To cite this guideline:

• Lowrance WT, Breau RH, Chou R et al: Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART I. J Urol 2021; 205: 14
• Lowrance WT, Breau RH, Chou R et al: Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II. J Urol 2021; 205: 22.

Guideline as it appears in The Journal of Urology® Part I [pdf]

Guideline as it appears in The Journal of Urology® Part II [pdf]

Unabridged version of this guideline [pdf]

Algorithm associated with this guideline [pdf]

Español translated guideline courtesy of Sociedad Colombiana de Urologia (SCU) [pdf]

William Lowrance, MD, MPH, MBA; Rodney Breau, MSc, MD, FRCSC; Roger Chou, MD; Brian F. Chapin, MD; Tony Crispino; Robert Dreicer, MD, MS, MACP, FASCO; 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

Purpose

The management of advanced prostate cancer is rapidly evolving. Clinicians are challenged to remain up-to-date and informed with respect to a multitude of treatment options for patients with advanced prostate cancer. 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. 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. 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.

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

Biochemical Recurrence without Metastatic Disease after Exhaustion of Local Treatment Options

Prognosis

4. 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)

5. In patients with PSA recurrence after exhaustion of local therapy who are at higher risk for the development of metastases (e.g., PSADT <12 months), clinicians should perform periodic staging evaluations consisting of cross-sectional imaging (CT, MRI) and technetium bone scan. (Clinical Principle)

6. Clinicians may utilize novel PET-CT scans (e.g., fluciclovine, choline, PSMA) in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging. (Expert Opinion)

Treatment

7. For patients with a rising PSA after failure of local therapy and no demonstrated metastatic disease by conventional imaging, clinicians should offer observation or clinical trial enrollment. (Clinical Principle)

8. ADT should not be routinely initiated in this population (Expert Opinion). However, if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT. (Conditional Recommendation; Evidence Level: Grade B)

Metastatic Hormone-Sensitive Prostate Cancer

Prognosis

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

10. In newly diagnosed mHSPC patients, clinicians should assess the extent of metastatic disease (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. (Moderate Recommendation: Evidence Level: Grade B)

11. 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)

12. 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 conventional imaging. (Clinical Principle)

13. In patients with mHSPC, regardless of age and family history, clinicians should offer genetic counseling and germline testing. (Expert Opinion)

Treatment

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

15. In patients with mHSPC, clinicians should offer continued ADT in combination with either androgen pathway directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel). (Strong Recommendation; Evidence Level: Grade A)

16. In selected mHSPC patients with low-volume metastatic disease, clinicians may offer primary radiotherapy to the prostate in combination with ADT. (Conditional Recommendation; Evidence Level: Grade C)

17. 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)

18. Clinicians should not offer oral androgen pathway directed therapy (e.g., abiraterone acetate plus prednisone, apalutamide, bicalutamide, darolutomide, enzalutamide, flutamide, nilutamide) without ADT for patients with mHSPC. (Expert Opinion)

Non-Metastatic Castration-Resistant Prostate Cancer

Prognosis

19. 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)

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

Treatment

21. 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)

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

23. 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

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

25. In mCRPC patients, clinicians should assess the extent of metastatic disease using conventional imaging at least annually or at intervals determined by lack of response to therapy. (Expert Opinion)

26. In patients with mCRPC, clinicians should offer germline and somatic tumor genetic testing to identify DNA repair deficiency mutations and microsatellite instability status that may inform prognosis and counseling regarding family risk as well as potential targeted therapies. (Expert Opinion)

Treatment

27. In newly diagnosed mCRPC patients, clinicians should offer continued ADT with abiraterone acetate plus prednisone, docetaxel, or enzalutamide. (Strong Recommendation; Evidence Level: Grade A [abiraterone acetate plus prednisone and enzalutamide]/B [docetaxel])

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

29. 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)

30. In sequencing agents, clinicians should consider prior treatment and consider recommending therapy with an alternative mechanism of action. (Moderate Recommendation; Evidence Level: Grade B)

31. In mCRPC patients who received prior docetaxel chemotherapy with or without prior abiraterone acetate plus prednisone or enzalutamide for the treatment of CRPC, clinicians may offer cabazitaxel. (Conditional Recommendation; Evidence Level: Grade B)

32. In mCRPC patients who received prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamide, clinicians should recommend cabazitaxel rather than an alternative androgen pathway directed therapy. (Strong Recommendation; Evidence Level: Grade B)

33. Clinicians should offer a PARP inhibitor to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy. Platinum based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor. (Moderate Recommendation; Evidence Level: Grade C)

34. In patients with mismatch repair deficient or microsatellite instability high mCRPC, clinicians should offer pembrolizumab. (Moderate Recommendation; Evidence Level: Grade C)

Bone Health

35. 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)

36. Clinicians should recommend preventative 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)

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

38. 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)

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.

