
Summary of Guidelines Updates Principles of Survivorship in Prostate Cancer (PROS-B) Find an NCCN Member
Initial Prostate Cancer Diagnosis (PROS-1)
Institution: https://
Principles of Genetics and Molecular/Biomarker
Analysis (PROS-C) [Link]/home/
Initial Risk Stratification and Staging Workup for
Clinically Localized Disease (PROS-2) Principles of Quality of Life and Shared Decision-Making member-institutions.
Low-Risk Group (PROS-3) (PROS-D)
Favorable Intermediate-Risk Group (PROS-4) Principles of Imaging (PROS-E)
Principles of Active Surveillance and Observation (PROS-F)
NCCN Categories
Unfavorable Intermediate-Risk Group (PROS-5) of Evidence and
High- or Very-High-Risk Group (PROS-6) Principles of Androgen Deprivation Therapy (PROS-G)
Consensus: All
Regional Prostate Cancer (PROS-7) Principles of Risk Stratification and Biomarkers (PROS-H) recommendations are
Monitoring (PROS-8) Principles of Focal/Subtotal Therapy or Whole Gland Ablative category 2A unless
Therapy (PROS-I)
Radical Prostatectomy PSA Persistence/Recurrence (PROS-9) otherwise indicated.
Principles of Radiation Therapy (PROS-J)
Radiation Therapy Recurrence (PROS-10) See NCCN Categories
Principles of Surgery (PROS-K)
Workup for Second Biochemical Recurrence (BCR2) (PROS-11)
Principles of Local Secondary Therapy Post-Radiation
of Evidence and
Treatment and Monitoring for Second Biochemical Recurrence (PROS-L) Consensus.
(M0) (PROS-12)
Principles of Metastasis-Directed Therapy (MDT) (PROS-M)
Workup and Treatment of Metachronous Oligometastatic M1
CSPC (PROS-13) Principles of Non-Hormonal Systemic Therapy (PROS-N)
NCCN Categories of
Workup and Treatment of Low-Volume M1 (Metachronous or Staging (ST-1) Preference:
Synchronous) or Synchronous Oligometastatic CSPC (PROS-
14) Abbreviations (ABBR-1) All recommendations
Workup and Treatment of High-Volume M1 CSPC (PROS-15)
are considered
appropriate.
Workup and Treatment of M0 Castration-Resistant
Prostate Cancer (CRPC) (PROS-16) See NCCN Categories
Workup and Treatment of M1 CRPC (PROS-17) of Preference.
Systemic Therapy for M1 CRPC: Adenocarcinoma (PROS-18)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2025.

NCCN Guidelines Version 4.2026 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 4.2026 of the NCCN Guidelines for Prostate Cancer include:
PROS-J (9 of 11)
• Table 1, sub-header modified: EBRT + Brachytherapy Boost (combined with 45-50.4 Gy in 25-28 fx or 37.5 Gy in 15 fx).
MS-1
• The remainder of the Discussion section was updated to reflect the changes in the algorithm.

Updates in Version 3.2026 of the NCCN Guidelines for Prostate Cancer from Version 2.2026 include:
PROS-G (3 of 6)
• ADT for Patients with M0 CSPC BCR2
Sub-heading modified: For High-Risk BCR2 Useful in Certain Circumstances
Bullet 1 modified: Enzalutamide with or without Leuprolide (for high-risk BCR2)
Bullet 2 modified: Apalutamide with LHRH agonist or LHRH antagonist (for high-risk BCR2)
PROS-H
• Section extensively revised.
PROS-N (3 of 4)
• Immunotherapy, bullet 2, sub-bullet 3 added: Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV
pembrolizumab. Pembrolizumab and berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab.
MS-1
• The section of the Discussion regarding "Advanced Risk Stratification Tools" was updated to reflect the changes in the algorithm.

Updates in Version 2.2026 of the NCCN Guidelines for Prostate Cancer from Version 1.2026 include:
MS-1
• The sections of the Discussion regarding mCSPC and mCRPC were updated to reflect the changes in the algorithm.

Updates in Version 1.2026 of the NCCN Guidelines for Prostate Cancer from Version 2.2025 include:
Global
• Very-low-risk group has been removed from the Guidelines.
• Androgen receptor pathway inhibitors ("ARPIs") has replaced "other hormonal agents" throughout the Guidelines.
• References have been updated throughout the Guidelines.
PROS-1
• Workup
Top pathway
◊ Bullet 3 modified: Perform and/or collect prostate-specific antigen (PSA) and calculate PSA density.
◊ Bullet 4 modified:Obtain and Review diagnostic prostate biopsies.
Bottom pathway
◊ Bullet 3 modified: Consider Perform DRE to confirm clinical stage.
◊ Last column, pathway added: See Workup and Treatment of High-Volume M1 CSPC (PROS-15).
• Footnote d added: Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for
Distress Management (DIS-A).
• Footnote h added: See "Number of Metastatic Sites" in the Principles of MDT (PROS-M). (Also for PROS-2A, 7A, -8A, -9A, -10A, -11, -12, -13, and
-15A, and 18A)
Continued
Version 4.2026, 12/04/25 © 2025 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
UPDATES
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Lim Tze Ying Benjamin on 12/14/2025 6:04:38 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 4.2026 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Prostate Cancer from Version 2.2025 include:
PROS-2
• Additional Evaluation for Intermediate, High, and Very high, sub-bullets for soft-tissue imaging
Sub-bullet 1 modified: If regional or distant metastases are found, see PROS-7 or
Sub-bullet added: If distant metastases are found, see PROS-14 for Low-Volume M1 (Metachronous or Synchronous) or Synchronous Oligometastatic
CSPC or PROS-15 for High-Volume M1 CSPC.
PROS-2A
• Footnote removed: An ultrasound-, MRI-, or DRE-targeted lesion that is biopsied more than once and demonstrates cancer (regardless of percentage
core involvement or number of cores involved) can be considered as a single positive core.
PROS-3
• Footnote n added: Principles of Focal/Subtotal Therapy or Whole Gland Ablative Therapy (PROS-I). (Also for PROS-4, -5, -6, and -7A)
PROS-6
• ≤5 y and asymptomatic
Initial therapy modified: Observation or RT ± ADT or ADT ± RT.
PROS-7A
• Footnote x modified: Adverse laboratory/pathologic features include: positive margin(s), seminal vesicle invasion, or extracapsular extension, or
detectable PSA.
• Footnote removed: The Panel remains concerned about the problems of overtreatment related to the increased diagnosis of early prostate cancer from
PSA testing. See NCCN Guidelines for Prostate Cancer Early Detection. Active surveillance is recommended for this subset of patients.
• Footnote removed: The fine-particle formulation of abiraterone can be used instead of the standard form (category 2B; other recommended option).
(Also for PROS-9A, -10A, -15A)
PROS-9
• PSA persistence/recurrence
Life expectancy >5 y: treatment recommendations extensively revised based on No evidence of M1 and M1 disease.
PROS-9A
• Footnote q, sentence 1 modified: Observation involves monitoring the course of disease with the expectation to deliver definitive or palliative therapy for
the development of symptoms or a change in examination or PSA that suggests symptoms are imminent.
• Footnote jj added: Treatment for a first biochemical recurrence has historically been referred to as 'salvage' therapy. In efforts to use language that is
more sensitive to patients, the NCCN Guidelines for Prostate Cancer refer to treatment in this setting as 'secondary' therapy. (Also for PROS-10A)
• Footnote ll added: For patients with PSA progression who have not received treatment for a first BCR, continue monitoring or consider treatment for first
PSA persistence/recurrence. See PROS-9 for RP PSA persistence/recurrent or PROS-10 for RT recurrence. (Also for PROS-10A)
• Footnote removed: If considering treatment, reinitiate the PROS-10 algorithm.
PROS-10
• PSA recurrence or positive DRE
Life expectancy >5 y: treatment recommendations extensively revised based on No evidence of M1 and M1 disease.
PROS-11
• New page added: Second Biochemical Recurrence (BCR2).
PROS-12
• Page changed
New algorithm added: Treatment and Monitoring for Second Biochemical Recurrence (N0M0).
Algorithm removed: Treatment and Monitoring for Progressive M0 Castration-Sensitive Prostate Cancer (CSPC) After Maximal Pelvic Therapy.
• Footnote pp added: PSA level and PSADT should be considered when deciding whether to begin ADT for patients considered to have low risk disease.
High-risk BCR has different definitions in different clinical trials that generally includes a PSADT ≤9 months and other adverse prognostic features.
Continued
Version 4.2026, 12/04/25 © 2025 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
UPDATES
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Lim Tze Ying Benjamin on 12/14/2025 6:04:38 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 4.2026 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Prostate Cancer from Version 2.2025 include:
PROS-12(continued)
• Footnote qq modified: For patients with non-metastatic castration-sensitive disease, (by CT, MRI, or bone scan) who are not candidates for pelvic
therapy, monitoring until diagnosis of metastatic disease is preferred. PSADT and Grade Group should be considered when deciding whether to begin
ADT for patients with M0 disease. For ADT alone If favorable PSA response, an intermittent ADT approach should be considered. can be considered to
reduce toxicity.
PROS-13
• New page added: Workup and Treatment of Metachronous Oligometastatic CSPC.
PROS-14
• Page header modified: Workup and Treatment of Low-Volume M1 (Metachronous or Synchronous) or Synchronous Oligometastatic CSPC.
• Synchronous low-volume metastases or Synchronous oligometastatic disease, second option modified: ADT with docetaxel and one of the following
(low-volume disease only).
• Progression modified: Progression on ADT ± ARPI.
PROS-15
• Page header modified: Workup and Treatment of High-Volume M1 CSPC.
PROS-15A
• Footnote zz added: Concurrent MDT can be considered in select patients with oligometastatic disease. See Principles of MDT (PROS-M).
• Footnote removed: Stereotactic body RT (SBRT) to metastases can be considered in appropriate clinical situations. See Principles of Radiation Therapy
(PROS-I).
PROS-18
• Systemic Therapy for M1 CRPC: Adenocarcinoma
Page extensively revised and reorganized by Pre-ARPI, Post-ARPI/Pre-Docetaxel, Post-ARPI/Post-Docetaxel, Additional Options Irrespective of Prior
ARPI or Prior Docetaxel.
PROS-18A
• Footnote kkk modified: Novel hormone ARPI therapies include abiraterone, enzalutamide, darolutamide, or apalutamide. Abiraterone given as part of
neoadjuvant/concomitant/adjuvant ADT with EBRT is not considered post-ARPI prior novel hormone therapy.
• Footnote mmm added: Principles of MDT (PROS-M).
• Footnote ooo, sentence 3 added: There are limited data to support the efficacy of Sipuleucel-T in the post-chemotherapy setting.
• Footnote removed: Principles of Radiation Therapy (PROS-I).
• Footnote removed: Visceral metastases refers to liver, lung, adrenal, peritoneal, and brain metastases. Soft tissue/lymph node sites are not considered
visceral metastases.
• Footnote removed: Pan-cancer, tumor-agnostic treatments can be considered for patients with actionable mutations.
• Footnote removed: The fine-particle formulation of abiraterone can be used instead of the standard form (other recommended option).
• Footnote removed: The fine-particle (category 2B; other recommended option) or standard formulation of abiraterone can be given with single-agent
niraparib as a substitute for the combination of niraparib/abiraterone tablet.
PROS-B
• Section renamed: Principles of Survivorship.
PROS-B (5 of 6)
• New page added: Cardiovascular Disease in Prostate Cancer.
PROS-B (6 of 6)
• New page added: Cardiovascular Disease in Prostate Cancer: Risk Assessment.

Continued
Version 4.2026, 12/04/25 © 2025 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
UPDATES
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Lim Tze Ying Benjamin on 12/14/2025 6:04:38 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 4.2026 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Prostate Cancer from Version 2.2025 include:
PROS-D
• Bullet 5 added: Consider geriatric assessment. See NCCN Guidelines for Older Adult Oncology for tools to aid optimal assessment and management of
disease in older adults.
• Bullet 6 added: Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for
Distress Management (DIS-A).
PROS-E (2 of 5)
• Bone Imaging
Bullet 2 modified: Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 piflufolastat prostate-specific membrane antigen (PSMA), Ga-68 PSMA-11,
F-18 flotufolastat PSMA, F-18 fluciclovine, F-18 sodium fluoride, or C-11 choline can be considered for equivocal results on initial bone scan.
PROS-E (3 of 5)
• Full Body Imaging
Positron Emission Tomography
◊ Bullet 1
– Sub-bullet 1, last sentence modified: See Table 1 on PROS-E (5 of 5) 2 in the discussion section for more details.
– Sub-bullet 3 modified: PSMA-PET/CT or PET/MRI can be considered as an alternative to CT, MRI, and bone scans for initial staging in
unfavorable intemediate-, high-, and very-high-risk disease, the detection...
– Sub-bullet 4 added: PSMA-PET imaging should only be used in the setting of M1 CRPC to determine if a patient is a candidate for Lu-177-
PSMA-617.
– Sub-bullet 5 added: Changes in systemic therapy should not be made solely based on a positive PSMA-PET in patients with M0 CRPC.
– Sub-bullet 6 added: Bone scans can be considered to confirm osseous uptake on PET scans.
– Sub-bullet 8 modified: C-11 choline or F-18 fluciclovine PET/CT or PET/MRI...
– Sub-bullet 9 modified: Studies suggest that PSMA-PET imaging has a higher sensitivity than C-11 choline or F-18 fluciclovine PET imaging,
especially at very low PSA levels (eg, <0.5 ng/mL).
PROS-E (4 of 5)
• Sub-bullet modified (continued from PROS-E [3 of 5]) ...interpretation of scans. The use of a standardized reporting system is encouraged. Several
reporting systems have been proposed but will not have been validated or widely used.
• Sub-bullet 3 modified: Table 1 on PROS-E (5 of 5) in the discussion section provides a summary of the main imaging tracers utilized for study in
prostate cancer both before definitive therapy and at recurrence.
• Imaging as Workup for Progression
Bullet 2 modified: Imaging for patients with progressive mCRPC should included chest CT, bone imaging, and abdomen/pelvis CT with contrast or
abdomen/pelvis MRI with and without contrast.
Bullet 3 modified: There is a lack of evidenced to support the use of PET imaging in this the CRPC setting and it should only be used in the setting of
M1 CRPC to determine if a patient is a candidate for Lu-177-PSMA-617. Changes in treatment should not be made solely based on a positive PSMA-
PET in patients with M0 CRPC.
PROS-E (5 of 5)
• New table added: FDA-Cleared PET Imaging Tracers Studied in Prostate Cancer.
• Footnote a added: Interpret with caution. Wherever possible, studies were included that used histopathologic confirmation, but not all studies used
confirmatory histology as the gold standard. Values may vary depending upon the site of the lesion and phase of the disease process.
• Footnote b added: CLR: Correct localization rate. Patient-level positive predictive value + anatomic lesion co-localization. Preferred over sensitivity and
specificity in analyses of patients with BCR.

Continued
Version 4.2026, 12/04/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
UPDATES
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Lim Tze Ying Benjamin on 12/14/2025 6:04:38 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 4.2026 NCCN Guidelines Index

Table of Contents
Prostate Cancer Discussion

Updates in Version 1.2026 of the NCCN Guidelines for Prostate Cancer from Version 2.2025 include:
PROS-F
• Principles of Active Surveillance: Section extensively revised.
PROS-G (1 of 6)
• Neoadjuvant, Concurrent, and/or Adjuvant ADT with RT
Bullet 4 modified: First M0 RP PSA persistence/recurrence (without maximal pelvic therapy).
Notes
◊ Bullet 1 added: ADT is not recommended with RT for most patients with favorable intermediate-risk prostate cancer. If it is given (see Principles of
Risk Stratification), the duration should be short term (4–6 months).
◊ Bullet 4 modified: For high-risk and very-high-risk prostate cancer...
◊ Bullet 6 modified: First M0 PSA persistence/recurrence:
– Sub-bullet 3 added: For patients treated with secondary RT in the setting of first RP recurrence, if ADT is given, it should be for a duration of 6 to
24 months.
PROS-G (2 of 6)
• ADT for Patients with M0 CSPC, bullet 2 modified: First M0 RT recurrence (without maximal pelvic therapy).
PROS-G (3 of 6)
• ADT for Patients with M0 CSPC BCR2 After Maximal Pelvic Therapy.
Useful in Certain Circumstances
◊ Bullet 1 modified: Enzalutamide with or without leuprolide (for high-risk BCR2).
◊ Bullet 2 modified: Apalutamide with LHRH agonist or LHRH antagonist (category 2B) (for high-risk BCR2).
Notes, bullet 1 modified: Monitoring until diagnosis of metastatic disease is preferred for patients with M0 CSPC in the low-risk BCR2 setting non-
metastatic castration-sensitive disease who are not candidates for pelvic therapy.
Footnote c added: For patients receiving MDT with ADT, the ADT options are LHRH agonist or LHRH antagonist.
PROS-G (5 of 6)
• ADT Monotherapy
Notes
◊ Bullet 1 modified: ADT monotherapy is appropriate for patients with life expectancy ≤5 years whose cancer progressed on observation of localized
disease, who are symptomatic or who have N1M0 disease and in select patients with high- or very-high-risk disease, where complications, such as
hydronephrosis or metastasis, can be expected within 5 years.
◊ Bullet 2 modified: ADT monotherapy is also used for asymptomatic patients with high-risk, very-high-risk, and regional disease and life expectancy
≤5 years whether or not RT is given.
• Footnote h added: In the mCRPC setting, this option should only be used for select patients who are not candidates for other recommended mCRPC
therapies.
PROS-G (6 of 6)
• Optimal ADT, bullet removed: Data are limited on long-term adherence to oral relugolix and the potential effects on optimal ADT. Ongoing monitoring
for sustained suppression of testosterone (<50 ng/dL) can be considered, and relugolix may not be a preferred agent if adherence to the prescribed
regimen is uncertain.
PROS-I
• New section added: Principles of Focal/Subtotal Therapy or Whole Gland Ablative Therapy.
PROS-J
• Principles of Radiation Therapy: Section extensively revised.

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Updates in Version 1.2026 of the NCCN Guidelines for Prostate Cancer from Version 2.2025 include:
PROS-K
• Pelvic Lymph Node Dissection
Bullet 1, sub-bullet 5 modified: PLND can be performed using an open, laparascopic, or robotic technique and can provide staging and prognostic
information.
Bullet removed: While PLND at the time of RP has not been shown to improve oncologic outcomes, it can provide staging and prognostic information.
PROS-L (1 of 2)
• Bullet 1 modified: Patients with biopsy-proven recurrence in the prostate after prior RT and without distant metastatic disease can be considered for
local therapy. Monitoring is also an option (see PROS-10). ADT may also be included, but it should not be reflexively ordered.
• Bullet 3 modified: Local therapy options for patients with recurrence in the prostate only include:...
Sub-bullet 2 modified: High-intensity focused ultrasound (HIFU) (category 2B).
Sub-bullet 3 added: Irreversible electroporation (IRE) (category 2B).
Sub-bullet removed: Non-surgical strategies.
• Bullet and sub-bullets removed: Local therapy options for patients with recurrence in the regional nodes with or without prostate recurrence include:
ADT + pelvic lymph node radiation (if not previously done), ADT + pelvic lymph node reirradiation (category 2B), ADT + PLND (category 2B), Pelvic
lymph node radiation, PLND.
• Footnote a added: Reirradiation with LDR brachytherapy, HDR brachytherapy, and SBRT is supported by phase II trials with >36 months of median
follow-up and should be strongly considered as an option in patients with >2 years interval from prior radiation who do not have ongoing moderate
or higher grade radiation-associated toxicities. Phase II data with >36 months of median follow-up are available, albeit to a more limited scope, for
secondary RP, cryotherapy, and HIFU.
• Footnote b added: Currently, all phase II and/or prospectively accrued registries reporting oncologic outcomes with >36 months of follow-up have
pursued whole gland treatments. Focal therapy for prostate-only recurrences is the subject of active investigation. See Principles of Focal/Subtotal
Therapy or Whole Gland Ablative Therapy (PROS-I).
• Footnote c added: There are no prospective data to guide the use and duration of ADT with reirradiation for prostate-only recurrences. The Panel
recommends extrapolation from the definitive treatment setting to suggest that adding ADT or prolonging it in this setting likely offers an improvement in
biochemical control. See Principles of Radiation Therapy (PROS-J).
PROS-M
• New section added: Principles of Metastasis-Directed Therapy.
PROS-N (1 of 4)
• Non-Hormonal Systemic Therapy for M1 Castration-Sensitive Prostate Cancer
Bullet 1 modified: Patients with low-volume synchronous or high-volume castration-sensitive metastatic prostate cancer who are fit for chemotherapy
should be considered for Triple therapy with ADT, certain ARPIs, and docetaxel is an option for certain patients with mCSPC who are fit for
chemotherapy based on phase 3 studies:
PROS-N (2 of 4)
• Non-Hormonal Systemic Therapy for M1 CRPC
Chemotherapy
◊ Bullet 1
– Sub-bullet 4 modified: Docetaxel retreatment can be attempted after progression on an ARPI and docetaxel novel hormone therapy in patients
with mCRPC whose cancer has not yet demonstrated definitive evidence of progression on prior docetaxel therapy in either the castration-

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Updates in Version 1.2026 of the NCCN Guidelines for Prostate Cancer from Version 2.2025 include:
sensitive setting or the mCRPC setting.
– Sub-bullet 5 added: Rare patients may have exposure to docetaxel without prior ARPI (ie, in the setting of EBRT to the primary tumor for low-
volume synchronous mCSPC). Docetaxel rechallenge is not recommended for such patients in the pre-ARPI mCRPC setting.
Bullet 2, sub-bullet 5 added: Biweekly cabazitaxel at 16 mg/m2 dose with G-CSF in patients ≥65 years in a Phase 3 trial. Clinical outcomes were
comparable between the 2 groups.
PROS-N (3 of 4)
• Non-Hormonal Systemic Therapy for M1 CRPC
PARP Inhibitors With or Without ARPIs: Subsection extensively revised.
Immunotherapy
◊ Bullet 2 modified: Pembrolizumab is an option for certain patients with MSI-H/dMMR mCRPC and MSI-H, dMMR, or TMB ≥10 mut/mB (PROS-18).
– Sub-bullet 2 added: Limited data suggest that pembrolizumab may be associated with some benefit in patients with mCRPC and TMB ≥10 mut/
mB. Lenis AT, et al. Clin Canc Res 2024;30:3894-3903.
◊ Bullet removed: Patients with asymptomatic or minimally symptomatic mCRPC may consider immunotherapy.
PROS-N (4 of 4)
• Table added: Table 1. PARP Inhibitors with or without ARPIs.

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INITIAL PROSTATE CANCER WORKUP

DIAGNOSISa,b,c,d
• Perform physical exam
• Perform digital rectal examination (DRE) to confirm
clinical stage
• Perform and/or collect prostate-specific antigen
(PSA) Initial Risk
• Review diagnostic prostate biopsies Stratification and
Clinically localized prostate cancer
• Estimate life expectancy (Principles of Life Staging Workup for
(Any T, N0, M0 or Any T, NX, MX)
Expectancy Estimation [PROS-A]) Clinically Localized
• Inquire about known high-risk germline mutations Disease (PROS-2)
and family historye
Perform somatic and/or germline testing as
appropriatee
• Assess quality-of-life measuresf
Regional Prostate
• Perform physical examination Cancer (PROS-7)
• Perform bone and soft tissue imaging for stagingg
Workup and Treatment
Regional prostate cancer • Consider DRE to confirm clinical stage
of Low-Volume M1
(Any T, N1, M0) • Perform and/or collect PSA and calculate PSA
(Metachronous
doubling time (PSADT)
or Synchronous)
• Estimate life expectancy (Principles of Life
or Synchronous
Expectancy Estimation [PROS-A])
Oligometastatich
Metastatic prostate cancer • Inquire about known high-risk germline mutations
Castration-Sensitive
(Any T, Any N, M1) and family historye
Prostate Cancer (CSPC)
Perform somatic and/or germline testing as
(PROS-14)
appropriatee
• Assess quality-of-life measuresf Workup and
Treatment of
High-Volume M1
a See NCCN Guidelines for Older Adult Oncology for tools to aid optimal assessment and management of disease in older adults. CSPC (PROS-15)
b NCCN Guidelines for Prostate Cancer Early Detection.
c Principles of Survivorship in Prostate Cancer (PROS-B).
d Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management (DIS-A).
e Principles of Genetics and Molecular/Biomarker Analysis (PROS-C).
f Principles of Quality of Life and Shared Decision-Making (PROS-D).
g Principles of Imaging (PROS-E).
h See Number of Metastatic Sites in the Principles of MDT (PROS-M).

Note: All recommendations are category 2A unless otherwise indicated.

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INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASEi

Clinical/Pathologic Features
Risk Group Additional Evaluationg,l Initial Therapy
(Staging, ST-1)
Has all of the following:
• cT1–cT2a • Confirmatory testing can be used to assess the
Lowj • Grade Group 1 appropriateness of active surveillance (PROS-F 2 of 5) PROS-3
• PSA <10 ng/mL
Has all of the Has all of the following:
following: • 1 IRF
• No high-risk group Favorable • Grade Group 1 or 2 • Confirmatory testing can be used to assess the
intermediate • <50% biopsy cores PROS-4
features appropriateness of active surveillance (PROS-F 2 of 5)
• No very-high-risk positive (eg, <6 of 12
group features cores)k
Intermediatej • Has one or more Has one or more of the • Soft tissue imaging and consider bone imagingg
intermediate risk following: If regional metastases are found, see PROS-7
factors (IRFs): • 2 or 3 IRFs If distant metastases are found, see PROS-14 for Low-
Unfavorable
cT2b–cT2c • Grade Group 3 PROS-5
Grade Group 2 intermediate Volume M1(Metachronous or Synchronous) or Synchronous
• ≥50% biopsy cores
or 3 positive (eg, ≥6 of 12 Oligometastatich CSPC or PROS-15 for High-Volume M1
PSA 10–20 ng/mL cores)k CSPC
Bone and soft tissue imagingg
Has one or more high-risk features, but does not meet criteria If regional metastases are found, see PROS-7
for very high risk: If distant metastases are found, see PROS-14 for Low-
High • cT3–cT4 PROS-6
• Grade Group 4 or Grade Group 5 Volume M1 (Metachronous or Synchronous) or Synchronous
• PSA >20 ng/mL Oligometastatich CSPC or PROS-15 for High-Volume M1
CSPC
Bone and soft tissue imagingg
Has at least two of the following: If regional metastases are found, see PROS-7
• cT3–cT4 If distant metastases are found, see PROS-14 for Low-
Very high PROS-6
• Grade Group 4 or 5 Volume M1 (Metachronous or Synchronous) or Synchronous
• PSA >40 ng/mL Oligometastatich CSPC or PROS-15 for High-Volume M1
CSPC

Note: All recommendations are category 2A unless otherwise indicated. Footnotes on PROS-2A

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INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASE
g Principles of Imaging (PROS-E).
h See Number of Metastatic Sites in the Principles of MDT (PROS-M).
i Tumor-based molecular assays and germline genetic testing are other tools that can assist with risk stratification. See CRIT-6 in the NCCN Guidelines for Genetic/
Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and HRS-3 in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal,
Endometrial, and Gastric to determine if a patient is an appropriate candidate for germline genetic testing, and see Principles of Risk Stratification and Biomarkers
(PROS-H) to determine if a patient is an appropriate candidate for tumor-based molecular assays.
j For patients who are asymptomatic in low- and intermediate-risk groups with life expectancy ≤5 years, no imaging or treatment is indicated until the patient becomes
symptomatic, at which time imaging can be performed [Principles of Imaging (PROS-E)] and androgen deprivation therapy (ADT) should be given [Principles of
Androgen Deprivation Therapy (PROS-G)].
k Percentage of positive cores in the intermediate-risk group is based on biopsies that include systematic biopsies with or without targeted MRI-guided biopsies. The
Panel considers biopsies from a single region of interest (ROI) to count as a single sample.
l Bone imaging should be performed for any patient with symptoms consistent with bone metastases.

Note: All recommendations are category 2A unless otherwise indicated.

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LOW-RISK GROUP
EXPECTED INITIAL THERAPYn
PATIENT
SURVIVALm
Progressive diseaser
Active surveillance (preferred for most patients)o,p,s Initial Risk Stratification and
Active Surveillance Program (PROS-F 2 of 5) Staging Workup for Clinically
Localized Disease (PROS-2)

Radiation Therapy Recurrence

Biochemical recurrencev
(PROS-10)
≥10 y Radiation therapy (RT)t
No biochemical recurrence
Monitoring for Initial
Definitive Therapy
No adverse featuresx
(PROS-8)
and no lymph node
metastases
Undetectable PSA
Monitoring (category 1,
Adverse feature(s)x preferred for adverse features)
Radical or (PROS-8)
prostatectomyu (RP) lymph node metastases OR
Consider treatment (PROS-9)

Radical Prostatectomy PSA

PSA persistencew
Persistence/Recurrence (PROS-9)

<10 yj Observationq Monitoring (PROS-8)

Note: All recommendations are category 2A unless otherwise indicated. Footnotes on PROS-7A

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FAVORABLE INTERMEDIATE-RISK GROUP

EXPECTED INITIAL THERAPYn
PATIENT
Progressive diseaser
SURVIVALm
Initial Risk Stratification and
Active surveillanceo,p,y
Staging Workup for Clinically
Active Surveillance Program (PROS-F 2 of 5)
Localized Disease (PROS-2)

No adverse featuresx and Monitoring for Initial Definitive

no lymph node metastases Therapy (PROS-8)
Undetectable PSA
Monitoring (category 1,
Adverse feature(s)x preferred for adverse features)
or (PROS-8)
>10 y RPu lymph node metastases OR
Consider treatment (PROS-9)
Radical Prostatectomy PSA
PSA persistencew Persistence/Recurrence
(PROS-9)

Radiation Therapy Recurrence

Biochemical recurrencev
(PROS-10)
RTt
Monitoring for Initial Definitive
No biochemical recurrence
Therapy (PROS-8)

5–10 yj

Observation (preferred)q Monitoring (PROS-8)

Note: All recommendations are category 2A unless otherwise indicated. Footnotes on PROS-7A

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UNFAVORABLE INTERMEDIATE-RISK GROUP

EXPECTED INITIAL THERAPYn
PATIENT
SURVIVALm
No adverse featuresx and Monitoring for Initial Definitive
no lymph node metastases Therapy (PROS-8)

Undetectable PSA
Monitoring (category 1,
Adverse feature(s)x preferred for adverse features)
or (PROS-8)
RPu lymph node metastases OR
Consider treatment (PROS-9)
Radical Prostatectomy PSA
PSA persistencew Persistence/Recurrence
>10 yz (PROS-9)

Radiation Therapy
Biochemical recurrencev Recurrence (PROS-10)
RTt + ADTc,aa
(4–6 mo)
Monitoring for Initial Definitive
No biochemical recurrence Therapy (PROS-8)

5–10 yj

Observationq Monitoring (PROS-8)

Note: All recommendations are category 2A unless otherwise indicated. Footnotes on PROS-7A

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HIGH- OR VERY-HIGH-RISK GROUP

EXPECTED INITIAL THERAPYn
PATIENT
SURVIVALm
RTt + androgen deprivation therapy
(ADT) (12–36 mo)c,aa (category 1) Biochemical recurrencev
Radiation Therapy
Recurrence (PROS-10)
or
No biochemical recurrence
RTt + ADT (24 mo)c,aa + abiraterone
(for very-high-risk only)
Monitoring for Initial
Definitive Therapy (PROS-8)
No adverse featuresx and no
>5 y or lymph node metastases
symptomaticz
Undetectable PSA
Monitoring (category 1, preferred
Adverse feature(s)x
for adverse features)cc (PROS-8)
or
OR
lymph node metastases
RPu,bb Consider treatment (PROS-9)

Radical Prostatectomy PSA

PSA persistencew Persistence/Recurrence
(PROS-9)

Workup and Treatment of Metachronous

Oligometastatich M1 CSPC (PROS-13)

Observationq Workup and Treatment of Low-Volume M1

≤5 y and
or Symptomatic progression (Metachronous or Synchronous) or Synchronous
asymptomatic
RTt ± ADTc,aa Oligometastatich CSPC (PROS-14)
Workup and Treatment of High-Volume M1
CSPC (PROS-15)

Note: All recommendations are category 2A unless otherwise indicated. Footnotes on PROS-7A

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REGIONAL PROSTATE CANCER (ANY T, N1, M0)

EXPECTED INITIAL THERAPY
PATIENT
SURVIVALm Radiation Therapy
RTt + ADTc,aa (24 mo) + Biochemical recurrencev
Recurrence (PROS-10)
abiraterone (preferred)
or
RTt + ADTc,aa (24–36 mo) No biochemical recurrence

Monitoring for Initial

Definitive Therapy (PROS-8)
>5 y or ADTc,aa ± abiraterone
symptomatic
No adverse featuresx and no
lymph node metastases

Undetectable PSA
Adverse feature(s)x Monitoring (PROS-8)
RPu in or OR
select lymph node metastases Consider treatment (PROS-9)
patientsdd

Radical Prostatectomy PSA

PSA persistencew Persistence/Recurrence
(PROS-9)
Workup and Treatment of Metachronous
Oligometastatich M1 CSPC (PROS-13)
Observationq Workup and Treatment of Low-Volume M1
Symptomatic progression (Metachronous or Synchronous) or Synchronous
or
≤5 y and RTt Oligometastatich CSPC (PROS-14)
asymptomatic or Workup and Treatment of High-Volume M1 CSPC
(PROS-15)
ADTc,aa ± RTt Symptomatic progression Workup and Treatment of M1 CRPC (PROS-17)

Note: All recommendations are category 2A unless otherwise indicated. Footnotes on PROS-7A

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FOOTNOTES
c Principles of Survivorship in Prostate Cancer (PROS-B). v RTOG-ASTRO (Radiation Therapy Oncology Group - American Society for
h See Number of Metastatic Sites in the Principles of MDT (PROS-M). Radiation Oncology) Phoenix Consensus: 1) PSA increase by ≥2 ng/mL above the
j For patients who are asymptomatic in low- and intermediate-risk groups with nadir PSA is the standard definition for PSA recurrence after external beam RT
life expectancy ≤5 years, no imaging or treatment is indicated until the patient (EBRT) with or without hormone therapy; and 2) a recurrence evaluation should
becomes symptomatic, at which time imaging can be performed [Principles of be considered when PSA has been confirmed to be increasing after radiation even
Imaging (PROS-E)] and ADT should be given [Principles of Androgen Deprivation if the increase above nadir is <2 ng/mL, especially in candidates for secondary
Therapy (PROS-G)]. local therapy who are young and healthy. Retaining a strict version of the ASTRO
m Principles of Life Expectancy Estimation (PROS-A). definition allows comparison with a large existing body of literature. Rapid increase
n Principles of Focal/Subtotal Therapy or Whole Gland Ablative Therapy (PROS-I). of PSA may warrant evaluation (prostate biopsy) prior to meeting the Phoenix
o Active surveillance involves actively monitoring the course of disease with the definition, especially in patients who are younger or healthier.
w PSA persistence/recurrence after RP is defined as when PSA does not fall to
expectation to intervene with potentially curative therapy if the cancer progresses.
See Principles of Active Surveillance and Observation (PROS-F). undetectable levels (PSA persistence) or undetectable PSA after RP with a
p Confirmatory testing can be used to assess the appropriateness of active subsequent detectable PSA that increases on ≥2 determinations (PSA recurrence)
surveillance (PROS-F 2 of 5). If higher grade and/or higher T stage is found during or increases to PSA >0.1 ng/mL. Trials indicating noninferiority of early RT
confirmatory testing, see PROS-2. compared with adjuvant RT after RP have used a PSA threshold of 0.1 or 0.2
q Observation involves monitoring the course of disease with the expectation ng/mL to trigger treatment. Imaging and treatment at lower PSA levels may be
to deliver definitive or palliative therapy for the development of symptoms or appropriate in patients at high risk for progression based on pretreatment risk
a change in examination or PSA that suggests symptoms are imminent. See factors, pathologic parameters, timing of recurrence, and genomic classifier (GC)
Principles of Active Surveillance and Observation (PROS-F). score, among other factors.
r Criteria for progression are not well-defined and require physician judgment; x Adverse pathologic features include: positive margin(s), seminal vesicle invasion,
however, a change in risk group strongly implies disease progression. See or extracapsular extension.
y Particular consideration to active surveillance may be appropriate for those
Discussion.
s The Panel recognizes that there is heterogeneity across the low-risk group, and patients in the favorable intermediate-risk group with a low percentage of Gleason
that some factors may be associated with an increased probability of near-term pattern 4 cancer, low tumor volume, low PSA density, and/or low genomic
grade reclassification, including high PSA density, a high number of positive cores risk (from tissue-based molecular tumor analysis). See Principles of Active
(eg, ≥3), high genomic risk (from tissue-based molecular tumor analysis), and/or a Surveillance and Observation (PROS-F).
z Active surveillance of unfavorable intermediate and high-risk clinically localized
known BRCA2 germline mutation. In some of these cases, upfront treatment with
RP or prostate RT may be preferred based on shared decision-making with the cancers is not recommended in patients with a life expectancy >10 years
patient. See Principles of Active Surveillance and Observation (PROS-F). (category 1).
t Principles of Radiation Therapy (PROS-J). aa For details on the use of ADT and androgen receptor pathway inhibitors (ARPIs) ,
u Principles of Surgery (PROS-K). see Principles of Androgen Deprivation Therapy (PROS-G) and Discussion.
bb RP + pelvic lymph node dissection (PLND) can be considered in patients who are
younger and healthier without tumor fixation to the pelvic sidewall.
cc Monitoring is not preferred for patients with multiple high-risk features.
dd There is limited evidence that RP + PLND is beneficial in the setting of node-
positive disease. Use of this approach should be limited to patients with >10-year
life expectancy and resectable disease and should be used in the context of a
clinical trial or planned multimodality approach.

Note: All recommendations are category 2A unless otherwise indicated.

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Prostate Cancer Discussion

MONITORING RECURRENCE
See NCCN Guidelines for Survivorship
Radical Prostatectomy
PSA PSA Persistence/
Post-RP
persistence/recurrencew Recurrence (PROS-9)

• PSA every 6–12 mo

for 5 y,ee then every PSA recurrencev Radiation
year Post-RT or Therapy Recurrence
Initial definitive therapy • Consider DRE Positive DRE (PROS-10)
if suspicion of
recurrence Workup and Treatment of
Metachronous Oligometastatich
CSPC (PROS-13)
Radiographic
evidence of Workup and Treatment of Low-Volume
Biopsy of M1 (Metachronous or Synchronous) or
metastatic metastatic
disease without Synchronous Oligometastatich CSPC
site (PROS-14)
PSA persistence/
recurrence Workup and Treatment of High-
Volume M1 CSPC (PROS-15)

Systemic Therapy for

• Physical examination N1,M0 M0 CRPC (PROS-16)
N1 on ADT
+ PSA every 3–6 mo
or Progressionff,gg
• Imaging for symptoms
Localized on observation Workup and Treatment of
or increasing PSAg M1 M1 CRPC (PROS-17)

Footnotes on PROS-8A
Note: All recommendations are category 2A unless otherwise indicated.

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MONITORING AND RECURRENCE

FOOTNOTES
g Principles of Imaging (PROS-E).
h See Number of Metastatic Sites in the Principles of MDT (PROS-M).
v RTOG-ASTRO Phoenix Consensus: 1) PSA increase by ≥2 ng/mL above the nadir PSA is the standard definition for PSA recurrence after EBRT with or without
hormone therapy; and 2) a recurrence evaluation should be considered when PSA has been confirmed to be increasing after radiation even if the increase above nadir
is <2 ng/mL, especially in candidates for secondary local therapy who are young and healthy. Retaining a strict version of the ASTRO definition allows comparison with
a large existing body of literature. Rapid increase of PSA may warrant evaluation (prostate biopsy) prior to meeting the Phoenix definition, especially in patients who
are younger or healthier.
w PSA persistence/recurrence after RP is defined as when PSA does not fall to undetectable levels (PSA persistence) or undetectable PSA after RP with a subsequent
detectable PSA that increases on ≥2 determinations (PSA recurrence) or increases to PSA >0.1 ng/mL. Trials indicating non-inferiority of early RT compared with
adjuvant RT after RP have used a PSA threshold of 0.1 or 0.2 ng/mL to trigger treatment. Imaging and treatment at lower PSA levels may be appropriate in patients at
high risk for progression based on pretreatment risk factors, pathologic parameters, timing of recurrence, and GC score, among other factors.
ee PSA as frequently as every 3 mo may be necessary to clarify disease status, especially in patients at high risk of recurrence.
ff Document
castrate levels of testosterone if clinically indicated. Workup for progression should include bone and soft tissue evaluation. See Principles of Imaging
(PROS-E).
gg Treatment for patients with life expectancy ≤5 y whose cancer progressed on observation of localized disease is ADT. See Principles of Androgen Deprivation
Therapy (PROS-G).

Note: All recommendations are category 2A unless otherwise indicated.

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RADICAL PROSTATECTOMY PSA TREATMENT FOR FIRST PSA

PERSISTENCE/RECURRENCEhh PERSISTENCE/RECURRENCEjj

EBRTt (preferred) ±
Workup
ADTc,aa
Second for Second
No evidence (± abiraterone for N1
Monitoringkk biochemical Biochemical
of M1 [category 2B])
recurrence (BCR)ff Recurrence
or
(PROS-11)
Life expectancy >5 y: Monitoringkk,ll
• Risk stratificationii
Consider:
• Bone and soft tissue
imagingg
• Prostate bed biopsy Workup and Treatment of Metachronous
Oligometastatich
Oligometastatich CSPC (PROS-13)

M1 Workup and Treatment of Low-Volume M1

(Metachronous or Synchronous) or Synchronous
PSA Oligometastatich CSPC (PROS-14)
persistence/ Polymetastatic
recurrencew,hh
Workup and Treatment of High-
Volume M1 CSPC (PROS-15)

Life
Palliative therapy/
expectancy Observationq Progressionff,gg
Best supportive care
≤5 y

Footnotes on PROS-9A
Note: All recommendations are category 2A unless otherwise indicated.

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RADICAL PROSTATECTOMY PSA PERSISTENCE/RECURRENCE

FOOTNOTES
c Principles of Survivorship in Prostate Cancer (PROS-B).
g Principles of Imaging (PROS-E).
h See Number of Metastatic Sites in the Principles of MDT (PROS-M).
q Observation involves monitoring the course of disease with the expectation to deliver definitive or palliative therapy for the development of symptoms or a change in
examination or PSA that suggests symptoms are imminent. See Principles of Active Surveillance and Observation (PROS-F).
t Principles of Radiation Therapy (PROS-J).
w PSA persistence/recurrence after RP is defined as when PSA does not fall to undetectable levels (PSA persistence) or undetectable PSA after RP with a subsequent
detectable PSA that increases on ≥2 determinations (PSA recurrence) or increases to PSA >0.1 ng/mL. Trials indicating noninferiority of early RT compared with
adjuvant RT after RP have used a PSA threshold of 0.1 or 0.2 ng/mL to trigger treatment. Imaging and treatment at lower PSA levels may be appropriate in patients at
high risk for progression based on pretreatment risk factors, pathologic parameters, timing of recurrence, and GC score, among other factors.
aa For details on the use of ADT and ARPIs, see Principles of Androgen Deprivation Therapy (PROS-G) and Discussion.
ff Document castrate levels of testosterone if clinically indicated. Workup for progression should include bone and soft tissue evaluation. See Principles of Imaging
(PROS-E).
gg Treatment for patients with life expectancy ≤5 y whose cancer progressed on observation of localized disease is ADT. See Principles of Androgen Deprivation Therapy
(PROS-G).
hh Recommendations for RP PSA persistence/recurrence may also apply to patients with undetectable PSA with multiple adverse features or lymph node metastases if
treatment is being considered.
ii Principles of Risk Stratification and Biomarkers (PROS-H).
jj Treatment for a first biochemical recurrence has historically been referred to as 'salvage' therapy. In efforts to use language that is more sensitive to patients, the
NCCN Guidelines for Prostate Cancer refer to treatment in this setting as 'secondary' therapy.
kk Monitoring should include physical exam, PSA every 3–6 months, and imaging for symptoms or increasing PSA.
ll For patients with PSA progression who have not received treatment for a first biochemical recurrence (BCR), continue monitoring or consider treatment for first PSA
persistence/recurrence. See PROS-9 for RP PSA persistence/recurrence or PROS-10 for RT recurrence.

Note: All recommendations are category 2A unless otherwise indicated.

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RADIATION THERAPY RECURRENCE TREATMENT FOR FIRST RECURRENCEjj

• Monitoringkk,ll

No
evidence
of M1 • Local secondary therapy ± ADT
Workup
(± abiraterone for N1)c,aa,oo
Second for Second
or
Monitoringkk biochemical Biochemical
• ADT based on PSADTc,aa,nn
recurrenceff Recurrence
or
(PROS-11)
• Risk • ADTc,aa,nn ± abiraterone for N1
Life stratificationmm
expectancy PSADTnn
>5 y • Bone and soft
tissue imagingg
• Consider
prostate/ Workup and Treatment of Metachronous
Oligometastatich
seminal vesicle Oligometastatich CSPC (PROS-13)
biopsy
PSA M1
Workup and Treatment of Low-Volume M1
recurrencev
(Metachronous or Synchronous) or Synchronous
or
Oligometastatich CSPC (PROS-14)
Positive DRE Polymetastatic
Workup and Treatment of High-
Volume M1 CSPC (PROS-15)

Life
Palliative therapy/
expectancy Observationq Progressionff,gg
Best supportive care
≤5 y

Footnotes on PROS-10A

Note: All recommendations are category 2A unless otherwise indicated.

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RADIATION THERAPY RECURRENCE

FOOTNOTES
c Principles of Survivorship in Prostate Cancer (PROS-B).
g Principles of Imaging (PROS-E).
h See Number of Metastatic Sites in the Principles of MDT (PROS-M).
q Observation involves monitoring the course of disease with the expectation to deliver definitive or palliative therapy for the development of symptoms or a change in
examination or PSA that suggests symptoms are imminent. See Principles of Active Surveillance and Observation (PROS-F).
v RTOG-ASTRO Phoenix Consensus: 1) PSA increase by ≥2 ng/mL above the nadir PSA is the standard definition for PSA recurrence after EBRT with or without
hormone therapy; and 2) A recurrence evaluation should be considered when PSA has been confirmed to be increasing after radiation even if the increase above nadir
is <2 ng/mL, especially in candidates for secondary local therapy who are young and healthy. Retaining a strict version of the ASTRO definition allows comparison with
a large existing body of literature. Rapid increase of PSA may warrant evaluation (prostate biopsy) prior to meeting the Phoenix definition, especially in patients who
are younger or healthier.
aa For details on the use of ADT and ARPIs, see Principles of Androgen Deprivation Therapy (PROS-G) and Discussion.
ff Document
castrate levels of testosterone if clinically indicated. Workup for progression should include bone and soft tissue evaluation. See Principles of Imaging
(PROS-E).
gg Treatment for patients with life expectancy ≤5 y whose cancer progressed on observation of localized disease is ADT. See Principles of Androgen Deprivation Therapy
(PROS-G).
jj Treatment for a first biochemical recurrence has historically been referred to as 'salvage' therapy. In efforts to use language that is more sensitive to patients, the NCCN
Guidelines for Prostate Cancer refer to treatment in this setting as 'secondary' therapy.
kk Monitoring should include physical exam, PSA every 3–6 mo, and imaging for symptoms or increasing PSA.
ll For patients with PSA progression who have not received treatment for a first BCR, continue monitoring or consider treatment for first PSA persistence/recurrence. See
PROS-9 for RP PSA persistence/recurrence or PROS-10 for RT recurrence.
mm PSADT can be calculated to inform nomogram use and counseling.
nn PSADT and Grade Group should be considered when deciding whether to begin ADT. See Principles of Androgen Deprivation Therapy (PROS-G).
oo Principles of Local Secondary Post-Recurrence Therapy (PROS-L).

Note: All recommendations are category 2A unless otherwise indicated.

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WORKUP FOR SECOND BIOCHEMICAL RECURRENCE (BCR2)

Treatment and Monitoring for Second

N0M0 CSPC
Biochemical Recurrence (N0M0) (PROS-12)

M0 CRPC Workup and Treatment of M0 CRPC

(N0 or N1) (PROS-16)

Second
Biochemical Perform imaging
Recurrence for stagingg
(BCR2)

Workup and Treatment of Metachronous

N1M0 CSPC Oligometastatich CSPC
Oligometastatich CSPC (PROS-13)

Workup and Treatment of Low-Volume

M1 (Metachronous or Synchronous) or
Synchronous Oligometastatich CSPC
(PROS-14)
M1 Polymetastatic CSPC

Workup and Treatment of High-Volume

M1 CSPC (PROS-15)

M1 CRPC Workup and Treatment of M1 CRPC (PROS-17)

g Principles of Imaging (PROS-E).

h See Number of Metastatic Sites in the Principles of MDT (PROS-M).

Note: All recommendations are category 2A unless otherwise indicated.

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TREATMENT AND MONITORING FOR SECOND BIOCHEMICAL RECURRENCE (N0M0)

N0M0
Workup and
Treatment of
Metachronous
• Monitoringkk,pp Oligometastatich Oligometastatich
Low-risk (preferred) CSPC CSPC (PROS-13)
BCRpp or
Second • ADTc,aa,pp Workup and
Biochemical Risk Treatment of
Recurrence Stratificationpp Low-Volume M1
(M0) • Monitoringkk,pp Monitoringkk Progressionff (Metachronous
High-risk • Enzalutamide ± or Synchronous)
BCRpp leuprolidec,aa,qq,rr or Synchronous
• Apalutamide + Oligometastatich
ADTc,aa,qq,ss Polymetastatic CSPC (PROS-14)
(category 2B) CSPC
• ADTc,aa,qq Workup and
Treatment of
High-Volume M1
CSPC (PROS-15)
M1 Workup and Treatment
c Principles of Survivorship in Prostate Cancer (PROS-B).
h See Number of Metastatic Sites in the Principles of MDT (PROS-M).
CRPC of M1 CRPC (PROS-17)
aa For details on the use of ADT and ARPIs, see Principles of Androgen
rr
Deprivation Therapy (PROS-G) and Discussion. Enzalutamide with or without leuprolide is an option for patients who have the
ff Document castrate levels of testosterone if clinically indicated. Workup for following high-risk criteria: M0 by CT, MRI, or bone scan; PSADT ≤9 months; PSA
progression should include bone and soft tissue evaluation. See Principles of ≥2 ng/mL above nadir after RT or ≥1 ng/mL after RP with or without postoperative
Imaging (PROS-E). RT; and not considered a candidate for pelvic-directed therapy (Freedland SJ, et
kk Monitoring should include physical exam, PSA every 3–6 months, and imaging al. N Engl J Med 2023;389:1453-1465). See Principles of Androgen Deprivation
for symptoms or increasing PSA. Therapy (PROS-G).
pp PSA level and PSADT should be considered when deciding whether to begin ss Apalutamide plus ADT is an option for patients with biochemical recurrence after
ADT for patients considered to have lower risk disease. High-risk BCR has RP who meet the following high-risk criteria: PSADT ≤9 months; PSA ≥0.5 ng/
different definitions in different clinical trials that generally include a PSADT ≤9 mL; and prior adjuvant or secondary RT or not considered a candidate for RT
months and other adverse prognostic features. (Aggarwal R, et al. J Clin Oncol 2024;42:1114-1123.) See Principles of Androgen
qq If favorable PSA response, an intermittent ADT approach should be considered. Deprivation Therapy (PROS-G).

Note: All recommendations are category 2A unless otherwise indicated.

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WORKUP AND TREATMENT OF METACHRONOUS OLIGOMETASTATIC CSPCc,h,tt,uu,vv,ww

WORKUP FOR METASTASESxx
Workup and Treatment
of Low-Volume M1
(Metachronous
or Synchronous)
• Perform physical exam
or Synchronous
• Perform imaging for
Oligometastatich CSPC
stagingg
(PROS-14)
• Perform and/or collect PSA
and calculate PSADT • Physical examination
MDTyy ± ADTaa
• Estimate life expectancy + PSA every 3–6 mo
or
(Principles of Life • Imaging for Workup and Treatment
For M1 only, treat Progressionff
Expectancy Estimation symptomsg of High-Volume M1 CSPC
as metachronous
[PROS-A]) • Consider periodic (PROS-15)
low-volume M1
• Perform germline and imaging to monitor
(see PROS-14)
somatic genetic testinge treatment response
(if not previously done) Workup and Treatment of
• Obtain family historye M1 CRPC (PROS-17)
• Assess quality-of-life
measuresf

c Principles of Survivorship in Prostate Cancer (PROS-B).

e Principles of Genetics and Molecular/Biomarker Analysis (PROS-C). vv The term "castration-sensitive" is used to define disease in patients who
f Principles of Quality of Life and Shared Decision-Making (PROS-D). have not been treated with ADT and those who are not on ADT at the time
g Principles of Imaging (PROS-E). of progression. The NCCN Prostate Cancer Panel uses the term "castration-
h See Number of Metastatic Sites in the Principles of MDT (PROS-M). sensitive" even when patients have had neoadjuvant, concurrent, or adjuvant
aa For details on the use of ADT and ARPIs, see Principles of Androgen ADT as part of RT provided they have recovered testicular function.
Deprivation Therapy (PROS-G) and Discussion. ww ADT is strongly recommended in combination therapy for metastatic castration-
ff Document castrate levels of testosterone if clinically indicated. Workup for sensitive disease. The use of ADT monotherapy in metastatic castration-sensitive
progression should include bone and soft tissue evaluation. See Principles of disease is discouraged unless there are clear contraindications to combination
Imaging (PROS-E). therapy. If ADT monotherapy is given, intermittent ADT can be considered to
tt EBRT to sites of bone metastases can be considered if metastases are in weight- reduce toxicity. See Principles of Androgen Deprivation Therapy (PROS-G).
bearing bones or if the patient is symptomatic. xx ADT alone (PROS-G) or observation are recommended for asymptomatic
uu Bone antiresorptive therapy is indicated for elevated fracture risk based upon patients with metastatic disease or M0 CRPC and life expectancy ≤5 years.
FRAX in the castration-sensitive setting. See PROS-B. yy See Principles of MDT (PROS-M).

Note: All recommendations are category 2A unless otherwise indicated.

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WORKUP AND TREATMENT OF LOW-VOLUME M1 (METACHRONOUS OR SYNCHRONOUS) OR SYNCHRONOUS OLIGOMETASTATIC

CSPCc,h,tt,uu,vv,ww
WORKUP FOR METASTASESxx
ADTaa,zz with one of the following:
• Preferred:
Abiraterone (category 1)aa
Apalutamide (category 1)aa
Enzalutamide (category 1)aa
• Other Recommended:
Synchronous Darolutamide (category 2B)aa
low-volume or
metastases ADTaa,zz with docetaxel and one of the
• Perform physical or following (low-volume disease only):
exam Synchronous Abiraterone (category 2B)aa
• Perform imaging for oligometastatic Apalutamide (category 2B)aa
disease • Physical
stagingg Darolutamide (category 2B)aa examination + Progressionff
• Perform and/or collect Enzalutamide (category 2B)aa PSA every 3–6 mo on ADT ±
PSA and calculate or Workup and
• Imaging for androgen
PSADT ADTaa,zz with EBRTt to the primary symptomsg receptor
Treatment
• Estimate life tumoraaa alone or with one of the • Periodic imaging pathway
of M1 CRPC
expectancy following: (PROS-17)
to monitor inhibitor
(Principles of Abirateroneaa treatment (ARPI)
Life Expectancy Apalutamide (category 2B)aa response
Estimation [PROS-A]) Docetaxel (category 2B)
• Perform germline Enzalutamide (category 2B)aa
and somatic genetic
testinge (if not
previously done) ADTaa,zz with one of the
• Obtain family historye following:
Metachronous • Preferred:
• Assess quality-of-life low-volume
measuresf Abiraterone (category 1)aa
metastases Apalutamide (category 1)aa
Enzalutamide (category 1)aa
• Other Recommended:
Darolutamide (category 2B)aa

Footnotes on PROS-15A
Note: All recommendations are category 2A unless otherwise indicated.

