(Published 2020; Amended 2023, 2026)

Unabridged version of this Guideline [pdf]

Algorithm for this Guideline [pdf]

Amendment summary for this Guideline [pdf]

William Lowrance, MD, MPH, MBA; Rodney Breau, MSc, MD; Roger Chou, MD; Brian F. Chapin, MD; Tony Crispino; Robert Dreicer, MD, MS, MACP; David F. Jarrard, MD; Adam S. Kibel, MD; Todd M. Morgan, MD; Alicia K. Morgans, MD, MPH; William K. Oh, MD; Matthew Resnick, MD, MPH, MMHC; Anthony Zietman, MD; Michael S. Cookson, MD, MMHC

2023 Guideline Amendment Panel

William Lowrance, MD, MPH, MBA; Robert Dreicer, MD, MS, MACP; David F. Jarrard, MD; Kristen R. Scarpato, MD, MPH; Michael S. Cookson, MD, MMHC

2026 Guideline Amendment Panel

Kristen R. Scarpato, MD, MPH; Michael S. Cookson, MD, MMHC; Robert Dreicer, MD, MS, MACP, FASCO; Mutlay Sayan, MD; Alice Yu, MD, MPH

Staff and Consultants

David I. Buckley, MD, MPH; Roger Chou, MD; Kristen E. D’Anci, PhD; Jessica C. Griffin, MS; Erin Kirkby, MS; Lauren J. Pak, MHS, MS

SUMMARY

Purpose

The management of advanced prostate cancer is rapidly evolving. To assist in clinical decision-making, evidence-based guideline statements were developed to provide a rational basis for evidence-based treatment. This guideline covers advanced prostate cancer, including disease stages that range from prostate-specific antigen (PSA) recurrence after exhaustion of local treatment options to widespread metastatic disease.

Methodology

The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020.

In 2023, the Advanced Prostate Cancer guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines. The methodology team searched Ovid MEDLINE(R) ALL and the Cochrane Libraries for studies published between 2018 and March 16, 2022.

In 2026, the Advanced Prostate Cancer guideline was updated through the AUA amendment process. The methodology team searched PubMed for studies published between March 16, 2022 and August 26, 2025.

GUIDELINE STATEMENTS

Early Evaluation and Counseling

1. In patients with suspicion of advanced prostate cancer and no prior histologic confirmation, clinicians should obtain tissue diagnosis from the primary tumor or site of metastases when clinically feasible. (Clinical Principle)
2. Clinicians should discuss treatment options with advanced prostate cancer patients based on life expectancy, comorbidities, preferences, and tumor characteristics. Patient care should incorporate a multidisciplinary approach when available. (Clinical Principle)
3. Clinicians should optimize pain control or symptom support in advanced prostate cancer patients and encourage engagement with professional or community-based resources, including patient advocacy groups. (Clinical Principle)
4. For all patients with advanced prostate cancer, clinicians should offer germline testing. For patients with metastatic disease, somatic tumor testing should also be offered. (Clinical Principle)

Biochemical Recurrence without Metastatic Disease after Exhaustion of Local Treatment Options

Prognosis

5. Clinicians should inform patients with PSA recurrence after exhaustion of local therapy regarding the risk of developing metastatic disease and follow such patients with serial PSA measurements and clinical evaluation. Clinicians may consider radiographic assessments based on overall PSA and PSA kinetics. (Clinical Principle)
6. In patients with PSA recurrence after exhaustion of local therapy who are at higher risk for the development of metastases, clinicians should perform periodic staging evaluations consisting of imaging preferentially with prostate-specific membrane antigen positron emission tomography (PSMA PET) and/or computed tomography (CT), magnetic resonance imaging (MRI), and technetium bone scan. (Clinical Principle)
7. Clinicians should utilize PSMA PET imaging preferentially in patients with PSA recurrence after exhaustion of local therapy due to its greater sensitivity, or in the setting of negative conventional imaging. (Expert Opinion)

Treatment

8. For patients with a rising PSA after exhaustion of local therapy and no demonstrated metastatic disease, clinicians should risk stratify as low- or high-risk. High-risk patients generally are defined as patients with PSA doubling time (PSADT) ≤ 9 months. (Clinical Principle)
9. Androgen deprivation therapy (ADT) should not be routinely initiated for low-risk patients (PSADT > 9 months) with biochemical recurrence after exhaustion of local therapy. (Expert Opinion)
   • For patients with a rising PSA after exhaustion of local therapy with low-risk features, including PSADT > 9 months, clinicians should offer observation and ADT should not be routinely initiated.
   • For patients with a rising PSA after exhaustion of local therapy with high-risk features, including PSADT ≤ 9 months, clinicians should offer ADT with enzalutamide.
   • For patients with a rising PSA after exhaustion of local therapy with high-risk features and no metastatic disease in whom ADT +/- androgen receptor pathway inhibitor (ARPI) is initiated, intermittent therapy may be offered in lieu of continuous therapy in the setting of a favorable response to therapy.

Metastatic Hormone-Sensitive Prostate Cancer

Prognosis

10. Clinicians should assess the extent of metastatic disease (lymph node, bone, and visceral metastases) in newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) patients. (Clinical Principle)
11. In newly diagnosed mHSPC patients, clinicians should assess the extent of metastatic disease (lymph node, bone, and visceral metastases) and stratify based on low- versus high-volume. High-volume is defined as greater than or equal to four bone metastases with at least one metastasis outside of the spine/pelvis and/or the presence of visceral metastases based on conventional imaging. (Moderate Recommendation; Evidence Level: Grade B)
12. Clinicians should assess if a newly diagnosed mHSPC patient is experiencing symptoms from metastatic disease at the time of presentation to guide discussions of prognosis and further disease management. (Moderate Recommendation; Evidence Level: Grade B)
13. Clinicians should obtain a baseline PSA and serial PSAs at three- to six-month intervals after initiation of ADT in mHSPC patients and consider periodic imaging. (Clinical Principle)

Treatment

14. Clinicians should offer ADT with either luteinizing hormone-releasing hormone (LHRH) agonists or antagonists or surgical castration in patients with mHSPC. (Strong Recommendation; Evidence Level: Grade B)
15. In addition to ADT, clinicians should also offer androgen pathway-directed therapy with abiraterone acetate plus prednisone, apalutamide, enzalutamide, or darolutamide to the majority of patients with mHSPC. (Strong Recommendation; Evidence Level: Grade A)
16. In select mHSPC patients, clinicians should offer ADT in combination with docetaxel and either abiraterone acetate plus prednisone or darolutamide. (Strong Recommendation; Evidence Level: [Abiraterone] Grade A/[Darolutamide] Grade B)
17. In select mHSPC patients, clinicians may offer primary radiotherapy to the prostate in combination with ADT with or without an ARPI. (Conditional Recommendation; Evidence Level: Grade C)
18. Clinicians should not offer first generation antiandrogens (bicalutamide, flutamide, nilutamide) in combination with LHRH agonists in patients with mHSPC, except to block testosterone flare. (Strong Recommendation; Evidence Level: Grade A)
19. In mHSPC patients with homologous recombination repair (HRR) gene alterations, particularly BRCA 2, clinicians may offer the combination of ADT, abiraterone, and niraparib. (Expert Opinion)

Non-Metastatic Castration-Resistant Prostate Cancer

Prognosis

20. In non-metastatic castration-resistant prostate cancer (nmCRPC) patients, clinicians should obtain serial PSA measurements at three- to six-month intervals and calculate a PSADT starting at the time of development of castration-resistance. (Clinical Principle)
21. Clinicians should assess nmCRPC patients for development of metastatic disease using conventional or PSMA PET imaging at intervals of 6 to 12 months. (Expert Opinion)

Treatment

22. Clinicians should offer apalutamide, darolutamide, or enzalutamide with continued ADT to nmCRPC patients at high risk for developing metastatic disease (PSADT ≤10 months). (Strong Recommendation; Evidence Level: Grade A)
23. Clinicians may recommend observation with continued ADT to nmCRPC patients, particularly those at lower risk (PSADT >10 months) for developing metastatic disease. (Clinical Principle)
24. Clinicians should not offer systemic chemotherapy or immunotherapy to nmCRPC patients outside the context of a clinical trial. (Clinical Principle)

Metastatic Castration-Resistant Prostate Cancer

Prognosis

25. In metastatic castration-resistant prostate cancer (mCRPC) patients, clinicians should obtain baseline labs (e.g., PSA, testosterone, lactate dehydrogenase [LDH], hemoglobin [Hgb], alkaline phosphatase level) and review location of metastatic disease (lymph node, bone, visceral), disease-related symptoms, and performance status to inform discussions of prognosis and treatment decision-making. (Clinical Principle)
26. In mCRPC patients without PSA progression or new symptoms, clinicians should perform imaging at least annually. (Expert Opinion)

Treatment

27. For most patients progressing to mCRPC who have not received prior ARPIs, clinicians should offer continued ADT with abiraterone acetate plus prednisone or enzalutamide. (Strong Recommendation; Evidence Level: Grade A)
28. In mCRPC patients with disease progression following treatment with an ARPI, clinicians should offer docetaxel. (Strong Recommendation; Evidence Level: Grade B)
29. In mCRPC patients who are asymptomatic or minimally symptomatic, clinicians may offer sipuleucel-T. (Conditional Recommendation; Evidence Level: Grade B)
30. Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy >3cm. (Strong Recommendation; Evidence Level: Grade B)
31. In mCRPC patients with disease progression following treatment with an ARPI (with or without prior docetaxel), and a positive PSMA PET/CT, clinicians should offer ¹⁷⁷Lu-PSMA-617. (Strong Recommendation; Evidence Level: Grade B)
32. In mCRPC patients who received prior docetaxel chemotherapy either in the mHSPC or mCRPC setting, clinicians may offer cabazitaxel. (Conditional Recommendation; Evidence Level: Grade B)
33. In mCRPC patients who received prior docetaxel chemotherapy and an androgen pathway inhibitor, clinicians should recommend cabazitaxel rather than an alternative androgen pathway inhibitor. (Strong Recommendation; Evidence Level: Grade B)
34. Clinicians may offer a poly (ADP-ribose) polymerase (PARP) inhibitor to select patients with deleterious germline or somatic HRR gene-mutated mCRPC who have progressed on prior ARPIs. Platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor. (Conditional Recommendation; Evidence Level: Grade C)
35. Clinicians may offer a PARP inhibitor in combination with an ARPI to select patients with deleterious germline or somatic HRR gene-mutated mCRPC. (Conditional Recommendation; Evidence Level: Grade C)
36. In patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) mCRPC, clinicians should offer pembrolizumab. (Moderate Recommendation; Evidence Level: Grade C)

Bone Health

37. Clinicians should discuss the risk of osteoporosis associated with ADT and should assess the risk of fragility fracture in patients with advanced prostate cancer. (Clinical Principle)
38. Clinicians should recommend preventive treatment for fractures and skeletal-related events, including supplemental calcium, vitamin D, smoking cessation, and weight-bearing exercise, to advanced prostate cancer patients on ADT. (Clinical Principle)
39. In advanced prostate cancer patients at high fracture risk due to bone loss, clinicians should recommend preventive treatments with bisphosphonates or denosumab and referral to physicians who have familiarity with the management of osteoporosis when appropriate. (Clinical Principle)
40. Clinicians should prescribe a bone-protective agent (denosumab or zoledronic acid) for mCRPC patients with bony metastases to prevent skeletal-related events. (Moderate Recommendation; Evidence Level: Grade B)

INTRODUCTION

Methodology

The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. Determination of the guideline scope and review of the final systematic review to inform guideline statements was conducted in conjunction with the Advanced Prostate Cancer Panel.