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 overall survival (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 hazards ratios 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. After dual review of abstracts and titles, 918 publications were selected for full-text dual review, and 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, hazard ratio (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. 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 AMSTAR 2 (Assessing the Methodological Quality of Systematic Reviews) criteria. 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. 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. Randomized controlled trials (RCT) 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 1)

The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (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.⁴

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.

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.⁵ 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.

Epidemiology

Prostate cancer is the most commonly diagnosed solid organ malignancy for men in the U.S. and remains the second leading cause of cancer deaths for this population. Approximately 175,000 new diagnoses of prostate cancer and over 31,000 deaths were estimated in the U.S. in 2019. ⁶ Importantly, the incidence of metastatic hormone-sensitive prostate cancer (mHSPC) has been increasing in recent years, and recent improvements in survival 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. ⁷ Furthermore, therapeutic advances in the treatment landscape for mHSPC and mCRPC render treatment decisions and sequencing increasingly complex. It is against this backdrop that the Panel provides evidence-based guidance for treatment of 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 state 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). ⁸ The patient population covered in this guideline is assumed to have already received local or pelvic therapy, including adjuvant and salvage therapy (i.e., 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 or radiation, the first sign of recurrence is typically a rising PSA in the absence of visible metastases. This is assuming also 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 for optimal treatment approaches is lacking.

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. ^9,10 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 disease 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. ^11,12 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 (PET)- computed tomography (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. ^13-15 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 for men with localized prostate cancer. ¹⁶ Additionally, recent press releases state that two of the three approved AR antagonists also improve OS in this population. ^17,18 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. ^19,20 Since the approval of docetaxel, multiple additional agents that show a survival benefit have been FDA-approved on the basis of RCTs. ^21-25 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 >2.0 ng/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 (<50 ng/dL). Contemporary lab testing indicates that testosterone levels decline to <20 ng/dL after orchiectomy. ²⁶ Progression may present as either a continuous rise in serum (PSA) levels (values identified at a minimum of 1 week intervals with a minimal value of 2.0ng/mL, 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. ⁹Low-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. ^9,27High-risk metastatic disease is defined per the LATITUDE definition for mHSPC that has a poorer prognosis in the presence of two of the three following high-risk features: Gleason > 8, > 3 bone lesions, or measurable visceral metastases. ²⁸De 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. ²⁹PSA doubling time (PSADT) is the number of months required for the PSA value to increase two-fold. 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. ^31,32 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, ^33,34 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 owing to the significant differences in sensitivity to detect metastatic disease between conventional and advanced imaging modalities. Nonetheless, for the purpose of this guideline, the practicing clinician should consider ‘metastatic’ disease that which is identified on conventional imaging.

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, ^35-38 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.

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.

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

Prognosis

4. 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)

5. In patients with PSA recurrence after exhaustion of local therapy who are at higher risk for the development of metastases (e.g., PSADT <12 months), clinicians should perform periodic staging evaluations consisting of cross-sectional imaging (CT, MRI) and technetium bone scan. (Clinical Principle)

6. Clinicians may utilize novel PET-CT scans (e.g., fluciclovine, choline, PSMA) in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging. (Expert Opinion)

7. For patients with a rising PSA after failure of local therapy and no demonstrated metastatic disease by conventional imaging, clinicians should offer observation or clinical trial enrollment. (Clinical Principle)

8. ADT should not be routinely initiated in this population (Expert Opinion). However, if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT. (Conditional Recommendation; Evidence Level: Grade B)

Prognosis

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

10. In newly diagnosed mHSPC patients, clinicians should assess the extent of metastatic disease (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. (Moderate Recommendation: Evidence Level: Grade B)

11. 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)

12. 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 conventional imaging. (Clinical Principle)

13. In patients with mHSPC, regardless of age and family history, clinicians should offer genetic counseling and germline testing. (Expert Opinion)

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

15. In patients with mHSPC, clinicians should offer continued ADT in combination with either androgen pathway directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel). (Strong Recommendation; Evidence Level: Grade A)

16. In selected mHSPC patients with low-volume metastatic disease, clinicians may offer primary radiotherapy to the prostate in combination with ADT. (Conditional Recommendation; Evidence Level: Grade C)

17. 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)

18. Clinicians should not offer oral androgen pathway directed therapy (e.g., abiraterone acetate plus prednisone, apalutamide, bicalutamide, darolutomide, enzalutamide, flutamide, nilutamide) without ADT for patients with mHSPC. (Expert Opinion)