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WORKUP AND TREATMENT OF HIGH-VOLUME M1 CSPCc,tt,uu,vv,ww,bbb

WORKUP FOR METASTASESxx

• Perform physical exam ADTaa with docetaxel and one of

• Perform imaging for the following:
stagingg • Preferred:
• Perform and/or collect Abiraterone (category 1)aa
• Physical
PSA and calculate Darolutamide (category 1)aa
examination + PSA
PSADT Synchronous • Other Recommended:
every 3–6 mo
• Estimate life expectancy or Apalutamide (category 2B)aa Workup and
• Imaging for
(Principles of Life metachronous Enzalutamide (category 2B)aa Treatment
symptomsg Progressionff
Expectancy Estimation high- or of M1 CRPC
• Periodic imaging
[PROS-A]) volumebbb ADTaa with one of the following: (PROS-17)
to monitor
• Perform germline and metastases • Preferred:
treatment
somatic genetic testinge Abiraterone (category 1)aa
response
(if not previously done) Apalutamide (category 1)aa
• Obtain family historye Enzalutamide (category 1)aa
• Assess quality-of-life • Other Recommended:
measuresf Darolutamideaa

Note: All recommendations are category 2A unless otherwise indicated. Footnotes on PROS-15A

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FOOTNOTES
c Principles of Survivorship in Prostate Cancer (PROS-B).
e Principles of Genetics and Molecular/Biomarker Analysis (PROS-C).
f Principles of Quality of Life and Shared Decision-Making (PROS-D).
g Principles of Imaging (PROS-E).
h See Number of Metastatic Sites in the Principles of MDT (PROS-M).
t Principles of Radiation Therapy (PROS-J).
aa For details on the use of ADT and ARPIs, see Principles of Androgen Deprivation Therapy (PROS-G) and Discussion.
ff Document castrate levels of testosterone if clinically indicated. Workup for progression should include bone and soft tissue evaluation. See Principles of Imaging
(PROS-E).
tt EBRT to sites of bone metastases can be considered if metastases are in weight-bearing bones or if the patient is symptomatic.
uu Bone antiresorptive therapy is indicated for elevated fracture risk based upon FRAX in the castration-sensitive setting. See PROS-B.
vv The term "castration-sensitive" is used to define disease in patients who have not been treated with ADT and those who are not on ADT at the time of progression.
The NCCN Prostate Cancer Panel uses the term "castration-sensitive" even when patients have had neoadjuvant, concurrent, or adjuvant ADT as part of RT provided
they have recovered testicular function.
ww ADT is strongly recommended in combination therapy for metastatic castration-sensitive disease. The use of ADT monotherapy in metastatic castration-sensitive
disease is discouraged unless there are clear contraindications to combination therapy. If ADT monotherapy is given, intermittent ADT can be considered to reduce
toxicity. See Principles of Androgen Deprivation Therapy (PROS-G).
xx ADT alone (PROS-G) or observation are recommended for asymptomatic patients with metastatic disease or M0 CRPC and life expectancy ≤5 years.
zz Concurrent MDT can be considered in select patients with oligometastatic disease. See Principles of MDT (PROS-M).
aaa EBRT to the primary tumor is associated with an overall survival (OS) benefit in patients with low metastatic burden at the time of diagnosis of metastatic disease,
which is defined by bone scan and CT or MRI as either non-regional, lymph-node-only disease OR <4 bone metastases and without visceral/other metastasis (Ali A, et
al. JAMA Oncol 2021;7:555-563). See Principles of Radiation Therapy (PROS-J).
bbb High-volume disease in this setting is defined based on CHAARTED criteria (the presence of visceral metastasis or ≥4 bone lesions with ≥1 beyond the vertebral
bodies and pelvis).

Note: All recommendations are category 2A unless otherwise indicated.

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Prostate Cancer Discussion

WORKUP AND TREATMENT OF M0 CASTRATION-RESISTANT PROSTATE CANCER (CRPC)xx,ccc

Change or
maintain
current
No
treatment and
metastases
continue
(M0)
Monitoringkk periodic
(preferred) PSA disease
PSADT increasing or assessment
or
>10 mo radiographic Imagingff
Other secondary
Continue hormone therapyaa evidence of
metastases
CRPC, ADTc,aa to Workup and
imaging maintain Metastases Treatment
studies castrate Consider of M1 CRPC
periodic (M1)
negative serum (PROS-17)
Preferred: disease
for distant levels of • Apalutamideaa
metastases testosterone assessment
(category 1) (PSA and
(<50 ng/dL) • Darolutamideaa imaging)g
(category 1)
PSADT
• Enzalutamideaa Stable PSA and Maintain current treatment
≤10 mo
(category 1) no evidence of and consider periodic disease
Other metastases assessment (PSA and imaging)g
Recommended:
• Other secondary
hormone therapyaa

c Principles of Survivorship in Prostate Cancer (PROS-B). kk Monitoring should include physical exam, PSA every 3–6 mo, and imaging for
g Principles of Imaging (PROS-E). symptoms or increasing PSA.
aa For details on the use of ADT and ARPIs, see Principles of Androgen xx ADT alone (PROS-G) or observation are recommended for asymptomatic
Deprivation Therapy (PROS-G) and Discussion. patients with metastatic disease or M0 CRPC and life expectancy ≤5 years.
ff Document castrate levels of testosterone if clinically indicated. Workup for ccc CRPC is prostate cancer that progresses clinically, radiographically, or
progression should include bone and soft tissue evaluation. See Principles of biochemically despite castrate levels of serum testosterone (<50 ng/dL). Scher
Imaging (PROS-E). HI, et al. J Clin Oncol 2008;26:1148-1159.

Note: All recommendations are category 2A unless otherwise indicated.

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PROS-16
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WORKUP AND TREATMENT OF M1 CRPCxx,ccc

• Metastatic lesion • Continue ADTc,aa to

biopsyddd maintain castrate levels of
• Somatic testing serum testosterone (<50
Adenocarcinomaddd PROS-18
for homologous ng/dL)
recombination repair • Additional treatment
(HRR), microsatellite options:
CRPC, imaging instability (MSI)/ Bone antiresorptive
studies positive mismatch repair therapy with denosumab
for metastases deficiency (dMMR), (category 1, preferred) First-line and subsequent treatment
and tumor mutational or zoledronic acid optionsfff
burden (TMB)e,eee if bone metastases • Chemotherapyggg
Recommended if not presentc Cisplatin/etoposide
previously done Palliative RTt for painful Small cell/
Carboplatin/etoposide
Re-evaluation may bone metastases neuroendocrine
Docetaxel/carboplatin
prostate cancer
be considered Best supportive care Cabazitaxel/carboplatinhhh
(NEPC)ddd
For additional options, see
NCCN Guidelines for Small Cell
Lung Cancer
• Best supportive care
c Principles of Survivorship in Prostate Cancer (PROS-B).
e Principles of Genetics and Molecular/Biomarker Analysis (PROS-C).
t Principles of Radiation Therapy (PROS-J).
aa For details on the use of ADT and ARPIs, see Principles of Androgen Deprivation
Therapy (PROS-G) and Discussion.
xx ADT alone (PROS-G) or observation are recommended for asymptomatic fff Documentcastrate levels of testosterone if progression occurs on ADT. See
patients with metastatic disease or M0 CRPC and life expectancy ≤5 years. Principles of Imaging (PROS-E) and Discussion.
ccc CRPC is prostate cancer that progresses clinically, radiographically, or ggg For details on the efficacy and safety of these agents, see Principles of Non-
biochemically despite castrate levels of serum testosterone (<50 ng/dL). Scher HI, Hormonal Systemic Therapy (PROS-N).
et al. J Clin Oncol 2008;26:1148-1159. hhh Cabazitaxel 20 or 25 mg/m² plus carboplatin area under the curve [AUC] 4
ddd Histologic evidence of both adenocarcinoma and small cell carcinoma mg/mL per min with growth factor support can be considered for fit patients with
may be present, in which case treatment can follow either pathway. Treat as aggressive variant metastatic CRPC (mCRPC) (ie, visceral metastases, low PSA
adenocarcinoma if biopsy is not feasible or not performed. and bulky disease, high lactate dehydrogenase [LDH], high carcinoembryonic
eee Germline testing for HRR mutations is recommended if not performed antigen [CEA], lytic bone metastases, NEPC histology) or unfavorable genomics
previously. See Principles of Genetics and Molecular/Biomarker Analysis (defects in at least 2 of PTEN, TP53, and RB1). Corn PG, et al. Lancet Oncol
(PROS-C). 2019;20:1432-1443.

Note: All recommendations are category 2A unless otherwise indicated.

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Prostate Cancer Discussion

SYSTEMIC THERAPY FOR M1 CRPC: ADENOCARCINOMAg,aa,iii,jjj

Pre-ARPIaa,kkk Post-ARPIkkk/Pre-Docetaxelaa Post-ARPIkkk/Post-Docetaxelaa

Preferred: Preferred: Preferred:
• Abiraterone (category 1) • Docetaxelggg (category 1) • Cabazitaxelggg (category 1)
• Enzalutamide (category 1) • Docetaxel rechallengeggg
Useful in Certain Circumstances:
Other Recommended: • Molecular Biomarker-Directed Therapy Useful in Certain Circumstances:
• Docetaxelggg (category 1) BRCA mutation • Molecular Biomarker-Directed Therapy
◊ Olapariblll (category 1, preferred) BRCA mutation
Useful in Certain Circumstances: ◊ Rucapariblll (category 1, preferred) ◊ Olapariblll (category 1)
• Molecular Biomarker-Directed Therapy ◊ Niraparib/abirateronelll (category 2B) ◊ Rucapariblll
BRCA mutation ◊ Talazoparib/enzalutamidelll (category 2B) HRRm (other than BRCA1/2)
◊ Niraparib/abirateronelll (category 1) HRRm (other than BRCA1/2) ◊ Olapariblll
◊ Olaparib/abirateronelll (category 1) ◊ Olapariblll Other FDA-approved agents for tissue agnostic
◊ Talazoparib/enzalutamidelll (category 1) ◊ Talazoparib/enzalutamidelll (category 2B) indicationsggg
HRRm (other than BRCA1/2)
◊ Talazoparib/enzalutamidelll (category 1) • Disease State-Specific Therapy • Disease State-Specific Therapy
PSMA-positive metastases PSMA-positive metastases
• Disease State-Specific Therapy ◊ Lutetium Lu 177 vipivotide tetraxetan (Lu- ◊ Lu-177-PSMA-617ppp (category 1)
Bone metastases 177-PSMA-617)ppp Aggressive varianthhh
◊ Radium-223nnn/enzalutamide Aggressive varianthhh ◊ Cabazitaxel/carboplatinggg
◊ Cabazitaxel/Carboplatinggg Palliation for symptomatic patients unable to
tolerate other therapies
◊ Mitoxantroneggg
Additional Options Irrespective of Prior ARPI or Prior Docetaxel
(Useful in Certain Circumstances)
• Disease State-Specific Therapy • Molecular Biomarker-Directed Therapy
Asymptomatic without visceral metastases MSI-High (MSI-H)/dMMR
◊ Sipuleucel-Tggg,ooo ◊ Pembrolizumabggg (category 2B)
Oligometastatich/Oligoprogressive disease
◊ Metastasis-directed therapymmm with
metastatic castration-resistant prostate
cancer (mCRPC) systemic therapy
Symptomatic bone-predominant metastases
◊ Radium-223nnn (category 1)

Footnotes on PROS-18A
Note: All recommendations are category 2A unless otherwise indicated.

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THERAPY FOR M1 CRPC: ADENOCARCINOMA

FOOTNOTES
g Principles of Imaging (PROS-E). mmm Principles of MDT (PROS-M).
h See Number of Metastatic Sites in the Principles of MDT (PROS-M). nnn Radium-223 should not be used in patients with visceral metastases.
aa For details on the use of ADT and ARPIs, see Principles of Androgen Concurrent use with systemic therapies other than enzalutamide should be
Deprivation Therapy (PROS-G) and Discussion. pursued with caution. Concomitant use of denosumab or zoledronic acid is
ggg For details on the efficacy and safety of these agents, see Principles of Non- recommended. See Principles of Radiation Therapy (PROS-J).
Hormonal Systemic Therapy (PROS-N). ooo Sipuleucel-T is recommended only for asymptomatic or minimally symptomatic,
hhh Cabazitaxel 20 or 25 mg/m² plus carboplatin AUC 4 mg/mL per min with growth no liver metastases, life expectancy >6 months, and ECOG performance status
factor support can be considered for fit patients with aggressive variant mCRPC 0–1. Benefit with sipuleucel-T has not been reported in patients with visceral
(ie, visceral metastases, low PSA and bulky disease, high LDH, high CEA, lytic metastases and is not recommended if visceral metastases are present. There
bone metastases, NEPC histology) or unfavorable genomics (defects in at least 2 are limited data to support the efficacy of Sipuleucel-T in the post-chemotherapy
of PTEN, TP53, and RB1). Corn PG, et al. Lancet Oncol 2019;20:1432-1443. setting. Sipuleucel-T is not recommended for patients with small cell prostate
iii Document castrate levels of testosterone if progression occurs on ADT. Consider cancer/NEPC.
metastatic lesion biopsy. If small cell neuroendocrine is found, see PROS-17. ppp Lu-177–PSMA-617 is a treatment option for patients with ≥1 PSMA-positive
jjj Patients can continue through all treatment options listed. Best supportive care, lesion and/or metastatic disease that is predominately PSMA-positive and with no
which can include androgen-directed therapy or steroid, is always an appropriate dominant PSMA-negative metastatic lesions who have been treated previously
option. with androgen receptor-directed therapy and a taxane-based chemotherapy or
kkk ARPI therapies include abiraterone, enzalutamide, darolutamide, or are considered appropriate to delay a taxane-based chemotherapy. Sartor O, et
apalutamide. Abiraterone given as part of neoadjuvant/concomitant/adjuvant ADT al. N Engl J Med 2021;385:1091-1103; Morris MJ, et al. Lancet 2024;404:1227-
with EBRT is not considered post-ARPI. 1239. See Principles of Radiation Therapy (PROS-J).
lll PARP inhibitors with or without ARPI have different biomarker and previous
treatment requirements. See Principles of Non-Hormonal Systemic Therapy
(PROS-N).

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF LIFE EXPECTANCY ESTIMATION

• Life expectancy estimation is critical to informed decision-making in prostate cancer early detection and treatment.

• Estimation of life expectancy is possible for groups of patients but challenging for individuals.

• Life expectancy can be estimated using:

The Social Security Administration tables ([Link]/OACT/STATS/[Link])
The WHO’s Life Tables by country ([Link]
The Memorial Sloan Kettering Male Life Expectancy tool ([Link]
University of California San Francisco (UCSF) Lee Schonberg Index ([Link]

• If using a life expectancy table, life expectancy should be adjusted using the clinician’s assessment of overall health as follows:
Best quartile of health - add 50%
Worst quartile of health - subtract 50%
Middle two quartiles of health - no adjustment

• Examples of upper, middle, and lower quartiles of life expectancy at selected ages are included in the NCCN Guidelines for Older Adult
Oncology for life expectancy estimation.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF SURVIVORSHIP
BONE HEALTH IN PROSTATE CANCER
Treatment-Related Bone Loss
• ADT increases the risk of bone loss, and this risk is exacerbated with more • Antiresorptive medications that increase bone mineral density
potent androgen suppression, longer duration of therapy or delayed testosterone and reduce disease-related skeletal complications during ADT for
recovery, and concurrent prednisone use. prostate cancer include denosumab (60 mg subcutaneously [SQ]
• The goal of osteoporosis screening is to identify patients at increased risk of every 6 months), zoledronic acid (5 mg IV annually), and alendronate
sustaining a low-trauma fracture who would benefit from intervention to minimize (70 mg PO weekly) (see Table 2). Treatment with either denosumab,
the fracture risk. Risk assessment for treatment-related bone loss should take zoledronic acid, or alendronate sodium is recommended when the
place for all patients initiating ADT of any duration. Fracture risk can be assessed absolute fracture risk warrants drug therapy.
using the Fracture Risk Assessment Tool (FRAX), the algorithm released by Choice of agent may depend on underlying comorbidities, whether
The University of Sheffield ([Link] FRAX was developed to the patient has been treated with zoledronic acid previously,
estimate the 10-year probability of hip fracture or major osteoporotic fractures logistics, and/or cost considerations.
combined (hip, spine, shoulder, or wrist) for an untreated individual using easily Bisphosphonates (zoledronic acid or alendronate) can cause
obtainable clinical risk factors for fracture with or without information on bone side effects of acute phase reaction, joint pain, hypocalcemia,
mineral density. When utilizing the FRAX algorithm select YES for secondary osteonecrosis of the jaw, nephrotoxicity with need for dose
osteoporosis for individuals with hypogonadism. ADT should be considered modification for renal insufficiency, ocular toxicities, and atypical
“secondary osteoporosis” when using the FRAX algorithm. A previous major femoral fractures with prolonged use (>3 to 5 years).
osteoporotic fracture (hip fracture or spine fracture) is considered clinical Denosumab can cause side effects of hypocalcemia, osteonecrosis
osteoporosis and warrants bone antiresorptive drug therapy independent of bone of the jaw, and atypical femoral fractures with prolonged use.
mineral density. The risk factors for denosumab-associated hypocalcemia include
• A baseline dual-energy x-ray absorptiometry (DEXA) scan should be obtained blastic bone metastases, renal impairment, vitamin D deficiency,
before starting ADT in patients at increased risk for fracture based on FRAX the lack of prophylactic supplementation of calcium and/or vitamin
screening and being considered for antiresorptive therapy (see Table 1). For D, preexisting hypoparathyroidism, hypomagnesemia, and gastric
patients at low risk of fracture based on the FRAX risk assessment, baseline DEXA bypass. Although renal monitoring is not required, denosumab is
scan can be omitted. The exact FRAX fracture risk threshold has not been defined not recommended in patients with a creatinine clearance <30 mL/
in this population. One approach is to set the threshold at 10-year risk of major min given the risk of severe hypocalcemia. Calcium, creatinine,
osteoporotic fracture (calculated without DEXA) greater than that of a 65-year old and vitamin D levels should be checked prior to initiating therapy.
white woman with no additional risk factors (defined as 8.4% in the United States). Periodic monitoring of serum calcium levels is recommended
• Treatment for osteoporosis is advised according to guidelines for the general with denosumab use. Stopping denosumab therapy can result in
population from the Bone Health and Osteoporosis Foundation.1 These guidelines rebound bone loss and fractures; therefore it is recommended
(see Table 1) include recommendations for: 1) calcium (1000–1200 mg daily from to administer at least one dose of a potent bisphosphonate
food, with supplements if intake is insufficient); 2) vitamin D3 (serum levels of (zoledronic acid 4 or 5 mg) to prevent rebound bone loss and
30–50 ng/mL with supplements prescribed if needed); and 3) pharmacologic presumably rebound fracture.2
treatment for patients aged ≥50 years with low bone mass (T-score between -1.0
and -2.5, osteopenia) at the femoral neck or total hip by DEXA scan with a 10-year
probability of hip fracture ≥3% or a 10-year probability of a major osteoporosis-
related fracture ≥20% based on FRAX screening (see Table 2).
References on PROS-B 4 of 6
Note: All recommendations are category 2A unless otherwise indicated.
PROS-B
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PRINCIPLES OF SURVIVORSHIP
BONE HEALTH IN PROSTATE CANCER
Treatment-Related Bone Loss Continued
The risk of osteonecrosis of the jaw is increased in patients who have tooth extractions, poor dental hygiene, or a dental appliance. To prevent
osteonecrosis of the jaw, it is recommended that all patients have a comprehensive dental evaluation prior to initiating an osteoclast inhibitor.3 If invasive
dental procedures are required, bone-targeted therapy should be withheld until the dentist indicates that the patient has healed completely from all dental
procedure(s). Stopping denosumab represents a dilemma is this context, and the clinician must carefully weigh the risk of rebound spine fractures
versus the risk of osteonecrosis of the jaw.
• Annual assessment of fracture risk using the FRAX risk assessment tool is recommended for all patients on ADT or those who remain hypogonadal after
completion of ADT (see Table 1). Depending on the fracture risk and prior DEXA scan results, repeat DEXA scan in 1 to 2 years is recommended for those
patients on ADT. For individuals initiated on antiresorptive therapy, a follow-up DEXA scan after 1 year of treatment is recommended by the International
Society for Clinical Densitometry, although there is no consensus on the optimal approach to monitoring the effectiveness of bone treatment. Use of
biochemical markers of bone turnover to monitor response to therapy is not recommended. There are currently no guidelines on how often to monitor
vitamin D levels.
• For patients receiving antiresorptive therapy, there are currently no consensus guidelines on duration of treatment. Due to concerns of long-term risks
of antiresorptive therapy, a “drug holiday” at 3 to 5 years can be considered based on agent utilized, stability of bone mineral density, prior fracture
history, and future fracture risk. Bone mineral density should be monitored approximately every 1 to 2 years after suspending therapy, and therapy should
generally be resumed if bone mineral density declines significantly or if the patient develops a new fragility fracture.

Table 1: Risk Assessment and Monitoring

Clinical Scenario Recommendation
Baseline at ADT initiation DEXA recommended for most patients. In select individuals at low probably of
fracture based on FRAX risk assessment tool, DEXA can be omitted
On ADT DEXA every 1–2 years, dependent on FRAX risk assessment tool

On antiresorptive therapy DEXA at 1 year

References on PROS-B 4 of 6
Note: All recommendations are category 2A unless otherwise indicated.
PROS-B
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PRINCIPLES OF SURVIVORSHIP
BONE HEALTH IN PROSTATE CANCER
Prevention of Symptomatic Skeletal-Related Events (SREs) in Patients with Bone-Metastatic CRPC
• In patients with CRPC who have bone metastases, denosumab and zoledronic acid have been shown to prevent disease-related skeletal complications,
which include fracture, spinal cord compression, or the need for surgery or RT to bone.
• When compared to zoledronic acid, denosumab was shown to be superior in prevention of SREs in patients with metastatic CRPC (mCRPC), albeit with
numerically higher hypocalcemia and osteonecrosis of the jaw risks. Initial studies investigated zoledronic acid and denosumab administered every 4
weeks. Subsequent studies demonstrated that every–12-week dosing of zoledronic acid compared to every–4-week dosing did not increase the risk of
skeletal events.4,5 Every–12-week dosing of zoledronic acid is recommended for symptomatic SRE reduction when indicated. Every–12-week dosing of
denosumab is under investigation and current data suggest noninferior symptomatic skeletal events compared to every–4-week dosing.5 Utilization of
zoledronic acid and denosumab for symptomatic SRE reduction requires consideration of degree of benefit and risk associated with therapy to optimize
use, dose, and schedule. It is important to recognize that testing of zoledronic acid and denosumab in bone-metastatic CRPC was conducted during an
era when treatment options for mCRPC were largely limited to docetaxel chemotherapy. Subsequent studies investigating abiraterone, enzalutamide,
cabazitaxel, radium-223, and Lu-177–PSMA-617 have demonstrated improvement of SREs with treatment. While radium-223 did improve symptomatic
SREs in patients with bone mCRPC, the combination of radium-223 with abiraterone was associated with increased frequency of bone fractures,
particularly in individuals not receiving an antiresorptive agent.6
• A phase 3 clinical trial that assessed the role for zoledronic acid in patients with castration-sensitive disease beginning ADT for bone metastases was
negative.7 Therefore, use of osteoclast inhibitors for reduction of symptomatic SREs in metastatic castration-sensitive disease with bone metastases is
not recommended. However, usage of these agents to prevent bone loss and fragility fractures at appropriate doses and dosing intervals should be utilized
when clinically appropriate in this context (see Treatment-Related Bone Loss, PROS-B 1 of 4).

Table 2: Optimization of Bone Health in Patients with Prostate Cancer

Patient Population Category Intervention
All patients receiving ADT Lifestyle modifications • Weight-bearing exercises (30 minutes per day),
balance training, safe movement strategies
• Limit alcohol consumption
• Smoking cessation
Calcium and vitamin D supplementation • Calcium 1000–1200 mg daily from food with
supplements if needed
• Maintain serum vitamin D3 levels of 30–50 ng/mL
with supplements if needed
For treatment-related bone loss in Antiresorptive agents • Alendronate 70 mg PO weekly
patients receiving ADT • Denosumab 60 mg SQ every 6 months
• Zoledronic acid 5 mg IV annually
For prevention of symptomatic SREs Antiresorptive agents • Denosumab 120 mg SQ every 4 weeks
in patients with bone-metastatic CRPC • Zoledronic acid 4 mg IV every 12 weeks

References on PROS-B 4 of 6
Note: All recommendations are category 2A unless otherwise indicated.
PROS-B
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PRINCIPLES OF SURVIVORSHIP
BONE HEALTH IN PROSTATE CANCER: REFERENCES
1 LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int 2022;33:2049-2102.
2 Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: A post hoc analysis of the randomized placebo-controlled freedom
trial and its extension. J Bone Miner Res 2018;33:190-198.
3 Yarom N, Shapiro CL, Peterson DE, et al. Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO Clinical practice guideline. J Clin Oncol 2019;37:2270-
2290.
4 Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases:
a randomized clinical trial. JAMA 2017;317:48-58.
5 Clemons M, Ong M, Stober C, et al. A randomised trial of 4- versus 12-weekly administration of bone-targeted agents in patients with bone metastases from breast or
castration-resistant prostate cancer. Eur J Cancer 2021;142:132-140.
6 Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer
and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:408-419.
7 Smith MR, Halabi S, Ryan CJ, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results
of CALGB 90202 (alliance). J Clin Oncol 2014;32:1143-1150.

Note: All recommendations are category 2A unless otherwise indicated.

PROS-B
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PRINCIPLES OF SURVIVORSHIP
CARDIOVASCULAR DISEASE IN PROSTATE CANCER

• Individuals with prostate cancer are at increased risk for cardiovascular disease (CVD) and cardiovascular events, and CVD is a leading
cause of death in this population.1
The main cause for this increased risk is the cardiovascular effects of ADT and ARPIs.2,3
Shared risk factors for prostate cancer and CVD (ie, smoking, poor health behaviors) also likely contribute to the increased risk of CVD in
this population.4
• CVD develops over time because of well-defined risk factors such as hypertension, hyperlipidemia, use of tobacco products, obesity,
diabetes, and the cardiotoxic effects of cancer treatment.
• CVD-related morbidity and mortality can occur in both the short- and long-term in prostate cancer survivors.
• Control of modifiable risk factors can decrease the risk of subsequent cardiovascular events.
• Therefore, prostate cancer survivors should assessed for and counseled on:
Pre-existing and emerging CVD (eg, coronary artery disease, congestive heart failure, peripheral vascular disease, arrhythmias including
atrial fibrillation)
Any increased risk of CVD based on prior treatment, comorbidity, or CVD risk factors (eg, hypertension, dyslipidemia, obesity, cigarette/
tobacco use, diabetes mellitus)
Lifestyle modification and interventions for modifiable risk factors (see the ABCDEs of CVD Prevention, Table 1)
• Aggressive risk factor management is recommended for those deemed to be at higher risk, and referral to a cardiologist or cardio-oncologist
in patients at elevated CVD risk should be considered at any stage of the prostate cancer journey.
• Cooperation and shared care with primary care providers, and cardiovascular specialists as needed, is key to optimizing cardiac and
vascular outcomes in prostate cancer survivors.
• For further information on cardiovascular risk assessment in cancer survivors, see the NCCN Guidelines for Survivorship.

1 Sturgeon KM, Deng L, Bluethmann SM, et al. A population-based study of cardiovascular disease mortality risk in US cancer patients. Eur Heart J 2019;40:3889-3897.
2 Okwuosa TM, Morgans A, Rhee JW, et al. Impact of hormonal therapies for treatment of hormone-dependent cancers (breast and prostate) on the cardiovascular
system: effects and modifications: a scientific statement from the American Heart Association. Circ Genom Precis Med 2021;14:e000082.
3 El-Taji O, Taktak S, Jones C, et al. Cardiovascular events and androgen receptor signaling inhibitors in advanced prostate cancer: A systematic review and meta-
analysis. JAMA Oncol 2024;20:874-884.
4 Bergengren O, Pekala KR, Matsoukas K, et al. 2022 update on prostate cancer epidemiology and risk factors - a systematic review. Eur Urol 2023;84:191-206.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF SURVIVORSHIP
CARDIOVASCULAR DISEASE IN PROSTATE CANCER: RISK ASSESSMENTa

Table 1: ABCDEs to Promote Cardiovascular Wellness in Cancer Survivorsb

A • Awareness of risks and presentation of heart disease
• Assessment of CVD and cardiovascular risk (consider use of a CVD risk assessment toolc)
• Aspirin use as appropriate (indicated for secondary prevention; clinician-survivor discussion required for
primary prevention with careful weighing of benefits and risks)d
B • Blood pressure monitoring/management (with clinician-survivor discussion regarding the use of
hypertension treatment and blood pressure goals)
C • Cholesterol assessment/management (with clinician-survivor discussion regarding the use of statin therapy
for primary prevention and lipid profile goals)
• Cigarette/tobacco cessation (NCCN Guidelines for Smoking Cessation)
D • Diet and weight management (see SNWM-1 in NCCN Guidelines for Survivorship)
• Diabetes mellitus prevention/treatment
E • Exercise (see SPA-1 in NCCN Guidelines for Survivorship)e
• Echocardiogram (ECHO) and/or electrocardiogram (ECG) based on individual risk (consider use of a CVD
risk assessment toolc)

a Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical
Practice Guideline. J Clin Oncol 2017;35:893-911.
b Adapted with permission from Montazeri K, Unitt C, Foody JM, et al. ABCDE steps to prevent heart disease in breast cancer survivors. Circulation
2014;130:e157-e159.
c The ASCVD Risk Estimator Plus from the American College of Cardiology is available at [Link] and The
American Heart Association's PREVENT Risk Calculator is available at [Link]
d U.S. Preventive Services Task Force; Davidson KW, Barry MJ, Mangione CM, et al. Aspirin use to prevent cardiovascular disease: U.S. Preventive Services Task
Force Recommendation Statement. JAMA 2022;327:1577-1584.
e Gilchrist SC, et al. Circulation 2019;139:e997-e1012.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF GENETICS AND MOLECULAR/BIOMARKER ANALYSIS

GERMLINE TESTING

For details regarding the nuances of genetic counseling and testing, see Principles of Cancer Risk Assessment and Counseling (EVAL-A) in
the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic and Prostate

• Pre-test Considerations
The Panel recommends inquiring about family and personal history of cancer, and known germline variants at time of initial diagnosis.
Criteria for germline testing (see CRIT-6 in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic
and Prostate and HRS-3 in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric) should
be reviewed at time of initial diagnosis and, if relevant, at recurrence.
Germline testing is also recommended for patients with metastatic, regional (node positive), very-high-risk localized, or high-risk localized
prostate cancer.
Germline testing should be considered in appropriate individuals where it is likely to impact the prostate cancer treatment and clinical trial
options, management of risk of other cancers, and/or potential risk of cancer in family members.
• Testing
If criteria are met, multigene testing is recommended (see GENE-1 in the NCCN Guidelines for Genetic/Familial High-Risk Assessment:
Breast, Ovarian, Pancreatic, and Prostate).
• Post-test Considerations
Post-test genetic counseling is strongly recommended if a germline mutation (pathogenic/likely pathogenic variant) is identified. Cascade
testing for relatives is critical to inform the risk for familial cancers in all relatives.
Post-test genetic counseling is recommended if positive family history but no pathogenic variant OR if only germline variants of uncertain
significance (VUS) are identified. This is to ensure accurate understanding of family implications and review indications for additional
testing and/or follow-up (including clinical trials of reclassification).
Resources are available to review the available data supporting pathogenic consequences of specific variants (eg, [Link]
[Link]/clinvar/; [Link]
Individuals should be counseled to inform providers of any updates to family cancer history.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF GENETICS AND MOLECULAR/BIOMARKER ANALYSIS

SOMATIC TUMOR TESTING

• Pre-test Considerations
At present, tumor molecular and biomarker analysis is recommended for patients with metastatic disease for treatment decision-making,
including understanding eligibility for biomarker-directed treatments, genetic counseling, and eligibility for clinical trials. Clinical trials may
include established and/or candidate molecular biomarkers for eligibility.
Tumor molecular profiles may change with subsequent treatments and re-evaluation may be considered at time of cancer progression for
treatment decision-making.
Patients should be informed that tumor molecular analysis by DNA sequencing has the potential to uncover germline findings.
Confirmatory germline testing may be recommended [see Post-test Considerations (below) and Tumor Testing:s Potential Implications for
Germline Testing in the Principles of Cancer Risk Assessment and Counseling (EVAL-A) in the NCCN Guidelines for Genetic/Familial High-
Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate].
• Testing
Somatic testing for alterations in DNA damage response:
◊ Multigene tumor testing for alterations in HRR genes, including but not limited to BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D,
CHEK2, and CDK12, is recommended in patients with metastatic prostate cancer. This testing can be considered in patients with regional
prostate cancer.
– Loss of BRCA1 and BRCA2 may be especially associated with response to PARP inhibitor therapy compared to other HRR gene
alterations.
◊ Tumor testing for MSI-H or dMMR is recommended in patients with mCRPC and may be considered in patients with regional or
castration-sensitive metastatic prostate cancer.
◊ TMB testing is recommended in patients with mCRPC.
• Tumor Specimen and Assay Considerations
The Panel strongly recommends a metastatic biopsy for histologic and molecular evaluation. This could include lymph node biopsy for
patients with N1 disease.
◊ When metastatic biopsy is unsafe or unfeasible, plasma circulating tumor DNA (ctDNA) assay is an option, preferably collected during
biochemical (PSA) and/or radiographic progression in order to maximize diagnostic yield. When diagnostic yield is low, the risk of false
negatives is higher, so ctDNA collection is not recommended when PSA is undetectable.
Caution is needed when interpreting ctDNA-only evaluation due to potential interference from clonal hematopoiesis of indeterminate
potential (CHIP), which can result in a false-positive biomarker signal.
DNA analysis for MSI and immunohistochemistry for mismatch repair (MMR) are different assays measuring different biological effects
caused by dMMR function. If MSI is used, testing using a next-generation sequencing assay validated for prostate cancer is preferred.
• Post-test Considerations
Post-test genetic counseling is recommended if pathogenic/likely pathogenic variant (mutation) identified in any gene that has clinical
implications if also identified in germline (eg, BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, PMS2).
Post-test genetic counseling to assess for the possibility of Lynch syndrome is recommended if MSI-H or dMMR is found.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF QUALITY OF LIFE AND SHARED DECISION-MAKING

• Treatments for patients with localized prostate cancer have risks and side effects that must be considered in the context of the risk posed by
the disease.1-4
• Baseline urinary, sexual, and bowel function are strongly associated with functional outcomes among patients undergoing treatment.1-4
• Thus, it is important to measure baseline disease-specific function (urinary, sexual, and bowel function), preferably using a standardized
patient-reported outcomes instrument (eg, EPIC-265).
• Shared decision-making in a multidisciplinary manner regarding initial management of localized prostate cancer should include an
explanation of the potential benefits and potential harms of each option. The provider should explain the likelihood of cure, recurrence,
disease progression, and disease-specific mortality with each management option, taking into account disease severity and competing
risks. In addition to the primary intended effects of treatment, the clinician should discuss the side effects of each treatment and predicted
impact on quality of life, including urinary, sexual, and bowel function. Patient preferences should be elicited and should be incorporated
into the disease management decision.6
• Consider geriatric assessment. See NCCN Guidelines for Older Adult Oncology for tools to aid optimal assessment and management of
disease in older adults.
• Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress
Management (DIS-A).

1 Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250-1261.
2 Chen RC, Basak R, Meyer AM, et al. Association between choice of radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance and
patient-reported quality of life among men with localized prostate cancer. JAMA 2017;317:1141-1150.
3 Hoffman KE, Penson DF, Zhao Z, et al. Patient-reported outcomes through 5 years for active surveillance, surgery, brachytherapy, or external beam radiation with or
without androgen deprivation therapy for localized prostate cancer. JAMA 2020;323:149-163.
4 Donovan JL, Hamdy FC, Lane JA, et al; ProtecT Study Group. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med
2016;375:1425-1437.
5 Szymanski KM, Wei JT, Dunn RL, Sanda MG. Development and validation of an abbreviated version of the expanded prostate cancer index composite instrument for
measuring health-related quality of life among prostate cancer survivors. Urology 2010;76:1245-1250.
6 Makarov D, Fagerlin A, Finkelstein J et al. AUA White Paper on Implementation of Shared Decision Making into Urological Practice. American Urological Association
2022. Available at: [Link]

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF IMAGING
Goals of Imaging
• Imaging is performed for the detection and characterization of disease to select treatment or guide change in disease management.
• Imaging techniques can evaluate anatomic or functional parameters.
Anatomic imaging techniques include ultrasound, CT, and MRI.
Functional imaging techniques include radionuclide bone scan, PET/CT, and advanced MRI techniques, such as spectroscopy and
diffusion-weighted imaging (DWI).

Efficacy of Imaging
• The utility of imaging for patients with early PSA persistence/recurrence after RP depends on risk group prior to operation, pathologic
Gleason grade and stage, PSA, and PSADT after recurrence. Low- and intermediate-risk groups with low serum PSAs postoperatively have a
very low risk of positive bone scans or CT scans.
• Frequency of imaging should be based on individual risk, age, PSADT, Gleason score, and overall health.
• Bone scans are rarely positive in asymptomatic patients with PSA <10 ng/mL. The relative risk for bone metastasis or death increases as
PSADT shortens. Bone imaging should be performed more frequently when PSADT is ≤8 months, where there appears to be an inflection
point.

Ultrasound
• Ultrasound uses high-frequency sound waves to image small regions of the body.
Standard ultrasound imaging provides anatomic information.
Vascular flow can be assessed using Doppler ultrasound techniques.
• Endorectal ultrasound is used to guide transrectal biopsies of the prostate. Endorectal ultrasound can be considered for patients with
suspected recurrence after RP to guide prostate bed biopsy.
• Advanced ultrasound techniques for imaging of the prostate and for differentiation between prostate cancer and prostatitis are under
evaluation.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF IMAGING
Bone Imaging
• The use of the term “bone scan” refers to the technetium-99m-MDP • Bone scans and soft tissue imaging (CT or MRI) in patients with
bone scan in which technetium is taken up by bone that is turning metastatic or non-metastatic prostate cancer may be obtained
over and imaged with a gamma camera using planar imaging or 3D regularly during systemic therapy to assess clinical benefit.
imaging with single-photon emission CT (SPECT). • Bone scans should be performed for symptoms and as often as
Sites of increased uptake imply accelerated bone turnover and may every 6 to 12 months to monitor ADT. The need for soft tissue
indicate metastatic disease. images remains unclear. In CRPC, 8- to 12-week imaging intervals
Osseous metastatic disease may be diagnosed based on the appear reasonable.
overall pattern of activity, or in conjunction with anatomic imaging.
• Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 piflufolastat • Plain Radiography
prostate-specific membrane antigen (PSMA), Ga-68 PSMA-11, F-18 Plain radiography can be used to evaluate symptomatic regions in
flotufolastat PSMA, F-18 fluciclovine, F-18 sodium fluoride, or C-11 the skeleton. However, plain films will not detect a bone lesion until
choline can be considered for equivocal results on initial bone scan. nearly 50% of the mineral content of the bone is lost or gained.
• Ga-68 PSMA-11, F-18 piflufolastat PSMA, or F-18 flotufolastat PSMA- CT or MRI may be more useful to assess fracture risk as
PET/CT or PET/MRI (full body imaging) can be considered as an these modalities permit more accurate assessment of cortical
alternative to bone scan. involvement than plain films where osteoblastic lesions may
• Bone imaging is indicated in the initial evaluation of patients at high obscure cortical involvement.
risk for skeletal metastases.
• Bone imaging can be considered for the evaluation of the patient Soft Tissue Imaging
post-prostatectomy when PSA does not fall to undetectable levels, • Soft tissue imaging of the pelvis, abdomen, and chest can include:
or when there is undetectable PSA after RP with a subsequent Chest CT and abdomen/pelvis CT or abdomen/pelvis MRI or
detectable PSA that increases on ≥2 subsequent determinations. PSMA-PET/CT or PSMA-PET/MRI for bone and soft tissue (full
• Bone imaging can be considered for the evaluation of patients body) imaging.
with an increasing PSA or positive DRE after RT if the patient is a
candidate for additional local therapy or systemic therapy. • Computed Tomography
• Bone scans are helpful to monitor metastatic prostate cancer to CT provides a high level of anatomic detail, and may detect gross
determine the clinical benefit of systemic therapy. However, new extracapsular disease, nodal metastatic disease, and/or visceral
lesions seen on an initial post-treatment bone scan, compared to the metastatic disease.
pretreatment baseline scan, may not indicate disease progression. CT is generally not sufficient to evaluate the prostate gland.
• New lesions in the setting of a falling PSA or soft tissue response CT may be performed with IV contrast, and CT technique should be
and in the absence of pain progression at that site may indicate optimized to maximize diagnostic utility while minimizing radiation
bone scan flare or an osteoblastic healing reaction. For this dose.
reason, a confirmatory bone scan 8 to 12 weeks later is warranted CT can be used for examination of the pelvis and/or abdomen for
to determine true progression from flare reaction. Additional new initial evaluation (PROS-2) and as part of workup for recurrence or
lesions favor progression. Stable scans make continuation of progression (see PROS-9 through PROS-18).
treatment reasonable. Bone scan flare is common, particularly on
initiation of new hormonal therapy, and may be observed in nearly
half of patients treated with the newer agents, enzalutamide and
abiraterone. Similar flare phenomena may exist with other imaging
modalities, such as CT or PET/CT imaging.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF IMAGING
• Magnetic Resonance Imaging PSMA-7.3), and Ga-68 PSMA-11 (also known as PSMA HBED-CC).
The strengths of MRI include high soft tissue contrast and Throughout these Guidelines, “PSMA-PET” refers to any of these
characterization, multiparametric image acquisition, multiplanar FDA-approved PSMA ligands. See Table 1 on PROS-E (5 of 5) for
imaging capability, and the use of specific MRI sequences to more details.
assess function. F-18 flotufolastat PSMA is a PET imaging agent that is part
◊ MRI can be performed with and without the administration of IV of a class of tracers referred to as radiohybrid (rh) ligands.
contrast material. These tracers have two binding sites for radionuclides for both
◊ Resolution of MRI images in the pelvis can be augmented using imaging and treatment, but the significance of this remains to be
a phased array/endorectal coil. determined.
Standard MRI techniques can be used for examination of the pelvis PSMA-PET/CT or PET/MRI can be considered as an alternative
and/or abdomen for initial evaluation (PROS-1) and as part of to CT, MRI, and bone scans for initial staging of unfavorable
workup for recurrence or progression (see PROS-9 through PROS- intermediate, high, and very-high-risk disease, the detection of
18). biochemically recurrent disease, and as workup for progression.
MRI may be considered in patients after RP when PSA does not In the setting of M1 CRPC, PSMA-PET imaging should only be used
fall to undetectable levels or when an undetectable PSA becomes to determine if a patient is a candidate for Lu-177-PSMA-617.
detectable and increases on ≥2 subsequent determinations, or Changes in systemic therapy should not be made solely based on
after RT for increasing PSA or positive DRE if the patient is a a positive PSMA-PET in patients with M0 CRPC.
candidate for additional local therapy. MRI-ultrasound fusion Bone scans can be considered to confirm osseous uptake on PET
biopsy may improve the detection of higher grade (Grade Group scans.
≥2) cancers. Synthesis of Ga-68 PSMA-11 requires that the PSMA-11 ligand is
Multiparametric MRI (mpMRI) can be used in the staging and labeled with Ga-68 from a generator or cyclotron. Two commercial
characterization of prostate cancer. mpMRI images are defined as kits to perform this in nuclear pharmacies have been approved by
images acquired with at least one more sequence in addition to the the FDA.
anatomical T2-weighted images, such as DWI or dynamic contrast- C-11 choline or F-18 fluciclovine PET/CT or PET/MRI may be used
enhanced (DCE) images. mpMRI may be used to better risk stratify to detect small-volume recurrent disease in soft tissues and in
patients who are considering active surveillance. Additionally, bone.
mpMRI may detect large and poorly differentiated prostate cancer Studies suggest that PSMA-PET imaging has a higher sensitivity
(Grade Group ≥2) and detect extracapsular extension (T staging) than C-11 choline or F-18 fluciclovine PET imaging, especially at
and is preferred over CT for abdomen/pelvis staging. mpMRI has very low PSA levels (eg, <0.5 ng/mL).
been shown to be equivalent to CT scan for pelvic lymph node Because of the increased sensitivity and specificity of PSMA-PET
evaluation. tracers for detecting micrometastatic disease compared to CT, MRI,
and bone scan at both initial staging and BCR, PSMA-PET/CT or
Full Body Imaging PSMA-PET/MRI can serve as a more effective frontline imaging tool
• Positron Emission Tomography for these patients.
PSMA-PET refers to a growing body of radiopharmaceuticals that Histologic or radiographic confirmation of involvement detected
target PSMA on the surface of prostate cells. There are multiple by PET imaging is recommended whenever feasible due to
PSMA radiopharmaceuticals at various stages of investigation. the presence of false positives. Although false positives exist,
At this time, the NCCN Guidelines only recommend the currently literature suggests that these are outweighed by the increase in
FDA-approved PSMA agents: F-18 piflufolastat PSMA (also known true positives detected by PET relative to CT, MRI, and bone scans.
as F-18 DCFPyL), F-18 flotufolastat PSMA (also known as rh- To reduce the false-positive rate, physicians should consider the

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF IMAGING
intensity of PSMA-PET uptake and correlative CT findings in the Fluorodeoxyglucose (FDG)-PET/CT should not be used routinely
interpretation of scans. The use of a standardized reporting system for staging prostate cancer since data are limited in this setting.
is encouraged. F-18 FDG-PET has been shown to be prognostic in patients with
PSMA imaging should be done before initiation of ADT because progressive CRPC.1,2
ADT may affect detection sensitivity. The increasing use of PSMA-PET has identified the potential for
High variability among PET/CT or PET/MRI equipment, protocols, considerable biological diversity among disease foci within a given
interpretation, and institutions provides challenges for application individual with prostate cancer, especially mCRPC, and that this
and interpretation of the utility of PET/CT or PET/MRI. heterogeneity can be detected with a combination of PSMA-PET
Table 1 on PROS-E (5 of 5) provides a summary of FDA-approved and FDG-PET. Initial data suggest that metastases with PSMA-
PET imaging tracers utilized for study in prostate cancer. negative/FDG-positive mismatches may exist in patients with
PET/CT or PET/MRI results may change treatment but may not mCRPC undergoing Lu-PSMA radioligand therapy and that patients
change oncologic outcome. with these mismatches may have worse outcomes. Currently, no
When patients with the worst prognosis move from one risk robust clinical trial data exist to support the incorporation of FDG-
group to the higher risk group, the average outcome of both risk PET into routine clinical use alongside PSMA-PET. To overcome
groups will improve even if treatment has no impact on disease. the limitations of PSMA-PET in PSMA-negative metastatic disease,
This phenomenon is known as the Will Rogers effect, in which the Panel currently recommends the use of contrast-enhanced
the improved outcomes of both groups could be falsely attributed CT or MRI in these patients, as the non-contrast CT component of
to improvement in treatment, but would be due only to improved PSMA-PET/CT is insufficient to detect visceral metastatic disease.
risk group assignment. As an example, F-18 sodium fluoride PET/
CT may categorize some patients as M1b who would have been Imaging as Workup for Progression
categorized previously as M0 using a bone scan (stage migration). • Workup for progression should include bone and soft tissue
Absent any change in the effectiveness of therapy, the overall evaluation.
survival (OS) of both M1b and M0 groups would improve. The See Bone Imaging (PROS-E [2 of 5]).
definition of M0 and M1 disease for randomized clinical trials See Soft Tissue Imaging (PROS-E [2 of 5]).
that added docetaxel or abiraterone to ADT was based on CT and • Imaging for patients with progressive CRPC should include
radionuclide bone scans. Results suggest that OS of M1 disease chest CT, bone imaging, and abdomen/pelvis CT with contrast or
is improved, whereas progression-free but not OS of M0 disease abdomen/pelvis MRI with and without contrast.
is improved. Therefore, a subset of patients now diagnosed with • There is a lack of evidence to support the use of PET imaging in
M1 disease using F-18 sodium fluoride PET/CT might not benefit the CRPC setting and it should only be used in the setting of M1
from the more intensive therapy used in these trials and could CRPC to determine if a patient is a candidate for Lu-177-PSMA-617.
achieve equivalent OS from less intensive therapy aimed at M0 Changes in treatment should not be made solely based on a positive
disease. Carefully designed clinical trials using proper staging PSMA-PET in patients with M0 CRPC.
will be necessary to prove therapeutic benefit, rather than making
assumptions compromised by stage migration.

1 Buteau JP, Martin AJ, Emmett L, et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus cabazitaxel for
metastatic castration-resistant prostate cancer (TheraP): A biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol 2022;23:1389-1397.
2 Pathmanandavel S, Crumbaker M, Nguyen A, et al. The prognostic value of posttreatment 68Ga-PSMA-11 PET/CT and 18F-FDG PET/CT in metastatic castration-
resistant prostate cancer treated with 177Lu-PSMA-617 and NOX66 in a phase I/II trial (LuPIN). J Nucl Med 2023;64:69-74.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF IMAGING
Table 1. FDA-Cleared PET Imaging Tracers Studied in Prostate Cancer
Half-Life
Tracer Excretion Detection Ratesa Panel Recommendation
(min)
• 40% sensitivity and 95% specificity to detect
nodal involvement in primary staging of patients
Ga-68 PSMA-11 (PSMA-
68 Renal with intermediate-, high-, and very-high-risk
HBED-CC)
disease
• 92% patient-level PPV in BCR • May be considered as an alternative to
CT, MRI, and bone scans for initial staging
• 31%–42% sensitivity and 96%–99% specificity
of unfavorable intermediate-, high-, and
to detect nodal involvement in primary staging
F-18 piflufolastat-PSMA very-high-risk disease, the detection of
110 Renal of patients with unfavorable intermediate-risk,
(18F-DCFPyL) biochemically recurrent disease, and as
high-risk, and very-high-risk disease
workup for progression
• 85%–87% patient-level CLRb in BCR
• May be considered for equivocal results on
• 23%–30% sensitivity and 93%–97% specificity initial bone scan
F-18 flotufolastat PSMA to detect nodal involvement in primary staging
110 Renal of patients with unfavorable-intermediate-, high-
(18F-rh-PSMA-7.3)6,7 , and very-high-risk disease
• 82% patient-level PPV in BCR
Hepatic and • May be used to detect small-volume
C-11 choline 20 • 53%–96% PPV in BCR
Renal recurrent disease in soft tissues and in bone
F-18 fluciclovine • May be considered for equivocal results on
110 Renal • 87%–91% CLRb in BCR initial bone scan
(FACBC)
• 77%–94% sensitivity, 92%–99% specificity, and • May be considered for equivocal results on
F-18 sodium fluoride 110 Renal
82%–97% PPV for bone metastases initial bone scan

a Interpretwith caution. Wherever possible, studies were included that used histopathologic confirmation, but not all studies used confirmatory histology as the gold
standard. Values may vary depending upon the site of the lesion and phase of the disease process.
b CLR: Correct localization rate. Patient-level positive predictive value (PPV) + anatomic lesion co-localization. Preferred over sensitivity and specificity in analyses of
patients with BCR.

Note: All recommendations are category 2A unless otherwise indicated.

PROS-E
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PRINCIPLES OF ACTIVE SURVEILLANCE AND OBSERVATION

• The NCCN Prostate Cancer Panel and the NCCN Prostate Cancer Early Detection Panel (NCCN Guidelines for Prostate Cancer
Early Detection) remain concerned about overdiagnosis and overtreatment of prostate cancer. The Prostate Cancer Panel recommends that
patients and their physicians carefully consider active surveillance based on the patient’s prostate cancer risk profile and estimated life
expectancy. In settings where the patient’s age and comorbidities suggest a shorter life expectancy, observation may be more appropriate.
Shared decision-making, after appropriate counseling on the risks and benefits of the various options, is critical.
• Life expectancy is a key determinant for the choice between observation and active surveillance. Multiple tools exist to assist in life
expectancy estimation. See Principles of Life Expectancy Estimation (PROS-A).
• There remains no high-level evidence showing clinical benefit of advanced risk stratification tools (eg, gene expression biomarkers,
germline or somatic testing, or artificial intelligence (AI)-based digital pathology models), to guide the candidacy for active surveillance.

ACTIVE SURVEILLANCE1
• Active surveillance involves actively monitoring the course of disease with the expectation to intervene with curative intent if the cancer
progresses. It involves PSA monitoring and longitudinal serial pathologic assessments via a prostate biopsy, often guided by MRI.
• There are three phases of active surveillance: 1) candidacy, 2) confirmation of candidacy, and 3) active surveillance.

• Candidacy for Active Surveillance:

NCCN Low-Risk:
◊ Active surveillance is the preferred management approach for patients with low-risk prostate cancer and a life expectancy ≥10 years.
◊ The Panel recognizes that there is heterogeneity across this risk group.
– Some factors may be associated with an increased probability of near-term grade reclassification including:
▪ High PSA density (≥0.15)2
▪ Increased number of positive cores3
▪ Higher body mass index (BMI)3
▪ Faster PSA kinetics3
– Conversely a negative biopsy following diagnosis is associated with a decreased probability of grade reclassification.
– The Canary PASS risk calculator can be used for more precise estimates of upgrading probability on active surveillance (Canary Pass
Risk Calculator)
– Higher risk features alone do not necessitate immediate treatment, but should be used as part of a shared-decision making discussion
and in tailoring the intensity of active surveillance.
◊ For patients who are at high-risk of suboptimal adherence to an active surveillance protocol, a careful discussion should be had about
the potential risks of active surveillance. For some of these patients, upfront treatment with definitive RP or RT may be preferred.

References on PROS-F 5 of 5
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF ACTIVE SURVEILLANCE AND OBSERVATION

• Candidacy for Active Surveillance (continued):
NCCN Favorable Intermediate-Risk (FIR)
◊ Patients with FIR prostate cancer and a life expectancy of >10 years may also consider active surveillance.
◊ The FIR group was not created for optimal selection of active surveillance candidacy, and there is considerable heterogeneity in this risk
group. Not all patients with FIR disease are suitable candidates for active surveillance. For example:
– A patient with Grade Group 1 in a single biopsy core, cT1c, PSA of 12 ng/mL, and PSA density of 0.15 ng/mL/g has FIR disease and a
favorable prognostic outcome. Therefore, active surveillance is preferred.
– A patient with GG2 in 5 of 12 cores, cribriform architecture, cT1c, PSA of 8 ng/mL, and PSA density 0.30 ng/mL/g has FIR disease, but
active surveillance would not be the preferred strategy.
◊ In addition to prognostic factors listed for Low Risk, additional prognostic factors relevant for FIR include:
– Increased percentage pattern 4.
– Presence of unfavorable histology such as expansile/large cribriform histology and/or intraductal carcinoma.
◊ Active surveillance is not recommended for patients with FIR and unfavorable histology (eg, expansile/large cribriform histology,
intraductal carcinoma). See Discussion.
◊ Intensity of active surveillance should generally be greater for patients with FIR disease.
◊ Patients should be counseled that long-term data show that patients with GG2 disease managed with active monitoring or watchful
waiting had an increase in the development of distant metastasis as compared to those receiving immediate radical treatment.4
Continued refinements in active surveillance protocols and active surveillance candidacy are expected to improve the safety of active
surveillance for GG2 FIR disease, and patients should be counseled on the importance of longitudinal follow-up.

• Confirmation of Candidacy:
Goals of confirmation testing are to help facilitate early identification of patients who may be at a higher risk of grade reclassification or
cancer progression.
An initial prostate biopsy may underestimate tumor grade or volume, thus confirmatory testing is strongly recommended for patients who
are considering active surveillance.
A repeat biopsy is a routine component of confirmatory testing.
◊ The timing of repeat biopsy can be based on the patient's risk of progression. Patients with a higher risk should have a repeat biopsy
earlier than those with a lower risk.
◊ If the initial prostate biopsy was performed without mpMRI guidance, then the Panel recommends an earlier repeat biopsy (eg, within the
first 6–12 months) and recommends mpMRI prior to the biopsy. A systematic biopsy should be included.
◊ For most patients, the timing is generally within 6 to 24 months of diagnostic biopsy, but all patients on active surveillance should
undergo a confirmatory prostate biopsy within 3 years of their diagnostic biopsy, irrespective of prior mpMRI findings.
Confirmatory testing should also include mpMRI with calculation of PSA density.
Advanced risk stratification tools lack high level evidence to obviate other testing at this time.
Other forms of imaging are discouraged.