Panel Formation

The Panel was created in 2018 by the American Urological Association Education and Research, Inc. (AUAER). This guideline was developed in collaboration with the American Society for Radiation Oncology (ASTRO), and Society of Urologic Oncology (SUO) with additional panel representation from the American Society of Clinical Oncology (ASCO). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair and Vice Chair who in turn appointed the additional panel members with specific expertise in this area in conjunction with ASTRO, SUO, and ASCO. Additionally, the Panel included patient representation. Funding of the Panel was provided by the AUA; panel members received no remuneration for their work.

The Advanced Prostate Cancer Amendment Panel was created in 2022 by the AUA to review new literature and provide updates herein. The panel members received no remuneration for their work.

Searches and Article Selection

A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles.

The methodology team developed criteria for inclusion and exclusion of studies based on the Key Questions and the populations, interventions, comparators, outcomes, and settings (PICOTS) of interest. The population was patients with advanced prostate cancer as described in Table 3. Treatments included first and second line antiandrogens, immunotherapy, chemotherapy, radiation therapy, surgery, radiopharmaceuticals, and surveillance strategies. Comparisons were against placebo, no therapy or another active intervention, and intermittent versus continuous therapy. Outcomes included OS, prostate cancer mortality, progression-free survival (PFS), prostate-specific antigen progression-free survival (PSA-PFS), failure-free survival, metastases-free survival, time to metastases, time to progression, skeletal events, and adverse events.

For evaluation of treatments, inclusion was restricted to randomized trials, with the exception of studies on sequencing of therapies for which cohort studies were also included. For evaluation of prognostic factors, the methodology team included primary studies and systematic reviews that reported hazard ratios (HR) or the area under the receiver operating characteristic curve (AUROC), a measure of discrimination. We excluded non-randomized studies of interventions and case reports, narrative reviews, case-control studies, and non-English language articles. We also excluded in vitro and animal studies. Articles were published in peer-reviewed journals in or after 1998, though the methodology team included studies published prior to 1998 that were identified from reference lists.

Using the pre-specified criteria, two investigators independently reviewed titles and abstracts of all citations. The methodology team used a two-phase method for screening full-text articles identified during review of titles and abstracts. In the first phase, methodologists reviewed full-text articles to identify relevant systematic reviews for inclusion. Methodologists selected systematic reviews that addressed Key Questions, were higher quality, and were published within the last five years. The second phase reviewed full-text articles to identify primary studies for key questions not sufficiently answered by previously published systematic reviews and new studies published subsequent to the systematic reviews.

Database searches resulted in 10,517 potentially relevant articles of which 918 were selected for full-text review; 230 publications met inclusion criteria and were included in this review. Forty-six studies were carried over from the prior AUA review.

Data Abstraction

For primary studies that met inclusion criteria, a single investigator abstracted information on study design, year, setting, country, sample size, eligibility criteria, dose and duration of the intervention, population characteristics (age, race, tumor stage, performance status, PSA level, prior treatments, type and extent of metastatic disease), results, and source of funding. For systematic reviews, investigators abstracted characteristics of the included studies (number, design and sample sizes of included studies, study settings), population characteristics (inclusion and exclusion criteria), interventions, methods and ratings for the risk of bias of included studies, synthesis methods, and results. For OS and PFS, HR estimates were based on the number of deaths or number of deaths or cases of progression, so that estimates <1 indicate improved survival. Data abstractions were reviewed by a second investigator for accuracy, and discrepancies were resolved through discussion and consensus.

Risk of Bias Assessment

Two investigators independently assessed risk of bias using predefined criteria. Disagreements were resolved by consensus. For randomized trials and cohort studies, methodologists adapted criteria for assessing risk of bias from the U.S. Preventive Services Task Force.³⁵ Criteria for randomized trials included use of appropriate randomization and allocation concealment methods, baseline comparability of groups, blinding, attrition, and use of intention-to-treat analysis. For cohort studies on prognostic factors, criteria included methods for assembling cohorts, attrition, blinding assessment of outcomes, and adjustment for potential confounding.

The methodology team assessed systematic reviews using Assessing the Methodological Quality of Systematic Reviews (AMSTAR 2) criteria.³⁶ Criteria included use of pre-specified methods, appropriate search methods, assessment of risk of bias, and appropriate synthesis methods. Studies were rated as “low risk of bias,” “medium risk of bias,” or “high risk of bias” based on the presence and seriousness of methodological shortcomings.

Studies rated “low risk of bias” are generally considered valid. “Low risk of bias” randomized trials include clear descriptions of the population, setting, interventions, and comparison groups; a valid method for allocation of patients to treatment; low dropout rates (defined as >20%, not counting those who died or met other endpoints) and clear reporting of dropouts; blinding of patients, care providers, and outcome assessors; and appropriate analysis of outcomes.

Studies rated “medium risk of bias” are susceptible to some bias, though not necessarily enough to invalidate the results. These studies do not meet all the criteria for a rating of low risk of bias, but no flaw is likely to cause major bias. Studies may be missing information, making it difficult to assess limitations and potential problems. The “medium risk of bias” category is broad, and studies with this rating vary in their strengths and weaknesses. Therefore, the results of some medium risk of bias studies are likely to be valid, while others may be only possibly valid.

Studies rated “high risk of bias” have significant flaws that may invalidate the results. They have a serious or “fatal” flaw in design, analysis, or reporting; large amounts of missing information; discrepancies in reporting; or serious problems in the delivery of the intervention. The results of high risk of bias studies could be as likely to reflect flaws in study design and conduct as true difference between compared interventions. The methodology team did not exclude studies rated high risk of bias a priori, but high risk of bias studies were considered to be less reliable than low or medium risk of bias studies, and the methodology team performed sensitivity analyses without high risk of bias studies to determine how their inclusion impacted findings.

Data Synthesis

The methodology team constructed evidence tables with study characteristics, results, and risk of bias ratings for all included studies, and summary tables to highlight the main findings. The methodology team reported pooled estimates and other results from systematic reviews and examined whether the findings of new studies were consistent with the reviews.

The methodology team graded the strength of evidence for interventions using the approach described in the AHRQ EPC Methods Guide for Comparative Effectiveness and Effectiveness Reviews.³⁷ For strength of evidence assessments, methodologists focused on the outcomes OS and PFS and key treatment comparisons. Strength of evidence assessments were based on the following domains:

• Study limitations, based on the overall risk of bias across studies (low, medium, or high) and the seriousness of methodological limitations
• Consistency of results across studies (consistent, inconsistent, or unable to determine when only one study was available)
• Directness of the evidence linking the intervention and health outcomes (direct or indirect)
• Precision of the estimate of effect, based on the number and size of studies and confidence intervals for the estimates (precise or imprecise)
• Reporting bias, based on whether the studies defined and reported primary outcomes and whether we identified relevant unpublished studies (suspected or undetected)

Determination of Evidence Strength

Based on assessments of the domains described above, the methodology team graded the strength of evidence for each intervention as high, moderate, low, or very low. RCTs of interventions start as “high” strength of evidence and are graded down based on the presence and severity of shortcomings in each domain. A “high” grade indicates high confidence that the evidence reflects the true effect and that further research is very unlikely to change confidence in the estimate of effect. A “moderate” grade indicates moderate confidence that the evidence reflects the true effect and further research may change the estimate. A “low” grade indicates low confidence that the evidence reflects the true effect and further research is likely to change the confidence in the estimate of effect and could increase the confidence in the estimate. A “very low” grade indicates evidence either is unavailable or is too limited to permit any conclusion due to extreme study limitations, inconsistency, imprecision, or reporting bias.

The AUA employs a three-tiered strength of evidence system to underpin evidence-based guideline statements. In short, high certainty by GRADE translates to AUA A-category strength of evidence, moderate to B, and both low and very low to C. (Table 2)

The AUA categorizes body of evidence strength as Grade A (e.g., well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (e.g., RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (e.g., RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.³⁸

Table 1: Strength of Evidence Definitions

AUA Nomenclature: Linking Statement Type to Evidence Strength

The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel’s judgment regarding the balance between benefits and risks/burdens. (Table 2) Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm, when benefits and harms are finely balanced, or when the balance between benefits and risks/burden is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Conditional Recommendations also can be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens; therefore, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

Table 2: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength

Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinions with consensus achieved using a modified Delphi technique if differences of opinion emerged.³⁹ A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there may or may not be evidence.

Peer Review and Document Approval

An integral part of the guideline development process at the AUA is external peer review. The AUA conducted a thorough peer review process to ensure that the document was reviewed by experts in the diagnosis and management of Advanced Prostate Cancer. In addition to reviewers from the AUA PGC, Science and Quality Council (SQC), and Board of Directors (BOD), the document was reviewed by representatives from ASTRO, SUO, and ASCO as well as external content experts. Additionally, a call for reviewers was placed on the AUA website from December 2-16, 2019 to allow any additional interested parties to request a copy of the document for review. The guideline was also sent to the Urology Care Foundation and representation from prostate cancer advocacy to open the document further to the patient perspective. The draft guideline document was distributed to 96 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 44 reviewers provided comments, including 34 external reviewers. At the end of the peer review process, a total of 522 comments were received. Following comment discussion, the Panel revised the draft as needed. Once finalized, the guideline was submitted for approval to the AUA PGC, SQC, and BOD as well as the governing bodies of ASTRO and SUO for final approval.