References on PROS-F 5 of 5
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF ACTIVE SURVEILLANCE AND OBSERVATION

• Active Surveillance Program
Patients who choose active surveillance should have regular follow-up.
Key principles include:
◊ PSA no more often than every 6 months, unless clinically indicated.
◊ DRE no more often than every 12 months, unless clinically indicated.
◊ Repeat prostate biopsy no more often than every 12 months, unless clinically indicated. While the intensity of surveillance may be
tailored based on patient and tumor factors (eg, grade, tumor volume), most patients should have prostate biopsies every 1 to 3 years as
part of their monitoring. Longer intervals between biopsies may be considered if maintained on active surveillance for >3 years without
progression.
◊ Consider repeat prostate MRI no more than every 12 months, unless clinically indicated.
◊ In patients with a suspicious lesion on prostate MRI, MRI-targeted biopsy improves the detection of higher grade (GG ≥2) cancers.
◊ Patients should be transitioned to observation when life expectancy is <10 years.
◊ A metastatic staging evaluation (PSMA PET, bone scan, CT scan, or whole-body MRI) should not be performed unless patient develops
unfavorable intermediate or higher-risk disease, or has concerning symptoms not explainable by other causes.

• Considerations for Treatment of Patients on Active Surveillance

Low risk: Grade reclassification on repeat biopsy to GG2 or higher is the most common factor to transition off active surveillance to
treatment. PSA alone or growth in size of the tumor on MRI (assuming organ confined) should not be used alone to stop active surveillance
without histologic confirmation of progression.
FIR: Grade reclassification, increase in percent pattern 4, increase in tumor volume on biopsy or imaging, or rise in PSA density are
common factors to transition off active surveillance to treatment.
Patient anxiety is commonly cited as a reason to transition off active surveillance. However, studies indicate patient anxiety is closely
linked with provider education on the safety of active surveillance. Thus, if a patient is an excellent candidate for active surveillance and
has anxiety, the provider should provide appropriate education on the safety of active surveillance.

• Advantages of Active Surveillance

Approximately 50% of those eligible for active surveillance may safely avoid treatment for 10 years.5-7 This varies by baseline risk.
Patients will avoid or delay possible side effects of treatment. Quality of life will be less affected while on active surveillance.
Risk of unnecessary treatment of small, indolent cancers will be reduced.

• Limitations of Active Surveillance

According to current data, the majority of patients on active surveillance receive treatment by 15 years post-diagnosis.
Although the risk is very low for patients diagnosed with GG1 disease (<1% at 10 years and 5% at 15 years), it is possible for cancer to
progress to a regional or metastatic stage.5-8
The majority of high quality evidence with >10 years of follow-up primarily limited active surveillance to patients with low-risk disease, low-
volume and low PSA density.
In early series, GG2 disease had higher rates of progression to metastatic disease.8 However, there has been grade migration, stage
migration with MRI, and refinement in active surveillance candidacy with assessment of percentage pattern 4 and unfavorable histologic
variants. Long-term follow-up (10–15 years) of patients with GG2 FIR disease continues to develop.

References on PROS-F 5 of 5
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF ACTIVE SURVEILLANCE AND OBSERVATION

OBSERVATION
• Observation involves monitoring with a history and physical examination no more often than every 12 months (without surveillance biopsies,
imaging, or PSA monitoring) until symptoms develop or are thought to be imminent.
• Low risk
Observation is recommended for asymptomatic patients with life expectancy <10 years.
• FIR
Observation is recommended for asymptomatic patients with a life expectancy ≤5 years.
Observation is preferred for asymptomatic patients with a life expectancy between 5 to 10 years.
• Observation may be considered for asymptomatic patients with high-risk, very-high-risk, regional, and metastatic prostate cancer and a life
expectancy ≤5 years.
• If patients under observation become symptomatic, an assessment of disease burden can be performed, and treatment per the appropriate
disease setting or palliation can be considered.

• Advantages of Observation
Patients will avoid possible side effects of unnecessary confirmatory testing and definitive therapy with a low probability that this would
compromise their survival.

• Limitations of Observation
There may be risk of local or systemic symptoms (eg, urinary retention, pathologic fracture) that could have been avoided with upfront
definitive treatment.

Note: All recommendations are category 2A unless otherwise indicated.

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REFERENCES
1 Ganz PA, Barry JM, Burke W, et al. NIH State-of-the-Science Conference Statement: Role of active surveillance in the management of men with localized prostate
cancer. NIH Consens State Sci Statements 2011;28:1-27.
2 Mcleod LC, Ellis WJ, Newcomb LF, et al. Timing of adverse prostate cancer reclassification on first surveillance biopsy: Results from the Canary prostate cancer active
surveillance study. J Urol 2017;197:1026-1033.
3 Cooperberg MR, Zheng Y, Faino AV, et al. Tailoring intensity of active surveillance for low-risk prostate cancer based on individualized prediction of risk stability. JAMA
Oncol 2020;6:e203187.
4 Wilt TJ, Vo TN, Langsetmo L, et al. Radical prostatectomy or observation for clinically localized prostate cancer: Extended follow-up of the prostate cancer intervention
versus observation trial (PIVOT). Eur Urol 2020;77:713-724.
5 Tosoian JJ, Mamawala M, Epstein JI, et al. Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer.
J Clin Oncol 2015;33:3379-3385.
6 Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol 2015;33:272-277.
7 Cooley LF, Emeka AA, Meyers TJ, et al. Factors associated with time to conversion from active surveillance to treatment for prostate cancer in a multi-institutional
cohort. J Urol 2021;206:1147-1156.
8 Musunuru HB, Yamamoto T, Klotz L, et al. Active surveillance for intermediate risk prostate cancer: Survival outcomes in the sunnybrook experience. J Urol
2016;196:1651-1658.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF ANDROGEN DEPRIVATION THERAPY

Neoadjuvant, Concurrent, and/or Adjuvant ADT with RTa:
• Clinically localized (N0, M0) disease
• Regional (N1, M0) disease
• Positive lymph nodes (pN1 disease) and/or adverse features post-RP
• First M0 RP PSA persistence/recurrence
RT with one of the following ADT options:
• Luteinizing hormone-releasing hormone (LHRH) agonist monotherapy
Goserelin, leuprolide, or triptorelin
• LHRH agonist (as above) plus first-generation antiandrogen
Nilutamide, flutamide, or bicalutamide
• LHRH antagonist
Degarelix or relugolix
LHRH agonist or antagonist plus abirateroneb (2 years; only for very-high-risk localized disease or positive lymph nodes)
Notes:
• ADT is not recommended with RT for most patients with favorable intermediate-risk prostate cancer. If it is given (see Principles of Risk
Stratification), the duration should be short term (4–6 months).
• For unfavorable intermediate risk prostate cancer treated with RT, short-term ADT (ST-ADT) (4–6 months) is recommended. Concurrent/
adjuvant ADT is preferred over neoadjuvant ADT in this setting.
• For high- and very-high-risk prostate cancer treated with EBRT alone, long-term ADT (LT-ADT) (18–36 months) is recommended.
• For high-risk prostate cancer treated with combination EBRT + brachytherapy, a shortened duration of ADT (12 months) can be considered.
• For additional details on the use of RT with ADT by risk group, see PROS-J.
• First M0 PSA persistence/recurrence:
The timing of secondary treatment for patients whose only evidence of cancer after definitive treatment is an increasing PSA is influenced
by PSA velocity, patient anxiety, the short- and long-term side effects of ADT, and the underlying comorbidities of the patient.
Earlier treatment may be better than delayed treatment, although the definitions of early and late (what level of PSA) are controversial.
Since the benefit of early treatment is not clear, treatment should be individualized until definitive studies are done. Patients with a shorter
PSADT (or a rapid PSA velocity) and an otherwise long life expectancy should be encouraged to consider treatment earlier.
For patients treated with secondary RT in the setting of first RP recurrence, if ADT is given, it should be for a duration of 6 to 24 months.
Patients with prolonged PSADTs (>12 months) and who are older are candidates for observation or monitoring.
Patients who choose ADT monotherapy in the secondary treatment setting should consider intermittent ADT.

Note: All recommendations are category 2A unless otherwise indicated.

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ADT for Patients with M0 CSPCa:
• Regional (N1, M0) disease
• First M0 RT recurrence
ADT Options:
• Orchiectomy
• LHRH agonist monotherapy
Goserelin, leuprolide, or triptorelin
• LHRH agonist (as above) plus first-generation antiandrogen
Nilutamide, flutamide, or bicalutamide
• LHRH antagonist
Degarelix or relugolix
• LHRH agonist, LHRH antagonist, or orchiectomy plus abirateroneb (only for positive lymph nodes)
Notes:
• M0 PSA persistence/recurrence:
The timing of secondary treatment for patients whose only evidence of cancer after definitive treatment is an increasing PSA is influenced
by PSA velocity, patient anxiety, the short- and long-term side effects of ADT, and the underlying comorbidities of the patient.
Earlier treatment may be better than delayed treatment, although the definitions of early and late (what level of PSA) are controversial.
Since the benefit of early treatment is not clear, treatment should be individualized until definitive studies are done. Patients with a shorter
PSADT (or a rapid PSA velocity) and an otherwise long life expectancy should be encouraged to consider treatment earlier.
Patients with prolonged PSADTs (>12 months) and who are older are candidates for observation or monitoring.
Patients who choose ADT monotherapy in the secondary treatment setting should consider intermittent ADT.

Note: All recommendations are category 2A unless otherwise indicated.

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ADT for Patients with M0 CSPC BCR2a:
ADT Optionsc:
• Orchiectomy
• LHRH agonist monotherapy
Goserelin, leuprolide, or triptorelin
• LHRH agonist (as above) plus first-generation antiandrogen
Nilutamide, flutamide, or bicalutamide
• LHRH antagonist
Degarelix or relugolix

For High-Risk BCR2:

• Enzalutamide with or without Leuprolided
• Apalutamide with LHRH agonist or LHRH antagoniste
Notes:
• Monitoring until diagnosis of metastatic disease is preferred for patients with M0 CSPC in the low-risk BCR2 setting.
• PSADT and Grade Group should be considered when deciding whether to begin ADT for patients with M0 disease.
• ADT monotherapy is an option for these patients, and intermittent ADT can be considered to reduce toxicity.

Note: All recommendations are category 2A unless otherwise indicated.

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ADT for Patients with mCSPCa:
ADT with treatment intensification (systemic therapy):
• Orchiectomy plus abiraterone,b apalutamide, darolutamide, or enzalutamide
• LHRH agonist plus abiraterone,b apalutamide, darolutamide, or enzalutamide
• LHRH antagonist plus abiraterone,b apalutamide, darolutamide, or enzalutamide
• Orchiectomy plus docetaxel and either abiraterone,b apalutamide, darolutamide, or enzalutamide
• LHRH agonist plus docetaxel and either abiraterone,b apalutamide, darolutamide, or enzalutamide
• LHRH antagonist plus docetaxel and either abiraterone,b apalutamide, darolutamide, or enzalutamide

ADT with treatment intensification (EBRT to the primary tumor):

EBRT with:
• Orchiectomy alone or with abiraterone,b apalutamide, docetaxel, or enzalutamide
• LHRH agonist alone or with abiraterone,b apalutamide, docetaxel,g or enzalutamide
• LHRH antagonist alone or with abiraterone,b apalutamide, docetaxel, or enzalutamide

ADT alone for select patientsf:

• Orchiectomy
• LHRH agonist monotherapyg
Goserelin, leuprolide, or triptorelin
• LHRH agonist (as above) plus first-generation antiandrogen
Nilutamide, flutamide, or bicalutamide
• LHRH antagonist
Degarelix or relugolix

a Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see PROS-5
through PROS-18). This chart delineates the forms of ADT that can be used and provides some additional details.
b The fine-particle formulation of abiraterone can be used instead of the standard form (category 2B; other recommended). Abiraterone should be given with concurrent
steroid: prednisone 5 mg PO once daily (in the CSPC setting without docetaxel) or twice daily (in the CSPC setting with docetaxel and in the CRPC setting) with the
standard formulation or methylprednisolone 4 mg PO twice daily with the fine-particle formulation. The standard formulation of abiraterone can be given at 250 mg/day
following a low-fat breakfast in patients who will not take or cannot afford the standard dose of 1000 mg/day after an overnight fast.
f ADT is strongly recommended in combination therapy for metastatic castration-sensitive disease. The use of ADT monotherapy in metastatic castration-sensitive
disease is discouraged unless there are clear contraindications to combination therapy. If ADT monotherapy is given, intermittent ADT can be considered to reduce
toxicity. Close monitoring of PSA and testosterone levels and possibly imaging is required when using intermittent ADT, especially during off-treatment periods, and
patients may need to switch to continuous ADT upon signs of disease progression.
g A first-generation antiandrogen must be given with LHRH agonist for ≥7 days to prevent testosterone flare if metastases are present in weight-bearing bone or if there
is a large prostate mass.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF ANDROGEN DEPRIVATION THERAPY

Secondary Hormone Therapy for Patients with M0 or M1 CRPCa:
Castrate levels of testosterone (<50 ng/dL) should be maintained while additional therapies are applied:
• Orchiectomy, LHRH agonist, or LHRH antagonist with specific therapies noted on PROS-16 [M0 CRPC], PROS-17 [NEPC], and PROS-18 [M1 CRPC]
• Orchiectomy, LHRH agonist, or LHRH antagonist with other secondary hormone options:
Abirateroneb or enzalutamide following progression on ARPIs (M1 only)
Abirateroneb plus 0.5 mg/day dexamethasone following progression on either formulation of abiraterone (M1 only)
Antiandrogen withdrawalh
Corticosteroids (hydrocortisone, prednisone, or dexamethasone)h
First-generation anti-androgen (nilutamide, flutamide, or bicalutamide)h
Ketoconazole plus hydrocortisoneh
Notes:
Although the optimal sequence of therapies remains undefined, some data are emerging that can help with treatment selection in some
cases. See Discussion.
ADT Monotherapya:
ADT Options:
• Orchiectomy
• LHRH agonist monotherapyg
Goserelin, leuprolide, or triptorelin
• LHRH antagonist
Degarelix or relugolix
Notes:
ADT monotherapy is appropriate for patients with life expectancy ≤5 years whose cancer progressed on observation of localized disease,
who are symptomatic, or who have N1M0 disease.
ADT monotherapy is also used for asymptomatic patients with regional disease and life expectancy ≤5 years whether or not RT is given.

a Specific recommendations, Categories of Evidence and Consensus, and Categories of Preference vary based on patient and disease characteristics (see PROS-5
through PROS-18). This chart delineates the forms of ADT that can be used and provides some additional details.
b The fine-particle formulation of abiraterone can be used instead of the standard form (category 2B; other recommended). Abiraterone should be given with concurrent
steroid: prednisone 5 mg PO once daily (in the CSPC setting without docetaxel) or twice daily (in the CSPC setting with docetaxel and in the CRPC setting) with the
standard formulation or methylprednisolone 4 mg PO twice daily with the fine-particle formulation. The standard formulation of abiraterone can be given at 250 mg/day
following a low-fat breakfast in patients who will not take or cannot afford the standard dose of 1000 mg/day after an overnight fast.
g A first-generation antiandrogen must be given with LHRH agonist for ≥7 days to prevent testosterone flare if metastases are present in weight-bearing bone or if there
is a large prostate mass.
h In the mCRPC setting, this option should only be used for select patients who are not candidates for other recommended mCRPC therapies.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF ANDROGEN DEPRIVATION THERAPY

Optimal ADT:

• Medical castration (ie, LHRH agonist or antagonist) and surgical castration (ie, bilateral orchiectomy) are equally effective.
• Patients who do not achieve adequate suppression of serum testosterone (<50 ng/dL) with medical or surgical castration can be considered
for additional hormonal manipulations (with antiandrogens, LHRH antagonists, or steroids), although the clinical benefit remains uncertain.
Consider monitoring testosterone levels 12 weeks after first dose of LHRH therapy, then upon increase in PSA. The optimal level of serum
testosterone to affect “castration” has yet to be determined.

Monitor/Surveillance:

• ADT has a variety of adverse effects, including hot flashes, loss of libido, erectile dysfunction, shrinkage of penis and testicles, loss
of muscle mass and strength, fatigue, anemia, breast enlargement and tenderness/soreness, depression and mood swings, hair loss,
osteoporosis, greater incidence of clinical fractures, obesity, insulin resistance, alterations in lipids, and greater risk for diabetes and
cardiovascular disease. The intensity and spectrum of these side effects vary greatly, and many are reversible or can be avoided or
mitigated. See NCCN Guidelines for Survivorship. Patients and their medical providers should be advised about these risks prior to
treatment.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RISK STRATIFICATION AND BIOMARKERS

General Principles:

• Currently, the primary method for personalization of treatment from localized to advanced prostate cancer is based on prognostic risk
stratification, rather than the use of predictive tools.
• NCCN uses multiple categories and subgroupings to capture prognostic risk to personalize treatment recommendations.
• The purpose of the NCCN categories and subgroupings are to provide a method for risk stratification to allow standardized treatment
recommendations to be provided.
It is acknowledged that there are methods of risk stratification with superior prognostic performance to NCCN risk groups. However, they
have not been routinely reported in clinical trials. This limits the ability to provide evidence-based guideline treatment recommendations
using these methods. Thus, the NCCN Guidelines continue to use NCCN categories and subgroups of risk as a framework.
Clinical trials have established the benefit of various treatments in prostate cancer and have commonly enrolled patients across a
spectrum of risk. Subgroup analyses, absolute benefit estimates, and expert opinion are used to provide treatment recommendations for
each NCCN risk group or disease state.
There is intrinsic heterogeneity in prognosis within a given NCCN category and subgroup. Thus, treatment recommendations for adjacent
subgroups or categories of risk may be appropriate when using additional risk stratification methods.
The Panel acknowledges the ability to personalize treatment decisions through additional tools and have created this section to assist.
• Tools that are prognostic or predictive in one disease state may not be in other disease states, or they may have other forms of clinical utility
beyond prognostication and prediction of treatment benefit.
For example, germline homologous recombination deficiency (HRD) mutations do not have an established prognostic or predictive role
in localized prostate cancer, but specific HRD mutations have been demonstrated to have a prognostic and predictive role in advanced
disease. Additionally, the utility of germline testing extends to inform screening recommendations for other cancers and cascade germline
testing for family members.
• Imaging is also a biomarker (ie, MRI, PSMA-PET/CT) and can aid in risk stratification. See Principles of Imaging (PROS-E).

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RISK STRATIFICATION AND BIOMARKERS

Biomarker Categories:

• Biomarkers and risk stratification methods are tools that may assist in personalization of treatment. For clarity these tools are separated by
type and category:

Type:
◊ Standard Tools: These include clinical and/or pathologic variables routinely collected to assign a patient to an NCCN category and/or
subgroup. Examples include TNM stage, Grade Group, PSA, and metastatic volume of disease.
◊ Clinical and Pathologic Tools: These include clinical and/or pathologic tools that are generally derived from standard tools. Examples
include multivariable models or nomograms, histologic variants, and PSA kinetics.
◊ Advanced Tools: These involve an additional test above what is collected to assign an NCCN category or subgroup. These may include,
but are not limited to, germline or somatic tests, gene expression tests, digital histopathology-based tests, additional imaging, and
circulating markers.

Category:
◊ Prognostic: Discriminates the risk of developing an oncologic endpoint (eg, distant metastasis). The relative benefit of a treatment (ie, the
treatment effect or hazard ratio) is generally similar across a prognostic spectrum, although the absolute benefit of an intervention may
vary by risk (ie, number needed to treat [NNT]).
– Ideally, prognostic biomarkers independently discriminate and are associated with a clinically meaningful endpoint above and beyond
standard tools relevant to that disease setting that ultimately helps guide a therapeutic decision.
◊ Predictive: Discriminates a difference in the relative benefit of a specific treatment for an oncologic endpoint.
– Ideally, predictive biomarkers have been demonstrated to measure differential treatment effects that ultimately help guide a therapeutic
decision in the context of a randomized trial, specifically randomizing the treatment of interest.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RISK STRATIFICATION AND BIOMARKERS

Clinical and Pathologic Tools:

• An extensive number of prognostic clinical or pathologic tools have been reported based on highly variable evidence quality (retrospective
or registry study vs. randomized trial), validation rigor, strength of endpoint (adverse pathology or BCR vs. distant metastasis), and
univariable versus multivariable association with an outcome. Thus, while some of these tools may have value, these limitations hinder the
ability to accurately provide guidance to specific treatment recommendations with confidence.
• A comprehensive list of these tools is outside the scope of this guideline.
Examples of such prognostic tools include multivariable models and nomograms (eg, CAPRA,1 STAR-CAP,2 MSKCC nomograms3),
histopathology (ie, cribriform, intraductal carcinoma, absolute and percent Gleason pattern 4, total mm of cancer), and clinical variables (ie,
PSA density, PSA velocity, PSA level, PSADT).

Advanced Tools:

• Advanced risk stratification tools generally offer either superior prognostic performance beyond clinical and pathologic tools AND/OR serve
as predictive biomarkers for identifying patient groups that differentially benefit from a specific treatment. In general, these tools are only
recommended when they have the potential ability to change management and should not be ordered reflexively.
Prognostic tools: Generally, the Panel recommends the use of prognostic tests that are validated in well-designed prospective studies with
clinically meaningful endpoints based on disease settings that guide a specific treatment indication based on a specific score or result.
These studies can be either prospective integral or integrated clinical trial(s) or post-hoc correlative analyses of prospective trials.
Predictive tools: Generally, the Panel recommends the use of predictive tests that are validated in a prospective, biomarker-directed,
randomized clinical trial of the treatment of interest. Alternatively, if validation is post-hoc in a trial not designed to test the tool, it should be
performed in more than one independent randomized trial of the treatment of interest.
• The Panel recognizes that there is an extensive number of advanced tools created with substantial variability in quality of reporting and
model design, endpoint selection, and quality and caliber of validation. There are risks in using advanced tools to change management
without robust validation, as they may drive patients or providers to inappropriate treatment options. If advanced tools are used, it is
recommended to use tests that have robust validation, ideally with high-quality, long-term clinical trial data and across multiple clinical trials.
• Only advanced tools with high evidence quality are shown in Table 1. Other prognostic tools that are commonly used are described in the
Discussion.

References
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF RISK STRATIFICATION AND BIOMARKERS

Table 1. Advanced Prognostic Toolsa
Intermediate-Risk Prostate Cancer
Tool Category Discussion
NRG/RTOG 0126 phase III randomized trial was profiled post-hoc with a prespecified analysis plan.4 The study demonstrated the
22-gene genomic independent prognostic effect of GC on biochemical failure, secondary therapy, DM, PCSM, MFS, and OS. Patients receiving RT alone
Gene with low GC scores had 10-year DM rates of 4%, compared with 16% for GC high risk. These results suggest that the benefit of short-
classifier (GC) term ADT in NCCN intermediate-risk prostate cancer is likely to be smaller in patients with low GC scores (≤0.45) than in patients with
Expression
(Decipher)4-6 high GC scores (≥0.60). A breakdown of outcomes between patients with favorable vs. unfavorable intermediate-risk disease was not
provided.
A post-hoc meta-analysis of eight phase III randomized trials (NRG/RTOG 9202, 9408, 9413, 9902, 9910, 0126, 0415, and 0521) with
MMAI scores have been reported.7,8 There were a total of 630 patients with NCCN intermediate-risk disease who primarily received RT
Multimodal artificial alone or RT+ST-ADT. Among patients with NCCN intermediate-risk disease, those with MMAI low-risk disease had 5-year and 10-year
DM rates of 1% and 4%, respectively. In contrast, those with MMAI intermediate- and high-risk tumors had 5-and 10-year DM rates of 7%
intelligence (MMAI) AI-Pathology and 40%. MMAI was independently prognostic for DM, PCSM, and death after DM. These results suggest that the benefit of short-term
(ArteraAI Prostate)b,7-11 ADT in NCCN intermediate-risk prostate cancer is likely to be smaller in patients with MMAI low-risk disease than in patients with MMAI
intermediate- or high-risk disease. Neither a breakdown of favorable vs. unfavorable intermediate risk, nor a breakdown of outcomes after
RT alone vs. RT+ST-ADT were provided.
DM = distant metastases; MFS = metastasis-free survival; PCSM = prostate cancer-specific mortality; ST-ADT = short-term ADT

a Inthe absence of prospective trials, caution is warranted if using these prognostic tools to influence treatment decisions. The Panel awaits future trials that confirm the initial results
described here.
b There is also an MMAI predictive biomarker that was validated post-hoc in RTOG 9408 to predict benefit of ST-ADT added to RT in patients with intermediate-risk prostate cancer. While
promising, due to differences in tissue sampling, grading, staging, and treatment, the Panel recommends further validation prior to using this predictive biomarker to guide treatment
decisions in isolation.
References
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF RISK STRATIFICATION AND BIOMARKERS

Table 1. Advanced Prognostic Toolsa
High-Risk and Very-High-Risk Prostate Cancer
Tool Category Discussion
A meta-analysis of three phase III randomized trials (NRG/RTOG 9202, 9413, and 9902) that included patients with high-/very-high-risk
prostate cancer were profiled post-hoc with a prespecified analysis plan.5 The study demonstrated the independent prognostic effect of
Gene GC on biochemical failure, DM, MFS, PCSM, and OS. Patients with low GC scores had 10-year DM rates of 6%, compared with 26% for
22-gene GC4-6 GC high risk. The absolute benefit of LT-ADT over ST-ADT was 11% for patients with high GC scores (NNT of 9), and 3% for patients with
Expression low GC scores (NNT of 33). These results suggest that the benefit of long-term ADT in NCCN high- and very-high-risk prostate cancer
is likely to be smaller in patients with low GC scores (≤0.45) than in patients with high GC scores (≥0.60). A breakdown of outcomes
between patients with high- vs. very high-risk disease was not provided.
Multiple post-hoc meta-analyses of patients with NCCN high- or very-high-risk disease from six randomized phase III randomized trials
(NRG/RTOG 9202, 9408, 9413, 9902, 9910, and 0521) with MMAI scores have been reported.8,10 A total of 1090 patients had NCCN
high-/very-high-risk disease and were treated predominately with RT+LT-ADT (with or without chemotherapy; 68%) or RT+ST-ADT (30%),
and a small number with RT alone (2%). Among patients with NCCN high-/very-high-risk disease, those with MMAI low-risk disease had
5-year rates of DM of 0% and 10-year rates of 3%. In contrast, those with MMAI intermediate- and high-risk tumors had 8% and 26% risk
of metastasis at 10 years post-treatment, respectively. MMAI was independently prognostic for DM, PCSM, and death after DM. These
results suggest that the benefit of ADT in NCCN high- and very-high-risk prostate cancer is likely to be smaller in patients with MMAI
low-risk disease than in patients with MMAI intermediate- or high-risk disease. Neither a breakdown of high- vs. very high-risk, nor a
MMAIb,7-12 AI-Pathology breakdown of outcomes between cohorts receiving RT+ST-ADT vs. RT+LT-ADT, were provided.

Published results from four phase III randomized trials from the STAMPEDE platform, which included 1575 patients with locally
advanced, M0 disease (ie, NCCN very-high-risk disease), with post-hoc derivation of MMAI scores have been reported.12 Overall,
patients with locally advanced N0M0 disease had a 5% PCSM event rate, but when divided by MMAI quartile, there was a significant
difference between the lower three quartiles (3%) vs. the highest quartile (11%). When restricting to patients receiving abiraterone, these
rates were 2% vs. 5%. These results suggest that the benefit of abiraterone in NCCN very-high-risk prostate cancer is likely to be smaller
in patients with MMAI low-risk disease than in patients with MMAI high-risk disease.
BCR Post-RP
Tool Category Discussion
Two phase III randomized trials post-RP were profiled post-hoc with prespecified analysis plans. NRG/RTOG 9601 demonstrated the
independent prognostic effect of GC on DM, PCSM, and OS, and found that for patients with lower entry PSAs (<0.7 ng/mL), the 12-year
Gene DM rate benefit from hormone therapy for patients with GC lower risk vs. GC higher risk was 0.4% vs. 11.2%.13 The SAKK 09/10 phase
22-gene GC13,14 III trial tested post-RP lower vs. higher dose RT alone. The study demonstrated the independent prognostic effect of GC on biochemical
Expression progression, clinical progression, secondary hormone therapy, DM, and MFS.c,14 These results suggest that the benefit of ADT added
to RT for patients with RP recurrence planned for early secondary RT is likely to be smaller in those with low or intermediate GC scores
(<0.6) than in those with high GC scores (≥0.60).
DM = distant metastases; LT-ADT = long-term ADT; MFS = metastasis-free survival; NNT = number needed to treat; PCSM = prostate cancer-specific mortality; ST-ADT = short-term ADT
a In the absence of prospective trials, caution is warranted if using these prognostic tools to influence treatment decisions. The Panel awaits future trials that confirm the initial results
described here.
b There is also an MMAI predictive biomarker that was validated post-hoc in RTOG 9408 to predict benefit of ST-ADT added to RT in patients with intermediate-risk prostate cancer. While
promising, due to differences in tissue sampling, grading, staging, and treatment, the Panel recommends further validation prior to using this predictive biomarker to guide treatment
decisions in isolation.
c SAKK 09/10 combined GC low and intermediate risk due to relatively similar prognosis. NRG/RTOG 9601 dichotomized patients by GC low versus intermediate and high risk. However,
due to the age of the tissue from NRG/RTOG 9601 (>20 years old), there is a known shifting of GC scores, and a more contemporary distribution of score distribution would approximate
closer to combining GC low and intermediate risk together.
References
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF RISK STRATIFICATION AND BIOMARKERS

REFERENCES
1 Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable
preoperative predictor of disease recurrence after radical prostatectomy. J Urol 2005;173:1938-1942. Erratum in: J Urol 2006;175:2369.
2 Dess RT, Suresh K, Zelefsky MJ, et al. Development and validation of a clinical prognostic stage group system for nonmetastatic prostate cancer using disease-
specific mortality results from the International Staging Collaboration for Cancer of the Prostate. JAMA Oncol 2020;6:1912-1920.
3 Memorial Sloan-Kettering Cancer Center. Pre-Radical Prostatectomy. Available at: [Link]
4 Spratt DE, Liu VYT, Michalski J, et al. Genomic classifier performance in intermediate-risk prostate cancer: Results from NRG Oncology/RTOG 0126 randomized
phase 3 trial. Int J Radiat Oncol Biol Phys 2023;117:370-377.
5 Nguyen PL, Huang HR, Spratt DE, et al. Analysis of a biopsy-based genomic classifier in high-risk prostate cancer: Meta-analysis of the NRG Oncology/Radiation
Therapy Oncology Group 9202, 9413, and 9902 phase 3 randomized trials. Int J Radiat Oncol Biol Phys 2023;116:521-529.
6 Spratt DE, Zhang J, Santiago-Jiménez M, et al. Development and validation of a novel integrated clinical-genomic risk group classification for localized prostate cancer.
J Clin Oncol 2018;36:581-590.
7 Esteva A, Feng J, van der Wal D, et al. Prostate cancer therapy personalization via multi-modal deep learning on randomized phase III clinical trials. NPJ Digit Med
2022;5:71. Erratum in: NPJ Digit Med 2023;6:27.
8 Tward JD, Huang HC, Esteva A, et al. Prostate cancer risk stratification in NRG Oncology phase III randomized trials using multimodal deep learning with digital
histopathology. JCO Precis Oncol 2024;e2400145.
9 Spratt DE, Tang S, Sun Y, et al. Artificial intelligence predictive model for hormone therapy use in prostate cancer. NEJM Evid 2023;2:EVIDoa2300023.
10 Spratt DE, Liu VYT, Jia AY, et al. Meta-analysis of individual patient-level data for a multimodal artificial intelligence biomarker in high-risk prostate cancer: Results
from six NRG/RTOG phase 3 randomized trials. Eur Urol 2024;86:369-371.
11 Ross AE, Zhang J, Huang HC, et al. External validation of a digital pathology-based multimodal artificial intelligence architecture in the NRG/RTOG 9902 phase 3 trial.
Eur Urol Oncol 2024;7:1024-1033.
12 Parker CTA, Mendes L, Liu VYT, et al. External validation of a digital pathology-based multimodal artificial intelligence-derived prognostic model in patients with
advanced prostate cancer starting long-term androgen deprivation therapy: a post-hoc ancillary biomarker study of four phase 3 randomised controlled trials of the
STAMPEDE platform protocol. Lancet Digit Health 2025;7:100885.
13 Feng FY, Huang HC, Spratt DE, et al. Validation of a 22-gene genomic classifier in patients with recurrent prostate cancer: An ancillary study of the NRG/RTOG 9601
randomized clinical trial. JAMA Oncol 2021;7:544-552. Erratum in: JAMA Oncol 2021;7:639.
14 Dal Pra A, Ghadjar P, Hayoz S, et al. Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical
prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial. Ann Oncol 2022;33:950-958.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF FOCAL/SUBTOTAL THERAPY OR WHOLE GLAND ABLATIVE THERAPY

General
• Ablative therapy refers to the use of a device to destroy tissue that can be directed at part of the prostate gland (termed partial gland, hemi-
gland, or focal therapy [FT]) or the whole prostate gland.
• FT includes ablative therapies and non-ablative therapies, such as partial prostatectomy and focal radiation therapy.a
• Presently, FT is an experimental and emerging technology for the initial treatment of localized prostate cancer that lacks randomized
controlled trial evidence with long-term follow-up showing its superiority or noninferiority to current recommended management strategies.
As such, FT meets the criteria as an alternative therapy, or a non-standard treatment.

Newly Diagnosed or Previously Untreated Prostate Cancer

• Pathologic confirmation of prostate cancer and risk stratification is required prior to consideration of ablative or FT.
• Active surveillance is the preferred treatment for low-risk prostate cancer, and ablative and focal therapies are discouraged in this
population.
• The Panel also believes that ablative FT should be discouraged in patients with high- or very-high-risk, regional, or metastatic prostate
cancer outside of a clinical trial.
• There is currently insufficient comparative effectiveness evidence for FT to be recommended for patients with intermediate-risk prostate
cancer, and the Panel believes there is uncertainty about the long-term efficacy and toxicity of these treatments. Therefore, ablative and focal
therapies in this population should be utilized only in the context of a clinical trial.
• The following device categories are currently FDA approved or cleared for the initial treatment of prostate cancer, but randomized evidence
to the superiority in long-term cancer control and/or quality of life are lacking when delivered as focal rather than whole gland therapy. These
treatments may be considered as FT for patients with previously untreated, localized prostate cancer only in the context of a clinical trial:
External beam radiotherapya
Brachytherapy
Cryotherapy ablation
• The following device categories are currently not FDA approved or cleared for the treatment of prostate cancer as focal or whole gland
therapy, and should only be used for patients with previously untreated, localized prostate cancer in the context of a clinical trial:
High-intensity focused ultrasound (HIFU)
Transurethral ultrasound ablation (TULSA)
Focal laser ablation (FLA)
Radiofrequency ablation (RFA)
Irreversible electroporation (IRE)
Photodynamic therapy (PDT)
Histotripsy
Partial prostatectomy
a Although ultra-hypofractionated EBRT, also known as stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR), is considered by some as an
ablative technology, it does not fall within the general class of ablative therapies. EBRT is recommended in multiple contexts for the treatment of prostate cancer, and
when delivered to the prostate it is recommended to be delivered to the whole prostate gland (discussed within Principles of Radiation Therapy (PROS-J). However,
when delivered as FT it should be viewed within the context of other ablative therapies at this time given similar quality of evidence and risks of residual cancer and
retreatment.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF FOCAL/SUBTOTAL THERAPY OR WHOLE GLAND ABLATIVE THERAPY

• Patients should be counseled prior to receiving FT or whole gland ablative therapy as follows:
HIFU, TULSA, FLA, RFA, IRE, PDT, and histotripsy are not FDA approved or cleared for the treatment of prostate cancer.
Currently, no treatment delivered as FT, including radiotherapy or partial prostatectomy, have demonstrated superiority or non-inferiority
to guideline-recommended therapies in randomized trials with long-term follow-up. The importance of long-term follow-up is of increased
importance in this setting given the high rates of secondary therapy after FTs and potential for increased toxicity.
For patients with low- and intermediate-risk disease1-7:
◊ Biopsy-detected (any) cancer after FT is common within 2 years post-treatment (20%–70%).
◊ Erectile dysfunction (10%–40%) and urinary incontinence (0%–20%) have been reported to occur of variable severity within 2 years post-
treatment.
FT or whole gland ablative therapy may impact the safety and/or efficacy of subsequent local therapy.
Moderate toxicity (grade 2) is common, and severe toxicity (grade 3 or higher) is possible with reported rates in trials from approximately
1%–14% in the first 2 years post-FT.1-7
Currently, there is no evidence-based, universally agreed upon follow-up protocol after FT. Patients often undergo serial imaging and
prostate biopsies.

1 Ehdaie B, Tempany CM, Holland F, et al. MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: a phase 2b, multicentre
study. Lancet Oncol 2022;23:910-918.
2 Duwe G, Boehm K, Haack M, et al. Single-center, prospective phase 2 trial of high-intensity focused ultrasound (HIFU) in patients with unilateral localized prostate
cancer: good functional results but ontologically not as safe as expected. World J Urol 2023;41:1293-1299.
3 Ganzer R, Hadaschik B, Pahernik S, et al. Prospective multicenter phase II study on focal therapy (hemiablation) of the prostate with high intensity focused ultrasound.
J Urol 2018;199:983-989.
4 Ghai S, Finelli A, Corr K, et al. MRI-guided focused ultrasound focal therapy for intermediate-risk prostate cancer: final results from a 2-year phase II clinical trial.
Radiol 2024;310:e231473.
5 Klotz L, Pavlovich CP, Chin J, et al. Magnetic resonance imaging-guided transurethral ultrasound ablation of prostate cancer. J Urol 2021;205:769-779.
6 Mehralivand S, George AK, Hoang AN, et al. MRI-guided focal laser ablation of prostate cancer: a prospective single-arm, single-center trial with 3 years follow-up.
Diagn Interv Radiol 2021;27:394-400.
7 Eggener SE, Yousuf A, Watson S, et al. Phase II evaluation of magnetic resonance imaging guided focal laser ablation of prostate cancer. J Urol 2016;196:1670-1675.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF FOCAL/SUBTOTAL THERAPY OR WHOLE GLAND ABLATIVE THERAPY

Management of Recurrence After Focal Ablative or Whole Gland Ablative Therapy
• Presently, the optimal management of residual or recurrent disease after receipt of these treatments is unknown and limited evidence exists.
A multi-disciplinary discussion with experienced prostate cancer specialists is recommended.
• If there is suspicion of residual or recurrent prostate cancer, a biopsy should be performed to confirm the presence of residual or recurrent
prostate cancer.
Histologic grading of the cancer is recommended if located in previously untreated areas of the prostate. Reliability of grading within a
previously treated area of the prostate is unknown at this time, and patients should be informed of this uncertainty.
• Staging imaging should be performed based on the patient’s NCCN risk group at time of recurrence (see PROS-2). However, PSA groupings
as used for newly diagnosed prostate cancer may underestimate the burden of disease after prior FT or ablative therapy.
Interpretation of imaging (ie, assessment of cT3 disease by MRI near ablation zone) after FT or whole gland ablative therapy may be less
reliable.8
Advanced risk stratification tools (eg, gene expression or digital pathology-based biomarkers) have not been adequately studied for use in
the context of focal or whole gland ablative therapy and are not recommended to guide treatment decisions in this setting.
• Patients with a clinically significant recurrence after initial focal therapy should be offered radical prostatectomy or prostate RT if appropriate
based on life expectancy.
• Patients should be counseled as follows:
There is limited evidence on how to optimally manage a FT or whole gland ablative therapy recurrence.
Patients are at an increased risk of toxicity from subsequent local therapy compared to the primary treatment setting.
It is not known if radical therapy has equivalent long-term success after FT or whole gland ablative therapy given lack of trials with long-
term follow-up in this setting.
Secondary treatment should be reserved for patients with appropriate life expectancy and Grade Group 2 and higher recurrences detected
on biopsy.
Local Recurrence After Radiation Therapy
• Patients with biopsy-proven recurrence in the prostate after prior RT and without distant metastatic disease can be considered for local
secondary therapy.
• However, clinicians and patients should be aware that no local therapy currently has level 1 evidence for the management of a local
recurrence after definitive RT.
• Treatments with higher quality of evidence are recommended. These are discussed in the Principles of Local Secondary Therapy Post-
Radiation (PROS-L) and include select forms of FT or whole gland ablative therapy.

8 Lai AL, Velaga J, Tay KJ, et al. Multiparametric MRI before and after focal therapy for prostate cancer: pearls and pitfalls for the reporting radiologist. Radiol;7:e240269.

Note: All recommendations are category 2A unless otherwise indicated.

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All patients diagnosed with intermediate-, high-, very-high-, regional-risk, low-volume mCSPC, biochemically recurrent, low-volume metastatic
castration-sensitive prostate cancer (mCSPC) and oligometastatic mCRPC are recommended to be evaluated by a radiation oncologist as part
of a multidisciplinary discussion of treatment options.

General
• EBRT
Treatment Planning: Intensity modulated RT (IMRT) is recommended over 3-dimensional conformal RT to improve dose conformality.
Image Guidance: Methods to improve accuracy of treatment delivery, thereby enabling reduction in planning target value (PTV) margins,
which generally result in reduced toxicity are encouraged and may include one or more of the following:
◊ Image guidance with daily 3D imaging is recommended with either a cone beam CT (CBCT) or MRI.
◊ Devices that assist with optimal image guidance (fiducial markers) or reduce motion (endorectal balloons).
◊ Real-time intrafraction volumetric tracking.
◊ Online adaptive radiotherapy if target is near mobile organs (ie, performing a simultaneous integrated boost to a positive pelvic lymph
node adjacent to bowel).
Beam Type: Photon and proton RT are acceptable forms of EBRT and appear to have similar outcomes in regard to toxicity, QOL, and
tumor control. Potential financial toxicity should be discussed with patients.
Fractionation: An extensive list of fractionation schedules have been studied. These are grouped into three categories, conventional
fractionation (1.8–2 Gy/fraction), moderate hypofractionation (>2.5 to 4 Gy/fraction), and ultra-hypofractionation (>6 Gy/fraction).1 Common
dose/fraction schedules are shown in Table 1. In general, iso-effective moderate hypofractionation dosing has demonstrated noninferior
tumor control, toxicity, and QOL over conventional fractionation and is more convenient for patients and thus preferred. Similarly, ultra-
hypofractionation has been demonstrated to be noninferior to both moderate hypofractionation and conventional fractionation.2 Thus, use
of conventionally fractionated radiotherapy is no longer preferred for localized prostate cancer.
◊ Ultra-hypofractionation encompasses stereotactic body radiation therapy (SBRT), which requires precision treatment setup and required
additional image guidance techniques.
◊ SBRT is recommended and preferred specifically when:
– Performing metastasis-directed radiotherapy (MDRT) (see Principles of MDT [PROS-M])
– There is limited progression (eg, oligoprogression) or limited residual disease and the patient is on otherwise effective systemic
therapy (eg, consolidation).
– The lesion occurs in or immediately adjacent to a previously irradiated treatment field.
– At physician discretion for more durable control of pain than achieved with typical palliative regimens.

References on PROS-J 10 of 11
Note: All recommendations are category 2A unless otherwise indicated.
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• Brachytherapy
Patient Selection: Providers should consider aspects of gland size, baseline urinary symptoms, and prior procedures (ie, transurethral
resection of prostate) that may increase risk of adverse effects. Neoadjuvant ADT to shrink a gland to allow treatment should be considered
in context of the balance between its additional toxicity with this benefit.
Dose Rate: Both low-dose rate (LDR) and high-dose rate (HDR) are acceptable to be used as either monotherapy or as a boost combined
with EBRT in higher risk disease. Data indicates that HDR may have lower toxicity than LDR, and while efficacy appears similar between
HDR and LDR when used as a boost combined with EBRT, it remains unknown if HDR as monotherapy provides equivalent tumor control to
LDR given lack of robust randomized comparisons. Post-implant dosimetry must be performed for LDR implants to verify dosimetry.
Monotherapy: Brachytherapy monotherapy has been shown to have fewer side effects than when used with EBRT without compromising
tumor control for intermediate-risk disease.3
Combination Therapy: EBRT with an LDR brachytherapy boost has been shown to improve biochemical control over conventionally
fractionated EBRT with ADT (12 months) without a focal/micro EBRT boost.4 This was at the expense of an increase in high-grade toxicity.5
Thus, careful patient selection and contemporary planning, use of recognized organ at risk (OAR) dose constraints, and use of high-quality
ultrasound and other imaging are essential.

• Elective Nodal Irradiation (ENI)

ENI can be considered in select patients.
Use of IMRT with image guidance is recommended when performing ENI. Advanced techniques that include online adaptive radiotherapy
may be considered to reduce ENI planning target volume margins.
If performing ENI, it is recommended to include the common, internal, and external iliac, pre-sacral, and obturator lymph node stations.
Peri-rectal/mesorectal lymph nodes may be included if there is evidence of lymph node involvement in this nodal station. Para-aortic lymph
nodes should not be included in patients who do not have evidence of para-aortic lymph node involvement.

Definitive RT
• Biocompatible and biodegradable perirectal spacers:
These devices may be implanted between the prostate and rectum in patients undergoing radiation therapy to the prostate in order to
displace the rectum from high radiation dose regions for the purpose of toxicity reduction. Patients with grossly apparent true posterior
extraprostatic extension should not undergo perirectal spacer implantation. NCCN high-risk disease without posterior extraprostatic
extension is not a contraindication to spacer use.
These devices should be placed by practitioners who can maintain a moderate to high volume of use to ensure quality.
Additional caution should be used in the re-irradiation setting due to potential changes in tissue planes.

References on PROS-J 10 of 11
Note: All recommendations are category 2A unless otherwise indicated.
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Definitive RT (continued)
• Low Risk
Patients with NCCN low-risk prostate cancer are encouraged to pursue active surveillance.6
Those electing treatment with RT may receive EBRT or brachytherapy as monotherapy.
The target should include the prostate and consideration of treatment of seminal vesicles (proximal).
Patients should not be treated with any of the following:
◊ ENI
◊ ADT
◊ Combination brachytherapy boost with EBRT

• Favorable Intermediate Risk

The target should include the prostate and consideration of treatment of seminal vesicles (proximal or full).
Those electing treatment with RT may receive EBRT or brachytherapy as monotherapy.
Patients should not be treated with any of the following:
◊ ENI
◊ Combination brachytherapy boost with EBRT3
ADT is generally not recommended, but can be considered if additional risk assessments suggest aggressive tumor behavior or increased
potential benefit from short-term ADT.7,8

• Unfavorable Intermediate Risk

The target should include the prostate and the seminal vesicles (proximal or full).
RT options include either EBRT, brachytherapy monotherapy, or EBRT with a brachytherapy boost.
Multiple randomized trials that included patients with unfavorable intermediate risk who did not demonstrate superiority of combination
therapy over brachytherapy monotherapy.3
Focal boosting with isotoxic delivery can be considered if there is sufficient provider and practice expertise to delineate the dominant
intraprostatic lesion (DIL) and OARs on MRI.9
ENI should not be used routinely.
ADT (level 1 data for ST-ADT) should be used unless additional risk assessments suggest less aggressive tumor behavior, or less predicted
benefit, or if medically contraindicated.8,10 Radiotherapy dose or modality has not clearly demonstrated the ability to obviate the benefit
of ADT. ST-ADT is recommended to be used as a concurrent and adjuvant approach with RT rather than a neoadjuvant and concurrent
approach.11

References on PROS-J 10 of 11
Note: All recommendations are category 2A unless otherwise indicated.
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Definitive RT (continued)
• High Risk
The target should include the prostate and the seminal vesicles (full).
RT options include EBRT or brachytherapy boost combined with EBRT. Carefully selected patients may receive brachytherapy
monotherapy.
Focal boosting with isotoxic delivery can be considered if there is sufficient provider and practice expertise to delineate the DIL and OARs
on MRI.9
Clinical trials have demonstrated varied results regarding the benefit of ENI. Multiple randomized trials have not demonstrated
improvement in outcomes from ENI. However, the benefit of ENI was shown in one trial of patients with high-risk prostate cancer staged
primarily with PSMA-PET/CT and who had a risk of nodal involvement >20%. Currently, the use of ENI is at the discretion of the treating
physician.
ADT (level 1 data for LT-ADT 12–36 months) is recommended for patients with life expectancy >5 years or who are symptomatic unless
medically contraindicated. Radiotherapy dose or modality has not clearly demonstrated the ability to obviate the benefit of LT-ADT.10

• Very-High-Risk
The target should include the prostate and the seminal vesicles (full).
RT options include EBRT. Carefully selected patients may receive EBRT with a brachytherapy boost.
Focal boosting with isotoxic delivery can be considered if there is sufficient provider and practice expertise to delineate the DIL and OARs
on MRI.
Combination brachytherapy boost with EBRT should not be used routinely. The primary randomized evidence to recommend combination
brachytherapy boost with EBRT comes from the ASCENDE-RT trial, which excluded patients with PSA >40 ng/mL and T3b.12
ADT (level 1 data for LT-ADT 18–36 months) is recommended for patients with life expectancy >5 years or who are symptomatic unless
medically contraindicated.
Currently, the use of ENI is at the discretion of the treating physician.
Addition of abiraterone should be used very selectively as the benefit in contemporary practice with modern staging is uncertain (see
PROS-6 and PROS-G 1 of 5).13 It is not recommended to be used routinely for patients with solely MRI defined T3a disease with low volume
Gleason 8 disease. Studies validating the post-hoc subset analysis of STAMPEDE for the benefit of abiraterone in very high-risk prostate
cancer using other ARPIs have not yet reported, and thus the benefit of using ARPIs with RT+LT-ADT remains uncertain in contemporary
patients with very high risk N0M0 disease. Radiotherapy dose or modality has not clearly demonstrated the ability to obviate the benefit of
LT-ADT.10

• Regional Disease
EBRT is recommended to include the prostate, seminal vesicles, and pelvic lymph nodes.
Simultaneous integrated boost to involved lymph nodes is recommended while respective adjacent OAR dose constraints.
Use of a brachytherapy boost is not recommended in these patients.
Addition of abiraterone is recommended (see PROS-7 and PROS-G [1 of 5]).13
References on PROS-J 10 of 11
Note: All recommendations are category 2A unless otherwise indicated.
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Postoperative RT:
• Adjuvant RT: Adjuvant RT (aRT) involves the use of EBRT post-radical prostatectomy for patients with adverse pathologic features (ie,
pT3 and/or positive surgical margins) in the setting of an undetectable postoperative PSA. This may result in some patients unnecessarily
receiving aRT and experience potential additional side effects.
The early results and aggregate meta-analysis of three trials comparing aRT to early secondary RT (sRT) did not demonstrate a difference
in biochemical recurrence for patients with generally a favorable prognosis. Thus, waiting for a detectable PSA and using an early sRT
approach is recommended for most patients who undergo a RP rather than an immediate aRT approach to avoid over treatment and
subsequent potential side effects.14
Use of aRT may be reasonable for patients with multiple adverse features and/or lymph node involvement.
◊ Patients with multiple adverse features and/or lymph node involvement were underrepresented in these trials, and in the RADICALS-RT
trial, the largest of the trials comparing aRT to early sRT, there was a significant reduction in prostate cancer-specific mortality with aRT
and numerical trends in superior freedom-from-distant metastasis with aRT.15 This raises uncertainty to the true noninferiority of early
sRT in these patients with high risk of recurrence post-RP.
Multiple dose/fraction schedules have been used with aRT that include both conventionally fractionated (60–64 Gy in 30–36 fractions) and
moderately hypofractionated regimens (52.5 Gy in 20 fractions).16
• Secondary RT is the use of EBRT post-RP when a patient has a detectable PSA; a lower limit is not defined and may be below 0.2 ng/mL.
Early sRT at a PSA of 0.1–0.2 ng/mL is recommended for most patients who experience BCR post-RP. The exception to this is in patients
who have delayed recurrence many years post-RP with very slow PSA doubling times (ie, >24 months), especially when a patient has
limited life expectancy.
Unlike in localized prostate cancer, the use of ADT in the post-RP setting has demonstrated survival improvements in only a small subset
of patients, primarily in those with high pre-sRT PSAs receiving late sRT (PSA >0.7 ng/mL).17 For patients receiving early sRT there is
no clear OS benefit from the addition of ADT in any of the four published randomized trials, irrespective of ADT duration, or on meta-
analysis.18 ADT does significantly delay the incidence of biochemical recurrence.
Use of ADT with sRT should be personalized based on pre-RT PSA, clinicopathologic risk factors, patient age, life expectancy,
comorbidities, and preferences, as well as advanced risk stratification tools (see PROS-H).18,19
◊ Generally, ST-ADT is recommended to balance toxicity, QOL, and tumor control. However, LT-ADT may be preferred for patients receiving
late sRT and/or those with multiple adverse pathologic features and/or lymph node involvement.
◊ Treatment intensification with an ARPI has not demonstrated an improvement in metastasis-free survival or overall survival in this
population in unselected patients.20,21
Multiple dose/fraction schedules have been used with sRT that include both conventionally fractionated (64–70.2 Gy in 32–39 fractions)
and moderately hypofractionated regimens (52.5 Gy in 20 fractions or 62.5 Gy in 25 fractions).16,22 The moderately hypofractionated
regimens have demonstrated noninferior tumor control, toxicity, and QOL. Multiple single arm trials and early follow-up of phase II
randomized trials have been reported using ultra-hypofractionated RT in the sRT setting, and generally are using 32.5–34 Gy in 5
fractions.23,24 These studies often leverage either intrafraction motion monitoring, online adaptive radiotherapy, and strict image guidance
with substantially modified contouring of target volumes to limit dose to OARs.
The addition of ENI to sRT plus ST-ADT has demonstrated improvements in biochemical control.25 It appears the benefit is greater in
patients with higher pre-sRT PSAs, as well as in patients who did not have their pelvic lymph nodes assessed, or minimally assessed, via
a pelvic lymph node dissection. Use of PSMA PET/CT has not been shown to be sensitive enough to rule out the presence of pelvic lymph
node micrometastases. References on PROS-J 10 of 11
Note: All recommendations are category 2A unless otherwise indicated.
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RT in Advanced Disease:
• Synchronous mCSPC
Treatment of the primary tumor:
◊ Minimizing toxicity is paramount when delivering RT to the primary tumor in patients with metastatic disease. As such, it is unclear if
dose escalation (ie, brachytherapy or focal boost) improves outcomes.
◊ Low Volume: Treatment of the primary is recommended with EBRT.26,27
– Volume of disease should be defined according to CT and bone scan, if performed.
– PET imaging should not be used to exclude a patient from treatment of the primary tumor.
– The strongest data for a benefit of adding RT to the primary tumor are in patients receiving either ADT alone, ADT+ docetaxel, or ADT +
abiraterone for those with ≤5 bony metastases.
◊ High Volume: Treatment of the primary tumor with EBRT can be considered for select patients with high-volume mCSPC (category 2B).27
– RT to the primary tumor in high volume mCSPC has demonstrated improvements in time to mCRPC and a reduction in the
development of severe genitourinary adverse events when given in the context of ADT with variable use of docetaxel and/or
abiraterone.
Treatment of Metastases
◊ MDT, which typically uses SBRT, may be used for patients who have a limited burden of lymph node or osseous disease. See Principles
of MDT (PROS-M).

• Metachronous mCSPC
A greater level of evidence supports the role of MDT in the metachronous setting as compared to synchronous mCSPC. This commonly is
delivered using SBRT, but moderately hypofractionated RT may be considered.
Use of MDT in this setting has been shown to delay the need for ADT compared to observation,28 the addition of RT to ADT has been
shown to prolong a treatment free eugonadal interval as compared to ADT alone,29 and the addition of ADT to RT has improved
progression-free survival (PFS).30
See Principles of MDT (PROS-M).

mCRPC
◊ The use of MDT has been shown to prolong PFS and rPFS when used for patients with oligometastatic CRPC treated with ADT+ARPI as
compared to systemic therapy alone. MDT may be considered when the goal is to prolong PFS and extend duration of systemic therapy
prior to needing to switch therapies.31 See Principles of MDT (PROS-M).

References on PROS-J 10 of 11
Note: All recommendations are category 2A unless otherwise indicated.
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Radiopharmaceutical Therapy
• Radiopharmaceutical therapies for prostate cancer are suitable options for improving survival and/or rPFS in select patients with advanced
castration-resistant disease. Due to prior therapy exposure, specific targets, and hematologic effects of these therapies, careful selection
and sequencing strategy with other therapies is important. This section discusses the two currently FDA-approved agents in use (Ra-223,
Lu-177–PSMA-617).

• Radium-223
Radium-223 has been shown to extend survival in patients who have CRPC with symptomatic bone metastases, but no visceral
metastases.32 Radium-223 alone has not been shown to extend survival in patients with visceral metastases or bulky nodal disease (>3 to 4
cm).
Radium-223 is administered IV once a month for 6 months by an appropriately licensed facility, usually in nuclear medicine or radiation
oncology facilities.
Concurrent use with enzalutamide and bone health agents may be considered given the overall survival benefit over enzalutamide alone.33
Concurrent use with other systemic therapies should be pursued with caution.
Bone fracture risk: Radium-223 may increase fracture risk when given concomitantly with an ARPI without use of a bone health agent.
Concomitant use of denosumab or zoledronic acid is recommended.34

• Lu-177–PSMA-61716
In patients with PSMA-positive disease, Lu-177–PSMA-617 has been shown to improve OS in patients with progressive mCRPC previously
treated with androgen receptor inhibitors and taxane chemotherapy.35 It has also been shown to improve rPFS in patients who have not
received taxanes with PSMA-positive mCRPC who were previously treated with an androgen receptor inhibitor compared with changing to
a different androgen receptor inhibitor.
This agent is approved for patients with mCRPC who have been treated with ARPI therapy and have received prior taxane-based
chemotherapy or are considered appropriate to delay receipt of chemotherapy.36
Lu-177–PSMA-617 is not recommended in patients with dominant PSMA-negative lesions. PSMA-negative lesions are defined as metastatic
disease that lack PSMA uptake including bone with soft tissue components ≥1.0 cm, lymph nodes ≥2.5 cm in short axis, and solid organ
metastases ≥1.0 cm in size.
Use of PSMA PET/CT SUVmean and use of an FDG PET/CT scan may aid in identifying patients with lower PSMA expression and non-PSMA
avid disease who will derive less or potentially no benefit from 177-Lu-PSMA-617.
Lu-177–PSMA-617 is typically administered IV 200 mCi (7.4 GBq) every 6 weeks for up to 6 treatments by an appropriately licensed facility.
Use of post-treatment SPECT or PET/CT imaging can be considered to monitor PSMA expression for adaptive dosing.
Because Lu-177 also emits gamma radiation, appropriate precautions should be taken to minimize exposure to personnel administering
the radiopharmaceutical. Treatment rooms should be monitored for potential contamination following treatments, and patients should be
provided written instructions regarding radiation safety precautions following treatment.
For information regarding the use of PSMA-PET to define PSMA-positive disease, see Principles of Imaging (PROS-E).

References on PROS-J 10 of 11
Note: All recommendations are category 2A unless otherwise indicated.
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Table 1: Below are examples of regimens that have shown acceptable efficacy and toxicity. The optimal regimen for an individual patient warrants evaluation of comorbid
conditions, voiding symptoms, and toxicity of therapy. Additional fractionation schemes may be used as long as sound oncologic principles and appropriate estimate of BED
are considered.
See treatment pages and Principles of ADT (PROS-G) for other recommendations, including recommendations for neoadjuvant/concomitant/adjuvant ADT.

Definitive RT Post-Treatment RT Advanced Disease

Primary
Post-RP Post-RT Metastases
Tumor
EBRT Regimen Preferred Dose/Fraction
Low FIR UIR High Very-High Regional mCSPC
aRT sRT sRT M0 CRPC MDT
mCRPC
1.8–2 Gy x 37–45 fx ☼ ☼   ☼
Conventional
1.8–2 Gy x 30–39 fx   ☼
3 Gy x 20 fx (preferred)a
2.7 Gy x 26 fx ☼      ☼ ☼ ☼
Moderate 2.5 Gy x 28 fx
Hypofractionation
2.63–2.75 Gy x 20 fx
  ☼  ☼
2.5 Gy x 25 fx
9.5 Gy x 4 fx
7.25–8 Gy x 5 fx
☼    ☼ ☼ ☼   
6 Gy x 6 fx
6.1 Gy x 7 fx
Ultra Hypofractionation
(SBRT) 9–10 Gy x 3 fx
12 Gy x 2 fx 
16–24 Gy x 1 fx
6.2–6.4 Gy x 5 fx ☼
EBRT Boost Techniques
EBRT with
simultaneous See footnote b. ☼   ☼ ☼ ☼ ☼ ☼
integrated boost
Prostate:
1.8 Gy x 23–28 fx
EBRT with sequential
Boost: ☼ ☼ ☼
SBRT boost
6 Gy x 3 fx
9.5 Gy x 2 fx
( Preferred; ☼ Acceptable based on clinical and medical need; Regimens shaded gray are not recommended)
Footnotes on PROS-J 8A of 11
Note: All recommendations are category 2A unless otherwise indicated.
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FOOTNOTES
a Based on the HYDRA individual patient meta-analysis of seven phase III randomized trials, isodose moderately hypofractionated radiotherapy (MHFRT) and dose-
escalated MHFRT both have similar efficacy compared with conventionally fractionated radiotherapy (CFRT), but dose-escalated MHFRT was associated with higher
toxicity. Isodose regimens (eg, 60 Gy in 20 fractions) are preferred for MHFRT for localized prostate cancer. Alternative regimens (eg, 70 Gy in 28 fractions) may be
used, but patients should be counseled on potentially increased risk of toxicity.1
b EBRT to whole prostate 2.2 Gy x 35 fx plus micro-boost to MRI-dominant lesion to ≤95 Gy (fractions ≤2.7 Gy).9 The micro-boost technique with level 1 data was
established for a modestly hypofractionated regimen but has been extrapolated reasonably to other regimens in ongoing clinical trials. Care must be taken in doing so
outside of clinical trials in order to respect normal tissue toxicity risk and above all in prioritizing normal organ tolerances over micro-boost coverage.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RADIATION THERAPY

Iodine 125 145 Gy

Palladium 103 125 Gy
Cesium 131 115 Gy ☼   ☼ 
13.5 Gy x 2 implants
Iridium 192
9.5 Gy BID x 2 implants
EBRT + Brachytherapy Boost (combined with 45-50.4 Gy in 25-28 fx or 37.5 Gy in 15 fx)
Iodine 125 110–115 Gy
Palladium 103 90–100 Gy
Cesium 131 85 Gy ☼  ☼
15 Gy x 1 fx
Iridium 192
10.75 Gy x 2 fx
( Preferred; ☼ Acceptable based on clinical and medical need; Regimens shaded gray are not recommended)

References on PROS-J 10 of 11
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PRINCIPLES OF RADIATION THERAPY

REFERENCES
1 Kishan AU, Sun Y, Tree AC, et al. Hypofractionated radiotherapy for prostate 12 Morris WJ, Tyldesley S, Rodda S, et al. Androgen suppression combined with
cancer (HYDRA): an individual patient data meta-analysis of randomised trials in elective nodal and dose escalated radiation therapy (the ASCENDE-RT trial):
the MARCAP consortium. Lancet Oncol 2025;26:459-469. an analysis of survival endpoints for a randomized trial comparing a low-dose-
2 van As N, Griffin C, Tree A, et al. A Phase III randomized controlled trial of rate brachytherapy boost to a dose-escalated external beam boost for high- and
Stereotactic Body Radiotherapy in localized prostate cancer. N Engl J Med intermediate-risk prostate cancer. Int J Rad Oncol Biol Phys 2017;98:275-285.
2024;391:1413-1425. 13 Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with
3 Michalski JM, Winter KA, Prestidge BR, et al. Effect of brachytherapy with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-
external beam radiation therapy versus brachytherapy alone for intermediate- analysis of primary results from two randomised controlled phase 3 trials of the
risk prostate cancer: NRG oncology RTOG 0232 randomized clinical trial. J Clin STAMPEDE platform protocol. Lancet 2022;399:447-460.
Oncol 2023;41:4035-4044. 14 Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for
4 Oh J, Tyldesley S, Pai H, et al. An updated analysis of the survival endpoints of the treatment of localised and locally advanced prostate cancer: a prospectively
ASCENDE-RT. Int J Rad Oncol 2023;115:1061-1070. planned systematic review and meta-analysis of aggregate data. Lancet
5 Rodda S, Tyldesley S, Morris WJ, et al. ASCENDE-RT: an analysis of treatment- 2020;396:1422-1431.
related morbidity for a randomized trial comparing a low-dose-rate brachytherapy 15 Parker CC, Petersen PM, Cook AD, et al. Timing of radiotherapy (RT) after
boost with a dose-escalated external beam boost for high- and intermediate-risk radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial
prostate cancer. Int J Rad Onocl Biol Phys 2017;98:286-295. (NCT00541047). ESMO 2024;24;656-666.
6 Hamdy FC, Donovan JL, Lane A, et al. Fifteen-year outcomes after monitoring, 16 Petersen PM, Cook AD, Sydes MR, et al. Salvage radiation therapy after radical
surgery, or radiotherapy for prostate cancer. N Engl J Med 2023;388:1547-1558. prostatectomy: analysis of toxicity by dose-fractionation in the RADICALS-RT
7 Zumsteg ZS, Spratt DE, Daskivich TJ, et al. Effect of androgen deprivation on trial. Int J Rad Oncol Biol Phys 2023;117:624-629.
long-term outcomes of intermediate-risk prostate cancer stratified as favorable 17 Dess RT, Sun Y, Jackson WC, et al. Association of presalvage radiotherapy PSA
or unfavorable: A secondary analysis of the RTOG 9408 randomized clinical trial. levels after prostatectomy with outcomes of long-term antiandrogen therapy in
JAMA Netw Open 2020;3:e2015083. men with prostate cancer. JAMA Oncol 2020;6:735-743.
8 Krauss DJ, Karrison T, Martinez AA, et al. Dose-escalated radiotherapy alone or 18 Burdett S, Fisher DJ, Tierney JF, et al. Duration of androgen suppression with
in combination with short-term androgen deprivation for intermediate-risk prostate postoperative radiotherapy (DADSPORT) for nonmetastatic prostate cancer: a
cancer: results of a phase III multi-institutional trial. J Clin Oncol 2023;41:3203- collaborative systematic review and meta-analysis of aggregate data. [online
3216. ahead of print] Eur Urol 2025;doi:/10.1016/[Link].2025.05.013.
9 Kerkmeijer LGW, Groen VH, Pos FJ, et al. Focal boost to the intraprostatic tumor 19 Feng FY, Huang HC, Spratt DE, et al. Validation of a 22-gene genomic classifier
in external beam radiotherapy for patients with localized prostate cancer: results in patients with recurrent prostate cancer: an ancillary study of the NRG/RTOG
from the FLAME randomized phase III trial. J Clin Oncol 2021;39:787-796. 9601 randomized clinical trial. JAMA Oncol 2021;7:544-552.
10 Kishan AU, Sun Y, Hartman H, et al. Androgen deprivation therapy use and 20 Posadas EM, Gay HA, Rodgers JP, et al. Intensification of ADT with
duration with definitive radiotherapy for localised prostate cancer: an individual enzalutamide in high-risk patients with biochemical relapse following radical
patient data meta-analysis. Lancet Oncol 2022;23:304-316. prostatectomy undergoing salvage radiation: Initial results from RTOG 3506
11 Spratt DE, Malone S, Roy S, et al. Prostate radiotherapy with adjuvant androgen (STEEL). J Clin Oncol 2024;42:5101.
deprivation therapy (ADT) improves metastasis-free survival compared to
neoadjuvant ADT: an individual patient meta-analysis. J Clin Oncol 2021;39:136-
144.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
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REFERENCES
21 Nguyen PL, Kollmeier M, Rathkopf DE, et al. FORMULA-509: A multicenter randomized trial of post-operative salvage radiotherapy (SRT) and 6 months of GnRH
agonist with or without abiraterone acetate/prednisone (AAP) and apalutamide (Apa) post-radical prostatectomy (RP). J Clin Oncol 2023;41:303.
22 Buyyounouski MK, Pugh SL, Chen RC, et al. Noninferiority of hypofractionated vs conventional postprostatectomy radiotherapy for genitourinary and gastrointestinal
symptoms: the NRG-GU003 Phase 3 randomized clinical trial. JAMA Oncol 2024;10:584-591.
23 Nagar H, Diven MA, Rippon B, et al. A randomized controlled phase 2 trial comparing salvage radiotherapy for prostate cancer delivered in 4 versus 2 weeks
(SHORTER): acute genitourinary and gastrointestinal patient-reported outcomes at a single institution. [online ahead of print] Eur Urol Oncol 2025;doi:10.1016/j.
euo.2025.05.014.
24 Ma TM, Ballas LK, Wilhalme H, et al. Quality-of-life outcomes and toxicity profile among patients with localized prostate cancer after radical prostatectomy treated with
stereotactic body radiation: the SIMITAR multicenter phase 2 trial. Int J Rad Oncol Biol Phys 2023;115:142-152.
25 Pollack A, Karrison TG, Balogh AG, et al. The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG
Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial. Lancet 2022;399:1886-1901.
26 Parker CC, James ND, Brawley CD, et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the
STAMPEDE randomised controlled trial. 2022;19:e1003998.
27 Bossi A, Foulon S, Maldonado X, et al. Efficacy and safety of prostate radiotherapy in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a
multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 2024;404:2065-2076.
28 Deek, MP, Van der Eecken K, Sutera P, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in
oligometastatic prostate cancer: analysis of STOMP and ORIOLE trials. J Clin Oncol 2022;40:3377-3382.
29 Tang C, Sherry AD, Haymaker C, et al. Addition of metastasis-directed therapy to intermittent hormone therapy for oligometastatic prostate cancer: the EXTEND
phase 2 randomized clinical trial. JAMA Oncol 2023;9:825-834.
30 Marvaso G, Corrao G, Zaffaroni M, et al. ADT with SBRT versus SBRT alone for hormone-sensitive oligorecurrent prostate cancer (RADIOSA): a randomised, open-
label, phase 2 clinical trial. Lancet Oncol 2025;26:300-311.
31 Francolini G, Allegra AG, Detti B, et al. Stereotactic body radiation therapy and abiraterone acetate for patients affected by oligometastatic castrate-resistant prostate
cancer: a randomized phase II trial (ARTO). J Clin Oncol 2023;41:5561-5568.
32 Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. NEJM 2013;369:213-223.
33 Tombal B, Choudhury A, Saad F, et al. Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: results of the EORTC 1333/PEACE-3 trial.
[online ahead of print] ESMO 2025;doi: [Link]
34 Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer
and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:408-419.
35 Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 2021;385:1091-1103.
36 Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with
progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet 2024;404:1227-1239.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF SURGERY
Pelvic Lymph Node Dissection Radical Prostatectomy
• For patients undergoing RP: • RP is an appropriate therapy for any patient not on an active
Pelvic lymph node dissection (PLND) can be considered in patients surveillance program with clinically localized prostate cancer that
with favorable intermediate-risk prostate cancer. can be completely excised surgically, who has a life expectancy of
PLND is recommended in patients with unfavorable intermediate, ≥10 years, and who has no serious comorbid conditions that would
high, very-high-risk, and regional prostate cancer. contraindicate an elective operation.
A PLND can be excluded in patients with low predicated probability • High-volume surgeons in high-volume centers generally provide
of nodal metastases by nomograms, although some patients better outcomes.
with lymph node metastases will be missed. There is no single • Blood loss can be substantial with RP, but can be reduced by using
evidence-based threshold for performing PLND. Based on the laparoscopic or robotic assistance or by careful control of the
risk of complications with PLND and extra time to perform the dorsal vein complex and periprostatic vessels when performed as
procedure, the published thresholds range from 2% to 7%.1-4 open surgery.
A patient who is above the threshold for performing a PLND, but • Urinary incontinence can be reduced by preservation of urethral
has a negative PSMA PET scan should still undergo PLND. In length beyond the apex of the prostate and avoiding damage to
two studies, the sensitivity of PSMA PET for pelvic lymph node the distal sphincter mechanism. Bladder neck preservation may
involvement among patients undergoing RP and PLND was low decrease the risk of incontinence. Anastomotic strictures increase
(about 40%), and the negative predictive value was about 81%.5,6 the risk of long-term incontinence.
Thus, basing the decision to perform PLND on a negative PSMA • Recovery of erectile function is directly related to age at RP,
PET scan could result in missing 19% of patients with positive preoperative erectile function, and the degree of preservation of the
lymph nodes. cavernous nerves. Replacement of resected nerves with nerve grafts
PLND can be performed using an open, laparoscopic, or robotic has not been shown to be beneficial. Early restoration of erections
technique and can provide staging and prognostic information. may improve late recovery.
• Extended PLND provides more complete staging and may cure
some patients with microscopic metastases; therefore, an extended Secondary Radical Prostatectomy
PLND is recommended when PLND is performed. • Secondary RP is an option for highly selected patients with local
• An extended PLND includes removal of all node-bearing tissue recurrence after external beam RT (EBRT), brachytherapy, or
from an area bound by the external iliac vein anteriorly, the pelvic cryotherapy in the absence of metastases, but the morbidity (ie,
sidewall laterally, the bladder wall medially, the floor of the pelvis incontinence, loss of erection, anastomotic stricture) is high and the
posteriorly, Cooper's ligament distally, and the internal iliac artery operation should be performed by surgeons who are experienced
proximally. with secondary RP.

References on PROS-K 2 of 2
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF SURGERY
REFERENCES
1 Cagiannos I, Karakiewicz P, Eastham JA, et al. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J
Urol 2003;170:1798-1803.
2 Briganti A, Larcher A, Abdollah F, et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node
dissection: the essential importance of percentage of positive cores. Eur Urol 2012;61:480-487.
3 Gandaglia G, Ploussard G, Valerio M, et al. A novel nomogram to identify candidates for extended pelvic lymph node dissection among patients with clinically localized
prostate cancer diagnosed with magnetic resonance imaging-targeted and systematic biopsies. Eur Urol 2019;75:506-514.
4 Gandaglia G, Martini A, Ploussard G, et al; EAU-YAU Prostate Cancer Working Group. External validation of the 2019 Briganti nomogram for the identification of
prostate cancer patients who should be considered for an extended pelvic lymph node dissection. Eur Urol 2020;78:138-142.
5 Hope TA, Eiber M, Armstrong WR, et al. Diagnostic accuracy of 68Ga-PSMA-11 PET for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic
lymph node dissection: A multicenter prospective phase 3 imaging trial. JAMA Oncol 2021;7:1635-1642.
6 Pienta KJ, Gorin MA, Rowe SP, et al. A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate specific membrane antigen PET/CT with
18F-DCFPyL in prostate cancer patients (OSPREY). J Urol 2021;206:52-61.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF LOCAL SECONDARY THERAPY POST-RADIATION

Local Secondary Therapy for Recurrent Prostate Cancer After Definitive Radiotherapy:

• Patients with biopsy-proven recurrence in the prostate after prior RT and without distant metastatic disease can be considered for local
therapy. Monitoring is also an option (see PROS-10). ADT may also be included, but it should not be reflexively ordered.
• The Panel recommends that patients receive multidisciplinary counseling about the risks and benefits of each of these options in the context
of the available comparative literature on this topic.1,2
• Local therapy options for patients with recurrence in the prostate includea,b,c:
Cryotherapy
High-intensity focused ultrasound (HIFU)
Irreversible electroporation (IRE) (category 2B)
Reirradiation
RP + PLND
• Reirradiation options include LDR brachytherapy, HDR brachytherapy, and SBRT.1-7
• There is no consensus as to the most appropriate reirradiation volume, and there are published experiences for both focal/partial and whole
gland reirradiation. The Panel recommends that patients receiving local therapy for RT recurrence are treated within the context of clinical
trials when available and/or at experienced centers.

a Reirradiation with LDR brachytherapy, HDR brachytherapy, and SBRT is supported by phase II trials with >36 months of median follow-up and should be strongly
considered as an option in patients with >2 years interval from prior radiation who do not have ongoing moderate or higher grade radiation-associated toxicities. Phase
II data with >36 months of median follow-up are available, albeit to a more limited scope, for secondary RP, cryotherapy, and HIFU.
b Currently, all phase II and/or prospectively accrued registries reporting oncologic outcomes with >36 months of follow-up have pursued whole gland treatments. Focal
therapy for prostate-only recurrences is the subject of active investigation. See Principles of Focal/Subtotal Therapy or Whole Gland Ablative Therapy (PROS-I).
c There are no prospective data to guide the use and duration of ADT with reirradiation for prostate-only recurrences. The Panel recommends extrapolation from the
definitive treatment setting to suggest that adding ADT or prolonging it in this setting likely offers an improvement in biochemical control. See Principles of Radiation
Therapy (PROS-J).
References on PROS-L 2 of 2
Note: All recommendations are category 2A unless otherwise indicated.
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PRINCIPLES OF LOCAL SECONDARY THERAPY POST-RADIATION

REFERENCES
1 Ingrosso G, Becherini C, Lancia A, et al. Nonsurgical salvage local therapies for radiorecurrent prostate cancer: A systematic review and meta-analysis. Eur Urol Oncol
2020;3:183-197.
2 Valle LF, Lehrer EJ, Markovic D, et al. A systematic review and meta-analysis of local salvage therapies after radiotherapy for prostate cancer (MASTER). Eur Urol
2021;80:280-292.
3 Crook J, Rodgers JP, Pisansky TM, et al. Salvage low-dose-rate prostate brachytherapy: Clinical outcomes of a phase 2 trial for local recurrence after external beam
radiation therapy (NRG Oncology/RTOG 0526). Int J Radiat Oncol Biol Phys 2022;112:1115-1122.
4 Yamada Y, Kollmeier MA, Pei X, et al. A phase II study of salvage high-dose-rate brachytherapy for the treatment of locally recurrent prostate cancer after definitive
external beam radiotherapy. Brachytherapy 2014;13:111-116.
5 Fuller DB, Chen RC, Crabtree T, et al. 10 year prostate stereotactic body radiotherapy outcomes: Relapse-free survival, PSA kinetics and toxicity from a pooled
analysis of two multi-institutional trials. Int J Radiat Oncol 2020;108:e857-e858.
6 Bergamin S, Eade T, Kneebone A, et al. Interim results of a prospective prostate-specific membrane antigen-directed focal stereotactic reirradiation trial for locally
recurrent prostate cancer. Int J Radiat Oncol Biol Phys 2020;108:1172-1178.
7 Pasquier D, Martinage G, Janoray G, et al. Salvage stereotactic body radiation therapy for local prostate cancer recurrence after radiation therapy: A retrospective
multicenter study of the GETUG. Int J Radiat Oncol Biol Phys 2019;105:727-734.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF METASTASIS-DIRECTED THERAPY (MDT)

General
• MDT is the treatment of metastatic sites with a local therapy to improve oncologic outcomes, not simply to provide symptom palliation. MDT
has been studied primarily with radiotherapy and with highly selected use of surgical resection in the form of lymph node dissections. MDT
is not recommended to be performed with other local therapies.
• MDT is mostly commonly delivered in the form of MDRT, which specifically refers to the use of higher than palliative dose radiotherapy
to provide durable local control of the areas targeted. This may be for the intended purpose of delaying the initiation of systemic therapy,
improving PFS, radiographic PFS, or overall survival. Similar to systemic therapies in the polymetastatic setting, MDRT is uncommonly
curative and should be viewed as a form of cytotoxic therapy, and it may need to be repeated.

Disease State
• The settings for which MDT may have utility with variable evidence quality are shown in Table 1:

Table 1.
mCSPC mCRPC
Treatment Synchronous
Regimen Metachronous
(de novo) Oligometastatic Oligoprogressive
Oligorecurrenta
Oligometastatic
MDT ☼   ☼

( Preferred; ☼ Acceptable based on clinical and medical need)

a Limited data suggest that lymphadenectomy may be beneficial for select patients with pelvic nodal recurrence after radical prostatectomy if they do not have evidence
of distant metastases.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF METASTASIS-DIRECTED THERAPY (MDT)

Number of Metastatic Sites
• The number of metastatic sites to define oligometastatic disease remains an evolving space and is impacted by sensitivity of imaging used.
Early studies limited metastatic sites to 1–3 or 1–5 by CT, MRI, or bone scan.1-4 More recent studies have included up to 10 metastatic sites
by PSMA-PET imaging (NCT04787744, NCT06150417, NCT03721341). The upper limit is not clearly established and is both a function of
oncologic limitations and technical limitations of treating numerous metastatic sites.
If CT, MRI, or bone scan is used, >5 metastasis is generally an exclusion for MDT.
If PSMA-PET is used, >10 metastatic sites is generally an exclusion for MDT.
• Lymph nodes in the same drainage chain (eg, two adjacent para-aortic lymph nodes) are to be considered 1 metastatic site and would be
treated together with one radiation therapy isocenter or plan.
• Discrete, non-contiguous bony metastases should be counted separately even if treated with one isocenter (eg, two discrete femur
metastases).
• The goal of MDT is generally to treat all metastatic sites, which may include regional lymph nodes and potentially treatment of the primary
tumor if untreated or evidence of local recurrence. The primary tumor in this setting should be counted as a site.

Location of Metastatic Sites

• The location of metastatic sites have generally consisted of lymph node and osseous metastatic sites, but some studies include lung and
liver metastases. Brain metastases are generally not included in studies of MDRT in prostate cancer. MDT should not be used to delay
systemic therapy when there is visceral organ involvement.
• Pelvic lymph nodes are also considered metastatic sites in the context of MDRT for metachronous mCSPC or mCRPC.

1 Marvaso G, Corrao G, Zaffaroni M, et al. ADT with SBRT versus SBRT alone for hormone-sensitive oligorecurrent prostate cancer (RADIOSA): a randomised, open-
label, phase 2 clinical trial. Lancet Oncol 2025;26:300-311.
2 Tang C, Sherry AD, Haymaker C, et al. Addition of metastasis-directed therapy to intermittent hormone therapy for oligometastatic prostate cancer: the EXTEND phase
2 randomized clinical trial. JAMA Oncol 2023;9:825-834.
3 Deek, MP, Van der Eecken K, Sutera P, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in
oligometastatic prostate cancer: analysis of STOMP and ORIOLE trials. J Clin Oncol 2022;40:3377-3382.
4 Francolini G, Allegra AG, Detti B, et al. Stereotactic body radiation therapy and abiraterone acetate for patients affected by oligometastatic castrate-resistant prostate
cancer: a randomized phase II trial (ARTO). J Clin Oncol 2023;41:5561-5568.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF METASTASIS-DIRECTED THERAPY (MDT)

Radiotherapy Details (Also see Principles of Radiation Therapy) Concurrent Systemic Therapy with MDRT
• Use of SBRT (also known in this setting as stereotactic ablative • Synchronous (de novo) oligometastatic mCSPC:
radiotherapy [SABR]) is most commonly recommended for MDRT. Systemic therapy, most commonly ADT+ARPI, and treatment of
Established dose/fraction regimens should be used with strict the primary tumor with RT is recommended for most patients. The
OAR constraints. Daily 3D image guidance is required and motion concurrent addition of MDRT may be considered in select patients.
management is recommended for thoracic and abdominal sites if For patient tolerance, it is reasonable to asynchronously treat the
relevant. Online adaptive radiotherapy, if available, may be preferred primary and metastatic sites in separate treatment courses.
if treatment of a metastatic site is near an OAR with frequent day-to- • Metachronous oligorecurrent mCSPC:
day setup uncertainty. Appropriate clinical target volume (CTV) and Oligorecurrent disease detected primarily by PET imaging may
PTV margins should be applied to account for microscopic spread be treated by MDRT alone or concurrently with short-term ADT (6
and setup uncertainty. months). The addition of ADT improved clinical and biochemical
• When treating a lymph node metastasis, one should generally PFS, but may simply delay the detection of recurrence rather than
include an elective nodal volume to the involved chain with a improve durable control of the disease.1
simultaneous integrated boost to the radiographic or biopsy Trials have not been reported showing a benefit of the addition of
confirmed lymph node. If lymph node(s) are in the pelvis, elective triplet chemotherapy or an ARPI in the setting of MDRT+ADT.
nodal irradiation fields should be considered, either ipsilateral or • Oligometastatic mCRPC:
bilateral. First-line treatment with ADT and an ARPI ± MDRT have
• Dose composites with special medical physics consults are required demonstrated improvements in PFS and radiographic PFS
to account for prior radiotherapy or overlap of multiple treatment from the addition of MDRT.4 MDRT should not be used without
plans. recommended mCRPC systemic therapies.
• If treatment involves more than two treatment plans simultaneously, • Oligoprogressive or oligopersistent mCRPC
consideration of splitting the treatment course into multiple For oligoprogressive or oligopersistent mCRPC, MDRT may be
sessions of SBRT may be required due to patient tolerance and delivered concurrently with mCRPC systemic therapy.
safety (eg, 4 treatment plans for 4 metastatic sites may need to be MDRT should not be used concurrently with PARP inhibition
delivered as 2 concurrent treatment plans as course 1, and then the (alone or in combination with abiraterone or enzalutamide) or
other 2 treatment plans are delivered concurrently at a later date chemotherapy outside of a clinical trial.
as a separate course of SBRT). Repeat simulation may be required Use of MDRT may be considered for oligoprogression sequentially
based on potential for anatomy changes or use of alternative after approved systemic mCRPC treatments.
immobilization for other treatments sites.

1 Marvaso G, Corrao G, Zaffaroni M, et al. ADT with SBRT versus SBRT alone for hormone-sensitive oligorecurrent prostate cancer (RADIOSA): a randomised, open-
label, phase 2 clinical trial. Lancet Oncol 2025;26:300-311.
4 Francolini G, Allegra AG, Detti B, et al. Stereotactic body radiation therapy and abiraterone acetate for patients affected by oligometastatic castrate-resistant prostate
cancer: a randomized phase II trial (ARTO). J Clin Oncol 2023;41:5561-5568.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF NON-HORMONAL SYSTEMIC THERAPY

• An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

Non-Hormonal Systemic Therapy for M1 Castration-Sensitive Prostate Cancer

• Triplet therapy with ADT, certain ARPIs, and docetaxel is an option for certain patients with mCSPC who are fit for chemotherapy based on phase 3
studies:
ADT with docetaxel and abiraterone was compared to ADT alone or with docetaxel in an open-label, randomized, phase 3 study. Radiographic PFS was
longer in patients who received abiraterone than in those who did not. The populations receiving the triplet and doublet therapies experienced similar
rates of neutropenia, febrile neutropenia, fatigue, and neuropathy, although grade ≥3 adverse events occurred in 63% of patients who received the triplet
combination compared with 52% of those receiving ADT and docetaxel.
ADT with docetaxel and darolutamide was compared with ADT with docetaxel and placebo in a randomized phase 3 trial. OS, time to CRPC, skeletal
event-free survival, and time to initiation of subsequent systemic antineoplastic therapy were improved in the patients who received darolutamide.
Adverse events of any grade, grade 3–5 adverse events, and serious adverse events occurred at similar incidence levels between the two arms. Many of
these were known effects of docetaxel. Exceptions were rash (16.6% vs. 13.5%) and hypertension (13.7% vs. 9.2%), which are known effects of androgen
receptor pathway inhibitors and were more frequent in the darolutamide group.
An open-label, randomized, phase 3 trial compared ADT with enzalutamide to ADT with a first-generation antiandrogen in this setting. Concurrent
docetaxel was allowed and used for stratification. OS was improved with the use of enzalutamide over first-generation anti-androgen regardless of the
addition of docetaxel. The most common grade ≥3 adverse events were febrile neutropenia associated with docetaxel use (6% in both groups), fatigue
(1% in the control group vs. 6% in the enzalutamide group), and hypertension (6% vs. 10%). The incidence of grade 1–3 memory impairment was 4%
versus 13%.
• The use of myeloid growth factors should follow the NCCN Guidelines for Hematopoietic Growth Factors, based on risk of neutropenic fever.

Non-Hormonal Systemic Therapy for M1 CRPC

• Chemotherapy
Docetaxel with concurrent steroid
◊ Concurrent steroid includes daily prednisone, which may be omitted on the day of chemotherapy administration when dexamethasone is given.
◊ Every–3-week docetaxel with concurrent steroid is the preferred first-line chemotherapy treatment based on phase 3 clinical trial data for patients
with symptomatic mCRPC. Adverse events associated with docetaxel include neutropenia, leukopenia, febrile neutropenia, neutropenic infections,
fluid retention, hypersensitivity reaction, hepatic function impairment, neuropathy, and other low-grade adverse events (eg, fatigue, nausea, vomiting,
alopecia, diarrhea).
◊ Only regimens utilizing docetaxel on an every–3-week schedule demonstrated beneficial impact on survival. The duration of therapy should be based
on the assessment of benefit and toxicities. In the pivotal trials establishing survival advantage of docetaxel-based chemotherapy, patients received
up to 10 cycles of treatment if no progression and no prohibitive toxicities were noted.
◊ Docetaxel retreatment can be attempted after progression on an ARPI and docetaxel in patients with mCRPC whose cancer has not demonstrated
definitive evidence of progression on prior docetaxel therapy in either the castration-sensitive setting or the mCRPC setting.
◊ Rare patients may have exposure to docetaxel without prior ARPI (ie, in the setting of EBRT to the primary tumor for low-volume synchronous
mCSPC). Docetaxel rechallenge is not recommended for such patients in the pre-ARPI mCRPC setting.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF NON-HORMONAL SYSTEMIC THERAPY

Non-Hormonal Systemic Therapy for M1 CRPC (continued)
• Chemotherapy
Cabazitaxel with concurrent steroid
◊ Concurrent steroid includes daily prednisone, which may be omitted on the day of chemotherapy administration when dexamethasone is given.
◊ Patients who are not candidates for docetaxel or who are intolerant of docetaxel should be considered for cabazitaxel with concurrent steroid, based
on results that suggest clinical activity of cabazitaxel in mCRPC. Cabazitaxel was associated with lower rates of peripheral neuropathy than docetaxel,
particularly at 20 mg/m2 (12% vs. 25%) and may be appropriate in patients with pre-existing mild peripheral neuropathy. Current data do not support
greater efficacy of cabazitaxel over docetaxel.
◊ Cabazitaxel at 25 mg/m² with concurrent steroid has been shown in a randomized phase 3 study (TROPIC) to prolong OS, PFS, PSA response, and
radiologic response when compared with mitoxantrone and prednisone and is FDA approved in the post-docetaxel second-line setting. Toxicity at this
dose was significant and included febrile neutropenia, severe diarrhea, fatigue, nausea/vomiting, anemia, thrombocytopenia, sepsis, and renal failure.
A recent trial, PROSELICA, compared cabazitaxel 25 mg/m² every 3 weeks to 20 mg/m² every 3 weeks. Cabazitaxel 20 mg/m² had less toxicity; febrile
neutropenia, diarrhea, and fatigue were less frequent. Cabazitaxel at 20 mg/m² had a significantly lower PSA response rate but non-significantly lower
radiographic response rate and non-significantly shorter PFS and OS (13.4 vs. 14.5 months) compared to 25 mg/m².
◊ Cabazitaxel at 25 mg/m2 with concurrent steroid improved radiographic PFS and reduced the risk of death compared with abiraterone or enzalutamide
in patients with prior docetaxel treatment for mCRPC in the CARD study.
◊ Biweekly cabazitaxel at 16 mg/m2 with prophylactic G-CSF significantly reduced the risk of neutropenia/neutropenic complications compared to the 25
mg/m2 dose with G-CSF in patients ≥65 years in a phase 3 trial. Clinical outcomes were comparable between the 2 groups.
◊ No chemotherapy regimen to date has demonstrated improved survival or quality of life after cabazitaxel, and trial participation should be encouraged.
Cabazitaxel/carboplatin with concurrent steroid
◊ Concurrent steroid includes daily prednisone, which may be omitted on the day of chemotherapy administration when dexamethasone is given.
◊ Cabazitaxel 20 or 25 mg/m² plus carboplatin AUC 4 mg/mL per minute with growth factor support can be considered for fit patients with aggressive
variant mCRPC (ie, visceral metastases, low PSA and bulky disease, high lactate dehydrogenase (LDH), high CEA, lytic bone metastases, NEPC
histology) or unfavorable genomics (defects in at least 2 of PTEN, TP53, and RB1). The most common grade 3–5 adverse events were fatigue, anemia,
neutropenia, and thrombocytopenia. Corn PG, et al. Lancet Oncol 2019;20:1432-1443.
– Cabazitaxel starting dose can be either 20 mg/m² or 25 mg/m² for patients with mCRPC whose cancer has progressed despite prior docetaxel
chemotherapy. Cabazitaxel 25 mg/m² with concurrent steroid may be considered for healthy patients who wish to be more aggressive. Growth factor
support may be needed with either dose.
Mitoxantrone with prednisone
◊ Mitoxantrone with prednisone may provide palliation but has not been shown to extend survival in two randomized trials. Adverse events associated
with mitoxantrone are similar to docetaxel, but with lower rates of grade 3 or 4 neutropenic fevers, cardiovascular events, nausea and vomiting,
metabolic disturbances, and neurologic events.
Increasing PSA should not be used as the sole criteria for progression. Assessment of response should incorporate clinical and radiographic criteria.
See NCCN Guidelines for Hematopoietic Growth Factors for recommendations on growth factor support.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF NON-HORMONAL SYSTEMIC THERAPY

Non-Hormonal Systemic Therapy for M1 CRPC (continued)
• PARP Inhibitors with or without ARPIs
Inactivation of HRR genes has been associated with response to PARP inhibitor (PARPi) therapy, and a number of FDA-approved agents and
combinations are now available (Table 1 and Discussion). Although there are multiple specific gene alterations included in the FDA labels for specific
PARPi and combinations (see Table 1), the response rates have been most pronounced for patients with BRCA2 mutation-associated prostate cancers.
Treatment responses have been variable for other genes alterations, and this information should be taken into account in decisions about treatment
sequencing and patient counseling. For example, responses have been less robust for patients whose cancers carry ATM mutations, and other
recommended regimen options may be favored until more data are available on a gene-by-gene level.
Loss of BRCA2 may be especially associated with response to PARPi therapy compared to other HRR gene alterations.
There has been heterogeneity of response to olaparib for non-BRCA mutations based on the specific gene mutation (Discussion).
The fine-particle (category 2B; other recommended option) or standard formulation of abiraterone can be given with single-agent niraparib as a substitute
for the combination niraparib/abiraterone tablet.
The fine-particle abiraterone (category 2B; other recommended option) may be given with olaparib as a substitute for standard abiraterone.

• Immunotherapy
Sipuleucel-T
◊ Sipuleucel-T is only for asymptomatic or minimally symptomatic patients with no liver metastases, life expectancy >6 months, and ECOG performance
status 0–1.
◊ Sipuleucel-T is not recommended for patients with small cell prostate cancer/NEPC.
◊ Sipuleucel-T has been shown in a phase 3 clinical trial to extend mean survival from 21.7 months in the control arm to 25.8 months in the treatment
arm, which constitutes a 22% reduction in mortality risk.
◊ Sipuleucel-T is well-tolerated; common complications include chills, pyrexia, and headache.
Pembrolizumab is an option for certain patients with MSI-H/dMMR mCRPC (PROS-18).
◊ Pembrolizumab may cause severe, life-threatening immune-mediated adverse reactions, which may include but are not limited to: pneumonitis, colitis,
hepatitis, myocarditis, endocrinopathies, exfoliative dermatologic conditions, renal failure and nephritis, and ocular toxicities. See NCCN Guidelines for
Management of Immunotherapy-Related Toxicities.
◊ Limited data suggest that pembrolizumab may be associated with some benefit in patients with mCRPC and TMB ≥10 mut/mB. Lenis AT, et al. Clin Canc
Res 2024;30:3894-3903.
◊ Pembrolizumab and berahyaluronidase alfa-pmph subcutaneous injection may be substituted for IV pembrolizumab. Pembrolizumab and
berahyaluronidase alfa-pmph has different dosing and administration instructions compared to IV pembrolizumab.

• Other Targeted Agents

Pan-cancer, tumor-agnostic treatments can be considered for patients with actionable mutations.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF NON-HORMONAL SYSTEMIC THERAPY

Table 1. PARP Inhibitors with or without ARPIs

Biomarker
Treatment FDA-Approved Disease State Indication Pathogenic variant or mutation in gene Clinical Trial
(germline and/or somatic)
BRCA2, BRCA1, ATM, BARD1, BRIP1, CDK12,
mCRPC that has progressed following prior treatment
Olaparib CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, PROfound1
with enzalutamide or abiraterone.
RAD51D, or RAD54L
mCRPC that has been treated with androgen receptor-
Rucaparib BRCA2, BRCA1 TRITON22,3
directed therapy and taxane-based chemotherapy
Olaparib/
mCRPC BRCA2, BRCA1 PROPel4
Abiraterone
Talazoparib/ BRCA2, BRCA1, ATM, ATR, CDK12, CHEK2,
mCRPC TALAPRO-25,6
Enzalutamide FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C
Niraparib/
mCRPC BRCA2, BRCA1 MAGNITUDE7,8
Abiraterone

1 de Bono JD, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. NEJM 2020;382:2091-2102.
2 Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin
Oncol 2020;38:3763-3772.
3 Abida W, Campbell D, Patnaik A, et al. Rucaparib for the treatment of metastatic castration-resistant prostate cancer associated with a DNA damage repair gene
alteration: final results from the Phase 2 TRITON2 study. Eur Urol 2023;84:321-330.
4 Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final
prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1094-1108.
5 Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised,
placebo-controlled, phase 3 trial. Lancet 2023;402:291-303.
6 Fizazi K, Azad AA, Matsubara N, et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3
TALAPRO-2 trial. 2023;30:257-264.
7 Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol 2023;41:339-3351.
8 Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous
recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. 2023;34:772-782.

Note: All recommendations are category 2A unless otherwise indicated.

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American Joint Committee on Cancer (AJCC)

TNM Staging System For Prostate Cancer (8th ed., 2017)
Pathological T (pT)
Table 1. Definitions for T, N, M
Clinical T (cT) T Primary Tumor
T Primary Tumor T2 Organ confined
TX Primary tumor cannot be assessed T3 Extraprostatic extension
T0 No evidence of primary tumor T3a Extraprostatic extension (unilateral or bilateral) or microscopic
T1 Clinically inapparent tumor that is not palpable invasion of bladder neck
T1a Tumor incidental histologic finding in 5% or less of T3b Tumor invades seminal vesicle(s)
tissue resected T4 Tumor is fixed or invades adjacent structures other than seminal
T1b Tumor incidental histologic finding in more than 5% vesicles such as external sphincter, rectum, bladder, levator
of tissue resected muscles, and/or pelvic wall
Note: There is no pathological T1 classification.
T1c Tumor identified by needle biopsy found in one or both sides,
Note: Positive surgical margin should be indicated by an R1 descriptor, indicating
but not palpable residual microscopic disease.
T2 Tumor is palpable and confined within prostate
T2a Tumor involves one-half of one side or less N Regional Lymph Nodes
T2b Tumor involves more than one-half of one side but NX Regional lymph nodes cannot be assessed
not both sides N0 No positive regional nodes
T2c Tumor involves both sides N1 Metastases in regional node(s)
T3 Extraprostatic tumor that is not fixed or does not invade
adjacent structures M Distant Metastasis
T3a Extraprostatic extension (unilateral or bilateral) M0 No distant metastasis
T3b Tumor invades seminal vesicle(s) M1 Distant metastasis
T4 Tumor is fixed or invades adjacent structures other M1a Nonregional lymph node(s)
than seminal vesicles such as external sphincter, rectum, M1b Bone(s)
bladder, levator muscles, and/or pelvic wall.
M1c Other site(s) with or without bone disease

Note: When more than one site of metastasis is present, the most advanced category
is used. M1c is most advanced.

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.

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Table 2. AJCC Prognostic Groups

Group T N M PSA (ng/mL) Grade Group Histopathologic Type
Stage I cT1a-c N0 M0 PSA <10 1 This classification applies to adenocarcinomas and squamous carcinomas,
cT2a N0 M0 PSA <10 1 but not to sarcoma or transitional cell (urothelial) carcinoma of the prostate.
Adjectives used to describe histologic variants of adenocarcinomas of
pT2 N0 M0 PSA <10 1 prostate include mucinous, signet ring cell, ductal, and neuroendocrine,
Stage IIA cT1a-c N0 M0 PSA ≥10 <20 1 including small cell carcinoma. There should be histologic confirmation of the
cT2a N0 M0 PSA ≥10 <20 1 disease.
pT2 N0 M0 PSA ≥10 <20 1 Definition of Histologic Grade Group (G)
cT2b N0 M0 PSA <20 1 Recently, the Gleason system has been compressed into so-called Grade
cT2c N0 M0 PSA <20 1 Groups.
Stage IIB T1-2 N0 M0 PSA <20 2
Grade Group Gleason Score Gleason Pattern
Stage IIC T1-2 N0 M0 PSA <20 3
1 ≤6 ≤3+3
T1-2 N0 M0 PSA <20 4
2 7 3+4
Stage IIIA T1-2 N0 M0 PSA ≥20 1-4
3 7 4+3
Stage IIIB T3-4 N0 M0 Any PSA 1-4
4 8 4+4, 3+5, 5+3
Stage IIIC Any T N0 M0 Any PSA 5
5 9 or 10 4+5, 5+4, 5+5
Stage IVA Any T N1 M0 Any PSA Any
Stage IVB Any T Any N M1 Any PSA Any
Note: W
hen either PSA or Grade Group is not available, grouping should be
determined by T category and/or either PSA or Grade Group as available.

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging System Manual, Eighth
Edition (2017) published by Springer International Publishing.

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ABBREVIATIONS

3D three-dimensional DCE dynamic contrast-enhanced IGRT image-guided radiation therapy

DEXA dual-energy x-ray absorptiometry IMRT intensity modulated RT
ACE-27 Adult Comorbidity Evaluation-27 DIL dominant intraprostatic lesion IRE irreversible elecroporation
Index IRF intermediate risk factor
DM distant metastases
ADT androgen deprivation therapy ITT intention to treat
dMMR mismatch repair deficient
AI artificial intelligence
DRE digital rectal examination
ARPI androgen receptor pathway LDH lactate dehydrogenase
inhibitor DWI diffusion-weighted imaging
LDR low dose rate
aRT adjuvant RT
LHRH luteinizing hormone-releasing
ASTRO American Society for Radiation EBRT external beam radiation therapy hormone
Oncology ECG electrocardiogram LT-ADT long-term androgen deprivation
AUC area under the curve ECHO echocardiogram therapy
ENI elective nodal irradiation
BCR biochemical recurrence mCRPC metastatic castration-resistant
BED biologically effective dose FDG fluorodeoxyglucose prostate cancer
BMI body mass index FFS failure-free survival mCSPC metastatic castration-sensitive
prostate cancer
FIR favorable intermediate-risk
CBRT cone beam CT MDRT metastasis-directed radiotherapy
FLA focal laser ablation
CEA carcinoembryonic antigen FRAX Fracture Risk Assessment Tool MFS metastasis-free survival
CHIP clonal hematopoiesis of FT focal therapy MMAI multimodal artificial intelligence
indeterminate potential MMR mismatch repair
CLR correct localization rate GC genomic classifier mpMRI multiparametric MRI
CRPC castration-resistant prostate cancer MSI microsatellite instability
CSPC castration-sensitive prostate HDR high dose rate MSI-H microsatellite instability-high
cancer
HIFU high-intensity focused ultrasound
ctDNA circulating tumor DNA
CVD cardiovascular disease
HRD homologous recombination
deficiency
HRR homologous recombination repair

Note: All recommendations are category 2A unless otherwise indicated.

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ABBREVIATIONS

NEPC neuroendocrine prostate cancer rh radiohybrid

NNT number needed to treat RFA radiofrequency ablation
ROI region of interest
OAR organ at risk RP radical prostatectomy
OS overall survival rPFS radiographic progression-free
survival
PARPi PARP inhibitor RTOG Radiation Therapy Oncology
PCSM prostate cancer-specific mortality Group
PCSS prostate cancer-specific survival
PDT photodynamic therapy SABR stereotactic ablative radiotherapy
PFS progression-free survival SBRT stereotactic body radiation
therapy
PLND pelvic lymph node dissection
sHR subdistribution hazard ratio
PNRT prophylactic nodal
radiotherapy SPECT single-photon emission computed
tomography
PPV positive predictive value
SRE skeletal-related event
PSA prostate-specific antigen
sRT secondary RT
PSADT prostate-specific antigen doubling
time ST-ADT short-term androgen deprivation
therapy
PSMA prostate-specific membrane
antigen
PTV planning target value TMB tumor mutational burden
TULSA transurethral ultrasound ablation
QOL quality of life
VUS variant of uncertain significance

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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is
uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the
intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the
intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred affordability.
Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
Other recommended or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

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Discussion
This discussion corresponds to the NCCN Guidelines for Prostate Cancer. Last updated: December 4, 2025.
Table of Contents

Overview ...................................................................................................... MS-2 Primary ADT for mCSPC ........................................................................ MS-39

Guidelines Update Methodology .................................................................. MS-2 Intermittent Versus Continuous ADT ...................................................... MS-40
Literature Search Criteria ............................................................................. MS-2 Adverse Effects of Traditional ADT ......................................................... MS-41
Sensitive/Inclusive Language Usage ........................................................... MS-3 Management of mCSPC ............................................................................. MS-43
Initial Prostate Cancer Diagnosis ................................................................. MS-3 Doublet Therapies for mCSPC ............................................................... MS-43
Estimates of Life Expectancy ....................................................................... MS-3 Triplet Therapies for mCSPC .................................................................. MS-46
Quality-of-Life and Shared Decision-Making ................................................ MS-4 EBRT to the Primary Tumor in Synchronous Low-Volume M1 Disease .. MS-48
Prostate Cancer Genetics ............................................................................ MS-4 MDT for Oligometastatic CSPC .............................................................. MS-48
Inequities Based on Race and Ethnicity ....................................................... MS-7 Progression to and Management of CRPC ................................................. MS-50
Risk Stratification for Clinically Localized Disease ....................................... MS-8 Secondary Hormone Therapy for CRPC .................................................... MS-51
NCCN Risk Groups .................................................................................. MS-8 Abiraterone Acetate in mCRPC .............................................................. MS-51
Nomograms ........................................................................................... MS-10 Enzalutamide in M0 and M1 CRPC ........................................................ MS-53
Advanced Risk Stratification Tools ......................................................... MS-10 Apalutamide in M0 CRPC ....................................................................... MS-54
Initial Clinical Assessment and Staging Evaluation .................................... MS-12 Darolutamide in M0 CRPC ..................................................................... MS-54
Imaging Techniques .................................................................................. MS-13 Other Secondary Hormone Therapies .................................................... MS-54
Multiparametric MRI (mpMRI) ................................................................ MS-13 Chemotherapy, Immunotherapy, and Targeted Therapy for mCRPC ......... MS-55
PET Imaging .......................................................................................... MS-14 Docetaxel ............................................................................................... MS-55
Risks of Imaging .................................................................................... MS-16 Cabazitaxel............................................................................................. MS-56
Observation ............................................................................................... MS-17 Cabazitaxel/Carboplatin ......................................................................... MS-57
Active Surveillance .................................................................................... MS-18 Sipuleucel-T ........................................................................................... MS-57
Radical Prostatectomy ............................................................................... MS-23 Pembrolizumab ...................................................................................... MS-58
Radiation Therapy ..................................................................................... MS-25 Mitoxantrone ........................................................................................... MS-59
Comparison of Treatment Options for Localized Disease .......................... MS-31 Treatment Options for Patients with DNA Repair Gene Mutations .......... MS-59
Other Local Therapies ............................................................................... MS-32 Radiopharmaceuticals for mCRPC ............................................................. MS-64
Disease Monitoring .................................................................................... MS-32 Lutetium Lu 177 vipivotide tetraxetan ..................................................... MS-64
Post-Radical Prostatectomy Approaches ................................................... MS-33 Radium-223 ............................................................................................ MS-65
Early Secondary or Adjuvant Treatment for Adverse Features After Radical MDT for mCRPC ........................................................................................ MS-66
Prostatectomy ........................................................................................ MS-33 Small Cell/Neuroendocrine Prostate Cancer .............................................. MS-67
Adjuvant or Early Secondary Therapy for pN1 ....................................... MS-34 Additional Treatment Options for Bone Metastases ................................... MS-67
Secondary Treatment for PSA Persistence or Biochemical Recurrence After Considerations for Visceral Metastases ..................................................... MS-68
Radical Prostatectomy ........................................................................... MS-34 Sequencing of Therapy in CRPC................................................................ MS-68
Post-Radiation Recurrence ........................................................................ MS-35 Summary .................................................................................................... MS-69
Second Biochemical Recurrence ............................................................... MS-36 References ................................................................................................. MS-71
Androgen Deprivation Therapy .................................................................. MS-37
ADT for Initial Treatment of Clinically Localized (N0,M0) Disease ......... MS-38
ADT for Initial Treatment of Regional Disease ....................................... MS-39
Palliative ADT ........................................................................................ MS-39

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Overview likely to have had a PSA test within the past year.11 The mortality rate from
An estimated 313,780 new cases of prostate cancer will be diagnosed in prostate cancer in this population is two to four times higher than all other
the United States in 2025, accounting for 30% of new cancer cases in racial and ethnic groups; prostate cancer accounts for 17% of male cancer
men.1 It is the most common cancer in men in the United States, who deaths in the United States.1,11 However, the overall prognosis by race
currently have a 1 in 8 lifetime risk of developing prostate cancer.1 The appears similar when patients are treated with the same guideline-
incidence of prostate cancer declined by approximately 40% from 2007 to concordant care.12
2014, but since that time has increased at a rate of 3% annually. These
Use of PSA for early detection of potentially fatal prostate cancer coupled
trends largely reflect the changes in prostate-specific antigen (PSA)
with the use of imaging and the consideration of risk calculators and/or
screening recommendations. The decrease in PSA screening that
biomarkers to improve the specificity of screening should decrease the risk
followed the 2012 USPSTF recommendations against routine testing was
of overdetection (see the NCCN Guidelines for Prostate Cancer Early
associated with a rise in the diagnosis of regional and metastatic
Detection, available at [Link]). This reduced overdetection along
disease.2-10
with the use of active surveillance in appropriate patients should reduce
Researchers further estimate that prostate cancer will account for 11% of overtreatment AND preserve the relatively low rates of prostate cancer
male cancer deaths in the United States in 2025, with an estimated 35,770 mortality.
deaths.1 The age-adjusted death rate from prostate cancer declined by
Guidelines Update Methodology
52% from 1993 to 2017, but the death rate has become more stable in
recent years, with a 0.5% annual decrease from 2012 through 2022.1 For The complete details of the Development and Update of the NCCN
all stages combined, the 5-year relative survival rate for prostate cancer is Guidelines are available at [Link].
97%.1 The comparatively low death rate suggests that increased public
awareness with earlier detection and treatment has affected mortality from
Literature Search Criteria
this prevalent cancer, but is also complicated by screening-related lead- Prior to the update of the NCCN Guidelines for Prostate Cancer, an
time bias and detection of indolent cancers. Maintenance of this low death electronic search of the PubMed database was performed to obtain key
rate is threatened by the rising prostate cancer incidence and diagnosis of literature in prostate cancer published since the previous Guidelines
advanced disease. update, using the search term “prostate cancer.” The PubMed database
was chosen because it remains the most widely used resource for medical
Unfortunately, large inequities exist in incidence of and mortality from literature and indexes peer-reviewed biomedical literature.13
prostate cancer across racial and ethnic groups. The incidence rate in
Black individuals is 67% higher than in white individuals, with prostate The search results were narrowed by selecting studies in humans
cancer accounting for 44% of cancer diagnoses in Black men and a 1 in 6 published in English. Results were confined to the following article types:
lifetime risk of a prostate cancer diagnosis.11 Black individuals are also Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Practice
more likely to be diagnosed with more aggressive disease and are less Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic

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Reviews; and Validation Studies. The data from key PubMed articles as [Link]). Definitive diagnosis requires biopsies of the prostate,
well as articles from additional sources deemed as relevant to these usually performed by a urologist using a needle under transrectal
Guidelines as discussed by the Panel during the Guidelines update have ultrasound (TRUS) guidance. A pathologist assigns a Gleason primary
been included in this version of the Discussion section. Recommendations and secondary grade to the biopsy specimen. Clinical staging is based on
for which high-level evidence is lacking are based on the Panel’s review of the TNM (tumor, node, metastasis) classification from the AJCC Staging
lower-level evidence and expert opinion. Manual, Eighth Edition.15 NCCN treatment recommendations are based on
risk stratification that includes TNM staging rather than on AJCC
Sensitive/Inclusive Language Usage prognostic grouping.
NCCN Guidelines strive to use language that advances the goals of
equity, inclusion, and representation.14 NCCN Guidelines endeavor to use Pathology synoptic reports (protocols) are useful for reporting results from
language that is person-first; not stigmatizing; anti-racist, anti-classist, anti- examinations of surgical specimens; these reports assist pathologists in
misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive providing clinically useful and relevant information. The NCCN Guidelines
of individuals of all sexual orientations and gender identities. NCCN Panel favors pathology synoptic reports from the College of American
Guidelines incorporate non-gendered language, instead focusing on Pathologists (CAP) that comply with the Commission on Cancer (CoC)
organ-specific recommendations. This language is both more accurate requirements.16
and more inclusive and can help fully address the needs of individuals of
Estimates of Life Expectancy
all sexual orientations and gender identities. NCCN Guidelines will
continue to use the terms men, women, female, and male when citing Estimates of life expectancy have emerged as a key determinant of
statistics, recommendations, or data from organizations or sources that do primary treatment, particularly when considering observation. Life
not use inclusive terms. Most studies do not report how sex and gender expectancy can be estimated for groups of individuals, but it is difficult to
data are collected and use these terms interchangeably or inconsistently. extrapolate these estimates to an individual patient. Life expectancy can
If sources do not differentiate gender from sex assigned at birth or organs be estimated using the Social Security Administration Life Insurance
present, the information is presumed to predominantly represent cisgender Tables,17 the Memorial Sloan Kettering Male Life Expectancy tool,18 or the
individuals. NCCN encourages researchers to collect more specific data in University of California San Francisco (UCSF) Lee Schonberg Index19 and
future studies and organizations to use more inclusive and accurate adjusted for individual patients by adding or subtracting 50% based on
language in their future analyses. whether one believes the patient is in the healthiest quartile or the
unhealthiest quartile, respectively.20 As an example, the Social Security
Initial Prostate Cancer Diagnosis Administration Life Expectancy for a 65-year-old American male is 17.5
Initial suspicion of prostate cancer is based on an abnormal digital rectal years. If judged to be in the upper quartile of health, a life expectancy of
exam (DRE) or an elevated PSA level. A separate NCCN Guidelines 26.3 years is assigned. If judged to be in the lower quartile of health, a life
Panel has written guidelines for prostate cancer early detection (see the expectancy of 8.8 years is assigned. Thus, treatment recommendations
NCCN Guidelines for Prostate Early Detection, available at could change dramatically using the NCCN Guidelines if a 65-year-old