The 2023 Advanced Prostate Cancer Amendment Panel was created in 2022 to review new literature and provide updates to this guideline, where appropriate. As a result of amendments to this guideline, a thorough peer review process was conducted in the same manner as with the original publication. A call for peer reviewers was posted December 2022. The draft guideline was distributed to 89 peer reviewers, 38 of whom submitted comments. The Amendment Panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the guideline was submitted for approval to the PGC, SQC, and BOD as well as SUO.

The 2026 Advanced Prostate Cancer Amendment Panel was created in 2025 by the AUA. The AUA conducted a thorough peer review process and a call for peer reviewers was posted on the AUA website from January 6-23, 2026, to allow any additional interested parties to request a copy of the document for review. The draft guideline document was distributed to 134 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 44 reviewers provided comments, including 35 external reviewers. Once finalized, the guideline was submitted for approval to the original panel and the AUA PGC, SQC, and BOD as well as the governing body of SUO for final approval.

Background

Epidemiology

Prostate cancer is the most common solid organ malignancy for men in the U.S. and remains the second leading cause of cancer deaths for this population. Approximately 333,830 new diagnoses of prostate cancer and 36,320 deaths are estimated in the U.S. in 2026.⁷ The incidence of prostate cancer is 70% higher in Black men as compared to White men for reasons that remain unclear.⁷ Importantly, the incidence of advanced stage disease including metastatic hormone-sensitive prostate cancer (mHSPC) has been increasing by about 5% per year in recent years. Unfortunately, prostate cancer mortality among Black men is approximately double that of men in most other groups. This disproportionate impact of prostate cancer morbidity and mortality on Black men is an area of active investigation that includes new approaches to screening, access to care, and treatment considerations among these men. ⁸ While metastatic prostate cancer remains a lethal disease, improvements in OS through combination therapies have resulted in a renaissance in the entire landscape for clinicians caring for men with advanced metastatic prostate cancer. Prostate cancer deaths are typically the result of progression to metastatic castration-resistant prostate cancer (mCRPC). Historically, the median survival for men with mCRPC was less than two years, but due to several factors including the impact of novel therapies, the median survival is now increasing with some men surviving beyond five years.⁹ Furthermore, rapid therapeutic advances in the treatment landscape for mHSPC and mCRPC render treatment decisions and sequencing increasingly complex. Therefore, at present, there is limited data driven evidence regarding optimal agent combination or sequence. It is against this backdrop that the Panel provides evidence-based guidance for treatment of men with advanced prostate cancer and looks to the future with cautious optimism.

Justification for a New Guideline

Clinicians treating men with advanced prostate cancer are challenged with the rapidly evolving prostate cancer landscape given the approval of new classes of agents for use in various prostate cancer disease states. The increasing complexity of advanced prostate cancer management underscores the need for the current clinical practice guideline, developed to provide a rational basis for treatment of patients with advanced disease, based on currently available published data. To assist in clinical decision-making, guideline recommendations are furnished according to disease states across the entire continuum of advanced prostate cancer.

Disease States

This guideline covers advanced prostate cancer as defined by the five disease states outlined below. It should be noted that this guideline does not cover local therapy (see AUA Guideline on Clinically Localized Prostate Cancer).¹⁰ The patient population covered in this guideline is assumed to have already received local or pelvic therapy, including adjuvant and salvage therapy (e.g., exhaustion of local treatment options). Further, neuroendocrine tumors and small cell variants were considered outside the scope of this guideline.

Biochemical Recurrence (“Rising PSA State”) Without Metastatic Disease After Exhaustion of Local Treatment Options

After local therapy including surgery and/or radiation, the first sign of recurrence is typically a rising PSA in the absence of visible metastases. This is also assuming that all forms of local therapy (e.g., salvage radiotherapy after radical prostatectomy, or salvage prostatectomy/salvage local ablative therapy after external beam radiotherapy [EBRT]) have been exhausted. Patients understand that their local treatment has not eradicated the cancer because of continued rises in PSA. Management of this disease state is controversial as evidence is lacking for optimal treatment approaches.

Metastatic Hormone-Sensitive Prostate Cancer

mHSPC has been increasingly diagnosed since 2013, likely due to multiple factors including greater imaging sensitivity and changes to PSA screening guidelines, amongst other reasons. In addition to being increasingly common, mHSPC and treatment of this disease state has shifted greatly since the first studies (CHAARTED and STAMPEDE) testing up-front docetaxel were reported beginning in 2014.^{11, 12} Metastatic hormone-sensitive disease can occur due to recurrence after initial local therapy for localized prostate cancer or as de novo metastatic disease, a distinction that may be useful when deciding upon systemic therapy. Additionally, the volume and site of metastatic disease are important factors that can affect prognosis and treatment choice.

Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC), whether metastatic (mCRPC) or non-metastatic (nmCRPC), generally occurs in response to therapeutic pressure, specifically the use of androgen deprivation therapy (ADT). The exact mechanism of transition from hormone-sensitive to castration-resistant disease is still not fully understood, and some diseases may be inherently resistant at presentation. However, it is clear that despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression in most cancers.^{13, 14} Because of this, multiple agents have been developed that further decrease androgen production or block AR signaling in addition to standard ADT with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists. It is hypothesized that there are additional biologic pathways that function independently of androgen signaling resulting in CRPC. With a greater understanding of tumor biology, there is hope for continued development of innovative treatment options that further improve survival for men with CRPC.

Non-Metastatic Castration-Resistant Prostate Cancer

Men with a rising PSA but no visible metastatic disease on conventional imaging, despite medical or surgical castration, represent a uniquely distinct disease state. The advent of improved imaging including next generation positron emission tomography- computed tomography (PET-CT) scanning has allowed for the discovery of small volume metastases that were previously undetected with standard clinical imaging such as bone scans, CT, and magnetic resonance imaging (MRI). Nevertheless, there remains a subset of patients whose disease remains defined by biochemical PSA rise only. Until recently, there have been no agents specifically FDA approved for the treatment of men with nmCRPC. However, three AR antagonists successfully prolonged metastasis-free survival (MFS), defined as the development of metastases or death from any cause, when compared with ADT plus placebo in men with nmCRPC.^15-17   

The use of MFS rather than OS as a regulatory endpoint is novel in solid tumors, and was partially based on the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) meta-analysis of 19 clinical trials demonstrating that MFS is a surrogate for OS in men with localized prostate cancer.¹⁸ Additionally, recent press releases state that two of the three approved AR antagonists also improve OS in this population.^{19, 20} Data from the third study continues to mature.

Metastatic Castration-Resistant Prostate Cancer

The treatment of men with mCRPC has dramatically changed over the past decade. Prior to 2004, once primary androgen deprivation failed to control the disease, treatments were administered solely for palliation. Landmark studies by Tannock et al. and Petrylak et al. demonstrated that docetaxel improved survival and quality of life (QOL) for such patients with mCRPC.^{21, 22} Since the approval of docetaxel, multiple additional agents that show a survival benefit have been FDA-approved on the basis of RCTs.^23-27 These agents have been tested in multiple "disease states" of mCRPC, both before and after docetaxel chemotherapy, to determine when patients might benefit from each treatment.

Terminology and Definitions

There are several key terms and definitions that should be considered when interpreting this guideline. First, biochemical recurrence is a rise in PSA in prostate cancer patients after treatment with surgery or radiation (PSA of 0.2ng/mL and a confirmatory value of 0.2ng/mL or greater following radical prostatectomy and nadir + 2.0ng/mL following radiation). This may occur in patients who do not have symptoms. HSPC refers to prostate cancer that has either not yet been treated with ADT or is still responsive to ADT as manifested by the absence of clinical progression, radiographic progression, or a rising PSA of ≥2.0ng/mL above nadir. This may also be referred to as castrate-sensitive prostate cancer, endocrine-sensitive prostate cancer, and hormone-naïve prostate cancer. CRPC is defined by disease progression despite ADT and a castrate level of testosterone (<50ng/dL). Contemporary lab testing indicates that testosterone levels decline to <20ng/dL after orchiectomy.²⁸ Progression may present as either a continuous rise in serum (PSA) levels (values identified at a minimum of 1 week intervals with estimations of PSA doubling time [PSADT] with at least 3 values measured ≥4 weeks apart), the progression of pre-existing or new radiographic disease, and/or clinical progression with symptoms. High-volume metastatic disease is used in the mHSPC setting, and is defined per the CHAARTED definition of the presence of visceral metastases and/or greater than or equal to four bone metastases with at least one outside of the vertebral column and pelvis.¹¹ Low-volume metastatic disease describes metastatic disease that does not meet high-volume criteria. These definitions can be useful when choosing treatment for mHSPC, particularly for radiation of the primary tumor, and are associated with better (low-volume) or poorer (high-volume) prognosis in the mHSPC disease state.^{11, 29} High-risk metastatic disease is defined per the LATITUDE definition for mHSPC that has a poorer prognosis in the presence of 2 of the 3 following high-risk features: Gleason ≥ 8, ≥ 3 bone lesions, or measurable visceral metastases.³⁰ De novo metastatic disease describes metastatic disease that is present at the time of initial prostate cancer diagnosis rather than recurring after previous treatment of localized cancer. This is associated with poorer prognosis than recurrent disease.³¹ PSA doubling time (PSADT) is the number of months required for the PSA value to increase two-fold.³² There are a number of web-based tools available to calculate PSADT, including that provided by Memorial Sloan Kettering Cancer Center available at https://www.mskcc.org/nomograms/prostate/psa_doubling_time. This tool also provides supporting text detailing the precise calculation of PSADT. Conventional imaging is defined as CT, MRI, and ^99mTc-methylene diphosphonate bone scan (bone scan). These terms are summarized in Table 3.

Radiologic Considerations

The prostate cancer community has witnessed considerable developments in the detection of disease with next generation prostate cancer imaging. PET-CT has emerged as a sensitive and specific imaging test to detect prostate cancer metastases, particularly among men with biochemical recurrence after primary therapy.³³ Multiple PET tracers have demonstrated promise in the evaluation of extent of prostate cancer including ¹⁸F-fluciclovine, ¹⁸F-sodium fluoride, ¹¹C-choline, and various tagged prostate-specific membrane antigen (PSMA) isoforms. While there is an emerging literature detailing the use of next generation imaging to guide management decisions in recurrent prostate cancer,^{34, 35}  there remains uncertainty about how these image-directed therapies will impact oncologic outcomes.