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patient was assessed to be in excellent health or if their health is in Prostate Cancer Genetics
decline. Family history of prostate cancer raises the risk of prostate cancer.31-34 In
addition, prostate cancer has been associated with hereditary breast and
Quality-of-Life and Shared Decision-Making
ovarian cancer (HBOC) syndrome (due to germline mutations in
Patient quality of life (QOL, also referred to as health-related quality of life homologous DNA repair genes) and Lynch syndrome (resulting from
[HRQOL]) should be taken into consideration when discussing and germline mutations in DNA mismatch repair [MMR] genes).34-39 In fact,
deciding upon management strategies for all types of cancer. In regards to approximately 11% of patients with prostate cancer and at least 1
prostate cancer, addressing QOL is especially important due to early additional primary cancer carry germline mutations associated with
detection and increased survival rates.21 The management of localized increased cancer risk.40 Therefore, the Panel recommends a thorough
prostate cancer can have risks and side effects related to radiation, review of personal and family history for all patients with prostate cancer at
surgery, and hormone therapy—including functional effects on urinary, the time of initial diagnosis.41,42
bowel, and sex organs.22-27 Some side effects have been linked to lasting
psychological effects; for example an association has been shown The presence of germline mutations has implications for family genetic
between erectile dysfunction and depressive symptoms.28,29 Additionally, counseling, cancer risk syndromes, and assessment of personal risk for
the use of androgen deprivation therapy (ADT) is associated with 23% subsequent cancers. Some patients with prostate cancer and their families
higher rates of depression compared to patients who did not receive may be at increased risk for breast and ovarian cancer, melanoma, and
ADT.29 Use of a standardized patient-reported outcomes instrument, such pancreatic cancer (HBOC); colorectal cancers (Lynch syndrome); and
as the abbreviated Expanded Prostate Cancer Index Composite (EPIC- other cancer types. While DNA repair defects carry a worse prognosis for
26), can aid in the assessment of baseline urinary, bowel, and sexual those with metastatic prostate cancer, it does not appear to be prognostic
function and serve as a basis for shared-decision making.21 in localized disease.43 Finally, there are possible treatment implications for
patients with DNA repair defects with advanced disease (see Treatment
Shared decision-making should be collaborative and informative. This Options for Patients with DNA Repair Gene Mutations, below).
approach is especially applicable when multiple treatment options are
considered clinically acceptable and when some treatment options have Prostate cancer is often associated with somatic mutations that occur in
greater potential for adverse effects on QOL than others. When patients the tumor but not in the germline. Both germline and tumor mutations are
have actively participated in making decisions about their medical care, discussed herein.
they generally report that they feel empowered, have better rates of
adherence to the medical plan, and are less likely to display regrets about Homologous DNA Repair Genes
the decisions that were made.30 When shared-decision making is utilized, Somatic mutations in DNA repair pathway genes occur in up to 19% of
patients can make informed decisions with more realistic expectations and localized prostate tumors and 23% of metastatic CRPC (mCRPC) tumors,
greater satisfaction over the long term. with most mutations found in BRCA2 and ATM.44,45 These tumor mutations
are often associated with germline mutations. For example, 42% of

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patients with mCRPC and somatic mutations in BRCA2 were found to germline mutations in BRCA1 and BRCA2, compared with 1.9% of control
carry the mutation in their germlines.44 In localized prostate cancer, that Ashkenazi Jewish males.56
number was 60%.45
Germline BRCA1 or BRCA2 mutations have been associated with an
Overall, germline DNA repair mutations have been reported with the increased risk for prostate cancer in numerous reports.38,39,56-66 In
lowest frequencies seen in patients with lower-risk localized prostate particular, BRCA2 mutations have been associated with a 2- to 6-fold
cancer (1.6%–3.8%), higher frequencies in those with higher-risk localized increase in the risk for prostate cancer, whereas the association of BRCA1
disease (6%–8.9%), and the highest frequencies in those with metastatic mutations and increased risks for prostate cancer are less
disease (7.3%–16.2%).44,46-52 One study found that 11.8% of patients with consistent.38,39,56,58,60,65,67,68 In addition, limited data suggest that germline
metastatic prostate cancer have germline mutations in 1 of 16 DNA repair mutations in ATM, PALB2, and CHEK2 increase the risk of prostate
genes: BRCA2 (5.3%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), cancer.69-72 Furthermore, prostate cancer in individuals with germline
RAD51D (0.4%), PALB2 (0.4%), ATR (0.3%), and NBN, PMS2, GEN1, BRCA mutations (BRCAm) appears to occur earlier, and in patients with
MSH2, MSH6, RAD51C, MRE11A, BRIP1, or FAM175A.51 metastatic prostate cancer, has a more aggressive phenotype, and is
associated with significantly reduced survival times than in patients without
An additional study showed that 9 of 125 patients with high-risk, very-high- these mutations.43,67,73-79
risk, or metastatic prostate cancer (7.2%) had pathogenic germline
mutations in MUTYH (4), ATM (2), BRCA1 (1), BRCA2 (1), and BRIP1 DNA Mismatch Repair Genes
(1).48 In this study, the rate of metastatic disease among those with a Tumor mutations in MLH1, MSH2, MSH6, and PMS2 may result in tumor
mutation identified was high (28.6%, 2 of 7 patients). Although having a microsatellite instability (MSI) and deficient MMR (dMMR; detected by
relative with breast cancer was associated with germline mutation immunohistochemistry) and are sometimes associated with germline
identification (P = .035), only 45.5% of the mutation carriers in the study mutations and Lynch syndrome. Patients with Lynch syndrome may have
had mutations that were concordant with their personal and family history. an increased risk for prostate cancer. In particular, studies show an
Another study also found that a family history of breast cancer increased increased risk for prostate cancer in patients who are older and have
the chances of identifying a germline DNA repair gene mutation in patients germline MSH2 mutations.80,81
with prostate cancer (OR, 1.89; 95% CI, 1.33–2.68; P = .003).53 In a study
of an unselected cohort of 3607 patients with a personal history of prostate In a study of >15,000 patients with cancer treated at Memorial Sloan
cancer who had germline genetic testing based on clinician referral, 11.5% Kettering Cancer Center who had their tumor and matched normal DNA
had germline mutations in BRCA2, CHEK2, ATM, BRCA1, or PALB2.54 sequenced and tumor MSI status assessed, approximately 5% of 1048
patients with prostate cancer had MSI-high (MSI-H) or MSI-indeterminate
More than 2% of Ashkenazi Jews carry germline mutations in BRCA1 or tumors, 5.6% of whom were found to have Lynch syndrome (0.29% of
BRCA2, and these carriers have a 16% chance (95% CI, 4%–30%) of patients with prostate cancer).35 In another prospective case series, the
developing prostate cancer by the age of 70.55 In a study of 251 tumors of 3.1% of 1033 patients with prostate cancer demonstrated MSI-
unselected Ashkenazi Jewish patients with prostate cancer, 5.2% had

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H/dMMR status, and 21.9% of these patients had Lynch syndrome (0.68% Genetic Testing Recommendations
of the total population).82 In a study of an unselected cohort of 3607 Germline Testing Based on Family History, Histology, and Risk Groups
patients with a personal history of prostate cancer who had germline The Panel recommends inquiring about family and personal history of
genetic testing based on clinician referral, 1.7% had germline mutations in cancer and known germline variants at time of initial diagnosis. Germline
PMS2, MLH1, MSH2, or MSH6.54 testing should be considered in appropriate individuals where it is likely to
impact the prostate cancer treatment and clinical trial options,
Effect of Intraductal/Cribriform or Ductal Histology
management of risk of other cancers, and/or potential risk of cancer in
Ductal prostate carcinomas are rare, accounting for approximately 1.3% of family members. Criteria for germline testing from the following NCCN
prostate carcinomas.83 Intraductal prostate cancer may be more common, Guidelines (available at [Link]) should be reviewed at time of
especially in higher risk groups, and may be associated with a poor initial diagnosis and, if relevant, at recurrence:
prognosis.84 It is important to note that there is significant overlap in • The NCCN Guidelines for Genetic/Familial High-Risk Assessment:
diagnostic criteria and that intraductal, ductal, and invasive cribriform Breast, Ovarian, Pancreatic, and Prostate (page CRIT-6)
features may coexist in the same biopsy. By definition, intraductal • The NCCN Guidelines for Genetic/Familial High-Risk Assessment:
carcinoma includes cribriform proliferation of malignant cells as long as Colorectal, Endometrial, and Gastric (page HRS-3).
they remain confined to a preexisting gland that is surrounded by basal
cells. These features are seen frequently with an adjacent invasive If criteria are met, multigene testing is recommended (see GENE-1 in the
cribriform component and would be missed without the use of basal cell NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,
markers. Ovarian, Pancreatic, and Prostate).
Limited data suggest that acinar prostate adenocarcinoma with invasive Genetic counseling resources and support are critical, and post-test
cribriform pattern, intraductal carcinoma of prostate (IDC-P), or ductal genetic counseling is recommended if a germline mutation
adenocarcinoma component have increased genomic instability.85-88 In (pathogenic/likely pathogenic variant) is identified. Cascade testing for
particular, tumors with these histologies may be more likely to harbor relatives is critical to inform the risk for familial cancers in all relatives.
somatic MMR gene alterations than those with adenocarcinoma Post-test genetic counseling is recommended if there is a positive family
histology.88-90 In addition, limited data suggest that germline homologous history but no pathogenic variant OR if only germline variants of uncertain
DNA repair gene mutations may be more common in prostate tumors of significance (VUS) are identified. This is to ensure accurate understanding
ductal or intraductal origin91,92 and that intraductal histology is common in of family implications and review indications for additional testing and/or
germline BRCA2 mutation carriers with prostate cancer.93 Overall, the follow up (including clinical trials of reclassification). Resources are
Panel believes that the data connecting histology and the presence of available to check the known pathologic effects of genomic variants (eg,
genomic alterations are stronger for intraductal than ductal histology at this [Link] [Link]
time. Information regarding germline mutations in patients with metastatic

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disease can be used to inform future treatments or to determine eligibility MLH1, MSH2, MSH6, PMS2). Virtually none of the NGS tests is designed
for clinical trials. or validated for germline assessment. Therefore, over-interpretation of
germline findings should be avoided. If a germline mutation is suspected,
Somatic Tumor Testing Based on Risk Groups
the patient should be recommended for genetic counseling and follow-up
Tumor testing recommendations are as follows: dedicated germline testing.
1. Tumor testing for somatic homologous recombination gene
mutations (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, Inequities Based on Race and Ethnicity
CHEK2, CDK12) can be considered in patients with regional (N1) A CDC analysis of population-based cancer registries found that the
prostate cancer and is recommended for those with metastatic
incidence of prostate cancer was 67% higher in Black individuals than in
disease. white individuals in the United States.11 Data also show that Black
2. Tumor testing for MSI-H or dMMR can be considered in patients Americans are more likely to be diagnosed with more advanced disease
with regional or metastatic castration-sensitive prostate cancer and less likely to receive PSA screening.11,98-101 Furthermore, the mortality
(CSPC) and is recommended in the mCRPC setting. rate from prostate cancer in the Black American population is two to four
3. Tumor mutational burden (TMB) testing is recommended in
times higher than all other racial and ethnic groups.1,11 Moreover, Black
patients with mCRPC. American patients with low-risk or favorable intermediate-risk prostate
cancer have an increase in all-cause mortality after treatment, potentially
The Panel strongly recommends a metastatic biopsy for histologic and due to cardiovascular complications after ADT.102
molecular evaluation. When unsafe or unfeasible, plasma ctDNA assay is
an option, preferably collected during biochemical (PSA) and/or Significant inequities also exist for other racial and ethnic groups. For
radiographic progression in order to maximize diagnostic yield. Caution is example, Hispanic patients are more likely than non-Hispanic white
needed when interpreting ctDNA-only evaluation due to potential patients to present with higher risk localized or metastatic prostate
interference from clonal hematopoiesis of indeterminate potential (CHIP), cancer.103,104 Furthermore, Hispanic individuals are less likely than non-
which can result in a false-positive biomarker signal.94 Hispanic white individuals to receive treatment and more likely to
experience treatment delays.103,104 Similarly, Asian American, Native
If MSI testing is performed, testing using an NGS assay validated for
Hawaiian, and Pacific Islander individuals are more likely to be diagnosed
prostate cancer is preferred.95-97 If MSI-H or dMMR is found, the patient
at a higher risk group than white individuals.105
should be referred for genetic counseling to assess for the possibility of
Lynch syndrome. MSI-H or dMMR indicate eligibility for pembrolizumab for The main drivers for these racial and ethnic inequities are lower rates of
patients with mCRPC (see Pembrolizumab, below). prostate cancer screening, diagnostic procedures, and overall access to
health care; treatment disparities; inadequate health insurance coverage;
Post-test genetic counseling is also recommended if pathogenic/likely and other factors related to social determinants of health (eg,
pathogenic somatic mutations in any gene that has clinical implications are environmental exposures, patient and physician behaviors, delays in
also identified in germline (eg, BRCA1, BRCA2, ATM, PALB2, CHEK2,

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diagnosis).98,100,106-112 For example, an analysis of SEER data from 2004 to NCCN Risk Groups
2011 determined that Black and Hispanic individuals had a decreased The NCCN Guidelines have, for many years, incorporated a risk
likelihood of receiving treatment than white individuals even when stratification scheme that uses a minimum of stage, Gleason grade, and
diagnosed with high-risk disease.113 Importantly, data show that Black PSA to assign patients to risk groups. Risk group stratification has been
patients who receive equitable prostate cancer treatment have similar published widely and validated, and provides a better basis for treatment
outcomes to white patients.12,114-116 recommendations than clinical stage alone.120-122

Risk Stratification for Clinically Localized Disease Prostate cancer grading continues to evolve. The grading system was
Unlike in some cancers where treatments for early-stage disease are updated during the 2014 International Society of Urological Pathology
guided by predictive biomarkers, such as ER/PR or HER2 status in breast (ISUP) Consensus Conference.123 Several changes were made to the
cancer, in localized prostate cancer treatment is based largely on risk assignment of Gleason pattern based on pathology. The new system
stratification of prognosis. assigns Grade Groups from 1 to 5, derived from the Gleason score.
• Grade Group 1: Gleason score ≤6; only individual discrete well-
NCCN and other risk classification schemas, such as CARPA117 or STAR- formed glands
CAP,118 are prognostic and have not been shown to be predictive of • Grade Group 2: Gleason score 3+4=7; predominantly well-formed
benefit to a specific treatment. Thus, common decision points, such as glands with lesser component of poorly formed/fused/cribriform
conservative management versus radical therapy, radiotherapy alone glands
versus the addition of short-term ADT, the use of radiotherapy with short- • Grade Group 3: Gleason score 4+3=7; predominantly poorly
term versus long-term ADT, or the addition of abiraterone formed/fused/cribriform glands with lesser component of well-
acetate/prednisone to radiotherapy plus long-term ADT are based on formed glands
clinical trial inclusion criteria, expert opinion, and estimates of absolute o For cases with >95% poorly formed/fused/cribriform glands
benefit and harm from a given therapy in the context of NCCN risk groups. or lack of glands on a core or at radical prostatectomy, the
There are newer risk classification schemas that have been shown to component of <5% well-formed glands is not factored into
the grade.
outperform NCCN risk groups,118,119 as well as tools (ie, imaging, gene
expression biomarkers) that together improve risk stratification. These • Grade Group 4: Gleason score 4+4=8; 3+5=8; 5+3=8
tools should not be ordered reflexively. They are recommended only when o Only poorly formed/fused/cribriform glands; or
they will have the ability to change management. Improved risk o Predominantly well-formed glands and lesser component
stratification can better identify patients who may derive greater or lesser lacking glands (poorly formed/fused/cribriform glands can
absolute benefit from a given treatment. be a more minor component); or
o Predominantly lacking glands and lesser component of
well-formed glands (poorly formed/fused/cribriform glands
can be a more minor component)

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• Grade Group 5: Gleason score 9–10; lack gland formation (or with
necrosis) with or without poorly formed/fused/cribriform glands The NCCN Guidelines Panel recognized that heterogeneity exists within
o For cases with >95% poorly formed/fused/cribriform glands each risk group.118 For example, an analysis of 12,821 patients showed
or lack of glands on a core or at radical prostatectomy, the that those assigned to the intermediate-risk group by clinical stage (T2b–
component of <5% well-formed glands is not factored into T2c) had a lower risk of recurrence than those categorized according to
the grade. Gleason score (7) or PSA level (10–20 ng/mL).133 A similar trend of
superior recurrence-free survival was observed in patients placed in the
The new Grade Group system was initially validated in two separate high-risk group by clinical stage (T3a) compared to those assigned by
cohorts of patients treated for prostate cancer with either radical Gleason score (8–10) or PSA level (>20 ng/mL), although it did not reach
prostatectomy or radiation: one with >26,000 patients and one with 5880 statistical significance. Other studies have reported differences in
patients.124,125 Both studies found that Grade Groups predicted the risk of outcomes in the high-risk group depending on risk factors or primary
recurrence after primary treatment with modest discrimination. For Gleason pattern.134,135 Evidence also shows heterogeneity in the low-risk
instance, in the larger study, the 5-year biochemical recurrence-free group, with PSA levels and percent positive cores affecting pathologic
progression probabilities after radical prostatectomy for Grade Groups 1 findings after radical prostatectomy.136,137
through 5 were 96% (95% CI, 95–96), 88% (95% CI, 85–89), 63% (95%
CI, 61–65), 48% (95% CI, 44–52), and 26% (95% CI, 23–30), respectively. In a retrospective study, 1024 patients with intermediate-risk prostate
The separation between Grade Groups was less pronounced in the cancer were treated with radiation with or without neoadjuvant and
radiation therapy (RT) cohort, likely because of increased use of ADT in concurrent ADT.138 Multivariate analysis revealed that primary Gleason
the higher risk groups. In another study of the new ISUP Grade Group pattern 4, number of positive biopsy cores ≥50%, and presence of >1
system, all-cause mortality and prostate cancer-specific mortality were intermediate-risk factors (IRFs; ie, T2b-c, PSA 10–20 ng/mL, Gleason
higher in patients in Grade Group 5 than in those in Grade Group 4.126 score 7) were significant predictors of increased incidence of distant
Additional studies have supported the validity of this new system.127-132 metastasis. The authors used these factors to separate the patients into
unfavorable and favorable intermediate-risk groups and determined that
The NCCN Panel has accepted the Grade Group system to inform better the unfavorable intermediate-risk group had worse PSA recurrence-free
treatment discussions compared to those using Gleason score. Patients survival and higher rates of distant metastasis and prostate cancer-
remain divided into low-, intermediate-, high-, and very-high-risk groups. If specific mortality than the favorable intermediate-risk group. The use of
a patient meets the criteria for intermediate risk, they are then further risk active surveillance in patients with favorable intermediate-risk prostate
stratified into favorable and unfavorable subsets based on the number of cancer is discussed below (see Active Surveillance in Favorable
intermediate risk factors, grade group, and the percentage of positive Intermediate Risk). The NCCN Panel has included the separation of the
biopsy cores, as delineated in the algorithm above. intermediate risk group into favorable and unfavorable subsets in their risk
stratification scheme.

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Advanced Risk Stratification Tools

Nomograms
The Panel strongly advocates the maximum utilization of all routine
A nomogram is a predictive instrument that takes a set of input data
clinical, pathologic, and patient information to risk stratify patients. This
(variables) and makes predictions about an outcome. Nomograms may
includes the information that forms the basis of the NCCN risk groups, as
potentially predict more accurately for the individual patient than risk
well as other routine information that can be derived from standard tests,
groups, because they utilize granular prognostic variables. The Partin
such as PSA density, PSA velocity, percentage or absolute pattern 4, and
tables are an early example of a nomogram for patients with clinically
intraductal and cribriform architecture. Other tools have been developed
localized prostate cancer.139-142 The tables give the probability (95% CI)
that, variably, have been shown to be superior to standard clinical tools at
that a patient with a certain clinical stage, Gleason score, and PSA will
estimating prognosis, and these are referred to as advanced risk
have a cancer of each pathologic stage. Nomograms can be used to
stratification tools. These currently include multigene expression tests and
inform treatment decision-making for patients contemplating active
digital pathology-based artificial intelligence tests, as discussed in more
surveillance,143-145 radical prostatectomy,146-149 neurovascular bundle
detail below.
preservation150-152 or omission of pelvic lymph node dissection (PLND)
during radical prostatectomy,153-156 brachytherapy,146,157-159 or external These advanced risk stratification tools should only be considered when
beam RT (EBRT).146,160 Biochemical progression-free survival (PFS) can they have the potential ability to change disease management; they
be reassessed postoperatively using age, diagnostic serum PSA, and should not be ordered reflexively. Importantly, the Panel notes that there
pathologic grade and stage.146,161-163 Potential success of adjuvant or post- are risks to using tools that lack robust validation to change management
recurrence RT after unsuccessful radical prostatectomy can be assessed decisions, as they may drive patients or providers to choose inappropriate
using a nomogram.146,164 options. For example, in one trial, 200 patients with very low to favorable-
intermediate risk prostate cancer (excluding those with grade group 2 and
None of the current models predicts with perfect accuracy, and only some
>3 positive cores and limiting inclusion of those with PSA 10–20 ng/mL to
of these models predict metastasis145,146,161,165,166 and cancer-specific
only those with PSA density <0.15) were randomized to standard
death.147,149,167-169 Given the competing causes of mortality, many patients
counseling with or without the 17-gene genomic prostate score (GPS)
who sustain PSA recurrence will not live long enough to develop clinical
assay.171 Patients with lower health literacy who received the GPS test
evidence of distant metastases or to die from prostate cancer. Not all PSA
were 7-fold less likely to choose active surveillance compared to controls.
recurrences are clinically relevant; thus, PSADT may be a more useful
Therefore, if advanced tools are used, the Panel recommends only tools
measure of risk of death.170 The NCCN Guidelines Panel recommends
that have high-quality, long-term clinical trial data, ideally across multiple
that NCCN risk groups be used to begin the discussion of options for the
clinical trials.
treatment of clinically localized prostate cancer and that nomograms be
used to provide additional and more individualized information. Currently, the Panel recommends using tests with high-quality,
prospective validation. For predictive tools, ideally this validation is from
dedicated prospective biomarker-focused trials (eg, NRG GU006).

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Alternatively, this can be from post-hoc assessment of the biomarker in signatures via creation of derived signatures for each test, and the
completed prospective trials, ideally multiple such trials. For prognostic correlation between the signatures was poor (R2, 0.32–0.36).176
tools, the Panel generally recommends the use of prognostic tests that are
validated in well-designed prospective studies with clinically meaningful While multiple gene expression tests have made claims to improve the
endpoints based on disease settings that guide a specific treatment safety and/or efficacy of active surveillance, such an improvement has not
indication based on a specific score or result. These studies can be either been born out in prospective studies. For example, evaluation of
prospective integral or integrated clinical trial(s) (eg, NRG GU009, NRG diagnostic biopsy tissue from patients enrolled in the Canary PASS
GU010) or post-hoc correlative analyses of prospective trials. multicenter active surveillance cohort suggested that results of a molecular
assay were not associated with adverse pathology in combination with
Tumor Multigene Expression Testing clinical variables nor was there an association with upgrading in
Gene testing of a tumor offers the potential of added insight into the surveillance biopsies.177 While this study utilized GPS, no other gene
biologic behavior of a cancer that could thereby aid in clinical decision- expression or digital pathology-based tool has positive prospective
making. validation in this setting.

Several tissue-based molecular assays have been developed to improve Currently, the above-mentioned validation criteria for prognostic biomarker
risk stratification. The 22-gene genomic classifier (GC; Decipher) is tests has been reached by the 22-gene GC prognostic assay, which has
discussed in more detail in the Principles of Risk Stratification in the reported outcomes from multiple post-hoc analyses of randomized
algorithm above; others are discussed below. The training and trials.178-181 The relevant disease settings and more details for this tool are
development of each assay is distinct, the genes analyzed are unique, and available in the Principles of Risk Stratification in the algorithm above.
there is heterogeneity in the robustness of validation. It is important to There are multiple biomarker-directed randomized trials utilizing the 22-
understand that companies may make invalid or inaccurate claims about gene GC assay that have completed enrollment or are ongoing (eg, NRG
these tests, which can create confusion for patients and providers. GU006, 009, 010).
Furthermore, the resulting test score, such as low or high risk, may be
discordant between different tests due to multiple factors. Multiple retrospective studies suggest that the 17-gene GPS tool
(previously called Oncotype Dx) may be prognostic for patients with
It is clear that use of tissue-based molecular assays will often change localized prostate cancer.182,183 GPS was also studied in the prospective
decisions about disease management.172-175 However, what is unclear Canary PASS active surveillance cohort with post-hoc biomarker
from such studies is if the change in management improved patient analysis.177 GPS results were obtained from 432 patients, 101 of whom
outcomes or was appropriate. Furthermore, it is increasingly clear that underwent radical prostatectomy after an initial period of active
each assay should be evaluated independently because they do not surveillance. The authors concluded that adding GPS to a model
capture the same biology. For example, a study of over 50,000 patients containing PSA density and diagnostic grade group did not significantly
was performed to compare three commonly used gene expression improve adverse pathology stratification over the clinical variables alone
(HR, 1.17; 95% CI, 1.00–1.43; P = .066). Additionally, there was no

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association observed between GPS and subsequent biopsy upgrade (P = the benefit of short-term versus long-term ADT and validated in RTOG
0.48). Event rates and sample size may have impacted the results. 9202.191 Given the considerable changes in staging, grading, and
Additionally, as previously referenced, the GPS test was evaluated in a treatment since the start of RTOG 9202 and 9408 (>30 years ago), it is
randomized trial and demonstrated that it decreased the relative odds of unclear if the predictive models still work in contemporarily treated
choosing active surveillance by approximately 50% with variable statistical patients, and further validation is recommended by the Panel.
significance depending on analysis method (P = .029 when excluding
participants with inadequate biopsy specimens who did not receive a The relevant disease settings and more details for this tool are available in
planned GPS result; P = .067 for all patients in an intention-to-treat the Principles of Risk Stratification in the algorithm above.
analysis).171
Initial Clinical Assessment and Staging Evaluation
Similarly, multiple retrospective institutional and tumor registry studies For patients with a life expectancy of ≤5 years without clinical symptoms
suggest that the 31-gene cell cycle progression test (CCP; Prolaris) may who have low- and intermediate-risk prostate cancer, further imaging and
have prognostic value for patients with localized prostate cancer.184-186 No treatment should be delayed until symptoms develop, at which time
prospective trials have been published to date. imaging can be performed and ADT should be given. Those with a life
expectancy ≤5 years who fall into the high- or very-high-risk groups should
Numerous other tests have been developed with variable evidence quality undergo bone imaging and, if indicated by nomogram prediction of lymph
that are currently outside of the Discussion presented here. node involvement, pelvic +/- abdominal imaging.
Digital Pathology-Based Tools
For symptomatic patients and those with unfavorable intermediate-risk,
More recently a new class of advanced risk stratification tool has been high-risk, and very-high-risk prostate cancer and a life expectancy of >5
developed that utilizes artificial intelligence (AI) to analyze digital years, bone and soft tissue imaging is appropriate:
pathology slides from a patient’s prostate biopsy or prostatectomy
• PSMA-PET/CT or PSMA-PET/MRI can be considered for bone and
specimen. Analogous to the multigene prognostic assays, these tools are
soft tissue (full body) imaging.
primarily focused to improve risk stratification. The multimodal AI (MMAI)
o Because of the increased sensitivity and specificity of
test (ArteraAI Prostate) is one such test, which gained FDA approval in
PSMA-PET tracers for detecting micrometastatic disease
July 2025. The MMAI test was validated in multiple post-hoc analyses of
compared to CT, MRI, and bone scan at both initial staging
completed randomized trials.187-189
and biochemical recurrence, PSMA-PET/CT or PSMA-
The MMAI test also has developed a potential predictive model to guide PET/MRI can serve as a more effective front-line imaging
the use of short-term ADT. The predictive model was validated in RTOG tool for these patients.
9408, a randomized trial of low-dose radiotherapy with or without 4 months • Bone imaging can be achieved by conventional technetium-99m-
of ADT, and was shown to identify patients more likely to benefit from MDP bone scan.
ADT.190 A similar, but unique model also was developed that may predict

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oPlain films, CT, MRI, PSMA-PET/CT or PSMA PET/MRI, or TRUS), where MRI datasets containing information on suspicious lesions
PET/CT or PET/MRI with F-18 sodium fluoride, C-11 identified by the radiologist are used by the urologist to navigate
choline, F-18 fluciclovine can be considered for equivocal ultrasound-guided biopsies of the prostate for more accurate diagnosis.192
results on initial bone imaging. More details on each technique are outlined in the algorithm under
• Soft tissue imaging of the pelvis, abdomen, and chest can include Principles of Imaging, above.
chest CT and abdominal/pelvic CT or abdominal/pelvic MRI.
Multiparametric MRI (mpMRI) is preferred over CT for pelvic Multiparametric MRI (mpMRI)
staging. The use of mpMRI in the staging and characterization of prostate cancer
has increased in the last few years. mpMRI examinations typically include
mpMRI may detect larger and clinically significant prostate cancer (Grade three sequences: T2-weighted imaging, DWI, and dynamic contrast
Group ≥2), extracapsular extension, and seminal vesicle invasion (T enhancement (DCE) imaging. There has been increased interest in
staging) and is preferred over CT for abdominal/pelvic staging. mpMRI has biparametric imaging that excludes the use of gadolinium contrast in
been shown to be equivalent to CT scan for pelvic lymph node evaluation. prostate MRI examinations; however, more data are needed to identify the
risk groups who would benefit most from this approach.193 In general, it is
See Imaging Techniques below for a more detailed discussion.
recommended that mpMRI be performed on a 3 Tesla (3T) magnetic
Imaging Techniques strength MRI scanner. This is the highest strength scanner in routine
clinical use and provides the best possible evaluation of prostate cancer.
Imaging techniques are useful for staging and for detecting metastases
and tumor recurrence. Current clinical imaging techniques for prostate Additional instrumentation can be used, such as an endorectal coil (ERC)
cancer include conventional radiography (ie, x-rays), ultrasound, CT, MRI, to improve image quality. If a lower strength (eg, 1.5T) MRI is required for
single photon emission computed tomography (SPECT, scintigraphy), and a patient because of indwelling medical device incompatibility with 3T MRI,
PET. Some of these modalities have the ability to assess both anatomy an ERC is recommended. Use of ERC in routine prostate imaging is
and tumor function/biology. For example, functional MR sequences can be controversial. Current data suggest that a 3T exam with ERC may not be
added to conventional anatomic MR sequences in a clinical examination significantly better than a 3T exam without ERC. Moreover, there may not
such as diffusion-weighted imaging (DWI) to assess tumor cellularity or be a significant difference in image interpretation between a 1.5T with
MR spectroscopy (MRS) to assess tumor metabolism. ERC and 3T without ERC.194 The use of ERC in prostate MRI also
introduces new problems into the clinical workflow including patient
Different modalities can also be merged to maximize prostate cancer
discomfort, prostate distortion, increased scanner time and expense, and
assessment. For example, the functional information obtained with PET
requirement of someone experienced to place the ERC.
can be combined with the spatial and anatomic information from either CT
(ie, PET/CT) or MRI (ie, PET/MRI) to inform about the locations of tumor Evidence supports the implementation of mpMRI in several aspects of
foci for diagnosis or therapy response. Another example of the advantage prostate cancer management.192 First, mpMRI helps detect larger and/or
of combining modalities is MR-ultrasound fusion guided biopsy (eg, MR-
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more clinically significant cancers (ie, Grade Group ≥2).195 mpMRI has Imaging above summarizes the FDA-cleared PET imaging tracers studied
been incorporated into MRI-TRUS fusion-targeted biopsy protocols, which in prostate cancer.
has led to an increase in the diagnosis of high-grade cancers with fewer
biopsy cores, while reducing detection of low-grade and insignificant PSMA-PET refers to a growing body of radiopharmaceuticals that target
cancers.196-198 In fact, a recently published clinical study identified that prostate specific membrane antigen (PSMA) on the surface of prostate
MRI-targeted biopsy synergized with conventional systematic biopsy to cells. Because of the high density of PSMA receptors on the surface of
identify more clinically significant cancers.199 Second, mpMRI aids in better cancer cells relative to adjacent prostate, PSMA-PET has the advantage
assessment of extracapsular extension (T staging), with high negative of high signal-to-noise relative to adjacent tissues. The mechanistic role of
predictive values (NPVs) in patients with low-risk disease.200 mpMRI androgen receptor signaling in PSMA regulation is still being investigated,
results may inform decision-making regarding nerve-sparing operation.201 as multiple reports in animals and humans suggest that androgen
Third, mpMRI is equivalent to CT scan for staging of pelvic lymph modulation can affect PSMA expression and may even be dichotomous in
nodes.202,203 Finally, mpMRI outperforms bone scan and targeted x-rays patients with castration-sensitive versus castrate-resistant disease.205-207
for detection of bone metastases, with a sensitivity of 98% to 100% and There are multiple PSMA radiopharmaceuticals at various stages of
specificity of 98% to 100% (vs. sensitivity of 86% and specificity of 98%– investigation. At this time, the NCCN Guidelines only recommend the
100% for bone scan plus targeted x-rays).204 currently FDA-approved PSMA tracers: F-18 piflufolastat, F-18
flotufolastat, and Ga-68 PSMA-11. PSMA-PET/CT or PSMA-PET/MRI can
PET Imaging be considered as an alternative to standard imaging of bone and soft
The use of PET/CT or PET/MRI imaging using tracers other than F-18 tissue for initial staging, the detection of biochemically recurrent disease,
fluorodeoxyglucose (FDG) for staging of small-volume recurrent or and as workup for progression with bone scan plus CT or MRI for the
metastatic prostate cancer has rapidly expanded in recent years.192 evaluation of bone, pelvis, and abdomen.
Currently, there are several PET tracers that are FDA approved for use in
Studies suggest that PSMA-PET imaging has a higher sensitivity than C-
patients with prostate cancer: Ga-68 PSMA-11 (PSMA-HBED-CC), F-18
11 choline or F-18 fluciclovine PET imaging, especially at very low PSA
piflufolastat (DCFPyL), F-18 flotufolastat PSMA (rh-PSMA-7.3), C-11
levels.208-215 The reported sensitivity and specificity for PSMA-11 PET/CT
choline, F-18 fluciclovine, and F-18 sodium fluoride. Although these
in the detection of nodal involvement in primary staging of patients with
tracers are approved for the evaluation of patients with biochemical
intermediate-, high-, and very-high-risk disease is 40% and 95%,
recurrence, the PSMA tracers are also approved for patients at initial
respectively.216 The patient-level positive predictive value (PPV) in
staging with suspected metastatic disease. Tracer distribution in patients
detection of lesions in patients with biochemical recurrence (BCR) is
with prostate cancer can be imaged with either PET/CT or PET/MRI
92%.217 Similarly, the reported sensitivity and specificity for piflufolastat
modalities. Although CT and MRI are equivalent in the assessment of
PET/CT in the detection of nodal involvement in primary staging of
lymphadenopathy, PET/MRI has the added advantage over PET/CT with
patients with unfavorable intermediate-, high-, and very-high-risk disease
enhanced tissue contrast that is especially important in evaluation of pelvic
are 31% to 42% and 96% to 99%, respectively.218,219 The patient-level
anatomy and prostate cancer assessment. Table 1 in the Principles of

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correct localization rate (CLR; patient-level PPV validated by anatomic change in disease management for 64% of patients.235 In addition, the
lesion co-localization) for piflufolastat PET/CT is 85% to 87%.220 Thus, LOCATE trial demonstrated that fluciclovine frequently changed disease
PSMA-11 and piflufolastat are considered equivalent. F-18 flotufolastat management plans for patients with biochemical recurrence.236 In a similar
PSMA is part of a novel class of tracers referred to as radiohybrid (rh) fashion, data also show that PSMA-PET has the ability to change radiation
ligands. These rh ligands have the unique advantage of offering two treatment planning in 53% (N = 45) of patients with high- and very-high-
binding sites for radionuclides (ie, F-18 or Ga-68), which increases its risk prostate cancer using PSMA-11 as well as change disease
flexibility in imaging. In addition, the presence of a chelator in these rh management in over half of a prospective cohort of 635 patients with
ligands also allows for chelation of Lu-177 for its use as a theranostic as BCR.237,238 However, whether changes to treatment planning because of
well as imaging agent. PET tracers have an impact on long-term survival remains to be studied.

Because of the increased sensitivity and specificity of PSMA-PET tracers The increasing use of PSMA-PET has identified the potential for
for detecting micrometastatic disease compared to CT, MRI, and bone considerable biological diversity among disease foci within a given
scan at both initial staging and biochemical recurrence, PSMA PET/CT or individual with prostate cancer, especially in the mCRPC setting. This
PSMA-PET/MRI can serve as a more effective front-line imaging tool for heterogeneity can be detected with a combination of PSMA-PET and
these patients. fluorodeoxyglucose (FDG)-PET. Initial data suggest that metastases with
PSMA-negative/FDG-positive mismatches may exist in patients with
PET/CT or PET/MRI detect small-volume disease in bone and soft mCRPC undergoing Lu-177-PSMA-617 radioligand therapy and that
tissues.221,222 The reported sensitivity and specificity of C-11 choline patients with these mismatches may have worse outcomes. To overcome
PET/CT in restaging patients with biochemical recurrence ranges from the limitations of PSMA-PET, the Panel currently recommends the use of
32% to 93% and from 40% to 93%, respectively.223-232 The reported MRI or a dedicated high resolution diagnostic contrast-enhanced CT in
sensitivity and specificity of F-18 fluciclovine PET/CT ranges from 37% to those with a negative PSMA-PET scan, because the non-contrast CT
90% and from 40% to 100%, respectively.229,233,234 A prospective study component of PSMA-PET/CT is insufficient to detect visceral metastatic
compared F-18 fluciclovine and C-11 choline PET/CT scans in 89 patients, disease, especially in the liver, due to its high physiological uptake.
and agreement was 85%.229 Thus, choline and fluciclovine are considered
equivalent in the evaluation of patients with biochemical recurrence. The F-18 sodium fluoride targets osteoblast activity where the fluoride is
Panel believes that F-18 fluciclovine PET/CT or PET/MRI or C-11 choline deposited into new bone formation, thus limiting use of this agent to the
PET/CT or PET/MRI may be used in patients with biochemical recurrence detection of osseous metastases. Fluoride PET/CT has greater sensitivity
after primary treatment for further soft tissue and/or bone evaluation after than standard bone scintigraphy in the detection of bone metastases, with
bone scan, chest CT, and abdominal/pelvic CT or abdominal/pelvic MRI. 77% to 94% sensitivity, 92% to 99% specificity, and 82% to 97% PPV.239
However, emerging evidence indicates that other tracers such as PSMA
The use of these PET tracers can lead to changes in clinical management. are at least equivalent to fluoride in the detection of osseous metastases
The FALCON trial showed that results of F-18 fluciclovine PET/CT in 104 with the added advantage of soft tissue metastasis detection.240
patients with biochemical recurrence after definitive therapy resulted in a

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Histologic or radiographic confirmation of involvement detected by PET imaging is always performed almost below the threshold for deterministic
imaging is recommended whenever feasible due to the presence of false effects. Stochastic effects tend to occur late, increase in likelihood as dose
positives. Although false positives exist, literature suggests that these are increases, and have no known lower “safe” limit. The major stochastic
outweighed by the increase in true positives detected by PET relative to effect of concern in medical imaging is radiation-induced malignancy.
bone scintigraphy. To reduce the false-positive rate, physicians should Unfortunately, no direct measurements are available to determine risk of
consider the intensity of PSMA-PET uptake and correlative CT findings in cancer arising from one or more medical imaging events, so risks are
the interpretation of scans. Several reporting systems have been proposed calculated using other models (such as from survivors of radiation
but have not been validated or widely used.241,242 Moreover, although PET exposure). The literature is conflicting about the precise risk of secondary
imaging may change treatment,236 it may not change oncologic outcome. malignancies in patients undergoing medical imaging procedures. There is
Earlier detection of bone metastatic disease, for instance, may result in a small but finite risk of developing secondary malignancies because of
earlier use of newer and more expensive therapies, which may not medical imaging procedures, and the risk is greatest in young patients.
improve oncologic outcomes or OS. However, the absolute risk of fatal malignancy arising from a medical
imaging procedure is very low and is difficult to detect given the
Risks of Imaging prevalence of cancer in the population and the multiple factors that
Medical imaging is a critical tool in the evaluation and comprehensive care contribute to oncogenesis.244 Efforts should be made to minimize dose
of patients with malignancy. However, as with any medical procedure, from these procedures, which begin with judicious use of imaging only
imaging is not without risk. Some of these risks are concrete and tangible, when justified by the clinical situation. Harm may arise from not imaging a
while others are less clear. Risks associated with imaging include patient, from disease non-detection or erroneous staging.
exposure to ionizing radiation, adverse reaction to contrast media, false-
positive scans, and overdetection. Inappropriate use of imaging also has Adverse Reaction to Contrast Media

been identified as a significant contributor to health care costs in the Many imaging studies use contrast material delivered by oral, intravenous,
United States and worldwide. Therefore, imaging should be performed or rectal routes. The use of contrast material may improve study
only when medically appropriate, and in a manner that reduces risk (eg, performance, but reactions to contrast material may occur and they should
minimizing radiation dose). An algorithmic approach to the use of imaging, therefore be used only when warranted. Some patients develop adverse
such as by NCCN and the Appropriateness Criteria developed by the reactions to iodinated intravenous contrast material. Most reactions are
American College of Radiology,243 can assist in medical decision-making. mild cutaneous reactions (eg, urticaria, pruritus) but occasionally severe
reactions can be life-threatening (bronchospasm or anaphylaxis). The risk
Exposure to Ionizing Radiation of severe reaction is low with non-ionic contrast materials.245 Both
Deterministic and stochastic are two types of effects from exposure to iodinated CT contrast material and gadolinium-based MR contrast
ionizing radiation by x-ray, CT, or PET/CT. Deterministic effects are those materials can be problematic in patients with reduced renal function.
that occur at a certain dose level and include events such as cataracts and Gadolinium MR contrast media, in particular, is contraindicated in patients
radiation burns. No effect is seen below the dose threshold. Medical with acute renal failure or stage V chronic kidney disease (glomerular

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NCCN Guidelines Version 4.2026

Prostate Cancer

filtration rate [GFR] <15).245 Patients in this category are significantly more surveillance biopsies) until symptoms develop or are thought to be
likely to develop nephrogenic systemic fibrosis (NSF). Centers performing imminent. If patients under observation become symptomatic, an
imaging studies with contrast materials should have policies in place to assessment of disease burden can be performed, and treatment or
address the use of contrast in these patients. palliation can be considered. Observation thus differs from active
surveillance. The goal of observation is to maintain quality of life (QOL) by
False-Positive Scans and Overdetection
avoiding noncurative treatment when prostate cancer is unlikely to cause
Every imaging test has limitations for sensitivity, specificity, and accuracy mortality or significant morbidity. The main advantage of observation is
that involve both the nature of the imaging modality as well as the avoidance of possible side effects of routine biopsies and unnecessary
interpretation by the physician. Harm can arise when a tumor or tumor definitive therapy or ADT. However, patients may develop urinary retention
recurrence is not detected (ie, false negative), but harm to the patient and or pathologic fracture without prior symptoms or increasing PSA level.
added expense to the medical system also can result from false-positive
scans. Extensive workup of imaging findings that may be benign or Observation is applicable to patients who are older or in declining health
indolent (ie, overdetection) can lead to significant patient anxiety, with comorbidity that are more likely than prostate cancer to be the cause
additional and unnecessary imaging, and invasive procedures that carry of death. Johansson and colleagues246 observed that only 13% of patients
their own risks for adverse outcomes. developed metastases 15 years after diagnosis of T0–T2 disease and only
11% had died from prostate cancer. Because prostate cancer will not be
Accurate and medically relevant interpretation of imaging studies requires treated for cure for patients with shorter life expectancies, observation for
familiarity and expertise in the imaging modality, attention to detail in as long as possible is a reasonable option based on physician discretion.
image review, knowledge of tumor biology, and familiarity with treatment When symptoms develop or are imminent, patients can begin palliative
options and algorithms. Challenging cases are best addressed through treatment.
direct communication, either physician-to-physician or in a multidisciplinary
tumor board setting. The SPCG-4 and PIVOT trials compared the use of observation versus
radical prostatectomy (RP) in patients with localized prostate cancer.247-249
The increased false positive detection of benign rib lesions with PSMA Results from SPCG-4 did not demonstrate a significant reduction in
PET/CT is well established. If these are called metastatic foci then patients prostate cancer-specific mortality with RP compared to observation in
may be inappropriately recategorized from localized prostate cancer patients with low-risk disease.247 In PIVOT, there was no difference in all-
where they may receive curative-intent local therapy, to now receive cause mortality between these two management strategies in those with
doublet systemic therapy. Thus, expert interpretation of PSMA PET/CT low-risk disease, strongly implying that treatment of low-risk prostate
scans is essential to avoid misclassification. cancer should generally be avoided. RP was superior to observation for
patients with intermediate-risk disease. However, RP did not significantly
Observation
improve death from any cause in those with high-risk disease in either
Observation involves monitoring the course of prostate cancer with a trial.247,249
history and physical exam no more often than every 12 months (without

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NCCN Guidelines Version 4.2026

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Active Surveillance prostate cancer choosing active surveillance has increased over time, and
The NCCN Guidelines Panel remains concerned about the problems of was at approximately 60% in 2021.257-259 This trend has also been
overtreatment related to the increased frequency of diagnosis of prostate observed in the Veterans Affairs Integrated Health Care System, in which
cancer from widespread use of PSA for early detection or screening (see active surveillance increased from 2005 to 2015: from 4% to 39% of those
the NCCN Guidelines for Prostate Cancer Early Detection, available at <65 years and from 3% to 41% of those ≥65 years.260
[Link]). The debate about whether it is necessary to diagnose
Active surveillance involves actively monitoring the course of the disease
and treat every individual who has prostate cancer is fueled by the high
with the expectation to deliver curative therapy if the cancer progresses.
prevalence of prostate cancer upon autopsy of the prostate250; the high
Unlike observation, active surveillance is mainly applicable to patients with
frequency of positive prostate biopsies in individuals with normal DREs
sufficient life expectancy who may benefit from early detection of cancer
and serum PSA values251; the contrast between the incidence and
progression and radical treatment. Because these patients have a longer
mortality rates of prostate cancer; and the need to treat an estimated 37
life expectancy, they should be followed closely, and treatment should
patients with screen-detected prostate cancer252,253 or 100 patients with
start promptly should the cancer progress so as not to miss the chance for
low-risk prostate cancer254 to prevent one death from the disease.
cure.
Several large, population-based prostate cancer screening trials have
Early versions of active surveillance were termed active monitoring. This
shown that properly applied early detection protocols can reduce prostate
approach differs from active surveillance as it primarily only relies on PSA
cancer mortality (see the NCCN Guidelines for Prostate Cancer Early
monitoring, whereas active surveillance typically involved serial prostate
Detection, available at [Link]). However, wide-spread screening
biopsies and potential for serial imaging.
has led to overdetection of clinically insignificant prostate cancer (grade
group 1). A growing body of high-level evidence supports the use of The ProtecT study, which randomized 1643 patients with localized
mpMRI to reduce unnecessary biopsies in individuals with an elevated prostate cancer to active monitoring, radical prostatectomy, or RT, found
PSA who are not likely to have clinically significant prostate cancer. Its use no significant difference in the primary outcome of prostate cancer
should decrease the risk of overdetection while maintaining the detection mortality at a median of 10 years follow-up.261 Of 17 prostate cancer
of potentially fatal prostate cancer. These improvements coupled with the deaths (1% of study participants), 8 were in the active surveillance group,
use of active surveillance in appropriate patients should reduce 5 were in the surgery group, and 4 were in the radiation group (P = .48 for
overtreatment while preserving the relatively low rates of prostate cancer the overall comparison). However, a 12.2% absolute increase in the rate
mortality. of disease progression and a 3.4% absolute increase in the rate of
metastases or prostate cancer death were seen in the active surveillance
Models of prostate cancer detection and progression from the early 2000’s
group.261,262 Approximately 23% of participants had Gleason scores 7–10,
estimated that 23% to 42% of all U.S. screen-detected cancers were
and 5 of 8 deaths in the active surveillance group were in this subset.
overtreated255 and that PSA detection was responsible for up to 12.3 years
Longer follow-up has been reported with a median follow-up of 15-years,
of lead-time bias.256 Encouragingly, the proportion of patients with low-risk
and overall survival remains similar across the 3 groups.263 However,

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metastases were more common in the active monitoring group (9.4% vs. patients identified only 8 prostate cancer deaths and 5 cases of
~5% in the surgery and RT groups), primarily driven by the patients with metastasis.283
intermediate-risk disease who were included in the study. By 15-years,
approximately 70% of patients in the active monitoring arm had received For low-risk prostate cancer, active surveillance is preferred.
treatment.
The favorable intermediate risk grouping was not developed to identify
An updated analysis from the ProtecT trial of 712 patients that had optimal active surveillance, but rather to identify patients with intermediate-
pathology available for re-review was reported.264 The authors risk disease who can safely receive RT alone without ADT. The favorable-
demonstrated that 13.1% of patients had cribriform-positive disease, which intermediate-risk group includes patients that are well suited for active
significantly increased the risk of developing metastases (HR, 3.61; 95% surveillance, such as those with Grade group 1 and PSA <10 ng/mL, with
CI, 1.60–8.11). RT with neoadjuvant ADT significantly reduced metastasis a low PSA density. However, it also includes patients with multiple cores
risk (HR, 0.35; 95% CI, 0.16–0.78; P = .04), whereas surgery did not of Grade group 2 disease with cribriform features and a high PSA density.
significantly improve long-term outcomes compared with active monitoring Patients should be counseled that unselected Grade group 2 intermediate-
(15-year cumulative incidence in patients with cribriform-positive disease: risk prostate cancer has been shown to have unacceptably high risks of
26% for surgery, 25% for active monitoring, and 8% for RT plus ADT). metastasis when managed by observation, active monitoring, or active
surveillance.284 Patients with low-volume disease (ie, 1–2 positive cores),
Patient-reported outcomes were compared among the 3 groups of low percent or absolute Gleason pattern 4, lack of cribriform features, and
ProtecT.25,265 The surgery group experienced the greatest negative effect low PSA density are likely better candidates for active surveillance among
on sexual function and urinary continence, whereas the RT group had a patients with Grade group 2 disease.264
slight decrease in bowel function. It has been noted that the RT utilized in
the trial was 3D radiotherapy without image guidance or use of hydrogel Therefore, for select patients with favorable intermediate-risk disease, a
spacers.266 In addition, studies have shown that active surveillance does recommendation for active surveillance must be based on careful
not adversely impact psychological well-being or QOL.25,267-271 individualized weighing of several factors: life expectancy, general health
condition, disease characteristics, potential side effects of treatment, and
Several large active surveillance cohort studies have shown that >50% of patient preference. Shared decision-making, after appropriate counseling
those eligible for active surveillance may safely avoid treatment, and thus on the risks and benefits of the various options, is critical. Data in these
the possible associated side effects of treatment, for at least 10 years (see settings are discussed under Patient Selection, below.
Table 1 below).] For example, in one study, 55% of the population
remained untreated at 15 years.272 Although a proportion of patients on The Panel believes there is an urgent need for further clinical research
active surveillance will eventually undergo treatment, the delay does not regarding the criteria for recommending active surveillance, the criteria for
appear to impact cure rates, and numerous studies have shown that active reclassification on active surveillance, and the schedule for active
surveillance can be a safe option for many patients.272-282 In fact, a 2015 surveillance especially as it pertains to prostate biopsies, which pose an
meta-analysis of 26 active surveillance cohort studies that included 7627 increasing burden.

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NCCN Guidelines Version 4.2026

Prostate Cancer

Patient Selection Gleason 6 or less with PSA 10–20 ng/mL, 94%; Gleason 3+4 with PSA 20
NCCN risk groups are the main determinant used to select patients who ng/mL or less, 84%; and Gleason 4+3 with PSA 20 ng/mL or less, 63%).288
can safely defer treatment. Furthermore, there was an unacceptably high 15-year distant metastasis
rate (16.4%) that largely occurred between 10 to 15 years after
Active Surveillance in Low-Risk Disease diagnosis.288 Likewise, Canary PASS included a small subset of patients
Panel consensus is that active surveillance is preferred for most patients with grade group 2 disease, but only 2 patients had 15 years of follow-up.
with low-risk prostate cancer and a life expectancy ≥10 years based on the Two patients with grade group 2 prostate cancer developed metastatic
data discussed above. However, the Panel recognizes that there is disease between 9 and 12 years,289 with an estimated 15-year risk of
heterogeneity across the low-risk group, and that some factors may be distant metastasis of approximately 10%.284 Thus, 5 to 10 years of follow-
associated with an increased probability of near-term grade up may be insufficient to assess active surveillance safety.
reclassification including high PSA density, a high number of positive
cores (eg, ≥3), high gene expression risk (from tissue-based molecular Overall, the Panel interpreted these data to show that a subset of patients
tumor analysis).285-287 Of note, core involvement in the major active with favorable intermediate-risk prostate cancer and life expectancy >10
surveillance cohort studies was generally low (see Table 1 below) and years may be considered for active surveillance, especially with grade
very few patients with grade group 2 disease were included. Therefore, in group 1 disease. However, the precise inclusion criteria and follow-up
very select patients with low-risk prostate cancer, upfront treatment with protocols need continued refinement. Patients must understand that a
radical prostatectomy or RT may be appropriate based on shared significant proportion of those clinically staged as having favorable
decision-making with the patient. Patient anxiety should be addressed so intermediate-risk prostate cancer may have higher risk disease.290-293
that it is not a deterrent to the appropriate use of active surveillance. Particular consideration to active surveillance may be appropriate for
those patients with a low percentage of Gleason pattern 4 cancer, low
Active Surveillance in Favorable Intermediate-Risk Disease tumor volume, low PSA density, and/or low genomic risk (from tissue-
The literature on outcomes of active surveillance in patients with based molecular tumor analysis), but should be approached with caution,
intermediate-risk prostate cancer is limited because few prospective include informed decision-making, and use close monitoring for
studies of active surveillance included patients with intermediate-risk progression. How to optimize active surveillance for patients with grade
prostate cancer (see Table 1, below). group 2 prostate cancer remains an active area of investigation.