It is important for the practicing clinician to note that the studies underpinning this guideline’s recommendations were largely predicated upon the use of conventional imaging including CT, MRI, and bone scan. As the medical evidence evolves to more consistently incorporate next generation imaging, the definition of ‘non-metastatic’ and ‘metastatic’ will evolve as likely will the definitions of “low-volume and high-volume” owing to the significant differences in sensitivity to detect metastatic disease between conventional and advanced imaging modalities.

Multidisciplinary Nature of Treatment in Today’s Advanced Prostate Cancer Care Paradigm

As the therapeutic landscape evolves to include increasingly complex combinations of systemic therapies with or without local therapies, advances in imaging, and germline and somatic genetic testing, treating men with advanced prostate cancer is increasingly one that must embrace multidisciplinary management approaches. Team members should include urologists, medical oncologists, and radiation oncologists at a minimum when supporting treatment decisions for advanced disease. Additional specialists may also include genitourinary pathology, genetic counseling, palliative care, and holistic specialists, as appropriate, in addition to primary care. Best practices must also include clinicians comfortable describing the use of germline and somatic genetic testing, and when advanced imaging techniques could be optimally used or avoided. Radiologists and nuclear medicine specialists are valuable in helping to accurately interpret scans. Palliative care team members may also play a key role when treating men with symptomatic metastatic disease. Palliative care itself is an interdisciplinary, holistic approach to managing an advanced disease such as prostate cancer with a guarded prognosis. It can include controlling symptoms that are physical, psychological, spiritual, and social. The goal of palliation is to prevent and relieve suffering and to support the best possible QOL for the patient and family.

Performance Status and Predicted Life Expectancy

Performance status and predicted life expectancy are both critical elements to incorporate into individualized clinical decision-making in men with advanced prostate cancer. Performance status remains a key factor in treatment decision-making, particularly among men with advanced prostate cancer. Indeed, performance status has been found to be strongly associated with survival among men with mCRPC,^36-39 and has been used to define index patients in prior versions of this guideline. Performance status generally describes an individual patient’s level of functioning and how one’s disease impacts a patient’s activities of daily living. The first of two commonly used scales to evaluate performance status include the Eastern Cooperative Oncology Group (ECOG) scale from 0 to 5 where 0 is fully functional and 5 is dead. The second is the Karnofsky scale where 10 represents a moribund individual and 100 represents an individual with no limitations.

It is important to acknowledge that clinical trials have generally excluded patients with a poor performance status from participation. Thus, most data regarding management of patients with limited performance status are extrapolated from randomized trials of eligible patients who had a better performance status, as well as from some smaller trials and registries. Incorporating performance status into shared treatment decision-making permits the treating clinician and patient to characterize the balance of risk and benefit associated with sometimes morbid treatments. While performance status is frequently used to predict an individual patient’s likelihood of tolerating a particular cancer treatment, it is equally important to consider the likelihood that a particular treatment improves disease-related symptoms and drives meaningful improvement in performance status.

Thoughtful assessment of performance status and life expectancy are essential components of evaluation and management of men with advanced prostate cancer. Indeed, assessment of performance status and life expectancy are core to establishing goals of care, incorporating individuals’ values and preferences to best align available management options with what is most important to patients and their families. While performance status is no longer included in the classification of disease states in this guideline, ongoing assessment of performance status is considered a necessary component of continuing care that will help the patient and clinician guide the cascade of management for advanced prostate cancer.

Clinical Trial Enrollment

Clinicians should inform patients about suitable clinical trials and encourage patients to consider participation in such trials based on eligibility and access. Treatment options can be characterized as standard and as investigational (clinical trial). In general, standard therapies have proven efficacy and risks determined by prospective trials. There are many types of clinical trials including trials evaluating novel systemic, surgical, or radiation therapies; new approaches to approved therapies; device trials; and trials focusing on QOL and other patient outcomes. All clinical trials include specified aim(s) with a predetermined statistical plan. Institutional Review Boards approve all clinical trials and patient consent forms, and all patients must sign consent for trial participation.

In appropriate patients, clinical trial options should be considered, and trial options should be discussed with patients as part of the shared decision-making process. Clinical trials are listed by diagnosis and stage on the Clinicaltrials.gov website.

GUIDELINE STATEMENTS

In patients with suspicion of advanced prostate cancer and no prior histologic confirmation, clinicians should obtain tissue diagnosis from the primary tumor or site of metastases when clinically feasible. (Clinical Principle)

Clinicians should discuss treatment options with advanced prostate cancer patients based on life expectancy, comorbidities, preferences, and tumor characteristics. Patient care should incorporate a multidisciplinary approach when available. (Clinical Principle)

Clinicians should optimize pain control or other symptom support in advanced prostate cancer patients and encourage engagement with professional or community-based resources, including patient advocacy groups. (Clinical Principle)

For all patients with advanced prostate cancer, clinicians should offer germline testing. For patients with metastatic disease, somatic tumor testing should also be offered. (Clinical Principle)

Clinicians should inform patients with PSA recurrence after exhaustion of local therapy regarding the risk of developing metastatic disease and follow such patients with serial PSA measurements and clinical evaluation. Clinicians may consider radiographic assessments based on overall PSA and PSA kinetics. (Clinical Principle)

In patients with PSA recurrence after exhaustion of local therapy who are at higher risk for the development of metastases, clinicians should perform periodic staging evaluations consisting of imaging preferentially with PSMA PET and/or CT, MRI, and technetium bone scan. (Clinical Principle)

Clinicians should utilize PSMA PET imaging preferentially in patients with PSA recurrence after exhaustion of local therapy due to its greater sensitivity, or in the setting of negative conventional imaging. (Expert Opinion)

For patients with a rising PSA after exhaustion of local therapy and no demonstrated metastatic disease, clinicians should risk stratify as low- or high-risk. High-risk patients generally are defined as patients with PSADT ≤ 9 months. (Clinical Principle)

Androgen deprivation therapy (ADT) should not be routinely initiated for low-risk patients (PSADT > 9 months) with biochemical recurrence after exhaustion of local therapy. (Expert Opinion)

• For patients with a rising PSA after exhaustion of local therapy with low-risk features, including PSADT > 9 months, clinicians should offer observation and ADT should not be routinely initiated.
• For patients with a rising PSA after exhaustion of local therapy with high-risk features, including PSADT ≤ 9 months, clinicians should offer ADT with enzalutamide.
• For patients with a rising PSA after exhaustion of local therapy with high-risk features and no metastatic disease in whom ADT +/- ARPI is initiated, intermittent therapy may be offered in lieu of continuous therapy in the setting of a favorable response to therapy.

Clinicians should assess the extent of metastatic disease (lymph node, bone, and visceral metastases) in newly diagnosed mHSPC patients. (Clinical Principle)

In newly diagnosed mHSPC patients, clinicians should assess the extent of metastatic disease (lymph node, bone, and visceral metastases) and stratify based on low- versus high-volume. High-volume is defined as greater than or equal to four bone metastases with at least one metastasis outside of the spine/pelvis and/or the presence of visceral metastases based on conventional imaging. (Moderate Recommendation; Evidence Level: Grade B)

Clinicians should assess if a newly diagnosed mHSPC patient is experiencing symptoms from metastatic disease at the time of presentation to guide discussions of prognosis and further disease management. (Moderate Recommendation; Evidence Level: Grade B)

Clinicians should obtain a baseline PSA and serial PSAs at three- to six-month intervals after initiation of ADT in mHSPC patients and consider periodic imaging. (Clinical Principle)

Clinicians should offer ADT with either LHRH agonists or antagonists or surgical castration in patients with mHSPC. (Strong Recommendation; Evidence Level: Grade B)

In addition to ADT, clinicians should also offer androgen pathway-directed therapy with abiraterone acetate plus prednisone, apalutamide, enzalutamide, or darolutamide to the majority of patients with mHSPC. (Strong Recommendation; Evidence Level: Grade A)

In select mHSPC patients, clinicians should offer ADT in combination with docetaxel and either abiraterone acetate plus prednisone or darolutamide. (Strong Recommendation; Evidence Level: [Abiraterone] Grade A/[Darolutamide] Grade B)

In select mHSPC patients, clinicians may offer primary radiotherapy to the prostate in combination with ADT with or without an ARPI. (Conditional Recommendation; Evidence Level: Grade C)

Clinicians should not offer first generation antiandrogens (bicalutamide, flutamide, nilutamide) in combination with LHRH agonists in patients with mHSPC, except to block testosterone flare. (Strong Recommendation; Evidence Level: Grade A)

In mHSPC patients with HRR gene alterations, particularly BRCA 2, clinicians may offer the combination of ADT, abiraterone, and niraparib. (Expert Opinion)

In nmCRPC patients, clinicians should obtain serial PSA measurements at three- to six-month intervals and calculate a PSADT starting at the time of development of castration-resistance. (Clinical Principle)

Clinicians should assess nmCRPC patients for development of metastatic disease using conventional or PSMA PET imaging at intervals of 6 to 12 months. (Expert Opinion)

Clinicians should offer apalutamide, darolutamide, or enzalutamide with continued ADT to nmCRPC patients at high risk for developing metastatic disease (PSADT ≤10 months). (Strong Recommendation; Evidence Level: Grade A)

Clinicians may recommend observation with continued ADT to nmCRPC patients, particularly those at lower risk (PSADT >10 months) for developing metastatic disease. (Clinical Principle)

Clinicians should not offer systemic chemotherapy or immunotherapy to nmCRPC patients outside the context of a clinical trial. (Clinical Principle)

In mCRPC patients, clinicians should obtain baseline labs (e.g., PSA, testosterone, LDH, Hgb, alkaline phosphatase level) and review location of metastatic disease (lymph node, bone, visceral), disease-related symptoms, and performance status to inform discussions of prognosis and treatment decision-making. (Clinical Principle)

In mCRPC patients without PSA progression or new symptoms, clinicians should perform imaging at least annually. (Expert Opinion)

For most patients progressing to mCRPC who have not received prior ARPI, clinicians should offer continued ADT with abiraterone acetate plus prednisone or enzalutamide. (Strong Recommendation; Evidence Level: Grade A)

In mCRPC patients with disease progression following treatment with an ARPI, clinicians should offer docetaxel. (Strong Recommendation; Evidence Level: Grade B)