In prospective studies that included patients with intermediate-risk Confirmatory Testing

disease, favorable prostate cancer-specific survival rates of 94% to 100% Confirmatory testing is critical to the process of active surveillance
were seen for the full cohorts.272,274,276 However, with extended follow-up, because a subset of patients will be found to no longer be candidates for
the Toronto group has demonstrated inferior metastasis-free survival for active surveillance after confirmatory testing. Active surveillance starts
patients with intermediate-risk prostate cancer (15-year metastasis-free after confirmatory testing. Since an initial prostate biopsy may
survival for cases of Gleason 6 or less with PSA <10 ng/mL, 94%; underestimate tumor grade or volume, confirmatory testing is strongly

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NCCN Guidelines Version 4.2026

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recommended within the first 6 to 12 months of diagnosis for patients who useful to exclude the presence of anterior cancer when PSA levels
are considering active surveillance. increase and systematic prostate biopsies remain negative.296

Before starting on an active surveillance program, mpMRI with calculation Results of a study of 211 patients with Grade Group 1 prostate cancer
of PSA density should be considered to confirm candidacy for active who had initial and repeat mpMRIs and PSA monitoring suggest that a
surveillance if not performed during initial workup.294 Patients with PI- negative initial mpMRI predicts a low risk of Gleason upgrading by
RADS 4 or 5 on mpMRI have an increased risk of biopsy progression systematic biopsy.297 In addition, PSA velocity was significantly associated
during active surveillance.295 with subsequent progression in those with an initial negative mpMRI. In
contrast, those with high-risk visible lesions on mpMRI before initiation of
In patients with low- and favorable-intermediate-risk disease, molecular active surveillance had an increased risk of progression. A meta-analysis
tumor analysis has not been shown in prospective studies to clearly of 43 studies found the sensitivity and NPV for mpMRI to be 0.81 and
improve long-term outcomes for patients receiving active surveillance. 0.78, respectively.298 An analysis of patients in Canary PASS found that
One study examined the role of molecular tumor analysis for predicting mpMRI had an NPV and PPV for detecting Grade Group ≥2 cancer of
upgrading on surveillance biopsy or the presence of adverse pathology on 83% and 31%, respectively.299 Another study found the NPV of mpMRI to
eventual radical prostatectomy in patients in an active surveillance be 80%.300
cohort.177 In this study, results of the molecular testing did not significantly
improve risk stratification over the use of clinical variables alone. In patients with a suspicious lesion on mpMRI, MRI-US fusion biopsy
improves the detection of higher grade (Grade Group ≥2) cancers. Early
If results of mpMRI and/or molecular testing are concerning, a repeat experience supports the utilization of mpMRI in biopsy protocols to better
biopsy may be appropriate. risk stratify patients under active surveillance.301-303 However, more recent
studies have shown that a significant proportion of high-grade cancers are
Early confirmatory testing may not be necessary in patients who have had
detected with systematic biopsy and not targeted biopsy in patients on
a complete workup including mpMRI prior to diagnostic biopsy. However,
active surveillance.304-306
all patients should undergo a confirmatory prostate biopsy within 1 to 2
years of their diagnostic biopsy. Whereas the intensity of surveillance may be tailored on an individual
basis (eg, based on life expectancy and risk of reclassification), most
Active Surveillance Program
patients should have prostate biopsies incorporated as part of their
The current NCCN recommendations for the active surveillance program monitoring, but no more often than every 12 months, because PSA
include PSA no more often than every 6 months unless clinically indicated; kinetics may not be reliable for predicting progression. Repeat biopsy is
DRE no more often than every 12 months unless clinically indicated; useful to determine whether higher Gleason grade exists, which may
repeat prostate biopsy no more often than every 12 months unless influence prognosis and hence the decision to continue active surveillance
clinically indicated; and consideration of repeat mpMRI no more often than or proceed to definitive local therapy.307 A repeat prostate biopsy should
every 12 months unless clinically indicated. mpMRI may be particularly also be considered if the prostate exam changes, if mpMRI (if done)

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NCCN Guidelines Version 4.2026

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suggests more aggressive disease, or if PSA increases. However, dealt with the validity of commonly used reclassification criteria. The
literature suggests that as many as 5% of patients undergoing prostate Toronto group demonstrated that a PSA trigger point of PSADT <3 years
biopsy will suffer an adverse event, including serious ones such as could not be improved upon by using a PSA threshold of 10 or 20, PSADT
infections requiring hospitalization.308-310 Therefore, many clinicians calculated in various ways, or PSA velocity >2 ng/mL/y.316 The Johns
choose to wait 2 years for a biopsy if there are no signs of progression. Hopkins group used biopsy-demonstrated reclassification to Gleason
pattern 4 or 5 or increased tumor volume on biopsy as their criteria for
Patients should be transitioned to observation (see Observation, above) reclassification. Of 290 patients on an annual prostate biopsy program,
when life expectancy is <10 years and they have low risk disease. 35% demonstrated reclassification at a median follow-up of 2.9 years.317
Neither PSADT (area under the curve [AUC], 0.59) nor PSA velocity
Considerations for Treatment of Patients on Active Surveillance
(AUC, 0.61) was associated with prostate biopsy reclassification. Both
Reliable parameters of prostate cancer progression await the results of groups have concluded that PSA kinetics cannot replace regular prostate
ongoing clinical trials. PSADT is not considered reliable enough to be used biopsy, although treatment of most patients who demonstrate
alone to detect disease progression.311 If repeat biopsy shows Grade reclassification on prostate biopsy prevents evaluation of biopsy
Group ≥3 disease, or if tumor is found in a greater number of biopsy cores reclassification as a criterion for treatment or reduction of survival.
or in a higher percentage of a given biopsy core, cancer progression may Treatment of all patients who developed Gleason pattern 4 on annual
have occurred. Grade reclassification on repeat biopsy is the most prostate biopsies has thus far resulted in only two prostate cancer deaths
common factor influencing a change in management approach from active among 1298 patients (0.15%) in the Johns Hopkins study.275 However, it
surveillance to treatment. Other factors affecting decisions to actively treat remains uncertain whether treatment of all who progressed to Gleason
patients on active surveillance include increase in tumor volume and a rise pattern 4 was necessary. Studies remain in progress to identify the best
in PSA density. Considerations for a change in management strategy trigger points when interventions with curative intent may still be
should be made in the context of the patient’s life expectancy. Patient successful.
anxiety over continued active surveillance should be addressed if
treatment does not appear warranted. The patients in the Toronto cohort were followed for a median of 6.8
years.313 Of the 30% (n = 145) of patients who progressed, 8% had an
Each of the major active surveillance series has used different criteria for increase in Gleason grade, 14% had a PSADT <3 years, 1% developed a
reclassification.272,275,278-281,312-315 Reclassification criteria were met by 23% prostate nodule, and 3% were treated because of anxiety. One hundred
of patients with a median follow-up of 7 years in the Toronto experience,313 thirty-five of these 145 patients were treated: 35 by radical prostatectomy,
36% of patients with a median follow-up of 5 years in the Johns Hopkins 90 by external beam RT (EBRT) with or without ADT, and 10 with ADT
experience,275 and 16% of patients with a median follow-up of 3.5 years in alone. The 10- and 15-year actuarial cause-specific survival rates for the
the University of California, San Francisco (UCSF) experience281 (also see entire cohort were 98.1% and 94.3%, respectively.272 Only 15 of 993
Table 1, below). Uncertainty regarding reclassification criteria and the (1.5%) patients had died of prostate cancer, an additional 13 patients
desire to avoid missing an opportunity for cure drove several reports that (1.3%) had developed metastatic disease, and only 36.5% of the cohort

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had received treatment by 10 years. In an analysis of 592 patients enrolled Radical prostatectomy was compared to watchful waiting in a randomized
in this cohort who had ≥1 repeat prostate biopsies, 31.3% of cases were trial of 695 patients with early-stage prostate cancer (mostly T2) in the
upgraded. Fifteen percent of upgraded cases were upgraded to Gleason SPCG-4 trial.247,323 With a median follow-up of 12.8 years, those assigned
≥8, and 62% of total upgraded cases proceeded to active treatment.318 to the radical prostatectomy group had significant improvements in
Another analysis of this cohort revealed that metastatic disease developed disease-specific survival, OS, and risk of metastasis and local
in 13 of 133 patients with Gleason 7 disease (9.8%) and 17 of 847 patients progression.323 The reduction in mortality was confirmed at 18-year follow-
with Gleason ≤6 disease (2.0%).319 PSADT and the number of positive up, with an absolute difference of 11%.247 Overall, 8 patients needed to be
scores were also predictors of increased risk for the development of treated to avert one death; that number fell to 4 for patients <65 years of
metastatic disease. age. Longer follow-up results were also reported, in which the cumulative
incidence of death from prostate cancer was 19.6% and 31.3% in the
In comparison, among 192 patients on active surveillance who underwent radical prostatectomy and watchful waiting groups, respectively, at 23
delayed treatment at a median of 2 years after diagnosis in the Johns years, with a mean increase of 2.9 years of life in the radical
Hopkins experience, 5-year biochemical PFS was 96% for those who prostatectomy group.248 However, in the small subset of patients with high-
underwent radical prostatectomy and 75% for those who underwent risk disease, there was no improvement in survival between treatment
radiation.315 The two groups were similar by pathologic Gleason grade, groups. A report of 30-year follow-up of this trial showed that the absolute
pathologic stage, and margin positivity. All patients treated by radical difference in death due to prostate cancer between groups increased over
prostatectomy after progression on active surveillance had freedom from time.324 Radical prostatectomy resulted in a 48% lower risk of death from
biochemical progression at a median follow-up of 37.5 months, compared prostate cancer and a mean of 2.2 life-years gained. The authors
to 97% of those in the primary radical prostatectomy group at a median concluded that treating six patients would result in one prostate cancer
follow-up of 35.5 months. A later publication from this group showed that death averted. The results of this trial offer high-quality evidence to
23 of 287 patients who were treated after active surveillance (8%) support radical prostatectomy alone as a treatment option for patients with
experienced biochemical recurrence, and the rate was independent of the intermediate-risk clinically localized prostate cancer.
type of treatment.275 Several studies have shown that delayed radical
prostatectomy does not increase the rates of adverse pathology.279,320-322 While the SPCG-4 and PIVOT trials comparing observation to surgery did
not clearly demonstrate an improvement in outcomes among those with
Radical Prostatectomy high-risk disease, these trials enrolled few patients and are not adequately
Radical prostatectomy is an appropriate option for patients whose cancer powered to rigorously assess the role of surgery in high-risk disease.248,249
appears clinically localized to the prostate and can safely undergo general Trials that have utilized surgery in high-risk disease generally demonstrate
anesthesia and an operation. Because of potential perioperative morbidity, a 70% to 80% risk of recurrence and thus surgery should be viewed as
radical prostatectomy should generally be reserved for patients whose life one component of a multi-modality approach.325 For example, in the
expectancy is ≥10 years. CALGB 90203 trial of patients who received surgery in the control arm,

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NCCN Guidelines Version 4.2026

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69% received adjuvant or secondary treatment, most commonly additional cancer therapies between open and robot-assisted radical
radiotherapy with or without ADT. prostatectomy, although the robotic approach was associated with higher
rates of genitourinary complications and lower rates of blood
There remains no high-level evidence for the use of radical prostatectomy transfusion.335 Oncologic outcomes of a robotic versus open approach
for patients with NCCN very-high-risk, regional/node-positive, or were similar when assessed by use of additional therapies334 or rate of
metastatic disease. Ideally surgery is used in the context of a clinical trial positive surgical margins,336 although longer follow-up is necessary. A
or when radiotherapy plus ADT is contraindicated. Surgery should be meta-analysis of 19 observational studies (n = 3893) reported less blood
discussed as one component of a planned multimodality approach in loss and lower transfusion rates with minimally invasive techniques than
these patients. There is an ongoing trial, SPCG-15, which aims to with open operation.336 Risk of positive surgical margins was the same.
compare RP versus RT plus ADT in patients with high-risk prostate Two more recent meta-analyses showed a statistically significant
cancer.326 advantage in favor of a robotic approach compared to an open approach
in 12-month urinary continence337 and potency recovery.338 Early results
Radical prostatectomy is also a treatment option for select patients
from a randomized controlled phase 3 study comparing robot-assisted
experiencing a local recurrence after primary EBRT, but morbidity
laparoscopic radical prostatectomy and open radical retropubic
(incontinence, erectile dysfunction, bladder neck contracture, and rectal
prostatectomy in 326 patients were published in 2016.339,340 Urinary
injury) remain significantly higher than when radical prostatectomy is used
function and sexual function scores and rates of postoperative
as initial therapy.327,328 Patient selection is important, and post-RT
complications did not differ significantly between the groups at 6, 12, and
recurrence radical prostatectomy should only be performed by highly
24 months after surgery. Rates of positive surgical margins were similar,
experienced surgeons.
based on a superiority test (10% in the open group vs. 15% in the robotic
Operative Techniques and Adverse Effects group). Assessment of oncologic outcomes from this trial will be limited
because postoperative management and additional cancer therapies were
The retropubic and the perineal approaches are reasonable to perform a
not standardized between the groups.339
radical prostatectomy. Surgeons who perform a high-volume of operations
in high-volume centers generally achieve superior outcomes.329,330 Return of urinary continence after radical prostatectomy may be improved
Laparoscopic and robot-assisted radical prostatectomy are commonly by preserving the urethra beyond the prostatic apex and by avoiding
used and are considered comparable to conventional approaches in damage to the distal sphincter mechanism. Bladder neck preservation
experienced hands.331-333 In a cohort study using SEER Medicare-linked may allow more rapid recovery of urinary control.341 Anastomotic strictures
data on 8837 patients, minimally invasive compared to open radical that increase the risk of long-term incontinence are less frequent with
prostatectomy was associated with shorter length of hospital stay, less modern surgical techniques. Recovery of erectile function is related
need for blood transfusions, and fewer surgical complications, but rates of directly to the degree of preservation of the cavernous nerves, age at
incontinence and erectile dysfunction were higher.334 A second large study surgery, and preoperative erectile function. Improvement in urinary and
reported no difference in overall complications, readmission, and sexual function has been reported with nerve-sparing techniques.342,343

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NCCN Guidelines Version 4.2026

Prostate Cancer

Replacement of resected nerves with nerve grafts does not appear to be Radiation Therapy
effective for patients undergoing wide resection of the neurovascular RT techniques used in prostate cancer can be described generally by the
bundles.344 The ability of mpMRI to detect extracapsular extension can aid following: delivery method (ie, internal vs. EBRT), source of radiation (ie,
in decision-making in nerve-sparing surgery.201 photon vs. proton), planning technique (ie, 3D vs. intensity modulated RT
[IMRT]), image guidance (none vs. cone beam CT [CBCT] or MRI),
Common adverse events after RP include urinary incontinence, erectile
adaptation (ie, online adaptive treatment), and fractionation (ie,
dysfunction, penile shortening, and urethral or bladder neck contracture or
conventional vs. moderate hypofractionation vs. stereotactic body
stricture. The rates of occurrence vary by patient population (eg, by age
radiotherapy).
and risk group), surgeon skill, and surgical technique (eg, unilateral vs.
bilateral nerve sparring). In the ProtecT trial and PACE-A, which both External Beam Radiation Therapy
randomized patients to RP versus RT, RP was associated with 40% to
Over the past several decades, EBRT techniques have evolved to allow
60% risk of erectile dysfunction and 20% to 50% risk of urinary
higher doses of radiation to be administered safely. EBRT can be
incontinence requiring at least one pad per day.25,345
delivered either with photons, also called x-rays, or proton beam. Photons
Pelvic Lymph Node Dissection are used in >95% of cases in the United States.
PLND can be considered with a radical prostatectomy for patients with Proton Therapy
favorable intermediate, unfavorable intermediate, high, or very-high-risk Proton therapy and x-ray–based therapies like IMRT can deliver highly
prostate cancer. If performed, it is recommended to be an extended conformal doses to the prostate. Proton-based therapies will deliver less
PLND.346,347 An extended PLND includes removal of all node-bearing low-dose radiation to some of the surrounding normal tissues not
tissue from an area bounded by the external iliac vein anteriorly, the pelvic immediately adjacent to the prostate, such as muscle, bone, vessels, and
side wall laterally, the bladder wall medially, the floor of the pelvis fat. These tissues do not routinely contribute to the morbidity of prostate
posteriorly, Cooper’s ligament distally, and the internal iliac artery radiation and are relatively resilient to radiation injury; therefore, the
proximally. Removal of more lymph nodes using the extended technique benefit of decreased dose to these types of normal, non-critical tissues
has been associated with increased likelihood of finding lymph node has not been clearly proven.
metastases, thereby providing more complete staging.348-350 A survival
advantage with more extensive lymphadenectomy has been suggested by Only one randomized trial has been performed, the PartiQOL trial, and
several studies, possibly due to elimination of microscopic results are reported in abstract only.355 This trial randomized 450 patients
metastases,349,351-353 although definitive proof of oncologic benefit is with low- and intermediate-risk prostate cancer to either proton or photons.
lacking.354 PLND can be performed safely laparoscopically, robotically, or After a median follow-up of 5-years, there were no significant differences
as an open procedure, and complication rates should be similar among in patient-reported quality of life, physician reported toxicity, or biochemical
the three approaches. recurrence. Thus, both treatments appear to offer excellent tumor control
and good safety profile.

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The costs associated with proton beam facility construction and proton dosimetry and enable margin reduction, which may result in reduced
beam treatment are high compared to the expense of building and using toxicity.358
the more common photon linear accelerator-based practice.356 These
higher costs may translate into higher charges for protons, a point that The advancements in treatment planning and IGRT have enabled greater
should be considered when tumor control and side effects appear similar comfort and confidence to test increasingly hypofractionated regimens.
between photon and proton beam therapy for prostate cancer, especially if Historically, conventionally fractionated RT was utilized with 1.8 to 2.0 Gy
these charges are incurred by the patient. per fraction over 8 to 9 weeks of daily RT. This schema has been
compared in numerous randomized trials to moderately hypofractionated
The NCCN Panel believes no clear evidence supports a benefit or RT in 2.5 to 4 Gy/fraction, which has been shown to be noninferior when
decrement to proton therapy over IMRT for either treatment efficacy or using iso-effective doses.359-368 Recently, the HYDRA individual patient
long-term toxicity. Conventionally fractionated or moderately meta-analyses of these trials demonstrated that 60 Gy in 20 fractions, or
hypofractionated prostate proton therapy can be considered a reasonable regimens with a similar iso-effective dose, should be preferred.369
alternative to x-ray–based regimens at clinics with appropriate technology, Reduction from >40 treatments to 20 treatments reduces both financial
physics, and clinical expertise. Insufficient data is present to recommend toxicity and increases patient convenience.
their delivery with ultra-hypofractionation.
The relatively slow proliferation rate of prostate cancer is reflected in a low
Photon (X-ray) Beam α/β ratio, most commonly reported between 1 and 4.370 Because the α/β
Treatment planning in the 1980s used two-dimensional planning ratio for prostate cancer is similar to or lower than the surrounding tissues
techniques. By the 1990s this was largely replaced by three-dimensional responsible for most of the toxicity reported with radiation, appropriately
planning. In the late 1990s IMRT planning techniques were increasingly designed radiation treatment fields and schedules using ultra
utilized, and as of 2010 nearly all centers utilize IMRT planning. This hypofractionated regimens were hypothesized to result in similar cancer
technique has been shown to improve dose conformality. control rates without increased risk of late toxicity.

In parallel, improvements in image guidance, also referred to as image SBRT is a technique that delivers highly conformal, high-dose radiation in
guided RT (IGRT), have occurred. The purpose of IGRT is to ensure the five or fewer treatment fractions, which are safe to administer only with
planned dose is delivered as intended. Given the potential changes in precise, image-guided delivery.371 Numerous prospective studies
anatomy day to day due to bladder and rectal filling, IGRT is essential to demonstrated safety and efficacy of SBRT in the setting of localized
ensure accurate alignment of the prostate and target volumes and prostate cancer.372 Two large randomized phase 3 trials have reported
avoidance of organs at risk. IGRT techniques often include use of results. HYPO-RT-PC trial enrolled 1200 patients with intermediate- and
implanted fiducials, electromagnetic targeting and tracking, or endorectal high-risk prostate cancer and demonstrated noninferiority of 42.7 Gy in
balloon, which have variably been shown to decrease complications and seven fractions to 78.0 Gy in 39 fractions with respect to FFS.373 Likewise,
allow margin reduction.357 More recently, the use of real-time tracking and PACE-B compared 5-fraction SBRT with a dose of 40 Gy to the prostate
online adaptive radiotherapy have also demonstrated the ability to improve and 36.25 Gy to the planning target volume versus moderate

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NCCN Guidelines Version 4.2026

Prostate Cancer

hypofractionated RT with 62 Gy in 20 fractions.374 Results showed rectum from high radiation dose regions. Patients with obvious rectal
noninferiority in tumor control and generally similar safety profiles. invasion or visible posterior extension should not undergo perirectal
spacer implantation.
SBRT regimens should utilize IMRT planning and daily IGRT. SBRT is an
appropriate standard RT method at clinics with appropriate technology, EBRT for Low-Risk Disease
physics, and clinical expertise. Active surveillance is preferred for low-risk disease. If EBRT is to be used,
it should be given as monotherapy without a brachytherapy boost, without
The Panel lists fractionation schemes that have shown acceptable efficacy nodal irradiation, and without ADT. Ideally it is given with SBRT or
and toxicity within the Principles of Radiation Therapy. moderately hypofractionated RT.

Relative contraindications or considerations to EBRT include prior pelvic EBRT for Intermediate-Risk Disease
irradiation, active inflammatory disease of the rectum, permanent The favorable/unfavorable distinction within the intermediate-risk group
indwelling Foley catheter, very low bladder capacity, chronic moderate or should be used to help guide treatment for these patients. Generally,
severe diarrhea, and bladder outlet obstruction requiring a suprapubic patients with favorable intermediate-risk disease should be treated with
catheter. EBRT alone without a brachytherapy boost, without nodal irradiation, and
without ADT.381 Use of SBRT or moderately hypofractionated RT are
Hydrogel Per-Rectal Spacers
preferred. Patients with unfavorable intermediate-risk disease generally
Biomaterials have been developed, tested, and FDA approved to serve as
should be considered for the addition of short-term ADT.382,383 Studies
spacer materials when inserted between the rectum and prostate.375,376 In
have shown that the addition of a focal EBRT boost may further improve
a randomized phase 3 multicenter clinical trial of patients undergoing
biochemical control in these patients.384 Similarly, the addition of a
image-guided IMRT (IG-IMRT), the risk of late (3-year) grade 2 or higher,
brachytherapy boost may improve biochemical control, at the expense of
physician-recorded rectal complications declined from 5.7% to 0% in the
increased toxicity.385 Trials to date that have enrolled patients with
control versus hydrogel spacer group.377 The control group had a
intermediate-risk disease have not shown improvements in disease control
significant reduction in bowel QOL decline. No significant differences in
from the use of elective nodal irradiation (ENI), and have generally seen
urinary adverse events were noted in those receiving hydrogel placement
an increase in toxicity.386
versus controls. Results of a secondary analysis of this trial suggest that
use of a perirectal spacer may decrease the sexual side effects of EBRT for Patients with High-Risk or Very-High-Risk Disease
radiation.378 Spacer implantation may be associated with rare EBRT represents the only local therapy for patients with high- or very-
complications such as rectum perforation and urethral damage.379,380 high-risk disease that has been shown to improve overall survival when
Retrospective data also support its use in similar patients undergoing compared to ADT alone.387-390 Furthermore, the addition of ADT,
brachytherapy. Overall, the Panel believes that biocompatible and specifically long-term ADT of >18 months, has been shown to improve
biodegradable perirectal spacer materials may be implanted between the overall survival as compared to RT alone or RT with short-term ADT.382
prostate and rectum in patients undergoing RT in order to displace the

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NCCN Guidelines Version 4.2026

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There are mixed results regarding the benefit of ENI in this patient EBRT for Node-Positive Disease
population. Three multicenter cooperative group trials have not EBRT with neoadjuvant, concurrent, and/or adjuvant ADT and abiraterone
demonstrated improvement in outcomes from ENI; GETUG-01, RTOG is the preferred option for patients with clinical N1 disease based upon the
9413, and recently in abstract form RTOG 0924.386,391,392 However, one previously discussed STAMPEDE trial.394 Other options in this setting
small single center trial from India, POP-RT, showed that pelvic radiation include EBRT with ADT, ADT alone or with abiraterone, and, for select
can improve biochemical FFS and DFS compared with prostate-only patients, RP plus PLND (see Radical Prostatectomy, above).
radiation in patients with high- and very-high-risk prostate cancer.393 With
Post-Recurrence EBRT
the recent results of NRG/RTOG 0924 ([Link] ID
NCT01368588) demonstrating no improvement in distant metastasis, The use of EBRT in patients with biochemical recurrence is discussed
prostate cancer-specific mortality, or overall survival from ENI in an under Post-Radical Prostatectomy Approaches, below.
approximately 2500 patient trial of unfavorable-intermediate and high-risk
Brachytherapy
prostate cancer, the role of ENI remains unclear.
Brachytherapy involves placing radioactive sources into the prostate
More recently, the STAMPEDE trial has reported a post-hoc analysis of tissue. Brachytherapy has been used traditionally for low-risk disease
the benefit of adding abiraterone acetate/prednisone to EBRT plus long- because earlier studies found it less effective than EBRT for high-risk
term ADT in patients with NCCN very-high-risk prostate cancer.394 Results disease.121,396 However, increasing evidence suggests that technical
demonstrated improvement in metastasis-free survival from the addition of advancements in brachytherapy may provide a role for contemporary
abiraterone at the expense of increased grade ≥3 side effects. Notably, brachytherapy in higher-risk localized and locally advanced prostate
the patients enrolled in this trial had markedly higher rates of metastasis cancer.397
and death from prostate cancer than those observed in other trials of high-
There are currently two methods for prostate brachytherapy: low dose-rate
risk prostate cancer conducted by NRG, EORTC, or TROG. Given some
(LDR) and high dose-rate (HDR). LDR brachytherapy consists of
patients had PSAs >1000 ng/mL on the STAMPEDE trial but were called
placement of permanent seed implants in the prostate. The short range of
non-metastatic, it remains unclear the true value of the addition of
the radiation emitted from these low-energy sources allows delivery of
abiraterone in contemporary very-high-risk disease. ENZARAD, a
adequate dose levels to the cancer within the prostate, with excessive
randomized trial of patients with high- and very-high-risk and clinical node
irradiation of the bladder and rectum avoided. Post-implant dosimetry
positive disease, recently reported results in abstract form and
should be performed to document the quality of an LDR implant.398 HDR
demonstrated that the addition of the APRI enzalutamide to RT+ADT did
brachytherapy, which involves temporary insertion of a radiation source, is
not improve metastasis-free survival or overall survival.395 Ongoing trials
a newer approach.
utilizing other ARPIs have not yet reported their results, such as ATLAS
(NCT02531516). Two groups have observed a lower risk of urinary frequency, urgency, and
rectal pain with HDR brachytherapy compared with LDR brachytherapy
(permanent seed implant).399,400 Vargas and colleagues401 reported that

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HDR brachytherapy results in a lower risk of erectile dysfunction than LDR concerns regarding the efficacy of both single fraction HDR and, more
brachytherapy. Commonly prescribed doses for LDR and HDR recently, two fraction HDR as monotherapy.402
brachytherapy are listed in the Principles of Radiation Therapy within the
algorithm above. There are no reported trials comparing SBRT or other contemporary
EBRT methods to brachytherapy. ASCENDE-SBRT is comparing a
For patients with very large or very small prostates, symptoms of bladder brachytherapy boost versus SBRT.403
outlet obstruction (high International Prostate Symptom Score), or a
Brachytherapy Boost
previous transurethral resection of the prostate (TURP), seed implantation
may be more difficult. These patients also have an increased risk of side LDR or HDR brachytherapy can be added as a boost to EBRT plus ADT in
effects. Neoadjuvant ADT may be used to shrink the prostate to an patients with unfavorable intermediate- or high-risk prostate cancer being
acceptable size; however, increased toxicity is expected from ADT, and treated with curative intent and for carefully selected patients with very-
prostate size may not decline in some patients. The potential toxicity of high-risk disease. Combining EBRT and brachytherapy allows dose
ADT must be weighed against the possible benefit of target reduction. escalation. This combination has demonstrated improved biochemical
control over EBRT plus ADT alone in randomized trials, but with higher
Ideally, the accuracy of brachytherapy treatment should be verified by toxicity.404-406
daily prostate localization with techniques of IGRT: CT, ultrasound,
implanted fiducials, or electromagnetic targeting/tracking. Endorectal The randomized ASCENDE-RT trial compared two methods of dose
balloons may be used to improve prostate immobilization. Perirectal escalation in 398 patients with intermediate- or high-risk prostate cancer:
spacer materials (discussed under External Beam Radiation Therapy, dose-escalated EBRT boost to 78 Gy or LDR brachytherapy boost.385 All
above) may be used when the previously mentioned techniques are patients were initially treated with 12 months of ADT and pelvic EBRT to
insufficient to reduce side effects due to anatomic geometry or other 46 Gy. An ITT analysis found that the primary endpoint of biochemical
patient-related factors (eg, medication usage, comorbid conditions). PFS was 86% versus 75% at 7 years for the LDR boost versus EBRT
Patients with obvious rectal invasion or visible cT3 and posterior extension boost arms (log-rank P < .001). Toxicity was higher in the brachytherapy
should not undergo perirectal spacer implantation. arm, with the cumulative incidence of grade 3 genitourinary events at 5
years of 18.4% for brachytherapy boost and 5.2% for EBRT boost (P <
Brachytherapy Alone for Localized Disease .001).407 A trend for increased gastrointestinal toxicity with brachytherapy
Active surveillance is preferred for low-risk disease, but brachytherapy boost was also seen (cumulative incidence of grade 3 events at 5 years,
alone is an option for select patients with low-risk disease. Brachytherapy 8.1% vs. 3.2%; P = .12). However, at 6-year follow-up, health-related QOL
alone is an option for patients with favorable intermediate-risk and for was similar between the groups in most domains, except that physical and
carefully selected patients with unfavorable intermediate-risk prostate urinary function scales were significantly worse in the LDR arm.408
cancer, depending on life expectancy. Patients with high-risk cancers are Whereas the toxicity is increased with the use of brachytherapy boost, this
not generally considered candidates for brachytherapy alone. Either LDR and other randomized controlled trials have not shown an improvement in
or HDR brachytherapy can be used in this setting; however, there are OS or cancer-specific survival.409

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NCCN Guidelines Version 4.2026

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The optimal duration of ADT with EBRT plus brachytherapy is unclear. recurrent-disease setting should consider comorbidities, extent of disease,
The TROG RADAR trial randomized patients to receive 6 versus 18 and potential complications. Brachytherapy in this setting is best
months of ADT, and a subset of participants received EBRT with an HDR performed at high-volume centers.
boost.410 In the subset who received EBRT plus HDR, the use of 18
months of ADT improved overall survival compared to 6 months. More Radiation for Distant Metastases
recently, the TRIP/TRIGU0907 randomized trial of EBRT plus LDR EBRT can be used for multiple purposes in the setting of metastatic
compared 6 versus 30 months of ADT.411 The study found no significant disease. Historically, it was only used as a means of palliation, often for
difference in biochemical progression between arms, both were <10% at bone pain, obstruction, or bleeding. A short course of 8 Gy x 1 is as
7-year follow-up. effective for palliation as, and less costly than, 30 Gy in 10 fractions.414 In
a randomized trial of 898 patients with bone metastases, grade 2–4 acute
To address concerns for increased toxicity incidence associated with toxicity was observed less often in the 8-Gy arm (10%) than in the 30-Gy
brachytherapy boost from historical trial data, careful patient selection and arm (17%) (P = .002); however, the retreatment rate was higher in the 8-
contemporary planning associated with lesser toxicity, such as use of Gy group (18%) than in the 30-Gy group (9%) (P < .001).415 In another
recognized organ at risk dose constraints, use of high-quality ultrasound study of 425 patients with painful bone metastases, a single dose of 8 Gy
and other imaging, and prescription of dose as close as possible to the was noninferior to 20 Gy in multiple fractions in terms of overall pain
target without excessive margins, should be implemented. response to treatment.416 The SCORAD randomized trial did not show
noninferiority for ambulatory status of single-fraction 8-Gy EBRT to 20 Gy
Post-Recurrence Brachytherapy
in 5 fractions.417
Brachytherapy can be considered in patients with biochemical recurrence
after EBRT. Results of a phase 2 study of post-recurrence HDR Eight Gy as a single dose is as effective for short-term (ie, 12 week) pain
brachytherapy after EBRT included relapse-free survival, distant palliation at any bony site as longer courses of radiation, but re-treatment
metastases-free survival, and cause-specific survival rates of 68.5%, rates are higher. Other regimens (eg, 30 Gy in 10 fractions) may be used
81.5%, and 90.3%, respectively, at 5 years.412 Toxicities were mostly as alternative palliative dosing depending on clinical scenario. Neither
grade 1 and 2 and included gastrointestinal toxicity and urethral strictures, regimen has demonstrated clear long-term pain or cancer control and are
and one case of Grade 3 urinary incontinence. In another prospective intended for transient pain control palliation.
phase 2 trial, the primary endpoint of grade ≥3 late treatment-related
gastrointestinal and genitourinary adverse events at 9 to 24 months after EBRT may also be used as an oncologic treatment and not solely for the
post-recurrence brachytherapy was below the unacceptable threshold, at palliation of symptoms in the metastatic setting. The topic of metastasis-
14%.413 directed radiation therapy is discussed in detail below (see MDT for
Oligometastatic CSPC and MDT for mCRPC).
Data on the use of brachytherapy after permanent brachytherapy are
limited, but the Panel agrees that it can be considered for carefully
selected patients. Decisions regarding the use of brachytherapy in the

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NCCN Guidelines Version 4.2026

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developing distant metastasis than patients treated with a surgical

Comparison of Treatment Options for Localized Disease approach, but there were no significant differences in death from prostate
Multiple randomized trials have compared RT to RP. The ProtecT trial cancer. As this was not a true randomized trial of the two treatment
demonstrated that, with a median follow-up of 15 years, patients with low approaches, confounding may impact the results.
and intermediate risk prostate cancer had similar rates of developing
metastasis or death.263,265 A post-hoc subset analysis of the ProtecT trial Numerous non-randomized studies have been reported that should be
demonstrated that patients with cribriform features on active monitoring interpreted with caution given the high risk for selection bias and residual
had significantly reduced rates of distant metastasis when treated with RT confounding. Barocas et al compared radical prostatectomy, EBRT, and
plus ADT, but not with RP.264 active surveillance in 2550 patients and found that, after 3 years, radical
prostatectomy was associated with a greater worsening in urinary and
The ProtecT trial demonstrated that urinary incontinence rates and sexual function than either EBRT or active surveillance.419 However,
impotence rates were significantly higher with RP than RT. There were radical prostatectomy was also associated with an improvement in urinary
small but significant increases in bowel side effects with RT as compared irritative symptoms that was not observed with radiation or active
to surgery. The RT utilized on this trial was 3D conformal radiotherapy surveillance. Health-related QOL measures including bowel and hormonal
without contemporary image guidance or rectal spacer use. function were similar among the groups, as was disease-specific survival.

More recently, results from PACE-A, which included patients with Chen et al compared radical prostatectomy, EBRT, and brachytherapy
intermediate-risk prostate cancer receiving either SBRT versus RP, were against active surveillance in 1141 patients.23 As in the Barocas study,
reported.345 No spacer gels were utilized. The study demonstrated that, radical prostatectomy was associated with greater declines in sexual and
with more modern RT, there were smaller differences in patient-reported urinary function than other treatments at 3 months. In this study, EBRT
bowel quality of life as compared to surgery. Furthermore, those receiving was associated with worse short-term bowel function, and both EBRT and
surgery were >3-fold more likely to develop impotence, and >8-fold more brachytherapy were associated with worsened urinary obstructive and
likely to develop urinary incontinence requiring ≥1 pads per day. irritative symptoms. By 2 years, however, differences among the groups
compared with active surveillance were insignificant. Results of a
Recently, a cross-trial comparison using two phase 3 randomized trials systematic review showed similar findings to these studies.420
was performed.418 Trials were matched by era, country, and
randomization. NRG/RTOG 0521 randomized patients with high-risk Another study examined patient-reported outcomes in >2000 patients with
prostate cancer to RT plus 24 months of ADT with or without 6 cycles of localized prostate cancer managed by radical prostatectomy,
docetaxel, and CALGB randomized patients with high-risk prostate cancer brachytherapy, EBRT with or without ADT, or active surveillance.24 By 5
to surgery with or without 6 cycles of docetaxel with concurrent ADT in the years, most functional differences were minimal between management
neoadjuvant setting. The patients in the RT trial were generally older and approaches. However, radical prostatectomy was associated with worse
had more aggressive prognostic features. This study demonstrated that incontinence in the full cohort and with worse sexual function in those with
patients receiving RT with ADT had significantly reduced risk of
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NCCN Guidelines Version 4.2026

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unfavorable intermediate-, high-, or very-high-risk disease than in those RT recurrence due to the overall lack of high-quality evidence in this
treated with EBRT and ADT. setting for any modality. Also see Post-Radiation Recurrence, below.

Other Local Therapies Disease Monitoring

Many therapies have been investigated for the treatment of localized Please refer to the NCCN Guidelines for Survivorship (available at
prostate. Cryotherapy was investigated as a potential whole gland [Link]) for recommendations regarding common consequences
treatment option. A study by Donnelly and colleagues included 244 of cancer and cancer treatment (eg, anxiety, depression, trauma, and
patients with T2 or T3 disease who were randomly assigned to either distress; hormone-related symptoms; sexual dysfunction) and on the
cryotherapy or EBRT.421 In this small trial, all patients received promotion of physical activity, weight management, and proper
neoadjuvant ADT. Patients who received cryotherapy reported poorer immunizations in cancer survivors. Prostate-cancer specific survivorship
sexual function.422 For patients with locally advanced cancer, cryoablation recommendations pertaining to bone health and cardiovascular disease
was associated with a lower 8-year biochemical progression-free rate are included in the algorithm above and are discussed in more detail in the
compared to EBRT in a small trial of 62 patients.423 section on Adverse Effects of Traditional ADT, below.

Other ablative therapies (eg, high-intensity focused ultrasound [HIFU], Patients After Initial Definitive Therapy
transurethral ultrasound ablation [TULSA], irreversible electroporation For patients initially treated with curative intent, serum PSA levels should
[IRE], photodynamic therapy [PDT]) are not recommended as primary be measured every 6 to 12 months for the first 5 years and then annually.
therapy for localized prostate cancer due to lack of long-term randomized PSA testing every 3 months may be better for patients at high risk of
data comparing these treatments to radiation or radical prostatectomy.424- recurrence. When prostate cancer recurred after radical prostatectomy,
430 Single arm phase I or II trials have shown high rates of residual or
Pound and colleagues found that 45% of patients experienced recurrence
recurrent cancer (20%–70%) and clinically meaningful toxicity (ie, within the first 2 years, 77% within the first 5 years, and 96% by 10
incontinence, obstruction, erectile dysfunction). Furthermore, monitoring years.431
strategies appear to be compromised (ie, MRI accuracy) and secondary
treatment may carry higher risk of complications. These ablative Patients with N1 CSPC on ADT
treatments can be utilized in the context of a clinical trial, ideally a The intensity of clinical monitoring for patients on ADT for N1 CSPC is
randomized trial compared them to a current standard treatment option. determined by the response to initial ADT, EBRT, or both. Follow-up
Companies and institutions may make non–evidenced-based claims to the evaluation of these patients should include physical examination and PSA
evidence, efficacy, and safety of focal therapy. measurement every 3 to 6 months. Imaging for symptoms or increasing
PSA. The relative risk for bone metastasis or death increases as PSADT
At this time, the only local therapy options that can be considered are
falls. Bone imaging should be performed more frequently in patients with
cryotherapy, HIFU, and IRE (category 2B) in the setting of non-metastatic
shorter PSADTs.432

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Patients with Localized Disease Under Observation and low postoperative serum PSA levels have a very low risk of positive
Patients with localized disease on observation follow the same monitoring bone scans or CT scans.433,434 In a series of 414 bone scans performed in
recommendations as patients with N1 CSPC who are on ADT. 230 patients with biochemical recurrence after radical prostatectomy, the
rate of a positive bone scan for patients with PSA >10 ng/mL was only
Workup for Progression 4%.435 In another study, the probability of a positive bone scan for a
Castrate levels of testosterone should be documented if clinically indicated patient not on ADT after radical prostatectomy was <5% unless the PSA
in patients with signs of progression, with adjustment of ADT as increased to 40 to 45 ng/mL.436 Thus bone imaging is appropriate when
necessary. If serum testosterone levels are <50 ng/dL, the patient should patients develop symptoms or when PSA levels are increasing rapidly. A
undergo disease workup with bone and soft tissue imaging (see Imaging prostate bed biopsy can also be considered. However, PSMA PET/CT
Techniques above for more details). imaging has increased sensitivity at low PSA levels post-RP, and
approximately 30% to 40% of patients will have detectable disease on
Post-Radical Prostatectomy Approaches PSMA PET/CT at PSA levels of 0.2 to 0.5 ng/mL.
Patients who have undergone radical prostatectomy should be monitored
Early Secondary or Adjuvant Treatment for Adverse Features After
as described above. However, some patients will have adverse pathologic Radical Prostatectomy
features, positive lymph nodes, or biochemical persistence or recurrence.
Patients with undetectable PSA levels and without lymph node metastases
Options for these patients include adjuvant radiation (the use of EBRT
following radical prostatectomy can be considered for immediate adjuvant
immediately following radical prostatectomy in the setting of an
treatment if adverse pathologic features are present (ie, positive margins,
undetectable postoperative PSA) with or without ADT, secondary radiation
seminal vesicle invasion, extracapsular extension). However, monitoring
(the use of EBRT after radical prostatectomy when PSA is detectable) with
these patients is the preferred option (category 1). Waiting for a detectable
or without ADT, or monitoring. Decisions about when to initiate post-
and rising PSA or PSA ≥0.1 ng/mL before initiating secondary radiation is
radical prostatectomy radiation and whether to include ADT for such
preferred in this setting, since this approach avoids over-treatment and
patients are complex. The Panel recommends use of nomograms and
subsequent potential side effects and does not appear to compromise
consideration of age and comorbidities, clinical and pathologic information,
oncologic outcomes.437,438
PSA levels, and PSADT to individualize treatment discussion. The various
scenarios are discussed in more detail below. In the RADICALS-RT trial, 1396 patients with adverse features after
radical prostatectomy were randomized to receive immediate adjuvant
Bone and soft tissue imaging and prostate bed biopsy should be
treatment or to be monitored with a policy to initiate secondary treatment if
considered in patients with PSA persistence/recurrence after RP if their life
PSA levels reached 0.1 ng/mL or rose three consecutive times.439
expectancy is >5 years. The utility of imaging for patients with an early
Participants were followed for a median 4.9 years and no differences were
biochemical recurrence after radical prostatectomy depends on disease
seen in 5-year biochemical PFS and freedom from non-protocol hormone
risk before operation and pathologic stage, Gleason grade, PSA, and
therapy. There was no statistically significant difference in the primary
PSADT after recurrence. Patients with low- and intermediate-risk disease

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endpoint of freedom from distant metastasis between the arms at 10 years Immediate adjuvant treatment with EBRT with or without ADT is one
(93% in the adjuvant arm vs. 90% in the early secondary therapy arm; approach for these patients based on historic data.448 However,
95% CI, 0.43–1.07; P = .095) and there was no difference in OS.438 retrospective data show that initial observation may be safe in some
Importantly, urinary incontinence and grade 3–4 urethral strictures were patients with pN1 disease at radical prostatectomy, because 28% of a
more frequent in the adjuvant therapy group. cohort of 369 patients remained free from biochemical recurrence at 10
years.449 Therefore, another option is monitoring with consideration of
The GETUG-AFU 17 trial and the TROG 08.03/ANZUP RAVES trial were early secondary treatment for a detectable and rising PSA or PSA >0.1
both terminated early for unexpectedly low event rates, but similarly found ng/mL. However, RADICALS-RT, GETUG-AFU 17, and TROG
no evidence of oncologic benefit with increased risk of genitourinary 08.03/ANZUP RAVES have very few pN1 patients that were enrolled.439-441
toxicity and erectile dysfunction when an adjuvant therapy approach was
used.440,441 One small randomized trial in Finland (n = 126) saw a An analysis of the National Cancer database identified 8074 patients with
significant improvement in 10-year survival for biochemical recurrence with lymph node metastases after radical prostatectomy. 450 The results
the use of adjuvant therapy in patients with positive margins or indicate that immediate adjuvant EBRT and ADT improved OS compared
extracapsular extension (HR, 0.26; 95% CI, 0.14–0.48; P < .001).442 to monitoring for those who also had adverse pathologic features but not
However, there was no difference in OS, and grade 3 adverse events for those without these features. Therefore, use of early secondary
were significantly higher in the adjuvant arm. radiotherapy can be considered for patients with pN1 disease, with careful
patient selection and monitoring.
Several meta-analyses have also shown that adjuvant radiotherapy
improved biochemical control, but not overall survival, in patients with The addition of abiraterone to EBRT with ADT can also be considered for
adverse features and that the approach leads to a higher incidence of patients with positive lymph after surgery (category 2B). However, these
adverse events, though some noted that careful patient selection is patients comprised <5% of patients on the STAMPEDE trial, and caution
warranted.437,443-445 Real world evidence supports the safety of this is warranted with extrapolation of data from cN1 disease.394
approach for most patients.446,447
Secondary Treatment for PSA Persistence or Biochemical
The Panel notes immediate adjuvant radiation may be reasonable for Recurrence After Radical Prostatectomy
patients with multiple adverse features, a population that was under- The timing of secondary treatment for patients whose only evidence of
represented in the above-mentioned clinical trials. True noninferiority of cancer after radical prostatectomy is a persistent or increasing PSA is
the delayed, early secondary therapy approach has not been influenced by PSA levels, PSADT, and the underlying comorbidities of the
demonstrated in patients with a high risk of recurrence after surgery. patient. PSADT should be calculated to inform nomogram use and
counseling for patients with PSA persistence or recurrence after radical
Adjuvant or Early Secondary Therapy for pN1
prostatectomy. Early secondary treatment (at a PSA of 0.1–0.2 ng/mL) is
Patients with positive lymph nodes found during or after radical recommended for most patients who experience a biochemical recurrence
prostatectomy have several disease management options to consider. after RP. However, patients who have a delayed recurrence (eg, many
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years post-RP) with very slow PSA doubling times (ie, >24 months) can node metastases (category 2B), based on extrapolation from
consider delaying secondary treatment, especially if they have limited life STAMPEDE.394
expectancy.
Monitoring patients without evidence of M1 disease in the setting of PSA
For those with PSA persistence or recurrence after RP without evidence of persistence or a rising PSA post-RP is another option, especially if the risk
M1 disease, secondary treatment with EBRT is the preferred approach. of rapid progression appears to be low based on factors such as PSA
Large retrospective cohort studies support the use of EBRT in the setting levels, PSADT, and results of nomograms and with consideration of
of biochemical recurrence, because it is associated with decreased all- patient age and comorbidities. It is important to note that some patients
cause mortality and increased prostate cancer-specific survival.451,452 have detectable PSA after radical prostatectomy due to benign prostate
tissue in the prostate fossa. They have low stable PSAs and a very low
Numerous phase 3 randomized trials have evaluated the role of hormone risk of prostate cancer progression.460,461 Serial PSA measurements can
therapy with secondary EBRT in this setting, as well as a harmonized be helpful for stratifying patients at highest risk of progression and
aggregate meta-analysis.453-457 In general, these studies have metastases.
demonstrated that 6 to 24 months of hormone therapy improved outcomes
primarily for patients receiving late secondary RT (PSA levels >0.5 Post-Radiation Recurrence
ng/mL), but a smaller or no benefit is clear at lower PSA levels. For The 2006 Phoenix definition was revised by ASTRO and the RTOG in
example, RTOG 9601 demonstrated an OS benefit with 2 years of Phoenix: 1) PSA rise by 2 ng/mL or more above the nadir PSA is the
bicalutamide with secondary EBRT, but enrolled patients primarily standard definition for biochemical recurrence after EBRT with or without
receiving late secondary EBRT.458 In contrast, the RADICALS-HD trial hormonal therapy; and 2) A recurrence evaluation should be considered
randomized patients to post-operative EBRT with or without 6 months of when PSA has been confirmed to be increasing after radiation even if the
ADT and enrolled mostly adjuvant or early secondary EBRT patients. They rise above nadir is not yet 2 ng/mL, especially in candidates for additional
showed that ADT did not improve MFS or OS. The DADSPORT meta- local therapy who are young and healthy.462 Retaining a strict version of
analysis did not show an OS benefit for the addition of ADT in patients the ASTRO definition allows comparison with a large existing body of
receiving early secondary RT, although an MFS and PCSS benefit were literature. Rapid increase of PSA may warrant evaluation (prostate biopsy)
seen.459 prior to meeting the Phoenix definition, especially in younger or healthier
patients.
Based on these data, short-term ADT is generally recommended to
balance toxicity, QOL, and tumor control. However, long-term ADT may be Workup for PSA recurrence or a positive DRE after RT for a patients with
preferred for patients receiving late secondary RT and/or those with a life expectancy >5 years typically includes PSADT calculation, bone and
multiple adverse pathologic features or lymph node involvement. soft tissue imaging, and consideration of a prostate/seminal vesicle
biopsy. Biopsy is particularly useful if the staging workup does not reveal
There remains no randomized data to support the addition of an ARPI to
EBRT and ADT. However, abiraterone is an option for patients with lymph

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metastatic disease and local recurrence is suspected. The junction of the second biochemical recurrence. A staging workup with imaging is
seminal vesicle and prostate is a common site of recurrence. recommended. For patients without evidence of lymph node or distant
metastases, risk stratification is essential to determine treatment options
Local radiation recurrences are most responsive to additional therapy and is based mainly on PSA levels and PSADT. The definition of high-risk
when PSA levels at the time of treatment are low (<5 ng/mL). Options for second biochemical recurrence differs between clinical trials but is
therapy for those without evidence of distant metastases include generally considered to include patients with a PSADT ≤9 months and
monitoring with physical exam, PSA every 3 to 6 months, and imaging for other adverse prognostic features.
symptoms or increasing PSA. For those deemed to be at higher risk of
rapid progression, treatment options are ADT and local secondary therapy For individuals deemed to be a low risk of rapid disease progression,
with or without ADT. For those with positive lymph nodes, abiraterone can monitoring until diagnosis of metastatic disease is preferred. ADT
be added. Treatment should be individualized based on the patient's risk monotherapy is also an option, and PSA levels and PSADT should be
of progression and the potential benefits and risks involved with each considered when deciding whether to begin ADT.
option.
For patients deemed to be at high risk of rapid disease progression,
Local secondary therapy options in the setting of RT recurrence include treatment intensification can be considered based on results of two trials
cryotherapy,463 HIFU,464-469 IRE470,471 (category 2B), reirradiation, and RP as discussed below. Monitoring and ADT are equally reasonable options
with PLND. The Panel recommends that patients receive multidisciplinary for these patients, and shared decision-making is key.
counseling about the risks and benefits of each of these options in the
context of the available comparative literature on this topic.472,473 In the phase 3 EMBARK trial, 1068 patients with prostate cancer and high-
Reirradiation options include LDR brachytherapy, HDR brachytherapy, risk biochemical recurrence were randomly assigned into one of three
and SBRT based on phase II and other prospective and retrospective groups using a 1:1:1 ratio.478 The “combination group” received
studies.412,474-476 Radical prostatectomy after RT recurrence can result in enzalutamide (160 mg/day) plus leuprolide, the “leuprolide-alone group”
long-term disease control, but is often associated with impotence and received placebo plus leuprolide, and the “monotherapy group” received
urinary incontinence.477 Overall, there is limited evidence for these enzalutamide alone. Eligibility for the trial included the following high-risk
approaches, and the Panel recommends that patients receiving local criteria: M0 by CT, MRI, or bone scan; PSADT ≤9 months; PSA ≥2 ng/mL
therapy for RT recurrence are treated within the context of clinical trials above nadir after RT or ≥1 ng/mL after radical prostatectomy with or
when available and/or at experienced centers. without postoperative RT; and patients were not considered a candidate
for pelvic-directed therapy. Patients were monitored for a median follow-up
Second Biochemical Recurrence time of 60.7 months. The trial demonstrated that the primary endpoint,
metastasis-free survival, was significantly improved for enzalutamide plus
Patients who have been treated for recurrence after definitive therapy for
leuprolide (HR for metastasis or death, 0.42; 95% CI, 0.30–0.61; P < .001)
localized prostate cancer may continue to experience a rise in PSA levels
and for enzalutamide alone (HR, 0.63; 95% CI, 0.46–0.87; P = .005) when
without developing metastases. The Panel refers to this disease setting as

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compared to leuprolide alone. The most common adverse events across treatment arms were hot flashes (78%), fatigue (55%), injection site
associated with combination therapy and enzalutamide monotherapy were reaction (33%), and hypertension (31%). Hypertension was the most
hot flashes and fatigue. Enzalutamide monotherapy was also significantly common grade ≥3 adverse event, experienced in 7%, 8%, and 19% of
associated with gynecomastia (45% compared with 8% to 9% in the patients in arms A, B, and C, respectively. Even though the study was not
combination and leuprolide alone groups), nipple pain (15% compared designed to directly compare the two experimental arms, there was not
with 1%–3%), and breast tenderness (14% compared with 1%). Based on shown to be further clinical benefit with the addition of AAP to apalutamide
these results, the Panel includes enzalutamide with or without leuprolide with ADT. Based on the results of this study, the Panel includes
as options for patients with high-risk biochemical recurrence after maximal apalutamide plus ADT as a category 2B option for patients with non-
pelvic therapy in the absence of metastatic disease. metastatic disease and high-risk of biochemical recurrence after radical
prostatectomy who have received maximal pelvic therapy.
In the phase 3 PRESTO trial, 503 patients with biochemically recurrent
prostate cancer were randomly assigned into one of three groups using a Androgen Deprivation Therapy
1:1:1 ratio.479 The three arms of the study included: ADT alone (control ADT is administered as primary systemic therapy for regional or advanced
arm A), ADT plus apalutamide (experimental arm B), or ADT plus disease and as neoadjuvant/concomitant/adjuvant therapy in combination
apalutamide plus abiraterone acetate/prednisone (AAP; experimental arm with radiation in patients with unfavorable-intermediate or higher risk
C). The dose of apalutamide was 240mg/day. To be eligible for the trial, localized prostate cancers. It is also used as palliative therapy for
patients had prostate cancer with biochemical recurrence after radical symptomatic patients with a life expectancy ≤5 years.
prostatectomy and the following high-risk criteria: PSADT ≤9 months; PSA
≥0.5 ng/mL; and prior adjuvant or secondary RT or not considered a Placing patients with early prostate cancer on ADT should not be routine
candidate for RT. The planned duration of treatment was 52 weeks. The practice.480,481 Bicalutamide monotherapy is not recommended to be used
primary endpoint of PSA progression-free survival (PSA-PFS) was met in and is recommended when used to be in combination with ADT as per the
patients in both experimental arms. PSA progression was defined as FDA label.
serum PSA >0.2 ng/mL after completion of treatment. At the first interim
analysis (median follow-up of 21.3 and 21.5 months in arms B and C, Medical castration (ie, LHRH agonist or antagonist) and surgical castration
respectively), both experimental arms had significant prolongation of PSA- (ie, bilateral orchiectomy) are equally effective options for ADT. Castrate
PFS compared to the control arm (ADT plus apalutamide, 24.9 months; levels of serum testosterone (<50 ng/dL; <1.7 nmol/L) should be achieved,
ADT plus apalutamide plus AAP, 26.0 months; ADT alone, 20.3 months). because low nadir serum testosterone levels were shown to be associated
For the comparison of ADT with and without apalutamide, the HR was with improved cause-specific survival in the PR-7 study.482 Patients who
0.52 (95% CI, 0.35–0.77; P = .00047), and for the comparison of ADT plus do not achieve adequate suppression of serum testosterone (<50 ng/dL)
apalutamide/AAP the HR was 0.48 (95% CI, 0.32–0.71; P = .00008). with medical or surgical castration can be considered for additional
There was no difference in median time to testosterone recovery across hormonal manipulations (with antiandrogens, LHRH antagonists, or
treatment arms. The most prevalent treatment-associated adverse events steroids), although the clinical benefit remains uncertain. Monitoring

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testosterone levels 12 weeks after first dose of LHRH therapy and upon Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for Unfavorable
increase in PSA should be considered. Intermediate-Risk Disease
The MARCAP consortium performed an individual patient meta-analysis of
The LHRH antagonist, relugolix, has been studied as ADT in patients with nearly every randomized trial assessing the use and prolongation of ADT
localized and advanced prostate cancer.483,484 In the HERO study, 622 with EBRT in localized prostate cancer.382 They demonstrated that the
patients received relugolix (120 mg orally once daily) and 308 received addition of 4 to 6 months of ADT improved OS for patients with
leuprolide (injections every 3 months) for 48 weeks. Sustained castrate intermediate- and high-risk disease. Additionally, the prolongation of
levels of testosterone (<50 ng per deciliter) through 48 weeks was adjuvant ADT for a total duration of 18 to 36 months further improved OS
superior with relugolix over leuprolide (96.7%; 95% CI, 94.9–97.9 vs. for patients primarily with high-risk prostate cancer. However, the
88.8% [95% CI, 84.6–91.8]; P < .001 for superiority). Time to castration prolongation of neoadjuvant ADT for multiple months did not significantly
and testosterone recovery were both faster in the relugolix arm. The improve biochemical control, MFS, or OS. Furthermore, post-hoc analyses
incidence of major adverse cardiovascular events was 2.9% in the of RTOG 9408 and subgroup analyses of RTOG 0815 demonstrate that
relugolix arm and 6.2% in the leuprolide arm (HR, 0.46; 95% CI, 0.24– patients with multiple intermediate-risk features have a greater absolute
0.88). benefit from ADT than those with a single intermediate-risk factor.381,383

ADT for Initial Treatment of Clinically Localized (N0,M0) Disease Thus, the Panel recommends 4 to 6 months of ADT when EBRT is given
ADT should not be used as monotherapy in clinically localized prostate to patients as initial treatment of unfavorable intermediate-risk prostate
cancer unless there is a contraindication to definitive local therapy, such cancer.
as life expectancy less than 5 years and comorbidities (see Palliative ADT,
Two randomized phase 3 trials assessed the optimal sequencing of ADT
below).
with EBRT: RTOG 9413 and the Ottawa 0101 trials.485 These trials were
In the clinically localized setting, ADT using an LHRH agonist—alone or pooled in an individual patient meta-analysis and demonstrated that
with a first-generation antiandrogen—or an LHRH antagonist can be used concurrent/adjuvant ADT significantly improved biochemical control,
as a neoadjuvant, concurrent, and/or adjuvant to EBRT in patients with distant metastasis, and MFS over a neoadjuvant/concurrent approach.
unfavorable intermediate-, high-, or very-high-risk prostate cancer, as Thus, concurrent/adjuvant ADT is preferred over neoadjuvant ADT in this
described in more detail below. setting.

ADT used as neoadjuvant treatment before radical prostatectomy is Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for High-Risk or
Very-High-Risk Disease
strongly discouraged outside of a clinical trial.
ADT combined with EBRT is an effective treatment for patients with high-
risk or very-high-risk disease, as discussed in the Radiation Therapy
section above. Combination therapy was consistently associated with

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improved disease-specific survival and OS compared to single-modality Another option for the treatment of patients initially diagnosed with node-
treatment in randomized phase 3 studies.382,388,389,486-488 positive disease is primary ADT. Primary ADT options are orchiectomy, an
LHRH agonist, an LHRH agonist with a first-generation antiandrogen, or
Evidence favors long-term over short-term ADT for patients with high- and an LHRH antagonist; or orchiectomy, LHRH agonist, or LHRH antagonist
very-high-risk disease. MARCAP performed an individual patient level with abiraterone.
meta-analysis of every randomized trial that compared short-term versus
long-term ADT with radiotherapy.382 This study demonstrated that long- Palliative ADT
term ADT significantly improved MFS and OS over short-term ADT, with a Palliative ADT can be given to patients with a life expectancy of ≤5 years
greater absolute benefit in patients with high-/very high-risk disease as who have regional or metastatic prostate cancer. Palliative ADT also can
compared with intermediate-risk disease. be given to patients with disease progression during observation, usually
when symptoms develop or when changes in PSA levels suggest that
While the TROG RADAR trial demonstrated that in patients who received
symptoms are imminent. The options in this setting are orchiectomy,
EBRT+HDR brachytherapy boost had an OS benefit from 18 months of
LHRH agonist, or LHRH antagonist.
ADT versus 6 months, the ASCENDE-RT trial of EBRT+LDR
brachytherapy boost utilized only 12 months as their fixed duration of Primary ADT for mCSPC
ADT.385,410 Thus, it may be reasonable for select patients with high-risk
ADT is strongly recommended in combination therapy for mCSPC (see
disease (not very high-risk) to use 12 months of ADT if receiving EBRT
Management of mCSPC, below). The use of ADT monotherapy in this
and LDR brachytherapy per the ASCENDE-RT trial regimen.
setting is discouraged unless there are clear contraindications to
ADT for Initial Treatment of Regional Disease combination therapy. If ADT monotherapy is given, intermittent ADT can
be considered to reduce toxicity. Close monitoring of PSA and
One option for patients with regional disease is EBRT with 2 to 3 years of
testosterone levels and possibly imaging is required when using
neoadjuvant/concurrent/adjuvant ADT with or without abiraterone.
intermittent ADT, especially during off-treatment periods, and patients may
Neoadjuvant/concurrent/adjuvant ADT options are an LHRH agonist, an
need to switch to continuous ADT upon signs of disease progression. ADT
LHRH agonist with a first-generation antiandrogen, or an LHRH
options for mCSPC include orchiectomy, LHRH agonist, or LHRH
antagonist. Abiraterone should not be co-administered with an
antagonist with various ARPIs and/or docetaxel. Metastasis-directed
antiandrogen.
therapy or EBRT to the primary tumor are also options for certain patients.
Data regarding the treatment of cN1 disease is limited. Exploratory Specific recommendations depend on prior therapy and volume of disease
analysis of STAMPEDE suggested that there may be benefit to the use of as described in more detail below (see Management of mCSPC).
RT in this setting.489 Failure-free survival was better in those for whom RT
In patients with overt metastases in weight-bearing bone who are at risk of
was planned than for those receiving ADT alone (HR, 0.48; 95% CI, 0.29–
developing symptoms associated with the flare in testosterone with initial
0.79).
LHRH agonist alone, antiandrogen therapy should precede or be

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coadministered with LHRH agonist for at least 7 days to diminish ligand was heterogenous, so it remains unclear which of these asymptomatic
binding to the androgen receptor.490,491 LHRH antagonists rapidly and patients benefited from treatment. It is possible that many of these patients
directly inhibit the release of androgens, unlike LHRH agonists that initially could have delayed ADT without harm. The population had a low disease
stimulate LHRH receptors prior to hypogonadism. Therefore, no initial flare burden, and 59% of deaths in the trial were not related to prostate cancer.
is associated with these agents and coadministration of antiandrogen is Follow-up longer than 6.9 years may be required for disease-specific
unnecessary. deaths to out-balance deaths by other causes.

Intermittent Versus Continuous ADT The multinational European ICELAND trial randomized 702 participants
ADT is associated with substantial side effects, which generally increase with locally advanced or biochemically recurrent prostate cancer to
with the duration of treatment. Intermittent ADT is an approach based on continuous or intermittent ADT.495 Clinical outcomes, which included time
the premise that cycles of androgen deprivation followed by re-exposure to PSA progression, PSA PFS, OS, mean PSA levels over time, QOL, and
may delay “androgen independence,” reduce treatment morbidity, and adverse events, were similar between the arms.
improve QOL.492,493 Some patients who have no ADT-related morbidity
A 2015 meta-analysis identified 6 randomized controlled trials comparing
may find the uncertainty of intermittent ADT not worthwhile. Intermittent
continuous with intermittent ADT in patients with locally advanced prostate
ADT requires close monitoring of PSA and testosterone levels, especially
cancer and found no difference in mortality and progression and an
during off-treatment periods, and patients may need to switch to
advantage of the intermittent approach in terms of QOL and adverse
continuous therapy upon signs of disease progression.
effects.496
Intermittent ADT in Non-Metastatic Disease
Therefore, the Panel believes that patients receiving ADT for M0 recurrent
The Canadian-led PR.7 trial was a phase 3 trial of intermittent versus
disease can consider intermittent ADT based on shared decision making.
continuous ADT in patients with non-metastatic prostate cancer who
experienced biochemical recurrence after primary or post-recurrence Intermittent ADT in Metastatic Disease
EBRT.494 One thousand three hundred eighty-six patients with PSA >3 Hussain and colleagues497 conducted the SWOG (Southwest Oncology
ng/mL were randomly assigned to intermittent ADT or continuous ADT. At Group) 9346 trial to compare intermittent and continuous ADT in patients
a median follow-up of 6.9 years, the intermittent approach was noninferior with metastatic disease. After 7 months of induction ADT, 1535 patients
to continuous ADT with respect to OS (8.8 vs. 9.1 years, respectively; HR, whose PSA dropped to 4 ng/mL or below (thereby demonstrating
1.02; 95% CI, 0.86–1.21). More patients died from prostate cancer in the androgen sensitivity) were randomized to intermittent or continuous ADT.
intermittent ADT arm (120 of 690 patients) than in the continuous ADT arm At a median follow-up of 9.8 years, median survival was 5.1 years for the
(94 of 696 patients), but this was balanced by more non-prostate cancer intermittent ADT arm and 5.8 years for the continuous ADT arm. The HR
deaths in the continuous ADT arm. Physical function, fatigue, urinary for death with intermittent ADT was 1.10 with a 90% CI between 0.99 and
problems, hot flashes, libido, and erectile dysfunction showed modest 1.23, which exceeded the prespecified upper boundary of 1.20 for
improvement in the intermittent ADT group. The population of participants noninferiority. The authors stated that the survival results were

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inconclusive, and that a 20% greater mortality risk with the intermittent Adverse Effects of Traditional ADT
approach cannot be ruled out. The study demonstrated better erectile ADT has a variety of adverse effects including hot flashes, vasomotor
function and mental health in patients receiving intermittent ADT at 3 instability, loss of libido, erectile dysfunction, shrinkage of penis and
months, but the difference became insignificant thereafter, most likely due testicles, loss of muscle mass and strength, fatigue, anemia, breast
to contamination on the intermittent arm of patients who may have enlargement and tenderness/soreness, depression and mood swings, hair
returned to continuous ADT at the prespecified time points. A secondary loss, osteoporosis, greater incidence of clinical fractures, obesity, insulin
analysis of SWOG 9346 showed that intermittent ADT did not reduce resistance, alterations in lipids, and greater risk for diabetes, acute kidney
endocrine, bone, or cognitive events, whereas it led to an unexpected injury, and cardiovascular disease.504-506 The intensity and spectrum of
increase in the incidence of ischemic and thrombotic events.498 these side effects vary greatly. In general, the side effects of continuous
ADT increase with the duration of treatment. In addition, some forms of
In a post-hoc stratification analysis of the trial, patients with minimal
ADT may result in lower risk than others. For example, post-hoc analysis
disease had a median survival of 5.4 years when receiving intermittent
of a randomized trial of LHRH antagonist versus LHRH agonist found
ADT versus 6.9 years when receiving continuous ADT (HR, 1.19; 95% CI,
lower risk of cardiac events in patients with existing cardiac disease
0.98–1.43).497 The median survival was 4.9 years in the intermittent ADT
treated with LHRH antagonist.507 In addition, relugolix was associated with
arm compared to 4.4 years in the continuous ADT arm for patients with
a lower risk of major adverse cardiovascular events than leuprolide in the
extensive disease (HR, 1.02; 95% CI, 0.85–1.22). These subgroup
phase 3 HERO study, although the FDA considered these results in
analyses are hypothesis-generating.
HERO to be exploratory and therefore did not allow for these data to be
A population-based analysis that included 9772 patients ≥66 years with included in the prescribing information for relugolix.483 Results from the
advanced prostate cancer showed that intermittent ADT reduced the risks randomized controlled PRONOUCE trial suggest that there is no
of total serious cardiovascular events by 36%, heart failure by 38%, and difference in cardiovascular safety between LHRH agonists and
pathologic fracture by 48%, compared with continuous ADT.499 antagonists.508 However, all patients had cardiovascular risk factors
Furthermore, several meta-analyses of randomized controlled trials optimized or addressed in both arms, which does not reflect real world
reported no difference in survival between intermittent ADT and practice.
continuous ADT,500-502 although another analysis concluded that the non-
Some evidence suggests that orchiectomy may be safer than an LHRH
inferiority of intermittent to continuous ADT in terms of survival has not
agonist. The heart and T lymphocytes have receptors for LHRH.
been clearly demonstrated.503 Still, the intermittent approach leads to
Therefore, LHRH agonists may affect cardiac contractility, vascular plaque
marked improvement in QOL compared to the continuous approach in
stability, and inflammation.509 Four hundred twenty-nine patients with
most studies, and the Panel believes that intermittent ADT should be
metastatic prostate cancer who underwent orchiectomy were compared to
strongly considered in appropriate patients with metastatic disease.
2866 patients who received LHRH agonist between 1995 and 2009.510
Orchiectomy was associated with lower risk of fracture, peripheral arterial
disease, and cardiac-related complications, although risk was similar for

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diabetes, deep vein thrombosis, pulmonary embolism, and cognitive treatment-related sarcopenia appears to contribute to frailty and increased
disorders. risk of falls in patients who are older.

Evidence suggests that a link between ADT and cognitive decline, The NCCN Guidelines Panel recommends screening and treatment for
dementia, or future Alzheimer’s disease may exist, although data are osteoporosis according to guidelines for the general population from the
inconsistent, the risk is low, and the link remains to be proven.511-518 Some Bone Health and Osteoporosis Foundation, as outlined in the algorithm
data suggests that the risk of cognitive effects may be increased with the above.528
addition of a second-generation ARPI.519
Earlier randomized controlled trials demonstrated that bisphosphonates
Patients and their medical providers should be advised about these risks increase bone mineral density, a surrogate for fracture risk, during ADT.529-
prior to treatment. Many side effects of ADT are reversible or can be 531
In 2011, the FDA approved denosumab as a treatment to prevent bone
avoided or mitigated. For example, physical activity can counter many of loss and fractures during ADT. Denosumab binds to and inhibits the
these symptoms and should be recommended (see NCCN Guidelines for receptor activator of NF-B ligand (RANKL) to blunt osteoclast function
Survivorship, available at [Link]). Specific recommendations for and delay generalized bone resorption and local bone destruction.
bone and cardiovascular health are included in the Principles of Approval was based on a phase 3 study that randomized 1468 patients
Survivorship in Prostate Cancer in the algorithm above and in the text that with non-metastatic prostate cancer undergoing ADT to either biannual
follows. denosumab or placebo. At 24 months, denosumab increased bone
mineral density by 6.7% and reduced fractures (1.5% vs. 3.9%) compared
Bone Health During ADT
to placebo.532 Denosumab also was approved for prevention of SREs in
Medical or surgical ADT is associated with greater risk for osteoporosis
patients with bone metastasis (see Chemotherapy, Immunotherapy, and
and clinical fractures. In large population-based studies, for example, ADT
Targeted Therapy).
was associated with a 21% to 54% relative increase in fracture risk.520-522
Longer treatment duration conferred greater fracture risk. Age and Currently, treatment with denosumab, zoledronic acid, or alendronate is
comorbidity also were associated with higher fracture incidence. In a recommended when the absolute fracture risk warrants drug therapy, as
population-based cohort of 3295 patients, surgical castration was outlined in the algorithm above. A baseline DEXA scan before start of
associated with a significantly lower risk of fractures than medical therapy and a follow-up DEXA scan after 1 year of therapy is
castration using an LHRH agonist (HR, 0.77; 95% CI, 0.62–0.94; recommended by the International Society for Clinical Densitometry to
P = .01).509 ADT increases bone turnover and decreases bone mineral monitor response. Use of biochemical markers of bone turnover is not
density,523-526 a surrogate for fracture risk in patients with non-metastatic recommended. There are no existing guidelines on the optimal frequency
disease. Bone mineral density of the hip and spine decreases by of vitamin D testing.
approximately 2% to 3% per year during initial therapy. Most studies have
reported that bone mineral density continues to decline steadily during
long-term therapy. ADT significantly decreases muscle mass,527 and

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Diabetes and Cardiovascular Disease Management of mCSPC

Cardiovascular disease and diabetes are leading causes of morbidity and
ADT with treatment intensification is strongly recommended for patients
mortality in the general population. Cardiovascular disease is also a with metastatic castration-sensitive prostate cancer (mCSPC). The use of
leading cause of death in patients with prostate cancer.533 In a landmark
ADT monotherapy in this setting is discouraged unless there are clear
population-based study, ADT was associated with higher incidence of contraindications to combination therapy. Treatment intensification options
diabetes and cardiovascular disease.534 After controlling for other include doublet therapy of ADT with an androgen receptor pathway
variables, which included age and comorbidity, ADT with an LHRH agonist
inhibitor (ARPI; abiraterone, apalutamide, darolutamide, or enzalutamide);
was associated with increased risk for new diabetes (HR, 1.44; P < .001), triplet therapy of ADT with docetaxel and one of the same ARPIs;
coronary artery disease (HR, 1.16; P < .001), and myocardial infarction
metastasis-directed therapy (MDT) for oligometastases (see MDT for
(HR, 1.11; P = .03). More recent data show that the main cause for the Oligometastatic CSPC, below); or ADT with EBRT to the primary tumor
increased risk in cardiovascular disease in this population is the use of with or without docetaxel, abiraterone, apalutamide, or enzalutamide for
ADT and ARPIs.535,536 low-metastatic burden (see EBRT to the Primary Tumor in Low-Metastatic-
Importantly, increased physical activity may decrease the symptoms and Burden M1 Disease, above). The specific recommended therapy options
cardiovascular side effects of patients treated with ADT.537 Management of vary depending on whether the metastases were diagnosed in the
modifiable cardiovascular disease risk factors can also decrease the risk synchronous or metachronous setting and on whether disease is
of subsequent cardiovascular events. oligometastatic, low-volume metastatic, or high-volume metastatic.

The data supporting doublet or triplet therapy in this setting are discussed
ADT may also prolong the QT/QTc interval. Providers should consider
whether the benefits of ADT outweigh the potential risks in patients with below. For some of the combinations recommended by the Panel,
supporting data are limited. They are included based on extrapolation from
congenital long QT syndrome, congestive heart failure, and frequent
electrolyte abnormalities, and in patients taking drugs known to prolong the studies of other agents, since the Panel considers the four ARPIs with
approval in prostate cancer to be generally interchangeable.
the QT interval. Electrolyte abnormalities should be corrected, and
periodic monitoring of electrocardiograms and electrolytes should be
Doublet Therapies for mCSPC
considered.
Abiraterone Acetate in mCSPC
Based on the observed adverse metabolic effects of ADT and the In February 2018, the FDA approved abiraterone in combination with
association between ADT and higher incidence of diabetes and prednisone for mCSPC. This approval was based on two randomized
cardiovascular disease, screening for and intervention to prevent/treat phase 3 clinical trials of abiraterone and low-dose prednisone plus ADT in
diabetes and cardiovascular disease are recommended for patients patients with newly diagnosed metastatic prostate cancer or high-risk or
receiving ADT, as described in the Principles of Survivorship in Prostate node-positive disease (STAMPEDE and LATITUDE) that demonstrated
Cancer, in the algorithm above. improved OS over ADT alone.538

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In LATITUDE, 1199 patients with high-risk mCSPC were randomized to STAMPEDE eligibility permitted patients with high-risk N0,M0 disease (2
abiraterone with prednisone 5 mg once daily or matching placebos. High- of 3 high-risk factors: stage T3/4, PSA >40, or Gleason score 8–10; n =
risk disease was defined as at least two of the following: Gleason score 8– 509), or N1,M0 disease (pelvic nodal metastases; n = 369) in addition to
10, ≥3 bone metastases, and visceral metastases.538 Efficacy was patients with metastatic disease, who made up the majority of patients (n
demonstrated at the first interim analysis, and the trial was unblinded. The = 941). Most patients were newly diagnosed, while a minority had
primary endpoint of OS was met and favored abiraterone (HR, 0.62; 95% recurrent, high-risk, or metastatic disease after local therapy (n = 98).
CI, 0.51–0.76; P < .0001). Estimated 3-year OS rates improved from 49% Thus, STAMPEDE was a heterogeneous mix of patients with high-risk,
to 66% at 30-month follow-up. Secondary endpoints were improved and non-metastatic, node-positive, or metastatic disease. In patients with M1
included delayed castration-resistant radiographic progression (from disease, treatment with abiraterone plus prednisone was continued until
median 14.8–33.2 months), PSA progression (7.4–33.2 months), time to progression. In patients with N1 or M0 disease, 2 years of abiraterone plus
pain progression, and initiation of chemotherapy. After the first interim prednisolone was used if curative-intent EBRT was utilized. OS was
analysis, 72 patients crossed over from placebo to abiraterone. Final OS improved in the overall population (HR, 0.63; 95% CI, 0.5–0.76; P < .0001)
analysis of LATITUDE after a median follow-up of 51.8 months showed and in the M1 and N1 subsets, without any heterogeneity of treatment
median OS was significantly longer in the abiraterone group than in the effect by metastatic status. The survival benefit of abiraterone was larger
placebo group (53.3 vs. 36.5 months; HR, 0.66; 95% CI, 0.56–0.78; P < in patients <70 years of age than those ≥70 years (HR, 0.94 vs. HR, 0.51).
.0001).539 Patients ≥70 years also suffered increased toxicities, which suggests
heterogeneity in clinical benefits by age and comorbidity. The secondary
Adverse events were higher with abiraterone and prednisone but were endpoint of FFS, which included PSA recurrence, was improved overall
generally mild in nature and largely related to mineralocorticoid excess (ie, (HR, 0.29; P < .0001) and in all subgroups regardless of M1 (HR, 0.31),
hypertension, hypokalemia, edema), hormonal effects (ie, fatigue, hot N1 (HR, 0.29), or M0 (HR, 0.21) status. No heterogeneity for FFS was
flushes), and liver toxicity.538 Cardiac events, such as atrial fibrillation, observed based on subgroups or by age. In this trial, subsequent life-
were rare but slightly increased with abiraterone. The overall prolonging therapy was received by 58% of those in the control group,
discontinuation rate due to side effects was 12%. Patient-reported which included 22% who received abiraterone and 26% who received
outcomes were improved with the addition of abiraterone, with enzalutamide. Thus, these data reflect a survival advantage of initial
improvements in pain intensity progression, fatigue, functional decline, abiraterone in newly diagnosed patients compared with deferring therapy
prostate cancer-related symptoms, and overall health-related QOL.540 A to the CRPC setting.
limitation of this trial is that only 27% of placebo-treated patients received
abiraterone or enzalutamide at progression, and only 52% of these Adverse events in STAMPEDE were similar to that reported in LATITUDE,
patients received any life-prolonging therapy.538 but were increased in patients ≥70 years, with higher incidences of grade
3–5 adverse events with abiraterone (47% vs. 33%) and 9 versus 3
The second randomized trial (STAMPEDE) of 1917 patients with CSPC treatment-related deaths. Severe hypertension or cardiac disorders were
demonstrated similar OS benefits.541 However, unlike LATITUDE, noted in 10% of patients and grade 3–5 liver toxicity in 7%, which

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illustrates the need for blood pressure and renal and hepatic function Apalutamide is a category 1 option for patients with mCSPC. The FDA
monitoring. approved this indication in September 2019.

Taken together, these data led the NCCN Panel to recommend Enzalutamide in mCSPC
abiraterone with 5-mg once-daily prednisone as a treatment option with The open-label randomized phase 3 ENZAMET clinical trial compared
ADT for patients with newly diagnosed mCSPC (category 1). Alternatively, enzalutamide (160 mg/day) plus ADT (LHRH analog or surgical castration)
the fine-particle formulation of abiraterone can be used with 4 mg with a first-generation antiandrogen (bicalutamide, nilutamide, or
methylprednisolone PO twice daily (category 2B; see Abiraterone Acetate flutamide) plus ADT in 1125 patients with mCSPC.546 Stratification was by
in mCRPC, below). volume of disease, planned use of early docetaxel, planned use of bone
antiresorptive therapy, comorbidity score, and trial site. The primary
The standard formulation of abiraterone can be given at 250 mg/day and endpoint of OS was met at the first interim analysis with median follow-up
administered following a low-fat breakfast as an alternative to the dose of of 34 months (HR for death, 0.67; 95% CI, 0.52–0.86; P = .002).
1000 mg/day after an overnight fast (see Abiraterone Acetate in mCRPC, Enzalutamide also improved secondary endpoints, such as PFS using
below).542 The cost savings may reduce financial toxicity and improve PSA levels and clinical PFS. An additional analysis was triggered at 470
adherence in those who will not take or cannot afford the standard dose. deaths.547 After a median follow-up of 68 months, the 5-year OS rate was
again lower in the first-generation antiandrogen group than in the
Apalutamide in mCSPC
enzalutamide group (HR, 0.70; 95% CI, 0.58–0.84; P < .0001). The
The double-blind phase 3 TITAN clinical trial randomized 1052 patients
median OS was not reached.
with mCSPC to ADT with apalutamide (240 mg/day) or placebo.543
Participants were stratified by Gleason score at diagnosis, geographic In the double-blind randomized phase 3 ARCHES clinical, 1150 patients
region, and previous docetaxel treatment. The median follow-up was 22.7 with mCSPC were randomized to receive ADT with either enzalutamide
months. Both primary endpoints were met: radiographic PFS (68.2% vs. (160 mg/day) or placebo. Participants were stratified by disease volume
47.5% at 24 months; HR for radiographic progression or death, 0.48; 95% and prior docetaxel use. The primary endpoint was radiographic PFS,
CI, 0.39–0.60; P < .001) and OS (82.4% vs. 73.5% at 24 months; HR for which was improved in the enzalutamide group after a median follow-up of
death, 0.67; 95% CI, 0.51–0.89; P = .005). Adverse events that were more 14.4 months (19.0 months vs. not reached; HR, 0.39; 95% CI, 0.30–0.50;
common with apalutamide than with placebo included rash, P < .001).548 At the final, prespecified OS analysis, median OS was not
hypothyroidism, and ischemic heart disease. Health-related QOL was met in either group, but a 34% reduction in the risk of death was observed
maintained during treatment.544 At final analysis of TITAN, median OS was in those receiving enzalutamide versus placebo (HR, 0.66; 95% CI, 0.53–
improved with apalutamide plus ADT compared with ADT alone after a 0.81; P < .001).549 This result could be an underestimate of the effect of
median follow-up of 44 months (not reached vs. 52.2 months; HR, 0.65; enzalutamide, since approximately 32% of the patients assigned placebo
95% CI, 0.53–0.79; P < .001).545 crossed over to enzalutamide after unblinding.

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The safety of enzalutamide in these trials was similar to that seen in Subgroup analysis showed that the survival benefit was more pronounced
previous trials in the castration-resistant setting. Adverse events in the 65% of participants with high-volume disease (HR, 0.63; 95% CI,
associated with enzalutamide in these trials included fatigue, seizures, and 0.50–0.79; P < .001). Patients with low metastatic burden in CHAARTED
hypertension.546,548 did not derive a survival benefit from the inclusion of docetaxel (HR, 1.04;
95% CI, 0.70–1.55; P = .86).
Enzalutamide is a category 1 option for patients with mCSPC. The FDA
approved this indication in December 2019. The STAMPEDE trial, a multi-arm, multi-stage phase 3 trial, included
patients with both M0 and M1 CSPC.551 The results in the M1 population
Darolutamide in mCSPC
confirmed the survival advantage of adding docetaxel (75 mg/m2 IV every
The phase 3 ARANOTE trial assessed darolutamide with ADT compared 3 weeks x 6 doses) to ADT seen in the CHAARTED trial. In STAMPEDE,
with placebo and ADT in 669 patients with mCSPC.550 The primary extent of disease was not evaluated in the 1087 patients with metastatic
endpoint of radiological PFS was improved in the darolutamide arm disease, but the median OS for all patients with M1 disease was 5.4 years
compared with the placebo arm (HR, 0.54; 95% CI, 0.41–0.71; P < .0001). in the ADT-plus-docetaxel arm versus 3.6 years in the ADT-only arm (a
The benefit was consistent across the low- and high-volume subgroups. difference of 1.8 years between groups compared with a 1.1-year
Some of the secondary endpoints were also met, including delayed time to difference in CHAARTED).
mCRPC and time to pain progression. However, a significant improvement
in OS was not evident in the current follow-up (HR, 0.81; 95% CI, 0.59– Patients with low metastatic burden did not have definitively improved
1.12). survival outcomes in the ECOG CHAARTED study or a similar European
trial (GETUG-AFU 15).552,554,555 Furthermore, the triplet options of ADT
The FDA approved this indication for darolutamide in June 2025. The with docetaxel and either abiraterone or darolutamide showed improved
Panel include darolutamide with ADT as an option for patients with low- OS over ADT with docetaxel (see below). The Panel therefore does not
and high-volume mCSPC. Because an OS benefit has not been include docetaxel with ADT as an option for patients with mCSPC. Rather,
demonstrated for darolutamide doublet therapy, it is not a category 1 patients with high-volume mCSPC who are fit for chemotherapy should be
recommendation at this time. considered for triplet therapy.
Docetaxel in mCSPC
Triplet Therapies for mCSPC
Docetaxel with ADT has been studied as an upfront option for patients
Data from the PEACE-1 and ARASENS trials indicate that triplet therapies
with mCSPC in two phase 3 trials (ECOG 3805/CHAARTED and
of ADT with docetaxel and an ARPI —either abiraterone or darolutamide—
STAMPEDE).551,552 CHAARTED randomized 790 patients with mCSPC to
improve OS over ADT with docetaxel in patients with high-volume
docetaxel (75 mg/m2 IV every 3 weeks x 6 doses) plus ADT or ADT
metastatic CSPC.556,557 These trials are discussed below. Both of these
alone.552 After a median follow-up of 53.7 months, the patients in the
combinations are included as category 1, preferred options for patients
combination arm experienced a longer OS than those in the ADT arm
with high-volume mCSPC, and their use is encouraged for patients with
(57.6 vs. 47.2 months; HR, 0.72; 95% CI, 0.59–0.89; P = .002).553

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high-volume disease who are fit for chemotherapy. However, the Panel (HR, 0.75; 95.1% CI, 0.59–0.95; P = .017) were longer in those receiving
notes that no studies have compared doublet therapies (ADT plus an all three therapies compared with those only receiving ADT and docetaxel.
ARPI; discussed above) to triplet therapies. Therefore, doublet therapies The populations receiving the triplet and doublet therapies experienced
are also suitable options for patients with high-volume metastatic disease. similar rates neutropenia, febrile neutropenia, fatigue, and neuropathy,
although grade ≥3 adverse events occurred in 63% of patients who
These triplet combinations are also included as options in the low-volume, received the triplet combination compared with 52% of those receiving
synchronous CSPC setting based on results of a meta-analysis, although ADT and docetaxel.
their use in this setting is controversial and should be reserved for patients
who desire aggressive treatment.558 No data support the use of triplet Based on these data, the Panel includes this regimen as a category 1
therapy in low-volume metachronous mCSPC, and they are not option for patients with high-volume mCSPC.
recommended in this setting.
Docetaxel Plus Darolutamide in CSPC
Docetaxel Plus Abiraterone in CSPC The international, phase 3 trial ARASENS trial, the second phase 3 trial
PEACE-1 was an international, open-label, randomized, phase 3 study evaluating a triplet therapy, randomized 1306 patients with mCSPC to
conducted in seven European countries.556 Using a 2 × 2 factorial design, receive ADT and docetaxel with either darolutamide or matching
1173 patients with de novo metastatic prostate cancer were randomized at placebo.557 The primary endpoint, OS, was improved in the darolutamide
a 1:1:1:1 ratio to standard of care (ADT alone or with docetaxel), standard group at 4 years (62.7%; 95% CI, 58.7–66.7) compared with the placebo
of care with RT, standard of care with abiraterone, or standard of care with group (50.4%; 95% CI, 46.3–54.6). The risk of death was lower in the
radiation and abiraterone. The two primary endpoints of the trial were darolutamide group by about 32% (HR, 0.68; 95% CI, 0.57–0.80; P <
radiographic PFS and OS. Adjusted Cox regression modelling showed no .001). The addition of darolutamide also showed significant benefits over
interaction between abiraterone and RT, so data were pooled for the placebo for secondary efficacy endpoints, including time to CRPC (HR,
analysis of abiraterone efficacy. Consistent with results of older studies, at 0.36; 95% CI, 0.30–0.42; P < .001), skeletal event–free survival (HR, 0.61;
a median follow-up of 3.5 years, radiographic PFS was longer in patients 95% CI, 0.52–0.72; P < .001), and time to initiation of subsequent
who received abiraterone than in those that did not (HR, 0.54; 99.9% CI, systemic antineoplastic therapy (HR, 0.39; 95% CI, 0.33–0.46; P < .001).
0.41–0.71; P < .0001) as was OS (HR, 0.82; 95.1% CI, 0.69–0.98; P = Subgroup analysis showed a similar improvement in OS in those with
.030). An OS benefit with abiraterone was also seen in the subset of high-volume disease as defined by CHAARTED criteria as in the overall
patients with high metastatic burden as defined by CHAARTED criteria population.559 An OS benefit was not observed in those with low metastatic
(HR, 0.77 ;95% CI, 0.62–0.96), but was not seen in those with low burden (HR, 0.68; 95% CI, 0.41–1.13), but median survival was not
metastatic burden (HR, 0.93 ;95% CI, 0.69–1.28). reached in either arm.

As part of the analysis, the efficacy of abiraterone was assessed in the Adverse events of any grade, grade 3 to 5 adverse events, and serious
population that received docetaxel. As in the overall population, adverse events occurred at similar incidence levels between the two arms.
radiographic PFS (HR, 0.50; 99.9% CI, 0.34–0.71; P < .0001) and OS Many of these were known effects of docetaxel. The most frequent

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adverse events were alopecia (40.5% of patients in the darolutamide arm Abiraterone may be added to ADT with EBRT to the primary tumor in
vs. 40.6% with placebo), neutropenia (39.3% vs. 38.8%), fatigue (33.1% patients with low-volume synchronous metastases based on results of
vs. 32.9%), and anemia (27.8% vs. 25.1%). Exceptions were rash (16.6% the PEACE-1, open-label, randomized trial. 562 In this trial, participants
vs. 13.5%) and hypertension (13.7% vs. 9.2%), which are known effects of were randomized 1:1:1:1 to ADT alone or with docetaxel (standard of
androgen receptor pathway inhibitors and were more frequent in the care, SOC), SOC with abiraterone, SOC with radiation to the prostate, or
darolutamide group. SOC with abiraterone and radiation to the prostate. Results
demonstrated that the addition of RT to the primary tumor in patients with
The FDA approved this indication in August 2022, and the Panel includes low-volume disease treated with abiraterone led to improvements in
this regimen as a category 1 option for patients with high-volume mCSPC. median radiographic PFS (4.4 vs. 7.5 years). RT to the primary tumor
also reduced rates of serious genitourinary toxicity regardless of disease
EBRT to the Primary Tumor in Synchronous Low-Volume M1
Disease volume, and time to castration resistance was delayed in the full
population. Thus, some patients with high-volume disease may also
Patients with newly diagnosed, low-volume metastatic prostate cancer can
benefit from RT to the primary tumor.
be considered for ADT with EBRT to the primary tumor based on results
from the randomized controlled phase 3 STAMPEDE trial.560 In this In PEACE-1, the benefits of RT to the primary tumor were only seen in
multicenter, international study, 2061 patients were randomized to lifelong patients receiving abiraterone, not in those receiving ADT alone or with
ADT with or without EBRT to the primary tumor (either 55 Gy in 20 daily docetaxel.562 However, in a secondary analysis of the STAMPEDE trial,
fractions over 4 weeks or 36 Gy in 6 weekly fractions over 6 weeks). The the benefits of RT on OS and FFS in patients with low-volume disease
primary outcome of OS by intention-to-treat (ITT) analysis was not met were seen regardless of planned docetaxel use. 563 The Panel therefore
(HR, 0.92; 95% CI, 0.80–1.06; P = .266), but EBRT improved the includes the addition of docetaxel to ADT and EBRT to the primary tumor
secondary outcome of failure-free survival (FFS; HR, 0.76; 95% CI, 0.68– as a category 2B recommendation for patients with low-volume
0.84; P < .0001). In a pre-planned subset analysis, outcomes of patients synchronous mCSPC.
with high-metastatic burden (defined as visceral metastases; ≥4 bone
metastases with ≥1 outside the vertebral bodies or pelvis; or both) and MDT for Oligometastatic CSPC
those with low-metastatic burden (all others) were determined. EBRT Treatment of metastatic sites with local therapy with the intent to improve
improved OS (adjusted HR, 0.68; 95% CI, 0.52–0.90), prostate cancer- oncologic outcomes (eg, delaying the initiation of systemic therapy or
specific survival (adjusted HR, 0.65; 95% CI, 0.47–0.90), FFS (adjusted ADT; improving PFS, radiographic PFS, or OS) is known as metastasis-
HR, 0.59; 95% CI, 0.49–0.72), and PFS (adjusted HR, 0.78; 95% CI, directed therapy, or MDT. MDT has been primarily studied as
0.63–0.98) in patients with low-metastatic burden, but not in patients with metastasis-directed RT (MDRT) and with the highly selected use of
high metastatic burden. Long-term results have been reported, confirming surgical lymph node dissection. MDRT is delivered at a higher-than-
the benefit of RT to the primary tumor in the setting of ADT with or without palliative dose to provide durable local control of the areas targeted and
docetaxel.561 is the most used form of MDT.

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MDT is used in patients with oligometastatic disease. The number of compared with observation (pooled HR, 0.44; 95% CI, 0.29–0.66; P <
metastatic sites to define oligometastatic disease remains an evolving .001) after a median follow-up of 52.5 months. 564
space and is impacted by the sensitivity of the imaging modality used.
Early studies included patients with 1 to 3 or 1 to 5 metastatic sites by The EXTEND trial included a more heterogeneous group of patients, as 24
CT, MRI, or bone scan. 564-567 More recent studies allow for up to 10 of the 87 enrolled patients had no prior definitive therapy to the prostate
metastatic sites by PSMA-PET imaging (NCT04787744, NCT06150417, and 7 patients had mCRPC.567 Participants had ≤5 metastases amenable
NCT03721341). The upper limit is not clearly established and is both a to MDRT and were randomized to MDRT with intermittent ADT or to
function of oncologic limitations and technical limitations of treating intermittent ADT alone. After a median follow-up of 22 months, median
numerous metastatic sites. It should be noted that the goal of MDT is PFS was improved in the MDRT/ADT group compared with the ADT-only
generally to treat all metastatic sites, which may include regional lymph group (not reached vs. 15.8 months; HR, 0.25; 95% CI, 0.12–
nodes and, potentially, the primary tumor if untreated or if there is 0.55; P < .001). Analysis of a separate basket of participants in EXTEND
evidence of local recurrence. The primary tumor in this setting should be who received continuous ADT have also been reported.570 Results showed
counted as a site. The Panel notes that general exclusion limits of >5 that the inclusion of MDT improved the primary endpoint of PFS improved
and >10 metastases by CT, MRI, or bone scan or by PSMA-PET in the participants who received continuous ADT (47 vs. 22 months; HR,
imaging, respectively, are appropriate. 0.50; one-sided P = .036) and in the combined group of intermittent or
continuous ADT (36 months vs. 17 months; HR, 0.45; P <.001).
The best evidence supporting the use of MDT in the CSPC setting
comes from randomized phase 2 studies in patients with metachronous The SABR-COMET phase 2 study, which enrolled patients with breast,
oligorecurrent disease. 564,567-569 These trials mostly used MDRT and lung, colorectal, and prostate cancers who had a controlled primary
showed that the approach improved ADT-free survival or PFS over tumor and 1 to 5 metastases amenable to MDRT, showed an
monitoring or ADT. For example, the ORIOLE trial included 54 previously improvement on OS with an MDT approach. 571 SABR-COMET included
treated patients with 1 to 3 metastases by conventional imaging who 16 patients with prostate cancer; 14 were randomized to the MDRT arm,
were randomized to receive MDRT or observation. 569 Median PFS was and 2 were randomized to receive palliative RT. Patients in both arms
better in the MDRT group than in the observation group (not reached vs. received palliative systemic therapy as appropriate. After a median
5.8 months; HR, 0.30; 95% CI, 0.11–0.81; P = .002), and the treatment follow-up of 51 months, improvements were seen in 5-year OS rate
was well tolerated. STOMP randomized 62 patients with biochemically (17.7% vs. 42.3%; 95% CI, 0.28-0.56; stratified log-rank P = .006) in the
recurrent CSPC and ≤3 metastases to surveillance or to MDT with total population of 99 patients. A post-hoc sensitivity analysis was used
surgery or RT.568 The median ADT-free survival was improved in the to address the imbalance in the distribution of patients with prostate
MDT arm after a median 3-year follow-up (13 vs. 21 months; HR, 0.60; cancer between the two arms of the study. When patients with prostate
80% CI, 0.40–0.90; log-rank P = .11). In a combined, longer-term cancer were excluded from the analysis, the 5-year OS rate continued to
analysis of ORIOLE and STOMP, median PFS was longer with MDT trend in favor of the MDRT group (16.2% vs. 33.1%; stratified log-rank
test P = .085).

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The benefit of adding ADT to MDRT in patients with oligorecurrent CSPC Patients with CRPC and no signs of distant metastasis on conventional
was assessed in the randomized, phase 2 RADIOSA trial. 566 The 105 imaging studies (M0) can consider monitoring with continued ADT if
enrolled patients were randomized to 6 months of ADT with MDRT or PSADT is >10 months (preferred), because these patients will have a
MDRT alone. After a median follow-up of 31 months, the median clinical relatively indolent disease history.573 Secondary hormone therapy with
PFS was improved in the group receiving ADT (32.2 vs. 15.1 months; continued ADT is an option mainly for patients with shorter PSADT (≤10
HR, 0.43; 95% CI, 0.26–0.72; P = .001). months) as described below.

Based on these data, the Panel recommends MDT with or without ADT as For patients who develop mCRPC, metastatic lesion biopsy is
an option for patients with metachronous oligometastatic CSPC. These recommended, as is MSI/MMR testing, if not previously performed. If MSI-
patients may alternatively be treated with ADT plus systemic therapy for H or dMMR is found, referral to genetic counseling should be made to
low-volume mCSPC with or without concurrent MDT. assess for the possibility of Lynch syndrome. These patients should also
have germline and tumor testing to check for mutations in homologous
There is currently no randomized evidence in the synchronous recombination repair (HRR) genes (eg, BRCA1, BRCA2, ATM, PALB2,
oligometastatic setting, just single-arm prospective trials and retrospective FANCA, RAD51D, CHEK2, CDK12) if not done previously.574 This
cohorts. However, the Panel believes that concurrent MDT with information may be used for genetic counseling, cascade germline testing
recommended systemic therapy can be considered in select patients with for family members, early use of platinum chemotherapy, and
synchronous oligometastatic disease. understanding eligibility for biomarker-directed treatments or clinical trials.
TMB testing is also recommended for patients with mCRPC.
Progression to and Management of CRPC
Most advanced disease eventually stops responding to traditional ADT ADT is continued in patients with mCRPC while additional therapies,
and is categorized as castration-resistant (also known as castration- including secondary hormone therapies, chemotherapies,
recurrent). CRPC is defined as prostate cancer that progresses clinically, immunotherapies, radiopharmaceuticals, and/or targeted therapies, are
radiographically, or biochemically despite castrate levels of serum applied sequentially or concurrently, as discussed in the sections that
testosterone (<50 ng/dL).572 Patients whose disease progresses to CRPC follow; all patients should receive best supportive care. The Panel defined
during primary ADT should receive a laboratory assessment to assure a treatment options for patients with mCRPC based on previous exposure to
castrate level of testosterone (<50 ng/dL; <1.7 nmol/L). Imaging tests may ARPIs (abiraterone, enzalutamide, darolutamide, or apalutamide) and
be indicated to monitor for signs of distant metastases. Factors affecting docetaxel. Abiraterone given as part of neoadjuvant/concomitant/adjuvant
the frequency of imaging include individual risk, age, overall patient health, ADT with EBRT is not considered prior ARPI therapy.
PSA velocity, and Gleason grade.
The decision to initiate therapy in the CRPC setting after disease
For patients who develop CRPC, ADT with orchiectomy or an LHRH progression on one or more treatments should be based on the available
agonist or antagonist should be continued to maintain castrate serum high-level evidence of safety, efficacy, and tolerability of these agents and
levels of testosterone (<50 ng/dL). the application of this evidence to an individual patient. Prior exposures to

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therapeutic agents should be considered. Data to inform the optimal docetaxel. This FDA approval in the post-docetaxel, mCRPC setting was
sequence for delivery of these agents in patients with mCRPC is evolving based on the results of a phase 3, randomized, placebo-controlled trial
(see Sequencing of Therapy in CRPC, below). Choice of therapy is based (COU-AA-301) in patients with mCRPC previously treated with docetaxel-
largely on clinical considerations, which include patient preferences, prior containing regimens.579,580 Patients were randomized to receive either
treatment, presence or absence of visceral disease, symptoms, and abiraterone 1000 mg orally once daily (n = 797) or placebo once daily (n =
potential side effects. 398), and both arms received daily prednisone. In the final analysis,
median survival was 15.8 versus 11.2 months in the abiraterone and
NCCN recommends that patients being treated for CRPC be closely placebo arm, respectively (HR, 0.74; 95% CI, 0.64–0.86; P < .0001).580
monitored with radiologic imaging (ie, CT, bone imaging), PSA tests, and Time to radiographic progression, PSA decline, and pain palliation also
clinical exams for evidence of progression. Therapy should be continued were improved by abiraterone.580,581
until clinical progression or intolerability, with consideration of the fact that
even in cases where PSA remains undetectable, bone imaging may reveal FDA approval in the pre-docetaxel setting occurred in December 2012,
progression.575,576 The sequential use of these agents is recommended in and was based on the randomized phase 3 COU-AA-302 trial of
patients who remain candidates for further systemic therapy. The Panel abiraterone and prednisone (n = 546) versus prednisone alone (n = 542)
also notes that Pan-cancer, tumor-agnostic treatments can be considered in patients with asymptomatic or minimally symptomatic, mCRPC.582 Most
for patients with mCRPC who have actionable mutations. Clinical trial and participants in this trial were not taking narcotics for cancer pain and none
best supportive care are additional options. had visceral metastatic disease or prior ketoconazole exposure. The
coprimary endpoint of radiographic PFS was improved from 8.3 to 16.5
Secondary Hormone Therapy for CRPC months with abiraterone (HR, 0.53; P < .001). OS was improved at final
Research has shown enhancement of autocrine and/or paracrine analysis with a median follow-up of 49.2 months (34.7 vs. 30.3 months;
androgen synthesis in the tumor microenvironment of patients receiving HR, 0.81; 95% CI, 0.70–0.93; P = .003).583 Key secondary endpoints of
ADT.577,578 Androgen signaling consequent to non-gonadal sources of time to symptomatic deterioration, time to chemotherapy initiation, time to
androgen in CRPC refutes earlier beliefs that CRPC was resistant to pain progression, and PSA PFS improved significantly with abiraterone
further hormone therapies. The development of novel ARPIs treatment; PSA declines (62% vs. 24% with >50% decline) and
demonstrating efficacy in the non-metastatic CRPC and mCRPC settings radiographic responses (36% vs. 16% RECIST responses) were more
dramatically changed the paradigm of CRPC treatment over the past two common.
decades.
The most common adverse reactions with abiraterone/prednisone (>5%)
Abiraterone Acetate in mCRPC were fatigue (39%); back or joint discomfort (28%–32%); peripheral
In April 2011, the FDA approved the androgen synthesis inhibitor, edema (28%); diarrhea, nausea, or constipation (22%); hypokalemia
abiraterone, in combination with low-dose prednisone, for the treatment of (17%); hypophosphatemia (24%); atrial fibrillation (4%); muscle discomfort
patients with mCRPC who have received prior chemotherapy containing (14%); hot flushes (22%); urinary tract infection; cough; hypertension

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(22%, severe hypertension in 4%); urinary frequency and nocturia; depending on which formulation is given) to abrogate signs of
dyspepsia; or upper respiratory tract infection. The most common adverse mineralocorticoid excess that can result from treatment. These signs
drug reactions that resulted in drug discontinuation were increased include hypertension, hypokalemia, and peripheral edema. Thus,
aspartate aminotransferase and/or alanine aminotransferase (11%–12%), monitoring of liver function, potassium and phosphate levels, and blood
or cardiac disorders (19%, serious in 6%). pressure readings on a monthly basis is warranted during abiraterone
therapy. Symptom-directed assessment for cardiac disease also is
Based on the studies described here, abiraterone is a category 1, warranted, particularly in patients with pre-existing cardiovascular disease.
preferred option for mCRPC without prior ARPI therapy. It can also be
considered in patients with mCRPC following progression on another A randomized phase 2 noninferiority study of 75 patients with mCRPC
ARPI, although other therapies are preferred in this setting. compared 1000 mg/day abiraterone after an overnight fast with 250
mg/day after a low-fat breakfast.542 The primary endpoint was log change
In May 2018, the FDA approved a novel, fine-particle formulation of in PSA, with secondary endpoints of PSA response (≥50%) and PFS. The
abiraterone, in combination with methylprednisolone, for the treatment of primary endpoint favored the low-dose arm (log change in PSA, -1.59 vs. -
patients with mCRPC. In studies of healthy males, this formulation at 500 1.19), as did the PSA response rate (58% vs. 50%), with an equal PFS of
mg was shown to be bioequivalent to 1000 mg of the originator 9 months in both arms. Noninferiority of the low dose was established
formulation.584,585 In a phase 2 therapeutic equivalence study, 53 patients according to the predefined criteria. Therefore, abiraterone can be given at
with mCRPC who were not treated previously with abiraterone, 250 mg/day administered following a low-fat breakfast, as an alternative to
enzalutamide, radium-223, or chemotherapy (docetaxel for mCRPC the dose of 1000 mg/day after an overnight fast in patients who will not
completed ≥1 year prior to enrollment was allowed) were randomized to take or cannot afford the standard dose. The cost savings may reduce
500 mg daily of the new, fine-particle formulation plus 4 mg financial toxicity and improve adherence. Food impacts absorption
methylprednisolone orally twice daily or to 1000 mg of the originator unpredictably; therefore, side effects should be monitored and standard
formulation daily plus 5 mg prednisone orally twice daily.586 dosing (1000 mg on empty stomach) utilized if excess toxicity is observed
Bioequivalence of these doses was confirmed based on serum on modified dosing (250 mg with food).
testosterone levels, PSA response, and abiraterone pharmacokinetics.
The rates of total and grade 3/4 adverse events were similar between the Abiraterone with Dexamethasone in mCRPC
arms, with musculoskeletal and connective tissue disorders occurring Switching from prednisone to dexamethasone 0.5 mg/day can be
more frequently in the originator-treated patients (37.9% vs. 12.5%). The considered for patients with mCRPC with disease progression on either
Panel believes that the fine-particle formulation of abiraterone can be used formulation of abiraterone. Trials show improved PSA responses and PFS
instead of the original formulation of abiraterone in the treatment of and acceptable safety using this strategy.587,588
patients with mCRPC (category 2A).
The SWITCH study was a single-arm, open-label, phase 2 study of this
Abiraterone should be given with concurrent steroid (either oral approach with 26 enrolled patients.587 The primary endpoint, the proportion
prednisone 5 mg twice daily or oral methylprednisolone 4 mg twice daily, of patients with a PSA decline ≥30% in 6 weeks, was 46.2%. No

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significant toxicities were observed, and two radiologic responses were placebo.592,593 The study was stopped early due to benefits shown in the
seen. In another study, 48 consecutive patients with mCRPC, with disease treatment arm. Compared to the placebo group, the enzalutamide group
progression on abiraterone with prednisone, were switched to abiraterone showed improved median PFS (20.0 vs. 5.4 months) and median OS
with 0.5 mg/day dexamethasone.588 The primary endpoint of median PFS (35.3 vs. 31.3 months). Improvements in all secondary endpoints were
was 10.35 months, and PSA levels decreased or stabilized in 56% of also observed (eg, the time until chemotherapy initiation or first SRE).
patients after switching to dexamethasone.
Thus, enzalutamide represents a category 1, preferred treatment option
Enzalutamide in M0 and M1 CRPC for patients with mCRPC without prior ARPI therapy. It can also be
In August 2012, the FDA approved enzalutamide, a next-generation considered in patients with mCRPC with prior exposure to another ARPI,
antiandrogen, for treatment of patients with mCRPC who had received although other therapies are preferred in this setting.
prior docetaxel chemotherapy. Approval was based on the results of the
The randomized, double-blind, placebo-controlled phase 3 PROSPER trial
randomized, phase 3, placebo-controlled AFFIRM trial.589,590 AFFIRM
assessed the use of enzalutamide in 1401 patients with non-metastatic
randomized 1199 patients to enzalutamide (160 mg daily) or placebo in a
CRPC.594 Patients with PSADT ≤10 months were stratified according to
2:1 ratio and the primary endpoint was OS. Median survival was improved
PSADT (<6 vs. ≥6 months) and use of bone-sparing agents and
with enzalutamide from 13.6 to 18.4 months (HR, 0.63; P < .001). Survival
randomized 2:1 to enzalutamide (160 mg/day) plus ADT or placebo plus
was improved in all subgroups analyzed. Secondary endpoints were also
ADT. Enzalutamide improved the primary endpoint of metastasis-free
improved significantly, which included the proportion of patients with >50%
survival over placebo (36.6 vs. 14.7 months; HR for metastasis or death,
PSA decline (54% vs. 2%), radiographic response (29% vs. 4%),
0.29; 95% CI, 0.24–0.35; P < .0001). Median OS was longer in the
radiographic PFS (8.3 vs. 2.9 months), and time to first skeletal-related
enzalutamide group than in the placebo group (67.0 vs. 56.3 months; HR
event (SRE) (16.7 vs. 13.3 months). QOL measured using validated
for death, 0.73; 95% CI, 0.61–0.89; P = 0.001).595 Adverse events included
surveys was improved with enzalutamide compared to placebo. Adverse
fatigue (33% vs. 14%), hypertension (12% vs. 5%), major adverse
events were mild, and included fatigue (34% vs. 29%), diarrhea (21% vs.
cardiovascular events (5% vs. 3%), and mental impairment disorders (5%
18%), hot flushes (20% vs. 10%), headache (12% vs. 6%), and seizures
vs. 2%). Patient-reported outcomes from PROSPER indicate that
(0.6% vs. 0%). The incidence of cardiac disorders did not differ between
enzalutamide delayed pain progression, symptom worsening, and
the arms. Patients in the AFFIRM study were maintained on LHRH
decrease in functional status, compared with placebo.596
agonist/antagonist therapy and could receive bone supportive care
medications. The seizure risk in the enzalutamide FDA label was 0.9% The FDA expanded its approval for enzalutamide to include patients with
versus 0.6% in the manuscript.589,591 non-metastatic CRPC in July 2018, and the Panel believes that patients
with M0 CRPC can be offered enzalutamide, if PSADT is ≤10 months
Another phase 3 trial studied enzalutamide in the pre-chemotherapy
(category 1, preferred option).
setting. The PREVAIL study randomly assigned 1717 patients with
chemotherapy-naïve metastatic prostate cancer to daily enzalutamide or

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Patients receiving enzalutamide have no restrictions for food intake and (600 mg twice daily) or placebo.600 Participants were stratified according to
concurrent prednisone is permitted but not required.589 PSADT (>6 vs. ≤6 months) and the use of osteoclast-targeted agents. The
median follow-up time was 17.9 months. Darolutamide improved the
Apalutamide in M0 CRPC primary endpoint of metastasis-free survival compared to placebo (40.4
The FDA approved apalutamide for treatment of patients with non- vs. 18.4 months; HR for metastasis or death, 0.41; 95% CI, 0.34–0.50; P <
metastatic CRPC in February 2018. This approval was based on the .001).
phase 3 SPARTAN trial of 1207 patients with M0 CRPC and PSADT ≤10
months.597 Participants were stratified according to PSADT (>6 vs. ≤6 Patients in the placebo group of ARAMIS crossed over to darolutamide (n
months), use of bone-sparing agents, and the presence of metastatic = 170) or received other life-prolonging therapy (n = 137). Final analysis
pelvic lymph nodes (N0 vs. N1). After a median follow-up of 20.3 months, occurred after a median follow-up time of 29.0 months. The risk of death
apalutamide at 240 mg/day with ADT improved the primary endpoint of was 31% lower in the darolutamide group than in the placebo group (HR
metastasis-free survival over placebo with ADT (40.5 vs. 16.2 months; HR for death, 0.69; 95% CI, 0.53–0.88; P = .003).601 OS at 3 years was 83%
for metastasis or death, 0.28; 95% CI, 0.23–0.35; P < .001). Adverse (95% CI, 80–86) in the darolutamide group compared with 77% (95% CI,
events included rash (24% vs. 5.5%), fracture (11% vs. 6.5%), and 72–81) in the placebo group. Adverse events that occurred more
hypothyroidism (8% vs. 2%). In a prespecified exploratory analysis of frequently in the treatment arm included fatigue (12.1% vs. 8.7%), pain in
SPARTAN, health-related QOL was maintained in both the apalutamide an extremity (5.8% vs. 3.2%), and rash (2.9% vs. 0.9%). The incidence of
and placebo groups.598 fractures was similar between darolutamide and placebo (4.2% vs.
3.6%).600
After a median follow-up of 52 months, final OS analysis showed that
participants in SPARTAN experienced an improved median OS with Darolutamide is a category 1, preferred option for patients with M0 CRPC
apalutamide versus placebo (73.9 vs. 59.9 months; HR, 0.78; 95% CI, if PSADT is ≤10 months.
0.64–0.96; P = .016).599 This longer OS reached prespecified statistical
Other Secondary Hormone Therapies
significance, even though 19% of participants crossed over from placebo
to apalutamide. Other options for secondary hormone therapy include a first-generation
antiandrogen, antiandrogen withdrawal, corticosteroid, or ketoconazole
Apalutamide is a category 1, preferred option for patients with M0 CRPC if (adrenal enzyme inhibitor) with hydrocortisone.602-604 However, none of
PSADT is ≤10 months. these strategies has been shown to prolong survival in randomized clinical
trials. In the mCRPC setting, these options should only be used for select
Darolutamide in M0 CRPC patients who are not candidates for other recommended mCRPC
The FDA approved darolutamide for treatment of patients with non- therapies.
metastatic CRPC in July 2019. The phase 3 ARAMIS study randomized
1509 patients with M0 CRPC and PSADT ≤10 months 2:1 to darolutamide A randomized phase 2 trial, TRANSFORMER, compared the effect of
bipolar androgen therapy (BAT) with that of enzalutamide on PFS in 195

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patients with asymptomatic, mCRPC with prior progression on Thus, docetaxel is a category 1 option for treatment of docetaxel-naïve
abiraterone.605 BAT involves rapid cycling between high and low serum mCRPC. It is the preferred option post-ARPI in patients without prior
testosterone to disrupt the adaptive upregulation of the androgen receptor docetaxel exposure.
that occurs with low testosterone levels. Patients in the BAT arm received
testosterone cypionate 400 mg intramuscularly once every 28 days. The The standard regimen is 75 mg/m2 every 3 weeks. An alternative to every-
PFS was 5.7 months in both arms (HR, 1.14; 95% CI, 0.83–1.55; P = .42). 3-week docetaxel is a biweekly regimen of 50 mg/m2. This regimen is
Crossover was allowed after disease progression, and OS was similar based on a large randomized phase 2 trial of 346 patients with mCRPC
between the groups. BAT resulted in more favorable patient-reported randomized to either every-2-week docetaxel or every-3-week docetaxel,
QOL. The Panel awaits more data on this approach. each with maintenance of ADT and prednisone.609 Patients treated with
the every-2-week regimen survived an average of 19.5 months compared
Chemotherapy, Immunotherapy, and Targeted Therapy to 17.0 months with the every-3-week regimen (P = .015). Time to
for mCRPC progression and PSA decline rate favored every-2-week therapy.
Research has expanded the therapeutic options for patients with mCRPC. Tolerability was improved with every-2-week docetaxel; febrile neutropenia
In addition to the hormonal and radiopharmaceutical therapies described rate was 4% versus 14% and other toxicities and overall QOL were
in other sections, options include chemotherapy, immunotherapy, and similar.
targeted therapy. As noted above, selection of therapy depends on patient
The duration of docetaxel therapy should be based on the assessment of
preferences, prior treatment exposures, the presence or absence of
benefit and toxicities. Treatment with ≥8 cycles of docetaxel may be
symptoms, the location of metastases, the presence of certain biomarkers,
associated with better OS than fewer cycles in the mCRPC setting.610
and consideration of potential side effects.
Retrospective analysis from the GETUG-AFU 15 trial suggests that
Docetaxel
docetaxel may benefit some patients with CRPC who received docetaxel
Docetaxel was FDA-approved for mCRPC in May 2004. Two randomized in the CSPC setting.611 Thus, the Panel believes that docetaxel can be
phase 3 studies evaluated docetaxel-based regimens in symptomatic or given as a rechallenge after progression on an ARPI in the mCRPC
rapidly progressive CRPC (TAX 327 and SWOG 9916).606-608 TAX 327 setting if the patient’s cancer did not demonstrate definitive evidence of
compared docetaxel (every 3 weeks or weekly) plus prednisone to progression on prior docetaxel therapy in either the castration-sensitive
mitoxantrone plus prednisone in 1006 patients.607 Every-3-week docetaxel setting or the mCRPC setting.
resulted in higher median OS than mitoxantrone (18.9 vs. 16.5 months; P
= .009). This survival benefit was maintained at extended follow-up.608 The Adverse events associated with docetaxel include neutropenia,
SWOG 9916 study showed improved survival with docetaxel when leukopenia, febrile neutropenia, neutropenic infections, fluid retention,
combined with estramustine compared to mitoxantrone plus prednisone.606 hypersensitivity reaction, hepatic function impairment, neuropathy, and
other low-grade adverse events (eg, fatigue, nausea, vomiting, alopecia,
diarrhea).