In mCRPC patients who are asymptomatic or minimally symptomatic, clinicians may offer sipuleucel-T. (Conditional Recommendation; Evidence Level: Grade B)

Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy >3cm. (Strong Recommendation; Evidence Level: Grade B)

In mCRPC patients with disease progression following treatment with an ARPI (with or without prior docetaxel), and a positive PSMA PET/CT, clinicians should offer ¹⁷⁷Lu-PSMA-617. (Strong Recommendation; Evidence Level Grade: B)

In mCRPC patients who received prior docetaxel chemotherapy either in the mHSPC or mCRPC setting, clinicians may offer cabazitaxel. (Conditional Recommendation; Evidence Level: Grade B)

In mCRPC patients who received prior docetaxel chemotherapy and an androgen pathway inhibitor, clinicians should recommend cabazitaxel rather than an alternative androgen pathway inhibitor. (Strong Recommendation; Evidence Level: Grade B)

Clinicians may offer a PARP inhibitor to select patients with deleterious germline or somatic homologous recombination repair gene-mutated mCRPC who have progressed on prior ARPIs. Platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor. (Conditional Recommendation; Evidence Level: Grade C)

Clinicians may offer a PARP inhibitor in combination with an ARPI to select patients with deleterious germline or somatic HRR gene-mutated mCRPC. (Conditional Recommendation; Evidence Level: Grade C)

In patients with MMR deficient or MSI-H mCRPC, clinicians should offer pembrolizumab. (Moderate Recommendation; Evidence Level: Grade C)

Several factors conspire to place the average patient with metastatic prostate cancer at a higher risk of bone complications. First, the median age of onset of the disease is in the late 60s, meaning that the average patient with metastatic disease may be in his 70s (or beyond), clearly a population at risk of physiologic, age-related decreases in bone mineral density. Secondly, a primary therapeutic intervention in patients with recurrent disease (e.g., ADT) is associated with progressive loss of bone mineral density, not infrequently to the point of measurable osteopenia or frank osteoporosis, increasing the patient's fracture risk, even in patients with non-metastatic disease.^{145, 146}  Finally, in patients with advanced disease, bones are the most common site of metastatic disease, with many patients at some point in their course demonstrating evidence of disease in this site.

Clinicians should discuss the risk of osteoporosis associated with ADT and should assess the risk of fragility fracture in patients with advanced prostate cancer. (Clinical Principle)

Clinicians should recommend preventive treatment for fractures and skeletal-related events, including supplemental calcium, vitamin D, smoking cessation, and weight-bearing exercise, to advanced prostate cancer patients on ADT. (Clinical Principle)

In advanced prostate cancer patients at high fracture risk due to bone loss, clinicians should recommend preventive treatments with bisphosphonates or denosumab and referral to physicians who have familiarity with the management of osteoporosis when appropriate. (Clinical Principle)

Clinicians should prescribe a bone-protective agent (denosumab or zoledronic acid) for mCRPC patients with bony metastases to prevent skeletal-related events. (Moderate Recommendation; Evidence Level: Grade B)

FUTURE DIRECTIONS

There are rapid and continued advancements across the spectrum of advanced prostate cancer and several key areas of future research need emphasis to optimize clinical care and patient-centric outcomes.

Integration of Care

Multidisciplinary care remains a key component of quality care as patients are commonly managed with multimodality approaches involving urologists, medical oncologists, radiation oncologists, radiologists, geneticists, pharmacists, palliative care specialists, and the patient’s primary care team.  Multidisciplinary clinics and multimodality treatment approaches can optimize treatment selection, maximize results, reduce overtreatment and better manage side-effects.¹⁶² Given the rapidly evolving therapeutic landscape for advanced prostate cancer, these interdisciplinary management discussions will need to include the option to participate in clinical trials locally or through referral to a tertiary center.

Many ongoing clinical trials are evaluating concepts of integrating systemic therapy with radiation and/or surgery assessing the benefit of local therapy in men with metastatic disease or determining the impact of MDT in the oligometastatic setting. The results of these studies are likely to substantially impact the standard approaches to newly diagnosed patients with advanced disease.

Currently, surgical resection of the primary tumor in the setting of metastatic prostate cancer is considered investigational with several retrospective single-arm studies demonstrating safety and feasibility, and many studies from large population-based registries show that improved survival is associated with local control in metastatic prostate cancer patients.^163-165 However, not all studies have found a survival benefit, and all of these reports should be considered hypothesis-generating as they have unknown biases that make it difficult to apply the data into clinical practice. Several single-arm phase I/II trials and randomized phase II clinical trials have been completed but are yet to be published.^{166, 167} The RAMPP trial¹⁶⁸ is a randomized controlled phase II study evaluating the addition of radical prostatectomy to best systemic therapy (BST) in patients with newly diagnosed oligometastatic prostate cancer which demonstrated improved 5 year cancer specific survival in patients randomized to radical prostatectomy plus BST but did not improve clinical progression or OS. Despite its randomized design, the trial was underpowered and prematurely stopped, limiting the strength of its conclusions, but providing hypothesis-generating evidence supporting a potential role for local therapy with surgery in oligometastatic disease.

The phase III RCT SWOG 1802 is evaluating standard systemic therapy with or without local control of the primary in men with hormone-sensitive ‘de novo’ metastatic prostate cancer.  Local control in the SWOG 1802 study may consist of surgery, radiation, or both, based on physician discretion and patient choice. This study aims to address whether local treatment of the primary in the setting of metastatic prostate cancer provides a benefit, with OS as the primary endpoint. In the absence of prospective data demonstrating that surgery leads to an oncologic benefit in men with metastatic prostate cancer, its use should be restricted to clinical trials.

PSMA PET/CT Imaging and Theranostics

PSMA PET imaging can identify sites of prostate cancer with superior specificity and sensitivity compared to conventional imaging and this imaging approach has been widely adopted in the approved indications for newly diagnosed high-risk patients, patients with biochemical failure post local therapy and to establish eligibility for Lutetium-177 PSMA therapy. Ongoing studies seek to provide data to support broader applications including but not limited to treatment response monitoring, guiding MDT in oligometastatic disease and serial imaging to monitor patients with PSA only disease.^{169, 170}

These findings are already impacting treatment planning by altering physician decision-making, but they have yet to demonstrate a clear benefit specific to patient outcomes.  To date, there is a lack of prospective randomized data evaluating PET as a staging study for untreated prostate cancer, mHSPC or CRPC.¹⁷¹ What will ultimately determine the role of these PET agents will be trials demonstrating imaging improved patient outcomes as a direct result of earlier intensification of systemic therapies, MDT, and/or prediction of responses to specific therapies. 

The role of theranostics in prostate cancer management has evolved rapidly following the approval of Lutetium-177 PSMA based upon the positive results of the VISION and PSMAfore trials in mCRPC.

Research is now turning to its earlier use within the hormone sensitive prostate cancer disease state with the PSMAddition study.

A myriad of novel theranostic agents with a number of different targets are in clinical trials with several actinium-based agents entering into phase III studies.  Theranostics is yet another area in which integrated multidisciplinary care will be important and will require the expertise of multiple specialties (e.g., medical oncology, nuclear medicine, radiation oncology).  

Metastasis-directed Therapy

Given the ability to identify metastatic sites earlier than was previously possible using newer PET imaging modalities, there has been renewed interest in the concept of MDT with radiation, surgery, or ablative technologies. The majority of data consists of retrospective studies and there are no phase III trials to date.¹⁷² However, in M1 patients with both hormone-sensitive and castration resistant oligometastatic disease several small randomized phase II trials explore the potential benefits of MDT. Utilizing PET choline imaging in 62 patients, the STOMP trial found that median ADT-free survival in mHSPC was 13 months for the surveillance group and 21 months for the MDT group (HR=0.6; 80% CI: 0.40 to 0.90; p=0.11).¹⁷³ QOL was comparable at baseline, 3 months, and 1 year of follow-up. In the phase II ORIOLE trial 54 mHPSC patients were randomized to receive stereotactic ablative radiotherapy (SABR) or observation alone using PSMA PET imaging. The primary endpoint was progression after 6 months which was significantly lower with SBRT than with surveillance (19% versus 61%, p=0.005). It was also found that consolidation of all PSMA-positive disease decreased the risk of new lesions at 6 months (16% versus 63%; p=0.006).⁶⁵ In the EXTEND phase II trial, 87 men with oligometastatic hormone sensitive prostate cancer on conventional imaging or F18 PET were randomized to MDT + intermittent hormone therapy or hormone therapy alone and results indicated improved progression free survival in the treatment arm (HR=0.25; 95% CI: 0.12 to 0.55; p<0.001).¹⁷⁴ Two recent phase II trials evaluated outcomes in oligometastatic CRPC, with GROUQ-PCS demonstrating that SBRT + ADT + enzalutamide improved rPFS when compared to ADT + enzalutamide and ARTO showing improved biochemical control and PFS in men treated with SBRT + ADT + abiraterone acetate and prednisone versus ADT + abiraterone acetate and prednisone alone.^{40, 128} A recent meta-analysis pooled individual patient data from 7 phase II randomized studies and found improved progression free survival and time to castration resistance.¹⁷⁵ While these results are promising, there remains a lack of data regarding OS as well as selection criteria to identify those patients who will benefit from MDT.

Genomics and Other Systemic Therapies

The steady rate of approval of new agents for use in advanced prostate cancer over the past five years, and the current dearth of comparative studies of these agents heightens the urgency to both identify predictive biomarkers and conduct randomized studies of novel agents with the use of an active control arm (i.e., minimizing the use of the alternative ARPI) to help inform treatment selection.  

Currently, the most promising markers are those associated with clinical interventions such as identification of germline or somatic alterations within DDR genes (e.g., BRCA1, BRCA2, and select other DDR mutations) providing evidence for PARP inhibitor use and MSI-H status providing evidence of immune checkpoint inhibitor use.  

Multiple trials combining PARP inhibitors plus ARPIs have been published as noted in guideline statements. The optimal use of these therapeutic approaches remains undefined as the vast majority of patients enrolled on these studies had not received prior ARPIs and the toxicity associated with these combinations is not insignificant. Next generation PARP inhibitors such as saruparib, which appears to spare PARP2 and selectively trap PARP1, may provide an improved therapeutic window compared to first generation agents and are being studies in a number of clinical trials.¹⁷⁶

In addition to novel theranostic agents there are a myriad of classes of agents currently in trial in mCRPC. These include androgen receptor degraders, bispecific T-Cell engagers, CAR-T Cell therapies, epigenetic modulators and pathway inhibitors and antibody-drug conjugates. For the agents undergoing phase III evaluation, there is a trend towards inclusion of active agents (i.e., docetaxel and other approved agents) in the control arms, which hopefully will provide prospective evidence to inform more optimal sequencing of these agents. 

Unmet Needs

While the field has witnessed very important progress across the disease spectrum, there remain a myriad of major challenges. Black patients with advanced prostate cancer demonstrate worse outcomes and understanding the societal and biological underpinnings of these disparities remains a critical area for ongoing research.  

For patients with metastatic prostate cancer, the ultimate unmet need is the inability to cure. While there are several agents approved for use for patients with mCPRC, all have modest impact on OS and compared to the major solid tumors, there is a paucity of comparative data to help clinicians make management decisions based upon prospective evidence.  Unlike many other solid tumors, advanced prostate cancer is for the most part unresponsive to immune checkpoint inhibition, however a new generation of immune based therapeutics (bispecific antibodies-BiTEs, Chimeric Antigen Receptor- CAR-T cells targeting multiple different prostate targets) are in clinical trials.

Personalized care with predictive markers for treatment selection based on tumor and host biology have not yet been achieved. There has been continued progress toward identification of prognostic markers using molecular markers based on immunohistochemistry and use of genomic signatures, but these have yet to yield predictive results.

While PSMA PET/CT imaging has been broadly adopted, none of our SOC therapeutic interventions for either localized, locally advanced or metastatic disease have been prospectively informed by this imaging modality, although prospective studies across the disease spectrum are ongoing.

Emerging evidence supports the use of SBRT as MDT for oligometastatic prostate cancer, although we do not yet have prospective evidence from adequately powered studies that demonstrate improvement in OS.

There are many additional unmet needs. These include studies to inform the potential to de-intensify many of the therapies we use, including testosterone suppression, ARPIs and PARP inhibitors in many settings across the disease spectrum. Given the well-known heterogeneity of prostate cancer, the ability to develop individualized approaches to therapeutic management to optimize outcome and minimize toxicity remains one of the highest goals of clinicians who manage this disease.