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Cabazitaxel The phase 3 open-label, multinational, noninferiority PROSELICA study

In June 2010, the FDA approved cabazitaxel, a semi-synthetic taxane compared 20 mg/m2 cabazitaxel with 25 mg/m2 cabazitaxel in 1200
derivative, for patients with mCRPC previously treated with a docetaxel- patients with mCRPC who progressed on docetaxel.617 The lower dose
containing regimen. An international randomized phase 3 trial (TROPIC) was found to be noninferior to the higher dose for median OS (13.4
randomized 755 patients with progressive mCRPC to receive cabazitaxel months [95% CI, 12.19–14.88] vs. 14.5 months [95% CI, 13.47–15.28]),
25 mg/m2 or mitoxantrone 12 mg/m2, each with daily prednisone.612 A 2.4- and grade 3/4 adverse events were decreased (39.7% vs. 54.5%). In
month improvement in OS was demonstrated with cabazitaxel compared particular, grade ≥3 neutropenia rates were 41.8% and 73.3% for the
to mitoxantrone (HR, 0.72; P < .0001). The improvement in survival was lower and higher dose groups, respectively.
balanced against a higher toxic death rate with cabazitaxel (4.9% vs.
Results from the phase 3 FIRSTANA study suggest that cabazitaxel has
1.9%), which was due, in large part, to differences in rates of sepsis and
clinical activity in patients with chemotherapy-naïve mCRPC.618 Median
renal failure. Febrile neutropenia was observed in 7.5% of patients treated
OS, the primary endpoint, was similar between 20 mg/m2 cabazitaxel, 25
with cabazitaxel versus 1.3% of patients treated with mitoxantrone. The
mg/m2 cabazitaxel, and 75 mg/m2 docetaxel (24.5 months, 25.2 months,
incidences of severe diarrhea (6%), fatigue (5%), nausea/vomiting (2%),
and 24.3 months, respectively). Cabazitaxel was associated with lower
anemia (11%), and thrombocytopenia (4%) also were higher in patients
rates of peripheral sensory neuropathy than docetaxel, particularly at 20
treated with cabazitaxel, which indicated the need for vigilance and
mg/m2 (12% vs. 25%). However, the Panel does not currently recommend
treatment or prophylaxis in this setting to prevent febrile neutropenia. The
cabazitaxel in docetaxel-naïve patients.
survival benefit was sustained at an updated analysis with a median
follow-up of 25.5 months.613 Furthermore, results of a post-hoc analysis of Based on these data, cabazitaxel is included in these Guidelines as a
this trial suggested that the occurrence of grade ≥3 neutropenia after category 1, preferred option after exposure to docetaxel and an ARPI in
cabazitaxel treatment was associated with improvements in both PFS and patients with mCRPC. Cabazitaxel at 20 mg/m2 every 3 weeks, with or
OS.614 without growth factor support, is the recommended dose for fit patients.
Cabazitaxel at 25 mg/m2 may be considered for healthy patients who opt
The multicenter CARD study was a randomized, open-label clinical trial
for more aggressive treatment. Biweekly cabazitaxel at 16 mg/m2 with
that compared cabazitaxel with either abiraterone or enzalutamide in 255
prophylactic G-CSF is an option for patients ≥65 years based on results
patients with mCRPC who had previously received docetaxel and either
from the phase 3 CABASTY trial.619 Using the lower dose significantly
abiraterone or enzalutamide.615 Cabazitaxel at 25 mg/m2 with concurrent
reduced the risk of neutropenia/neutropenic complications compared to
steroid improved the primary endpoint of radiographic PFS (8.0 vs. 3.7
the 25 mg/m2 dose with G-CSF. Clinical outcomes were comparable
months; HR, 0.54; P < .0001) and reduced the risk of death (13.6 vs. 11.0
between the 2 groups.
months; HR, 0.64; P = .008) compared with abiraterone or enzalutamide in
these patients. Cabazitaxel was also associated with an increased rate of Cabazitaxel should be given with concurrent steroids (daily prednisone or
pain response and delayed time to pain progression and SREs.616 dexamethasone on the day of chemotherapy). Physicians should follow
current guidelines for prophylactic white blood cell growth factor use,

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particularly in this heavily pretreated population. In addition, supportive Sipuleucel-T

care should include antiemetics (prophylactic antihistamines, H2 In April 2010, sipuleucel-T became the first in a new class of cancer
antagonists, and corticosteroids prophylaxis) and symptom-directed immunotherapeutic agents to be approved by the FDA. This autologous
antidiarrheal agents. Cabazitaxel was tested in patients with hepatic cancer “vaccine” involves collection of the white blood cell fraction-
dysfunction in a small, phase I, dose-escalation study.620 Cabazitaxel was containing, antigen-presenting cells from each patient; exposure of the
tolerated in patients with mild to moderate hepatic impairment. However, cells to the prostatic acid phosphatase-granulocyte macrophage colony-
cabazitaxel should not be used in patients with severe hepatic dysfunction. stimulating factor (PAP-GM-CSF recombinant fusion protein); and
Cabazitaxel should be stopped upon clinical disease progression or subsequent reinfusion of the cells. The pivotal study was a phase 3,
intolerance. multicenter, randomized, double-blind trial (D9902B).622 Five hundred
twelve patients with minimally symptomatic or asymptomatic mCRPC were
Cabazitaxel/Carboplatin
randomized 2:1 to receive sipuleucel-T or placebo. Eighteen-point two
Cabazitaxel 20 mg/m² plus carboplatin AUC 4 mg/mL per minute with percent of patients had received prior chemotherapy, which included
growth factor support can be considered post-ARPI for fit patients with docetaxel; eligibility requirements included no chemotherapy for 3 months
aggressive variant mCRPC (visceral metastases, low PSA and bulky and no steroids for 1 month prior to enrollment. Median survival in the
disease, high lactate dehydrogenase [LDH], high carcinoembryonic vaccine arm was 25.8 months compared to 21.7 months in the control
antigen [CEA], lytic bone metastases, and neuroendocrine prostate cancer arm. In a subset analysis, both those who did and those who did not
[NEPC] histology) or unfavorable genomics (defects in at least 2 of PTEN, receive prior chemotherapy benefited from sipuleucel-T treatment.
TP53, and RB1). This recommendation is based on a phase 1–2, open Sipuleucel-T treatment resulted in a 22% reduction in mortality risk (HR,
label, randomized study.621 In the phase 2 portion, 160 patients were 0.78; 95% CI, 0.61–0.98; P = .03). Common complications included mild
randomized to receive cabazitaxel alone or with carboplatin, and the to moderate chills (54.1%), pyrexia (29.3%), and headache (16.0%), which
primary endpoint was investigator-assessed PFS. In the ITT population, usually were transient.
median PFS was 4.5 months in the cabazitaxel arm versus 7.3 months in
the cabazitaxel/carboplatin arm (HR, 0.69; 95% CI, 0.50–0.95; P = .018). A prospective registry of patients with mCRPC, PROCEED, enrolled 1976
The most common grade 3–5 adverse events (fatigue, anemia, patients from 2011 to 2017, who were followed for a median of 46.6
neutropenia, and thrombocytopenia) were all more common in the months.623 The safety and tolerability of sipuleucel-T were consistent with
combination arm. Post-hoc analyses showed that patients with aggressive previous findings, and the median OS was 30.7 months (95% CI, 28.6–
variant disease had a longer median PFS in the combination arm than the 32.2 months).
cabazitaxel arm (7.5 vs. 1.7 months; P = .017). Patients without
aggressive variant tumors, on the other hand, had similar median PFS Sipuleucel-T is included in these Guidelines as an option for asymptomatic
regardless of treatment (6.5 vs. 6.3 months; P = .38). patients with mCRPC regardless of prior ARPI or docetaxel, although the
Panel notes that the data supporting its use post-docetaxel is limited.
Benefit of sipuleucel-T has not been reported in patients with visceral

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Prostate Cancer

metastases and is not recommended if visceral metastases are present. response (including a response in liver metastases). Of the remaining
Sipuleucel-T is also not recommended for patients with small cell prostate patients, three showed stable disease, and four displayed no evidence of
cancer/NEPC. The Panel prefers that sipuleucel-T be used as a therapy clinical benefit. Genetic analysis of biopsy tissue revealed that one patient
for asymptomatic or minimally symptomatic patients with mCRPC, so that whose disease showed PSA response had an MSI-H tumor, whereas the
disease burden is lower and immune function is potentially more intact. other patient with responsive disease and two with non-responsive
Patients should have good performance level (ECOG 0–1), estimated life disease did not. The nonrandomized phase Ib KEYNOTE-028 trial
expectancy >6 months, and no liver metastases. Clinicians and patients included 23 patients with advanced, progressive prostate cancer, of whom
should be aware that the usual markers of benefit (decline in PSA and 74% had received ≥2 previous therapies for metastatic disease.626 The
improvement in bone or CT scans) are not seen. Therefore, benefit to the objective response rate by investigator review was 17.4% (95% CI, 5.0%–
individual patient cannot be ascertained using currently available testing. 38.8%), with four confirmed partial responses. Eight patients (34.8%) had
stable disease. Treatment-related adverse events occurred in 61% of
Pembrolizumab patients after a median follow-up of 7.9 months; 17% of the cohort
The FDA approved the tumor-agnostic use of pembrolizumab, an anti-PD- experienced grade 3/4 events (ie, grade 4 lipase increase, grade 3
1 antibody, for treatment of patients with unresectable or metastatic MSI-H peripheral neuropathy, grade 3 asthenia, grade 3 fatigue).
or dMMR solid tumors who have progressed on prior treatment and who
have no satisfactory alternative treatment options in May 2017. This KEYNOTE-199 was a multi-cohort, open-label phase II study in 258
approval was based on the treatment of 149 patients across five clinical patients with mCRPC and prior treatment with docetaxel and at least one
studies involving MSI-H or dMMR colorectal (n = 90) or non-colorectal (n = ARPI that assessed pembrolizumab in patients regardless of MSI
59) cancer for an objective response rate of 40% (59/149).591 All patients status.629 Cohorts 1 and 2 included patients with programmed cell death
received ≥1 prior regimen. Among the non-colorectal cohorts, two patients ligand 1 (PD-L1)–positive (n = 133) and PD-L1–negative (n = 66) prostate
had mCRPC: one achieved a partial objective response, and the other cancer, respectively. Cohort 3 included those with bone-predominant
achieved stable disease for >9 months. disease with positive or negative PD-L1 expression (n = 59). The primary
endpoint of overall response rate (ORR) was 5% (95% CI, 2%–11%) in
Outcomes of additional patients with mCRPC treated with pembrolizumab cohort 1 and 3% (95% CI, <1% to 11%) in cohort 2. Responses were
have been reported.82,624-628 In an early study, 10 patients with CRPC and durable (range, 1.9 to ≥21.8 months).
non-visceral metastases (bone = 7; lymph nodes = 2; bone and liver = 1)
who had disease progression on enzalutamide were treated with The most common adverse events from pembrolizumab are fatigue,
pembrolizumab and enzalutamide.624 Some of the patients also had pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough,
experienced disease progression on additional therapies (docetaxel for dyspnea, and musculoskeletal pain. Pembrolizumab also may be
CSPC, abiraterone, and/or sipuleucel-T). Three of the 10 patients showed associated with immune-mediated side effects, which include colitis,
a near complete PSA response. Two of these three patients had hepatitis, endocrinopathies, pneumonitis, or nephritis.
radiographically measurable disease and achieved a partial radiographic

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Based on the available data, the Panel includes pembrolizumab as an Treatment Options for Patients with DNA Repair Gene Mutations
option for patients with MSI-H or dMMR mCRPC (category 2B). The Early studies suggest germline and somatic mutations in HRR genes (eg,
prevalence of MMR deficiency in metastatic CPRC is estimated at 2% to BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2) may be
5%,44,625,630 and testing for MSI-H or dMMR can be performed using DNA predictive of the clinical benefit of poly-ADP ribose polymerase (PARP)
testing or immunohistochemistry. If tumor MSI-H or dMMR is identified, the inhibitors.634-636 PARP inhibitors are oral agents that exert their activity
Panel recommends referral to genetic counseling for consideration of through the concept of synthetic lethality.637 PARP inhibitor therapy
germline testing for Lynch syndrome. options are discussed below.

In June 2020, the FDA granted accelerated approval for pembrolizumab’s DNA repair defects have also been reported to be predictive for sensitivity
tumor-agnostic use in patients with unresectable or metastatic TMB-high to platinum agents in CRPC and other cancers.638-642 Platinum agents
(TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors that have have shown some activity in patients with CRPC without molecular
progressed following prior treatment and who have no satisfactory selection.643 Studies of platinum agents in patients with CRPC that have
alternative treatment options. Results from prospective biomarker analysis DNA repair gene mutations are needed.
of the multicohort, non-randomized, open-label, phase 2 KEYNOTE-158
trial support this approval, but this trial did not include any patients with Results of one study suggested that patients with mCRPC and germline
prostate cancer.631 One retrospective study found that 1.5% of patients mutations in DNA repair genes may have better outcomes if treated with
with prostate cancer had TMB-H tumors.630 Of those patients, 8 had abiraterone or enzalutamide than with taxanes.52 However, it should be
received an immune checkpoint inhibitor; 4 patients (50%) experienced a noted that the response in patients with mCRPC and HRR gene mutations
reduction in PSA of ≥50% that lasted at least 1 week. The Panel therefore to standard therapies is similar to the response in patients without
notes that pembrolizumab may be associated with some benefit in patients mutations.644,645
with mCRPC and TMB ≥10 mut/Mb.
Patients with CDK12 mutations tend to have aggressive disease, with high
Mitoxantrone rates of metastases and short OS. Their disease also does not respond
Two randomized trials assessed the role of mitoxantrone in patients with well to hormonal therapy, PARP inhibitors, or taxanes. Two large, multi-
mCRPC.632,633 Although there was no improvement in OS, palliative institutional, retrospective studies have shown that 11% to 33% of patients
responses and improvements in QOL were seen with mitoxantrone. with mCRPC and CDK12 mutations experienced disease response to PD-
1 inhibitors (ie, nivolumab, pembrolizumab), some with durable
Mitoxantrone can be used for palliation in symptomatic patients with responses.646,647 There are also limited data from phase 2 trials indicating
mCRPC who cannot tolerate other therapies after disease progression on that ipilimumab plus nivolumab may have some activity against CDK12-
prior docetaxel and an ARPI. mutated mCRPC.648,649 The Panel awaits more data on the use of PD-1
inhibition in patients with CDK12 mutations.

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Prostate Cancer

Olaparib few patients in PROfound with mutations in some of the genes. For
Preliminary clinical data using olaparib suggested favorable activity of this example, only 4 patients had BRIP1 mutations (2 in olaparib arm and 2 in
agent in patients with HRR gene mutations, but not in those without HRR control arm), 2 patients had RAD51D mutations (both in olaparib arm), and
mutations.635,636,650 The phase 3 PROfound study was a randomized trial no patients had RAD51C mutations.651 Patients with PPP2R2A mutations
evaluating olaparib 300 mg twice daily versus physician’s choice of in PROfound experienced an unfavorable risk-benefit profile.
abiraterone or enzalutamide in patients with mCRPC and progression on
at least one novel hormonal agent (abiraterone or enzalutamide) and up to As a result of the favorable efficacy data from the PROfound trial, the FDA
one prior taxane agent (permitted but not required).651 Patients were approved olaparib (300 mg twice daily) in May 2020 for use in patients
required to have a somatic or germline HRR gene mutation, and were with mCRPC and deleterious or suspected deleterious germline or somatic
allocated to one of two cohorts: cohort A comprised patients with BRCA1/2 HRR gene mutations in at least one of 14 genes (BRCA1, BRCA2, ATM,
or ATM mutations, and cohort B comprised patients with a mutation in at BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B,
least one of 12 other HRR genes (BARD1, BRIP1, CDK12, CHEK1, RAD51C, RAD51D, or RAD54L) and who had previously received
CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or treatment with enzalutamide or abiraterone.
RAD54L). The primary endpoint of improving radiographic PFS with
Adverse events that may occur with olaparib treatment include anemia
olaparib versus abiraterone/enzalutamide was met in cohort A (HR, 0.34;
(including that requiring transfusion), fatigue, nausea or vomiting,
95% CI, 0.25–0.47; P < .001), and radiographic PFS was also superior in
anorexia, weight loss, diarrhea, thrombocytopenia, creatinine elevation,
the entire study population encompassing cohorts A+B (HR, 0.49; 95% CI,
cough, and dyspnea. Rare but serious side effects may include
0.38–0.63; P < .001).
thromboembolic events (including pulmonary emboli), drug-induced
In addition, final analysis of PROfound showed that OS was improved with pneumonitis, and a theoretical risk of myelodysplasia or acute myeloid
olaparib versus abiraterone/enzalutamide in cohort A (HR, 0.69; 95% CI, leukemia.651
0.50–0.97; P = .02), despite the fact that 86 of 131 patients (66%) crossed
Since some patients in PROfound had prior taxane therapy, olaparib use
over to olaparib after disease progression in the control arm.652
might be reasonable in patients with mCRPC before or after docetaxel
The Panel notes that there may be heterogeneity of response to olaparib treatment. The Panel therefore recommends olaparib as an option for
based on which gene has a mutation. Efficacy in PROfound appears to be patients with mCRPC, previous ARPI, and an HRRm regardless of prior
driven by the cohort of patients with at least one alteration in BRCA2, docetaxel therapy. The HRR genes to be considered for use of olaparib
BRCA1, or ATM, and in particular by patients with BRCA2 or BRCA1 are BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2,
mutations based on exploratory gene-by-gene analysis.652 Patients with FANCL, PALB2, RAD51B, RAD51C, RAD51D and RAD54L. Olaparib is
BRCA2 mutations in PROfound experienced an OS benefit with olaparib included in the Guidelines as a category 1 recommendation for BRCAm
(HR, 0.59; 95% CI, 0.37–0.95), whereas the HR for OS in patients with mCRPC and is a preferred option for these patients if they have not yet
ATM mutations was 0.93 (95% CI, 0.53–1.75).652 Furthermore, there were received docetaxel.

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Any commercially available analytically and clinically validated somatic median duration of imaging-based PFS, was significantly longer at 62
tumor and germline assays can be used to identify patients for treatment. months in the group of 270 participants assigned to receive rucaparib than
The Panel strongly recommends a metastatic biopsy for histologic and in the 135 participants who received a control medication (10.2 vs. 6.4
molecular evaluation; a plasma circulating tumor DNA (ctDNA) assay can months; HR, 0.61; 95% CI, 0.47–0.80; P < .001). This effect was also
be used if a metastatic biopsy is unsafe or not feasible. seen in the 201 patients and 101 patients in each group with a BRCAm
(11.2 vs. 6.4 months; HR, 0.50; 95% CI, 0.36–0.69). For those with ATM
Careful monitoring of complete blood counts and hepatic and renal mutations, an exploratory analysis suggested a possible improvement as
function, along with type and screens and potential transfusion support well (8.1 vs. 6.8 months; HR, 0.95; 95% CI, 0.59–1.52). As in TRITON2,
and/or dose reductions as needed for severe anemia or intolerance are the most frequent adverse events with rucaparib were fatigue and nausea.
recommended during olaparib therapy.
The Panel recommends rucaparib as an option for patients with mCRPC,
Rucaparib
a BRCA1 or BRCA2 mutation, and prior treatment with an ARPI. It is a
Rucaparib is another PARP inhibitor approved for use in patients with category 1, preferred option pre-docetaxel. Rucaparib should not be used
mCRPC. This agent received accelerated FDA approval in May 2020 in patients with HRR gene mutations other than BRCA1/2.656 Adverse
based on the preliminary favorable data from the TRITON2 clinical trial. In events that may occur with rucaparib include anemia (including that
that open-label, single-arm, phase 2 trial, patients with mCRPC harboring requiring transfusion), fatigue, asthenia, nausea or vomiting, anorexia,
a deleterious or suspected deleterious germline or somatic BRCA1 or weight loss, diarrhea or constipation, thrombocytopenia, increased
BRCA2 mutation, who had previously received therapy with an ARPI plus creatinine, increased liver transaminases, and rash. Rare but serious side
one taxane chemotherapy, were treated with rucaparib 600 mg twice effects of rucaparib include a theoretical risk of myelodysplasia or acute
daily.653 The primary endpoint of TRITON2 was the objective response myeloid leukemia, as well as fetal teratogenicity.653,656
rate in patients with measurable disease, and was 43.5% (95% CI,
31.0%–56.7%) in this BRCA1/2-mutated population. Median radiographic The preferred method of selecting patients for rucaparib treatment is
PFS, a key secondary endpoint, was 9.0 months (95% CI, 8.3–13.5 somatic and germline analysis of BRCA1 and BRCA2 from a metastatic
months). The most common adverse events were asthenia/fatigue, biopsy. A ctDNA sample can be used if biopsy is unsafe or not feasible.
nausea, and anemia/decreased hemoglobin, with grade ≥3
anemia/decreased hemoglobin in 25.2% of participants. Final analysis of As with olaparib, careful monitoring of complete blood counts and hepatic
TRITON2 confirmed results of the earlier analysis.654 and renal function, along with type and screens and potential transfusion
support and/or dose reductions as needed for severe anemia or
In the randomized phase 3 TRITON3 study, patients with mCRPC and a intolerance are recommended during treatment with rucaparib.
germline or somatic BRCA1/2 or ATM mutation who have previously
received an ARPI but no chemotherapy for mCRPC were randomized 2:1 Olaparib Plus Abiraterone
to rucaparib versus physician’s choice of therapy (abiraterone, Pre-clinical data suggest that PARP-1 promotes androgen receptor
enzalutamide, or docetaxel).655 The primary endpoint of TRITON3, the activity.657 Additional pre-clinical data show that androgen receptor

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inhibitors can down-regulate DNA repair genes, creating a situation similar seen in the HRRm group overall, and no OS benefit was evident in the
to that of HRR mutation.658,659 These results suggest that the combination non-HRRm and the non-BRCAm/other HRRm subgroups.
of PARP inhibition with androgen receptor inhibition may have an
enhanced antitumor effect and that this effect may not be limited to In May 2023, the FDA approved the combination of olaparib with
patients with HRR mutations. In fact, a randomized phase 2 trial showed abiraterone for the treatment of adult patients with BRCAm mCRPC.
that the combination of abiraterone with olaparib increased radiographic Based on the results of PROpel, olaparib/abiraterone is included in the
PFS over abiraterone and placebo in patients with mCRPC regardless of NCCN Guidelines as an option for patients with mCRPC and a pathogenic
HRR status (ITT population: HR, 0.65; 95% CI, 0.44–0.97; P = .034).636 BRCA1 or BRCA2 mutation (germline and/or somatic) who have not yet
received an ARPI (category 1).
The PROpel trial was an international, double-blind, phase 3 trial
Talazoparib Plus Enzalutamide
comparing abiraterone and olaparib with abiraterone and placebo in 796
patients with mCRPC regardless of HRR mutation status.660 Prior Talazoparib is another PARP inhibitor; it has had an FDA indication in
docetaxel in the localized or mCSPC setting was allowed, but patients breast cancer. The open-label, international phase 2 TALAPRO-1 trial
were untreated for CRPC. The primary endpoint, imaging-based PFS by included 127 patients with an HRR mutation and progressive, mCRPC, all
investigator assessment in the ITT population, was significantly longer in of whom received at least one dose of talazoparib.662 The objective
the abiraterone/olaparib group than in the abiraterone/placebo group (24.8 response rate after a median follow-up of 16.4 months was 29.8% (95%
vs. 16.6 months; HR, 0.66; 95% CI, 0.54–0.81; P < .001). HRR mutations CI, 21.2–39.6). The most common grade 3–4 treatment-emergent adverse
were identified in tumors of 226 patients; 552 patients did not have HRR events were anemia (31%), thrombocytopenia (9%), and neutropenia
tumor mutations. The HR for the primary endpoint in those with HRR (8%).
mutations was 0.50 (95% CI, 0.34–0.73). The safety profile of the
As noted above (see Olaparib Plus Abiraterone), pre-clinical data suggest
olaparib/abiraterone combination was as expected based on the known
that the PARP inhibition combined with androgen receptor inhibition may
safety profiles of the individual drugs, with the most common adverse
have an enhanced antitumor effect that may not be limited to those with
events being anemia, fatigue/asthenia, and nausea.
HRR mutations. The randomized, double-blind, phase 3 TALAPRO-2
Final OS data from PROpel showed that OS was not significantly study compared enzalutamide plus talazoparib with enzalutamide plus
improved with the abiraterone/olaparib combination therapy in the full placebo in 805 patients with untreated mCRPC.663 HRR gene alteration
cohort after a median follow up of approximately 36.5 months (42.1 vs status and treatment with docetaxel and/or abiraterone in the castration-
34.7 months; HR, 0.81; 95% CI, 0.67–1.00; P = .054).661 In a post-hoc sensitive setting were used to stratify the randomization. The primary
exploratory analysis, the BRCAm population saw an OS benefit, with a endpoint was radiographic PFS in the ITT population. At the planned
median OS of 23.0 months in the abiraterone arm and not reached in the primary analysis, median radiographic PFS was not reached (95% CI,
combination arm (HR, 0.29; 95% CI, 0.14–0.56). A smaller OS benefit was 27.5 months–not reached) for the talazoparib group and was 21.9 months
(95% CI, 16.6–25.1) for the control group (HR, 0.63; 95% CI, 0.51–0.78; P
< .0001).

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HRR mutations were present in 21% of TALAPRO-2 participants, with dose interruption due to adverse events in 75% of participants in the
BRCA alterations being the most common.663 The HR for radiographic talazoparib group compared with 23% in the placebo group. Dose
PFS in the HRR-deficient subgroup was more strongly in favor of the reductions due to adverse events occurred in 56% and 7% of the
talazoparib combination than in the HRR-proficient/unknown population talazoparib and placebo groups, respectively.
(0.46 [95% CI, 0.30–0.70; P = .0003] vs. 0.70 [95% CI, 0.54–0.89; P =
.0039]). Among HRR mutations, talazoparib conferred a 77% lower risk of Based on the results from the first TALAPRO-2 cohort, the FDA approved
radiographic progression or death in those with tumor mutations in BRCA1 talazoparib plus enzalutamide for HRRm mCRPC in June 2023. The Panel
or BRCA2 (HR, 0.23; 95% CI, 0.10–0.53; P = .0002), whereas the includes talazoparib plus enzalutamide as a category 1 treatment option
corresponding reduction was 34% (HR, 0.66; 95% CI, 0.39–1.12; P = .12) for patients with mCRPC and a pathogenic mutation (germline and/or
in those with non-BRCA HRR alterations. somatic) in one of certain HRR and other DNA repair genes (BRCA1,
BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN,
Prior therapy also affected the radiographic PFS outcomes in this trial.663 PALB2, or RAD51C) who have not yet had treatment with an ARPI. Use of
In the 179 participants in TALAPRO-2 who had received docetaxel in talazoparib/enzalutamide for those who have received prior ARPI therapy
earlier disease settings, the HR for radiographic PFS was 0.51 (95% CI, without prior docetaxel is controversial (category 2B) because a benefit of
0.32–0.81; P = .0034). In the small population of 50 participants in the ITT this combination over use of a PARP inhibitor alone has not been shown
population who had received prior novel hormonal therapy, the in this setting, but responses are likely.
corresponding HR was non-significant at 0.57 (95% CI, 0.28–1.16; P =
Niraparib Plus Abiraterone
.12).
Another PARP inhibitor, niraparib, has also been studied in combination
Final results from an HRRm-only cohort of TALAPRO-2 at a median with androgen inhibition in the setting of mCRPC. The randomized,
follow-up of 44.2 months showed that median OS was improved with the double-blinded phase 3 MAGNITUDE trial compared niraparib plus
combination compared with enzalutamide alone (45.1 vs. 31.1 months; abiraterone to placebo plus abiraterone in 423 patients with mCRPC and
HR, 0.62; 95% CI, 0.48–0.81; two-sided P = .0005).664 Median HRR mutations and an additional 247 patients without HRR mutations.665
radiographic PFS was also improved with the talazoparib/enzalutamide Prior chemotherapy and novel hormonal therapy were allowed in the
group compared with the enzalutamide group (30.7 vs. 12.3 months; HR, mCSPC or M0 CRPC settings, and were received by 3.1% and 20.1% of
0.47; 95% CI, 0.36–0.61; P < .0001). the total HRRm cohort, respectively.

The safety profile of enzalutamide plus talazoparib was consistent with the The primary endpoint of MAGNITUDE was radiographic PFS. After a
known safety profiles of the individual drugs, with the most common median follow-up of 18.6 months, radiographic PFS was improved for
adverse events in those who received talazoparib being anemia, those receiving niraparib in the HRRm group overall (16.5 vs. 13.7
neutropenia, and fatigue. However, hematologic adverse events were of months; HR, 0.73; 95% CI, 0.56–0.96; P = .022) as well as in the BRCAm
higher grades and occurred more frequently than would be expected with subgroup (16.6 vs. 10.9 months; HR, 0.53; 95% CI, 0.36–0.79; P = .001).
talazoparib alone. Overall, the combination had significant toxicity, with However, radiographic PFS was not improved in the subgroup of patients

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with non-BRCA HRR mutations (HR, 0.99; 95% CI, 0.68–1.44). For the Radiopharmaceuticals for mCRPC
cohort without HRR mutations, futility was declared based on prespecified Lutetium Lu 177 vipivotide tetraxetan
criteria. The secondary endpoints of time to symptomatic progression and
Lu-177-PSMA-617 is a radiopharmaceutical that is administered
time to initiation of cytotoxic chemotherapy were improved with the
intravenously and is indicated for PSMA-positive mCRPC that has been
combination therapy in the HRRm and BRCAm cohorts.
treated with androgen receptor pathway inhibition and taxane-based
A second interim analysis of MAGNITUDE included a prespecified, inverse chemotherapy. The active moiety is a radionuclide that delivers radiation
probability censoring weighting analysis of OS, which was designed to to PSMA-expressing and surrounding cells, which induces DNA damage
account for the receipt of subsequent therapies, including PARP and leads to cell death. The approval of Lu-177-PSMA-617 was based on
inhibitors.666 Results of this analysis suggest that there may be an OS the international, open-label phase III VISION trial of 831 patients with
benefit for the combination therapy (HR, 0.54; 95% CI, 0.33–0.90; nominal mCRPC and PSMA-positive metastatic lesions. Patients in VISION were
P = .0181). previously treated with at least one androgen receptor-directed therapy
and one or two taxane-based chemotherapy regimens.667 Patients had at
The incidence of grade 3/4 adverse events was higher with the least one PSMA-positive metastatic lesion and no PSMA-negative lesions
combination of niraparib plus abiraterone compared with placebo and determined by Ga-68 labeled PSMA-11 PET/CT imaging. Patients were
abiraterone (67.0% vs. 46.4%).665 Anemia (28.3% vs. 7.6%) and randomized in a 2:1 ratio to receive standard of care (abiraterone,
hypertension (14.6% vs. 12.3%) were the most reported grade ≥3 adverse enzalutamide, bisphosphonates, RT, denosumab, and/or glucocorticoids)
events. Overall, the combination was tolerable and QOL was maintained. and Lu-177-PSMA-617 (7.4 GBq or 200 mCi every 6 weeks for 4–6
cycles) or standard of care alone.
Based on these results, the FDA approved niraparib plus abiraterone for
the treatment of patients with BRCAm mCRPC in August 2023. The Panel The median OS was improved in the Lu-177-PSMA-617 group compared
includes niraparib plus abiraterone as a treatment option for patients with to the control group (15.3 vs. 11.3 months; HR, 0.62; 95% CI, 0.52–0.74;
mCRPC and a pathogenic BRCA1 or BRCA2 mutation (germline and/or P < .001). Similarly, the median PFS was improved in the Lu-177-PSMA-
somatic) who have not yet had treatment in the setting of mCRPC. This is 617 group compared to the control group (8.7 vs. 3.4 months; HR, 0.40;
a category 1 recommendation for those without prior ARPI. Use of 99.2% CI, 0.29–0.57; P < .001). The incidence of grade ≥3 adverse events
niraparib/abiraterone for those who have received a prior ARPI without (particularly anemia, thrombocytopenia, lymphopenia, and fatigue) was
prior docetaxel is controversial (category 2B) because a benefit of this significantly higher in the Lu-177-PSMA-617 group compared to the
combination over use of a PARP inhibitor alone has not been shown in control group. 667
this setting.
The FDA approved Lu-177-PSMA-617 in the post-ARPI setting in March
2022.

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Another randomized controlled phase 3 trial, PSMAfore, assessed the Radium-223

efficacy of Lu-177-PSMA-617 pre-docetaxel in 468 patients with mCRPC In May 2013, the FDA approved radium-223 dichloride, an alpha particle-
who experienced disease progression on an ARPI.668 The primary emitting radioactive agent. This first-in-class radiopharmaceutical was
endpoint of rPFS in the ITT population was improved with Lu-177-PSMA- approved for treatment of mCRPC in patients with symptomatic bone
617 compared with a change in ARPI. At a median of 24.1 months after metastases and no known visceral metastatic disease. Approval was
randomization, median radiographic PFS was 11.6 months in the Lu-177- based on clinical data from a multicenter, phase 3, randomized trial
PSMA-617 group versus 5.6 months in the control group (HR 0.49; 95% (ALSYMPCA) that included 921 patients with symptomatic CRPC, two or
CI, 0.39–0.61). There was no difference in OS, but OS data are difficult to more bone metastases, and no known visceral disease.669 Fifty-seven
interpret because patients were allowed to crossover from an ARPI percent of the patients received prior docetaxel and all patients received
change to Lu-177-PSMA-617 upon radiographic progression, and 57% of best supportive care. Patients were randomized in a 2:1 ratio to 6 monthly
patients in the control arm did so. Importantly, there were fewer grade 3–5 radium-223 intravenous injections or placebo. Compared to placebo,
toxicities in Lu-177-PSMA-617 arm. radium-223 significantly improved OS (median 14.9 vs. 11.3 months; HR,
0.70; 95% CI, 0.058–0.83; P < .001) and prolonged time to first SRE
Based on the results of the PSMAfore trial, the FDA expanded the
(median 15.6 vs. 9.8 months). Preplanned subset analyses showed that
indication for Lu-177-PSMA-617 to include adult patients with PSMA-
the survival benefit of radium-223 was maintained regardless of prior
positive mCRPC who have progressed after ARPI therapy and are
docetaxel use.670 ITT analyses from ALSYMPCA showed that radium-223
considered appropriate candidates for delaying taxane-based
also may reduce the risk of symptomatic SREs.671 Grade 3/4 hematologic
chemotherapy.
toxicity was low (3% neutropenia, 6% thrombocytopenia, and 13%
The NCCN Panel recommends Lu-177-PSMA-617 as a treatment option anemia), likely due to the short range of radioactivity.669 Fecal elimination
for patients with one or more PSMA-positive lesion and/or metastatic of the agent led to generally mild non-hematologic side effects, which
disease that is predominately PSMA-positive and with no dominant PSMA- included nausea, diarrhea, and vomiting. Radium-223 was associated with
negative metastatic lesions who have been treated previously with an improved or slower decline of QOL in ALSYMPCA.672
ARPI and a taxane-based chemotherapy (category 1) or who have prior
The multicenter, international, double-blind, placebo-controlled, phase 3
ARPI therapy and are considered appropriate to delay taxane-based
ERA 223 trial randomized patients with bone-metastatic chemotherapy-
chemotherapy.
naïve CRPC to abiraterone with or without radium-223.673 The patients
PSMA-negative lesions are defined as metastatic disease that lacks were asymptomatic or mildly symptomatic. The primary endpoint of
PSMA uptake including bone with soft tissue components ≥1.0 cm, lymph symptomatic skeletal event-free survival in the ITT population was not
nodes ≥2.5 cm in short axis, and solid organ metastases ≥1.0 cm in size. met. In fact, the addition of radium-223 to abiraterone was associated with
The Panel notes that Ga-68 PSMA-11, F-18 piflufolastat PSMA, or F-18 an increased frequency of bone fractures compared with placebo.
flotufolastat PSMA can be used to identify patients eligible for treatment
with Lu-177–PSMA-617.

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The randomized PEACE-3 trial also compared radium-223 with or without in combination with docetaxel or any other systemic therapy except ADT
an ARPI in patients who were ARPI-naive.674 Radium-223 with or enzalutamide should be pursued with caution. It should not be used in
enzalutamide was compared with enzalutamide therapy alone in 446 patients with visceral metastases. All patients receiving radium-223 should
patients with mildly symptomatic mCRPC. The use of bone-protecting be given concomitant denosumab or zoledronic acid.
agents (denosumab or zoledronic acid) was made mandatory following
results from ERA 223. The primary endpoint of radiological PFS was MDT for mCRPC
improved in the combination arm compared with enzalutamide alone (16.4 Although most data supporting the use of MDT for oligometastatic prostate
vs. 19.4 months; HR, 0.69; 95% CI, 0.54–0.87; P = .0009). At a cancer is in the oligorecurrent CSPC setting, as discussed in detail above
preplanned interim OS analysis, median OS was also improved with the (see MDT for Oligometastatic CSPC), MDT has also been studied in the
addition of radium-223 (35.0 vs. 42.3 months; HR, 0.69; 95% CI 0.52– oligoprogressive CRPC. As noted above, the EXTEND trial included 7
0.90; P = .0031). Grade ≥3 adverse events occurred more commonly in patients with oligoprogressive CRPC, although results of MDT in this
the combination arm (65.6% vs. 55.8%) and included hypertension (in subset specifically were not reported.567
34% of the combination arm), fatigue (6%), fracture (5%), anemia (5%),
and neutropenia (5%). Fractures were also more common in the ARTO is a phase 2 study that included 157 patients with CRPC and 1 to 3
combination arm (24.3% vs. 13.4%). metastatic lesions who were randomized to receive abiraterone alone or
abiraterone with MDRT.565 The rate of biochemical response (defined as a
In an earlier safety analysis of PEACE-3, the cumulative incidence of ≥50% decrease in PSA levels at 6 months compared to baseline), which
fractures at 1.5 years in patients who received a bone-protecting agent was the primary endpoint, was 92% in the MDRT group compared with
was 2.8% in participants receiving radium-223 plus enzalutamide and 68.3% in the control group (OR, 4.22; 95% CI, 2.12–8.38; P < .001). PFS,
3.9% in those receiving enzalutamide alone.675 In the absence of bone a secondary endpoint was also improved with the use of MDRT (HR, 0.35;
agents, these numbers were 45.9% and 22.3%, respectively. This result 95% CI, 0.21–0.57; P < .001). A subgroup analysis of ARTO further
suggests that radium-223 combined with an ARPI may be safe if suggested that MDRT for oligoprogressive mCRPC may result in similar
preventive administration of a bone agent is used. PFS as second-line systemic therapy.676

Radium-223 is a category 1 option to treat symptomatic bone metastases Initial results from the phase 2 GROUQ-PCS-9 were presented at the
without visceral metastases in patients with mCRPC regardless of prior 2025 ASCO Genitourinary Cancers Symposium.677 MDRT added to ADT
therapy. Radium-223 plus enzalutamide is included as an option for and enzalutamide in oligometastatic CRPC (with 1–5 metastases) led to
patients with bone-metastatic CRPC without prior exposure to an ARPI. improvements in radiological PFS, biochemical PFS, and time to next line
Hematologic evaluation should be performed according to the FDA label of therapy compared to ADT with enzalutamide alone.
before treatment initiation and before each subsequent dose.591 Radium-
223 given in combination with chemotherapy (such as docetaxel) outside The Panel includes MDT with mCRPC systemic therapy as an option for
of a clinical trial has the potential for additive myelosuppression.591 Its use patients with oligometastatic or oligoprogressive CRPC regardless of prior
therapy.
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Small Cell/Neuroendocrine Prostate Cancer Additional Treatment Options for Bone Metastases
De novo small cell carcinoma in untreated prostate cancer occurs rarely In a multicenter study, 643 patients with CRPC and asymptomatic or
and is very aggressive.678 Treatment-associated small cell prostate minimally symptomatic bone metastases were randomized to intravenous
cancer/NEPC that occurs in patients with mCRPC is more common.679 In a zoledronic acid every 3 weeks or placebo.683 At 15 months, fewer patients
multi-institution prospective series of 202 consecutive patients with in the zoledronic acid 4-mg group than patients in the placebo group had
mCRPC, all of whom underwent metastatic biopsies, small SREs (33% vs. 44%; P = .02). An update at 24 months also revealed an
cell/neuroendocrine histology was present in 17% of patients.679 Patients increase in the median time to first SRE (488 vs. 321 days; P = .01).684 No
with small cell/neuroendocrine tumors and prior abiraterone and/or significant differences were found in OS. Other bisphosphonates have not
enzalutamide had a shorter OS when compared with those with been shown to be effective for prevention of disease-related skeletal
adenocarcinoma and prior abiraterone and/or enzalutamide (HR, 2.02; complications.
95% CI, 1.07–3.82). Genomic analysis showed that DNA repair mutations
and small cell/neuroendocrine histology were almost mutually exclusive. The randomized TRAPEZE trial used a 2 X 2 factorial design to compare
clinical PFS (pain progression, SREs, or death) as the primary outcome in
Small cell/neuroendocrine carcinoma of the prostate should be considered 757 patients with bone-metastatic CRPC treated with docetaxel alone or
in patients with disease that no longer responds to ADT and who test with zoledronic acid, 89Sr, or both.685 The bone-directed therapies had no
positive for metastases. These relatively rare tumors are associated with statistically significant effect on the primary outcome or on OS in
low PSA levels despite large metastatic burden and visceral disease.680 unadjusted analysis. However, adjusted analysis revealed a small effect
Those with initial Grade Group 5 are especially at risk. Biopsy of for 89Sr on clinical PFS (HR, 0.85; 95% CI, 0.73–0.99; P = .03). For
accessible metastatic lesions to identify patients with small secondary outcomes, zoledronic acid improved the SRE-free interval (HR,
cell/neuroendocrine histomorphologic features is recommended in patients 0.78; 95% CI, 0.65–0.95; P = .01) and decreased the total SREs (424 vs.
with mCRPC. 605) compared with docetaxel alone.

These patients may be treated with cytotoxic chemotherapy (ie, Denosumab was compared to zoledronic acid in a randomized, double-
cisplatin/etoposide, carboplatin/etoposide, docetaxel/carboplatin, blind, placebo-controlled study in patients with CRPC.686 The absolute
cabazitaxel/carboplatin).621,681,682 Physicians should consult the NCCN incidence of SREs was similar in the two groups; however, the median
Guidelines for Small Cell Lung Cancer for additional options in the first and time to first SRE was delayed by 3.6 months by denosumab compared to
subsequent lines of therapy (available at [Link]), because the zoledronic acid (20.7 vs. 17.1 months; P = .0002 for noninferiority; P =
behavior of small cell/neuroendocrine carcinoma of the prostate is similar .008 for superiority). The rates of important SREs with denosumab were
to that of small cell carcinoma of the lung. similar to zoledronic acid and included spinal cord compression (3% vs.
4%), need for radiation (19% vs. 21%), and pathologic fracture (14% vs.
15%). Treatment-related toxicities reported for zoledronic acid and
denosumab were similar and included hypocalcemia (more common with

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denosumab 13% vs. 6%), arthralgias, and osteonecrosis of the jaw (ONJ, renal function (estimated creatinine clearance 30–60 mL/min) and held for
1%–2% incidence). creatinine clearance <30 mL/min. Denosumab may be administered to
patients with impaired renal function or even patients on hemodialysis;
Therefore, denosumab every 4 weeks (category 1, preferred) or zoledronic however, the risk for severe hypocalcemia and hypophosphatemia is
acid every 3 to 4 weeks is recommended for patients with CRPC and bone greater, and the dose, schedule, and safety of denosumab have not yet
metastases to prevent or delay disease-associated SREs. SREs include been defined. A single study of 55 patients with creatinine clearance <30
pathologic fractures, spinal cord compression, operation, or EBRT to mL/min or on hemodialysis evaluated the use of 60-mg-dose
bone. The optimal duration of zoledronic acid or denosumab in patients denosumab.591 Hypocalcemia should be corrected before starting
with CRPC and bone metastases remains unclear. A multi-institutional, denosumab, and serum calcium monitoring is required for denosumab and
open-label, randomized trial in 1822 patients with bone-metastatic prostate recommended for zoledronic acid, with repletion as needed.
cancer, breast cancer, or multiple myeloma found that zoledronic acid
every 12 weeks was noninferior to zoledronic acid every 4 weeks.687 In the Radium-223 is a category 1 option to treat symptomatic bone metastases
every-12-week and every-4-week arms, 28.6% and 29.5% experienced at in patients with mCRPC without visceral metastases (see Radium-223,
least 1 SRE within 2 years of randomization, respectively. above). The use of palliative RT is also an option.

Use of zoledronic acid in patients with CSPC and bone metastases is not Clinical research on the prevention or delay of disease spread to bone
associated with lower risk for SREs.688 Therefore, the routine use of these continues. A phase 3 randomized trial of 1432 patients with non-metastatic
agents in bone-metastatic CSPC is not recommended. Bone antiresorptive CRPC at high risk of bone involvement showed that denosumab delayed
agents should, however, be used for SRE prevention in patients with bone metastasis by 4 months compared to placebo.691 OS was not
CSPC if they have treatment-related bone loss (see Principles of improved, and the FDA did not approve denosumab for the prevention of
Survivorship, Bone Health in Prostate Cancer, in the algorithm above). bone metastases.

Oral hygiene, baseline dental evaluation for high-risk individuals, and Considerations for Visceral Metastases
avoidance of invasive dental surgery during therapy are recommended to The Panel defines visceral metastases as those occurring in the liver,
reduce the risk of ONJ.689 Most, but not all, patients who develop ONJ lung, adrenal gland, peritoneum, or brain. Soft tissue/lymph node sites are
have preexisting dental problems.690 If invasive dental surgery is not considered visceral metastases. In general, there are fewer data on
necessary, therapy should be deferred until the dentist confirms that the treatment of patients with CRPC and visceral metastases than for those
patient has healed completely from the dental procedure. Supplemental without visceral metastases.
calcium and vitamin D are recommended to prevent hypocalcemia in
patients receiving either denosumab or zoledronic acid. Sequencing of Therapy in CRPC
Monitoring of creatinine clearance is required to guide dosing of zoledronic The number of treatment options for patients with CRPC has expanded
acid. Zoledronic acid should be dose reduced in patients with impaired rapidly over the past several years. Although the optimal sequence of

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therapies remains undefined, some data that can help with treatment radiographic PFS than cabazitaxel in patients with BRCA1 or BRCA2
selection in some cases continues to emerge. mutations and prior treatment with docetaxel.698 Furthermore, data from
PROfound and TRITON3 suggest that a PARP inhibitor is preferred over a
After abiraterone or enzalutamide, data suggest that giving the alternate different ARPI in patients with BRCAm mCRPC and prior ARPI
ARPI may not be the optimal strategy considering the availability of other exposure.651,655
treatment options, including chemotherapy. The CARD trial, for instance,
showed that treatment with cabazitaxel significantly improved clinical No chemotherapy regimen has demonstrated improved survival or QOL
outcomes over enzalutamide or abiraterone in patients with mCRPC who after cabazitaxel or cabazitaxel/carboplatin in patients with mCRPC of
had been previously treated with docetaxel and the alternate hormonal adenocarcinoma histology, although several systemic agents other than
therapy (abiraterone or enzalutamide).615 Furthermore, data suggest mitoxantrone have shown palliative and radiographic response benefits in
cross-resistance between abiraterone and enzalutamide.692-695 Results of a clinical trials (ie, carboplatin, cyclophosphamide, doxorubicin, vinorelbine,
randomized, open-label, phase 2, crossover trial suggest that the carboplatin/etoposide, docetaxel/carboplatin, gemcitabine/oxaliplatin,
sequence of abiraterone followed by enzalutamide may be more paclitaxel/carboplatin).699-708 No survival benefit for any these combination
efficacious than the reverse.696 regimens over sequential single-agent regimens has been demonstrated,
and toxicity is higher. Treatment with these regimens could be considered
Some data inform the sequencing of therapies in patients with PSMA- after an informed discussion between the physician and an individual
positive mCRPC. The multicenter, unblinded, randomized phase 2 TheraP patient about treatment goals and risks/side effects and alternatives, which
trial compared PSA response after Lu-177-PSMA-617 versus cabazitaxel must include best supportive care. In patients not able to receive life
in 200 patients with PSMA-positive mCRPC who previously received prolonging therapy, prednisone and dexamethasone at low doses may
docetaxel.697 Prior androgen receptor-directed therapy was permitted. provide palliative benefits.709 Participation in a clinical trial is encouraged.
Among the ITT population, the PSA response rate was 66% in the Lu-177-
PSMA-617 arm compared with 37% in the cabazitaxel arm (difference Summary
29%; 95% CI, 16–42; P < .0001). These numbers were 66% and 44%, The intention of these guidelines is to provide a framework on which to
respectively, in those who received treatment (difference 23%; 95% CI, 9– base treatment decisions. Prostate cancer is a complex disease, with
37; P = .0016). Furthermore, grade 3–4 adverse events were less frequent many controversial aspects of management and with limited data to
in the Lu-177-PSMA-617 arm than in the cabazitaxel arm (33% vs. 53%). support some of the treatment recommendations. Several variables
Results from the phase 3 PSMAfore trial as discussed above (see (including adjusted life expectancy, disease characteristics, predicted
Lutetium Lu 177 vipivotide tetraxetan) showed that Lu-177-PSMA-617 outcomes, and patient preferences) must be considered by the patient and
improved rPFS compared with switching to a different ARPI in docetaxel- physician to tailor prostate cancer therapy for the individual patient.
naïve patients.668

Data for patients with HRRm mCRPC are more limited, but comparative
effectiveness research suggests that olaparib may result in superior

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Table 1: Selected Active Surveillance Experiences with Large Patient Cohorts

Cohort Toronto272,313,319 Johns UCSF281 Canary PASS289 Cooley/Catalona PRIAS278
Hopkins275, Meta-Dataset277
312,314,710

Initial Cohort Newer Cohort

Number of patients 993 1298 321 810 2155 6775 5302
Median age (y) 68 66 63 62 63 64 66
Core involvement and % of cohort with ≤2 Median # Mean % Not available Median % positive % of cohort with ≤2 % of cohort with
risk groups positive cores, 69 positive positive cores, 12.5% positive cores, 77.6 ≤2 positive cores,
cores, 1 cores, 20.3% 99
25% IR, D'Amico criteria 17% NCCN IR/HR

Median follow-up 77 60 43 60 86 80 120

(months)
Conversion to 36.5% (10-y) 50% (10-y) 24% (3-y) 40% (5-y) 49% (10-y) 33% (6.7-y) 52% (5-y)
treatment* 45% (15-y) 73% (10-y)
Systemic progression 6.6% systemic 0.15% 0% distant 0.1% 0.5% distant 0.4% 0.2%
progression in IR group distant metastases metastases
Lymph node metastases
involvement 3.1% (1.8% distant 0.2% pos. 0.5% pos.
and/or metastasis metastases; 1.3% 0.08% pos. lymph nodes lymph nodes
pos. lymph nodes) lymph nodes

Cancer-specific 98% (10-y) 99.9% (10-y) 100% (5-y) 100% (5-y) 99.9% (10-y) 99.8% (6.7-y) >99% (10-y)
survival
Overall survival 80% (10-y) 93% (10-y) 98% (10-y) 98% (5-y) 94.3% (10-y) — —
*Reason for conversion to treatment (% of entire cohort)
Gleason grade 9.5% 15.1% 38% — 43% (10-y) 49% 34% (5-y)
change 41% (20-y)a
PSA increase 11.7% — 26% — — 8.5% —
Tumor volume — — — — — 7.2% —
increase
Personal choice 1.6% 8% 8% — — 5% (anxiety) 5%
IR = intermediate risk; HR = high risk.
aProtocol-based reclassification (included change in Gleason grade, number of positive cores, or cT stage)

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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Prostate Cancer

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598. Saad F, Cella D, Basch E, et al. Effect of apalutamide on health- Prostate Cancer. J Clin Oncol 2021;39:1371–1382. Available at:
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