ABBREVIATIONS

REFERENCES

1. Harris, R. P., Helfand, M., Woolf, S. H. et al: Current methods of the us preventive services task force: A review of the process. Am J Prev Med 2001; 20: 21
2. Shea, B. J., Reeves, B. C., Wells, G. et al: Amstar 2: A critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. Bmj 2017; 358: j4008
3. Methods guide for effectiveness and comparative effectiveness reviews. Ahrq publication no. 10(14)-ehc063-ef. Rockville, MD: Agency for Healthcare Research and Quality. Chapters available at: www.effectivehealthcare.ahrq.gov/, vol. January 2014, 2014
4. Methods guide for effectiveness and comparative effectiveness reviews. Ahrq publication no. 10(14)-ehc063-ef, January ed. Rockville, MD: Agency for Healthcare Research and Quality 2014
5. Faraday, M., Hubbard, H., Kosiak, B. et al: Staying at the cutting edge: A review and analysis of evidence reporting and grading; the recommendations of the american urological association. BJU Int 2009; 104: 294
6. Hsu, C. a. S., B.A.: The delphi technique: Making sense of consensus. Practical Assessment, Research, and Evaluation 2007; 12: 1
7. Siegel, R. L., Kratzer, T. B., Wagle, N. S. et al: Cancer statistics, 2026. CA Cancer J Clin 2026; 76: e70043
8. Schafer, E. J., Jemal, A., Wiese, D. et al: Disparities and trends in genitourinary cancer incidence and mortality in the USA. Eur Urol 2023; 84: 117
9. Howard, L. E., Moreira, D. M., De Hoedt, A. et al: Thresholds for psa doubling time in men with non-metastatic castration-resistant prostate cancer. BJU Int 2017; 120: E80
10. Sanda, M. G., Cadeddu, J. A., Kirkby, E. et al: Clinically localized prostate cancer: Aua/astro/suo guideline. Part ii: Recommended approaches and details of specific care options. J Urol 2018; 199: 990
11. Sweeney, C. J., Chen, Y. H., Carducci, M. et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737
12. James, N. D., Sydes, M. R., Clarke, N. W. et al: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (stampede): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163
13. Montgomery, R. B., Mostaghel, E. A., Vessella, R. et al: Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Res 2008; 68: 4447
14. Mohler, J. L., Titus, M. A., Bai, S. et al: Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res 2011; 71: 1486
15. Hussain, M., Fizazi, K., Saad, F. et al: Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018; 378: 2465
16. Smith, M. R., Saad, F., Chowdhury, S. et al: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018; 378: 1408
17. Fizazi, K., Shore, N., Tammela, T. L. et al: Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2019; 380: 1235
18. Xie, W., Regan, M. M., Buyse, M. et al: Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol 2017; 35: 3097
19. Nubeqa® (darolutamide) plus androgen deprivation therapy achieved the secondary endpoint of overall survival (os) in men with non-metastatic castration-resistant prostate cancer.
20. Xtandi® (enzalutamide) demonstrates significant improvement in overall survival in phase 3 prosper trial of patients with nmcrpc
21. Petrylak, D. P., Tangen, C. M., Hussain, M. H. et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513
22. Tannock, I. F., de Wit, R., Berry, W. R. et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502
23. de Bono, J. S., Logothetis, C. J., Molina, A. et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995
24. de Bono, J. S., Oudard, S., Ozguroglu, M. et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010; 376: 1147
25. Kantoff, P. W., Higano, C. S., Shore, N. D. et al: Sipuleucel-t immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411
26. Parker, C., Nilsson, S., Heinrich, D. et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213
27. Scher, H. I., Fizazi, K., Saad, F. et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187
28. Oefelein, M. G., Feng, A., Scolieri, M. J. et al: Reassessment of the definition of castrate levels of testosterone: Implications for clinical decision making. Urology 2000; 56: 1021
29. Gravis, G., Boher, J. M., Joly, F. et al: Androgen deprivation therapy (adt) plus docetaxel versus adt alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 getug-afu15 trial. Eur Urol 2016; 70: 256
30. Fizazi, K., Tran, N., Fein, L. et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017; 377: 352
31. Finianos, A., Gupta, K., Clark, B. et al: Characterization of differences between prostate cancer patients presenting with de novo versus primary progressive metastatic disease. Clin Genitourin Cancer 2017;
32. Vickers, A. J. and Brewster, S. F.: Psa velocity and doubling time in diagnosis and prognosis of prostate cancer. Br J Med Surg Urol 2012; 5: 162
33. Calais, J., Fendler, W. P., Eiber, M. et al: Impact of (68)ga-psma-11 pet/ct on the management of prostate cancer patients with biochemical recurrence. J Nucl Med 2018; 59: 434
34. Akin-Akintayo, O. O., Jani, A. B., Odewole, O. et al: Change in salvage radiotherapy management based on guidance with facbc (fluciclovine) pet/ct in postprostatectomy recurrent prostate cancer. Clin Nucl Med 2017; 42: e22
35. Emmett, L., van Leeuwen, P. J., Nandurkar, R. et al: Treatment outcomes from (68)ga-psma pet/ct-informed salvage radiation treatment in men with rising psa after radical prostatectomy: Prognostic value of a negative psma pet. J Nucl Med 2017; 58: 1972
36. Bournakis, E., Efstathiou, E., Varkaris, A. et al: Time to castration resistance is an independent predictor of castration-resistant prostate cancer survival. Anticancer Res 2011; 31: 1475
37. Halabi, S., Lin, C. Y., Small, E. J. et al: Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy. J Natl Cancer Inst 2013; 105: 1729
38. Koo, K. C., Park, S. U., Kim, K. H. et al: Prognostic impacts of metastatic site and pain on progression to castrate resistance and mortality in patients with metastatic prostate cancer. Yonsei Med J 2015; 56: 1206
39. Nakabayashi, M., Hayes, J., Taplin, M. E. et al: Clinical predictors of survival in men with castration-resistant prostate cancer: Evidence that gleason score 6 cancer can evolve to lethal disease. Cancer 2013; 119: 2990
40. Mateo, J., Carreira, S., Sandhu, S. et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015; 373: 1697
41. Marcus, L., Lemery, S. J., Keegan, P. et al: Fda approval summary: Pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res 2019; 25: 3753
42. Pritchard, C. C., Mateo, J., Walsh, M. F. et al: Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016; 375: 443
43. de Bono, J., Mateo, J., Fizazi, K. et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 2020; 382: 2091
44. Fizazi, K., Clarke, N. W., De Santis, M. et al: Capivasertib plus abiraterone in pten-deficient metastatic hormone-sensitive prostate cancer: Capitello-281 phase iii study. Ann Oncol 2026; 37: 53
45. Jensen, K., Konnick, E. Q., Schweizer, M. T. et al: Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol 2021; 7: 107
46. Catalona, W. J. and Smith, D. S.: 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994; 152: 1837
47. Cooperberg, M. R., Hilton, J. F. and Carroll, P. R.: The capra-s score: A straightforward tool for improved prediction of outcomes after radical prostatectomy. Cancer 2011; 117: 5039
48. Kattan, M. W., Zelefsky, M. J., Kupelian, P. A. et al: Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J Clin Oncol 2000; 18: 3352
49. Pompe, R. S., Bandini, M., Preisser, F. et al: Contemporary approach to predict early biochemical recurrence after radical prostatectomy: Update of the walz nomogram. Prostate Cancer Prostatic Dis 2018; 21: 386
50. Røder, M. A., Berg, K. D., Loft, M. D. et al: The cpc risk calculator: A new app to predict prostate-specific antigen recurrence during follow-up after radical prostatectomy. Eur Urol Focus 2018; 4: 360
51. Van den Broeck, T., van den Bergh, R. C. N., Arfi, N. et al: Prognostic value of biochemical recurrence following treatment with curative intent for prostate cancer: A systematic review. Eur Urol 2019; 75: 967
52. Tilki, D., Preisser, F., Graefen, M. et al: External validation of the european association of urology biochemical recurrence risk groups to predict metastasis and mortality after radical prostatectomy in a european cohort. Eur Urol 2019; 75: 896
53. Kane, C. J., Amling, C. L., Johnstone, P. A. et al: Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology 2003; 61: 607
54. Odewole, O. A., Tade, F. I., Nieh, P. T. et al: Recurrent prostate cancer detection with anti-3-[(18)f]facbc pet/ct: Comparison with ct. Eur J Nucl Med Mol Imaging 2016; 43: 1773
55. Seltzer, M. A., Barbaric, Z., Belldegrun, A. et al: Comparison of helical computerized tomography, positron emission tomography and monoclonal antibody scans for evaluation of lymph node metastases in patients with prostate specific antigen relapse after treatment for localized prostate cancer. J Urol 1999; 162: 1322
56. Fda approves first psma-targeted pet imaging drug for men with prostate cancer, https://www.Fda.Gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer
57. Fda approves second psma-targeted pet imaging drug for men with prostate cancer, https://www.Fda.Gov/drugs/drug-safety-and-availability/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer
58. Jani, A. B., Ravizzini, G. C., Gartrell, B. A. et al: Diagnostic performance and safety of (18)f-rhpsma-7.3 positron emission tomography in men with suspected prostate cancer recurrence: Results from a phase 3, prospective, multicenter study (spotlight). Reply. J Urol 2023; 210: 411
59. Surasi, D. S., Eiber, M., Maurer, T. et al: Diagnostic performance and safety of positron emission tomography with (18)f-rhpsma-7.3 in patients with newly diagnosed unfavourable intermediate- to very-high-risk prostate cancer: Results from a phase 3, prospective, multicentre study (lighthouse). Eur Urol 2023; 84: 361
60. Nanni, C., Zanoni, L., Pultrone, C. et al: (18)f-facbc (anti1-amino-3-(18)f-fluorocyclobutane-1-carboxylic acid) versus (11)c-choline pet/ct in prostate cancer relapse: Results of a prospective trial. Eur J Nucl Med Mol Imaging 2016; 43: 1601
61. Fendler, W. P., Calais, J., Eiber, M. et al: Assessment of 68ga-psma-11 pet accuracy in localizing recurrent prostate cancer: A prospective single-arm clinical trial. JAMA Oncol 2019; 5: 856
62. Hope, T. A., Goodman, J. Z., Allen, I. E. et al: Metaanalysis of (68)ga-psma-11 pet accuracy for the detection of prostate cancer validated by histopathology. J Nucl Med 2019; 60: 786
63. Calais, J., Ceci, F., Eiber, M. et al: (18)f-fluciclovine pet-ct and (68)ga-psma-11 pet-ct in patients with early biochemical recurrence after prostatectomy: A prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol 2019; 20: 1286
64. Morris, M. J., Rowe, S. P., Gorin, M. A. et al: Diagnostic performance of (18)f-dcfpyl-pet/ct in men with biochemically recurrent prostate cancer: Results from the condor phase iii, multicenter study. Clin Cancer Res 2021; 27: 3674
65. Phillips, R., Shi, W. Y., Deek, M. et al: Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: The oriole phase 2 randomized clinical trial. JAMA Oncol 2020; 6: 650
66. Palma, D. A., Olson, R., Harrow, S. et al: Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: Long-term results of the sabr-comet phase ii randomized trial. J Clin Oncol 2020; 38: 2830
67. Radwan, N., Phillips, R., Ross, A. et al: A phase ii randomized trial of observation versus stereotactic ablative radiation for oligometastatic prostate cancer (oriole). BMC Cancer 2017; 17: 453
68. Freedland, S. J., de Almeida Luz, M., De Giorgi, U. et al: Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med 2023; 389: 1453
69. Shore, N. D., Luz, M. A., De Giorgi, U. et al: Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med 2025;
70. Shore, N. D., Luz, M. A., De Giorgi, U. et al: Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med 2026; 394: 563
71. Aggarwal, R., Heller, G., Hillman, D. W. et al: Presto: A phase iii, open-label study of intensification of androgen blockade in patients with high-risk biochemically relapsed castration-sensitive prostate cancer (aft-19). J Clin Oncol 2024; 42: 1114
72. Crook, J. M., O'Callaghan, C. J., Duncan, G. et al: Intermittent androgen suppression for rising psa level after radiotherapy. N Engl J Med 2012; 367: 895
73. Tunn, U. W., Canepa, G., Kochanowsky, A. et al: Testosterone recovery in the off-treatment time in prostate cancer patients undergoing intermittent androgen deprivation therapy. Prostate Cancer Prostatic Dis 2012; 15: 296
74. Parker, C. C., James, N. D., Brawley, C. D. et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (stampede): A randomised controlled phase 3 trial. Lancet 2018; 392: 2353
75. Antonarakis, E. S., Feng, Z., Trock, B. J. et al: The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: Long-term follow-up. BJU Int 2012; 109: 32
76. Andriole, G. L., Kostakoglu, L., Chau, A. et al: The impact of positron emission tomography with 18f-fluciclovine on the treatment of biochemical recurrence of prostate cancer: Results from the locate trial. J Urol 2019; 201: 322
77. Tangen, C. M., Faulkner, J. R., Crawford, E. D. et al: Ten-year survival in patients with metastatic prostate cancer. Clin Prostate Cancer 2003; 2: 41
78. Abdel-Rahman, O.: Prostascore: A simplified tool for predicting outcomes among patients with treatment-naive advanced prostate cancer. Clin Oncol (R Coll Radiol) 2017; 29: 732
79. Glass, T. R., Tangen, C. M., Crawford, E. D. et al: Metastatic carcinoma of the prostate: Identifying prognostic groups using recursive partitioning. J Urol 2003; 169: 164
80. Kadono, Y., Nohara, T., Ueno, S. et al: Validation of tnm classification for metastatic prostatic cancer treated using primary androgen deprivation therapy. World J Urol 2016; 34: 261
81. Makarov, D. V., Humphreys, E. B., Mangold, L. A. et al: The natural history of men treated with deferred androgen deprivation therapy in whom metastatic prostate cancer developed following radical prostatectomy. J Urol 2008; 179: 156
82. Hussain, M., Goldman, B., Tangen, C. et al: Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: Data from southwest oncology group trials 9346 (intergroup study 0162) and 9916. J Clin Oncol 2009; 27: 2450
83. Hussain, M., Tangen, C. M., Higano, C. et al: Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: Data from southwest oncology group trial 9346 (int-0162). J Clin Oncol 2006; 24: 3984
84. Harshman, L. C., Chen, Y. H., Liu, G. et al: Seven-month prostate-specific antigen is prognostic in metastatic hormone-sensitive prostate cancer treated with androgen deprivation with or without docetaxel. J Clin Oncol 2018; 36: 376
85. Scher, H. I., Morris, M. J., Stadler, W. M. et al: Trial design and objectives for castration-resistant prostate cancer: Updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol 2016; 34: 1402
86. Huggins C, H. C.: Studies on prostate cancer. I. The effects of castration, of estrogen and of androgen injuection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Research 1941; 1: 293
87. U.S. Food & drug administration: Fda approves relugolix for advanced prostate cancer
88. Shore, N. D., Saad, F., Cookson, M. S. et al: Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med 2020; 382: 2187
89. Mostaghel, E. A.: Steroid hormone synthetic pathways in prostate cancer. Transl Androl Urol 2013; 2: 212
90. Fizazi, K., Tran, N., Fein, L. et al: Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (latitude): Final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol 2019; 20: 686
91. James, N. D., de Bono, J. S., Spears, M. R. et al: Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017; 377: 338
92. Clegg, N. J., Wongvipat, J., Joseph, J. D. et al: Arn-509: A novel antiandrogen for prostate cancer treatment. Cancer Res 2012; 72: 1494
93. Chi, K. N., Agarwal, N., Bjartell, A. et al: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 2019; 381: 13
94. Uemura, H., Koroki, Y., Iwaki, Y. et al: Skin rash following administration of apalutamide in japanese patients with advanced prostate cancer: An integrated analysis of the phase 3 spartan and titan studies and a phase 1 open-label study. BMC Urol 2020; 20: 139
95. Chi, K. N., Chowdhury, S., Bjartell, A. et al: Apalutamide in patients with metastatic castration-sensitive prostate cancer: Final survival analysis of the randomized, double-blind, phase iii titan study. J Clin Oncol 2021; 39: 2294
96. Tran, C., Ouk, S., Clegg, N. J. et al: Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324: 787
97. Armstrong, A. J., Azad, A. A., Iguchi, T. et al: Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2022; 40: 1616
98. Saad, F., Vjaters, E., Shore, N. et al: Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase iii aranote trial. J Clin Oncol 2024; 42: 4271
99. Kyriakopoulos, C. E., Chen, Y. H., Carducci, M. A. et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase iii e3805 chaarted trial. J Clin Oncol 2018; 36: 1080
100. Fizazi, K., Foulon, S., Carles, J. et al: Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel 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 2022; 399: 1695
101. Hussain, M., Tombal, B., Saad, F. et al: Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase iii arasens trial. J Clin Oncol 2023; 41: 3595
102. Smith, M. R., Hussain, M., Saad, F. et al: Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 2022; 386: 1132
103. Hussain, M., Tangen, C. M., Berry, D. L. et al: Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013; 368: 1314
104. Boevé, L. M. S., Hulshof, M., Vis, A. N. et al: Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: Data from the horrad trial. Eur Urol 2019; 75: 410
105. Oh, W. K., Landrum, M. B., Lamont, E. B. et al: Does oral antiandrogen use before leuteinizing hormone-releasing hormone therapy in patients with metastatic prostate cancer prevent clinical consequences of a testosterone flare? Urology 2010; 75: 642
106. Attard, G., Agarwal, N., Graff, J. N. et al: Niraparib and abiraterone acetate plus prednisone for hrr-deficient metastatic castration-sensitive prostate cancer: A randomized phase 3 trial. Nat Med 2025; 31: 4109
107. Smith, M. R., Saad, F., Coleman, R. et al: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: Results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39
108. Bryce, A. H., Alumkal, J. J., Armstrong, A. et al: Radiographic progression with nonrising psa in metastatic castration-resistant prostate cancer: Post hoc analysis of prevail. Prostate Cancer Prostatic Dis 2017; 20: 221
109. Sternberg, C. N., Fizazi, K., Saad, F. et al: Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2020; 382: 2197
110. Penson, D. F., Armstrong, A. J., Concepcion, R. et al: Enzalutamide versus bicalutamide in castration-resistant prostate cancer: The strive trial. J Clin Oncol 2016; 34: 2098
111. Shore, N. D., Chowdhury, S., Villers, A. et al: Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (terrain): A randomised, double-blind, phase 2 study. Lancet Oncol 2016; 17: 153
112. Ryan, C. J., Crawford, E. D., Shore, N. D. et al: The imaagen study: Effect of abiraterone acetate and prednisone on prostate specific antigen and radiographic disease progression in patients with nonmetastatic castration resistant prostate cancer. J Urol 2018; 200: 344
113. Smith, M. R., Saad, F., Oudard, S. et al: Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: Exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol 2013; 31: 3800
114. Kim, K. H., Han, K. S., Kim, K. H. et al: The prognostic effect of prostate-specific antigen half-life at the first follow-up visit in newly diagnosed metastatic prostate cancer. Urol Oncol 2015; 33: 383.e17
115. Moreira, D. M., Howard, L. E., Sourbeer, K. N. et al: Predicting time from metastasis to overall survival in castration-resistant prostate cancer: Results from search. Clin Genitourin Cancer 2017; 15: 60
116. Armstrong, A. J., Garrett-Mayer, E. S., Yang, Y. C. et al: A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: A tax327 study analysis. Clin Cancer Res 2007; 13: 6396
117. Pond, G. R., Sonpavde, G., de Wit, R. et al: The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer. Eur Urol 2014; 65: 3
118. Gandaglia, G., Karakiewicz, P. I., Briganti, A. et al: Impact of the site of metastases on survival in patients with metastatic prostate cancer. Eur Urol 2015; 68: 325
119. Smaletz, O., Scher, H. I., Small, E. J. et al: Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol 2002; 20: 3972
120. Ryan, C. J., Smith, M. R., Fizazi, K. et al: Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (cou-aa-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16: 152
121. Ryan, C. J., Smith, M. R., de Bono, J. S. et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138
122. Beer, T. M., Armstrong, A. J., Rathkopf, D. E. et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424
123. 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. Ann Oncol 2025; 36: 1058
124. Berthold, D. R., Pond, G. R., Soban, F. et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the tax 327 study. J Clin Oncol 2008; 26: 242
125. 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
126. Sartor, O., de Bono, J., Chi, K. N. et al: Lutetium-177-psma-617 for metastatic castration-resistant prostate cancer. N Engl J Med 2021; 385: 1091
127. Morris, M. J., Castellano, D., Herrmann, K. et al: (177)lu-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
128. Oudard, S., Fizazi, K., Sengeløv, L. et al: Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase iii trial-firstana. J Clin Oncol 2017; 35: 3189
129. de Wit, R., de Bono, J., Sternberg, C. N. et al: Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med 2019; 381: 2506
130. Grasso, C. S., Wu, Y. M., Robinson, D. R. et al: The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239
131. Sonnenblick, A., de Azambuja, E., Azim, H. A., Jr. et al: An update on parp inhibitors--moving to the adjuvant setting. Nat Rev Clin Oncol 2015; 12: 27
132. Fizazi, K., Piulats, J. M., Reaume, M. N. et al: Rucaparib or physician's choice in metastatic prostate cancer. N Engl J Med 2023; 388: 719
133. Pomerantz, M. M., Spisák, S., Jia, L. et al: The association between germline brca2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 2017; 123: 3532
134. Saad, F., Clarke, N. W., 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
135. Clarke, N. W., Armstrong, A. J., Thiery-Vuillemin, A. et al: Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid 2022; 1: EVIDoa2200043
136. Chi, K. N., Rathkopf, D., Smith, M. R. et al: Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol 2023; 41: 3339
137. Chi, K. N., Sandhu, S., Smith, M. R. 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. Ann Oncol 2023; 34: 772
138. Chi, K. N., Castro, E., Attard, G. et al: Niraparib and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: Final overall survival analysis for the phase 3 magnitude trial. Eur Urol Oncol 2025; 8: 986
139. Agarwal, N., Azad, A. A., 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
140. Fizazi, K., Azad, A. A., Matsubara, N. et al: First-line talazoparib with enzalutamide in hrr-deficient metastatic castration-resistant prostate cancer: The phase 3 talapro-2 trial. Nat Med 2024; 30: 257
141. Agarwal, N., Azad, A. A., Carles, J. et al: Talazoparib plus enzalutamide in men with metastatic castration-resistant prostate cancer: Final overall survival results from the randomised, placebo-controlled, phase 3 talapro-2 trial. Lancet 2025; 406: 447
142. Fizazi, K., Azad, A. A., Matsubara, N. et al: Talazoparib plus enzalutamide in men with hrr-deficient metastatic castration-resistant prostate cancer: Final overall survival results from the randomised, placebo-controlled, phase 3 talapro-2 trial. Lancet 2025; 406: 461
143. Rodrigues, D. N., Rescigno, P., Liu, D. et al: Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest 2018; 128: 5185
144. Abida, W., Cheng, M. L., Armenia, J. et al: Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol 2019; 5: 471
145. Smith, M. R., Lee, W. C., Brandman, J. et al: Gonadotropin-releasing hormone agonists and fracture risk: A claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 2005; 23: 7897
146. Shahinian, V. B., Kuo, Y. F., Freeman, J. L. et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352: 154
147. Lassemillante, A. C., Doi, S. A., Hooper, J. D. et al: Prevalence of osteoporosis in prostate cancer survivors: A meta-analysis. Endocrine 2014; 45: 370
148. Gralow, J. R., Biermann, J. S., Farooki, A. et al: Nccn task force report: Bone health in cancer care. J Natl Compr Canc Netw 2013; 11 Suppl 3: S1
149. Watts, N. B., Adler, R. A., Bilezikian, J. P. et al: Osteoporosis in men: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 1802
150. Alibhai, S. M., Mohamedali, H. Z., Gulamhusein, H. et al: Changes in bone mineral density in men starting androgen deprivation therapy and the protective role of vitamin d. Osteoporos Int 2013; 24: 2571
151. Greenspan, S. L., Coates, P., Sereika, S. M. et al: Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab 2005; 90: 6410
152. Lee, H., McGovern, K., Finkelstein, J. S. et al: Changes in bone mineral density and body composition during initial and long-term gonadotropin-releasing hormone agonist treatment for prostate carcinoma. Cancer 2005; 104: 1633
153. Morote, J., Orsola, A., Abascal, J. M. et al: Bone mineral density changes in patients with prostate cancer during the first 2 years of androgen suppression. J Urol 2006; 175: 1679
154. Wadhwa, V. K., Weston, R., Mistry, R. et al: Long-term changes in bone mineral density and predicted fracture risk in patients receiving androgen-deprivation therapy for prostate cancer, with stratification of treatment based on presenting values. BJU Int 2009; 104: 800
155. Cosman, F., de Beur, S. J., LeBoff, M. S. et al: Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int 2014; 25: 2359
156. Serpa Neto, A., Tobias-Machado, M., Esteves, M. A. et al: Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: A systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2012; 15: 36
157. Zaheer, S., LeBoff, M. and Lewiecki, E. M.: Denosumab for the treatment of osteoporosis. Expert Opin Drug Metab Toxicol 2015; 11: 461
158. Saad, F., Gleason, D. M., Murray, R. et al: Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004; 96: 879
159. Fizazi, K., Carducci, M., Smith, M. et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. Lancet 2011; 377: 813
160. Himelstein, A. L., Foster, J. C., Khatcheressian, J. L. 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
161. Smith, M. R., Halabi, S., Ryan, C. J. 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
162. Tang, C., Hoffman, K. E., Allen, P. K. et al: Contemporary prostate cancer treatment choices in multidisciplinary clinics referenced to national trends. Cancer 2020; 126: 506
163. Culp, S. H., Schellhammer, P. F. and Williams, M. B.: Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A seer-based study. Eur Urol 2014; 65: 1058
164. Gratzke, C., Engel, J. and Stief, C. G.: Role of radical prostatectomy in metastatic prostate cancer: Data from the munich cancer registry. Eur Urol 2014; 66: 602
165. Rusthoven, C. G., Jones, B. L., Flaig, T. W. et al: Improved survival with prostate radiation in addition to androgen deprivation therapy for men with newly diagnosed metastatic prostate cancer. J Clin Oncol 2016; 34: 2835
166. Metcalfe, M. J., Smaldone, M. C., Lin, D. W. et al: Role of radical prostatectomy in metastatic prostate cancer: A review. Urol Oncol 2017; 35: 125
167. Yuh, B. E., Kwon, Y. S., Shinder, B. M. et al: Results of phase 1 study on cytoreductive radical prostatectomy in men with newly diagnosed metastatic prostate cancer. Prostate Int 2019; 7: 102
168. Graefen, M., Falkenbach, F., Maurer, T. et al: Best systemic therapy with or without radical prostatectomy in the management of men with oligometastatic prostate cancer: The rampp randomised controlled trial. Eur Urol 2025;
169. Fendler, W. P., Eiber, M., Beheshti, M. et al: Psma pet/ct: Joint eanm procedure guideline/snmmi procedure standard for prostate cancer imaging 2.0. Eur J Nucl Med Mol Imaging 2023; 50: 1466
170. Mazzone, E., Thomson, A., Chen, D. C. et al: The role of prostate-specific membrane antigen positron emission tomography for assessment of local recurrence and distant metastases in patients with biochemical recurrence of prostate cancer after definitive treatment: A systematic review and meta-analysis. Eur Urol 2025; 88: 129
171. Hofman, M. S., Murphy, D. G., Williams, S. G. et al: A prospective randomized multicentre study of the impact of gallium-68 prostate-specific membrane antigen (psma) pet/ct imaging for staging high-risk prostate cancer prior to curative-intent surgery or radiotherapy (propsma study): Clinical trial protocol. BJU Int 2018; 122: 783
172. Steuber, T., Jilg, C., Tennstedt, P. et al: Standard of care versus metastases-directed therapy for pet-detected nodal oligorecurrent prostate cancer following multimodality treatment: A multi-institutional case-control study. Eur Urol Focus 2019; 5: 1007
173. Ost, P., Reynders, D., Decaestecker, K. et al: Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: A prospective, randomized, multicenter phase ii trial. J Clin Oncol 2018; 36: 446
174. Tang, C., Sherry, A. D., 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
175. Tang, C., Sherry, A. D., Hwang, H. et al: Metastasis-directed therapy and standard of care versus standard of care for oligometastatic prostate cancer (wolverine): A systematic review and individual patient data meta-analysis from the x-met collaboration. Lancet Oncol 2026; 27: 181
176. Azad, A. A., Agarwal, N., Armstrong, A. J. et al: Saruparib in combination with androgen receptor pathway inhibitors in metastatic hormone-sensitive prostate cancer: Evopar-prostate01. Future Oncol 2026; 22: 1153