Prognosis

19. 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)

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

21. 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)

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

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

Prognosis

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

25. In mCRPC patients, clinicians should assess the extent of metastatic disease using conventional imaging at least annually or at intervals determined by lack of response to therapy. (Expert Opinion)

26. In patients with mCRPC, clinicians should offer germline and somatic tumor genetic testing to identify DNA repair deficiency mutations and microsatellite instability status that may inform prognosis and counseling regarding family risk as well as potential targeted therapies. (Expert Opinion)

27. In newly diagnosed mCRPC patients, clinicians should offer continued ADT with abiraterone acetate plus prednisone, docetaxel, or enzalutamide. (Strong Recommendation; Evidence Level: Grade A [abiraterone acetate plus prednisone and enzalutamide]/B [docetaxel])

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

29. 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)

30. In sequencing agents, clinicians should consider prior treatment and consider recommending therapy with an alternative mechanism of action. (Moderate Recommendation; Evidence Level: Grade B)

31. In mCRPC patients who received prior docetaxel chemotherapy with or without prior abiraterone acetate plus prednisone or enzalutamide for the treatment of CRPC, clinicians may offer cabazitaxel. (Conditional Recommendation; Evidence Level: Grade B)

32. In mCRPC patients who received prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamide, clinicians should recommend cabazitaxel rather than an alternative androgen pathway directed therapy. (Strong Recommendation; Evidence Level: Grade B)

33. Clinicians should offer a PARP inhibitor to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy. Platinum based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor. (Moderate Recommendation; Evidence Level: Grade C)

34. In patients with mismatch repair deficient or microsatellite instability high 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 (i.e., 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.^134,135 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.

35. 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)

36. Clinicians should recommend preventative 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)

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

38. 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)

Several key areas of future research need emphasis to improve clinical care and provide a path to better patient outcomes with advanced prostate cancer.

Integrations of care

It is now more clear than ever that multimodality approaches and integration of care are critical to improving the care for men with prostate cancer. Multidisciplinary clinics and the resulting multimodality treatment approaches can optimize treatment selection, maximize results and minimize overtreatment and side effects.¹⁵¹ Many clinical trials are evaluating the concepts of integrating systemic therapy with radiation and/or surgery, such as optimizing treatment of men with locally advanced primary tumors, assessing the benefit of local therapy in men with metastatic disease, or determine the impact of metastasis-directed therapy 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 experimental. There are 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.^152-154 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 to clinical practice. Several single-arm phase I/II trials and four randomized phase II clinical trials have been completed but are yet to be published.^155,156 While the data mature, there is a Phase III RCT—SWOG 1802—evaluating standard systemic therapy with or without local control of the primary in men with hormone-sensitive ‘de novo’ metastatic prostate cancer. There are also plans for a surgical treatment arm in the STAMPEDE study (NCT03678025). 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.

Advanced PET imaging

Advanced PET imaging and theranostics are likely to revolutionize prostate cancer staging and management. Currently their role in the management of advanced prostate cancer is not entirely clear. These imaging modalities identify sites of recurrent prostate cancer with superior specificity and sensitivity compared to conventional imaging.^157-159 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.¹⁶⁰ Use of these imaging agents will allow for identification of metastatic sites not otherwise seen with conventional imaging. As a result, it will be important to be cognizant of the stage migration that will occur with advanced PET imaging.

Given the ability to identify metastatic sites earlier than was previously possible, there has been renewed interest in the concept of MDT with radiation, surgery, or ablative technologies. Phase II trials have been designed and executed to determine if there is an impact on the biology of disease. Studies such as the STOMP trial have compared men with newly diagnosed metastatic disease detected on ¹¹C-Choline PET and randomized these men to observation versus MDT. This study was negative for its primary endpoint, but it did demonstrate a prolongation of time to initiation of systemic therapy.⁵⁸ Other trials are underway to evaluate this concept and also evaluate its use with concomitant systemic therapy. To date, there is little prospective randomized data evaluating PET as a staging study for untreated prostate cancer, mHSPC or CRPC.¹⁶¹ While studies are being completed to generate data for FDA registration based on safety and performance, what will ultimately determine the role of these PET agents will be trials demonstrating improved patient outcomes as a direct result of earlier intensification of systemic therapies, MDT, and/or prediction of responses to specific therapies. Until these trials are completed, use of PET imaging beyond identifying visible disease in patients with PSA recurrences is considered experimental.

PSMA-based therapeutics are another potential treatment currently emerging from the ability to target PSMA expressed on the surface of cancer cells. These aim to use the homing ability of PSMA-targeted antibodies or small molecules coupled to radioligands, such as ¹⁷⁷Lutetium, to target prostate cancer cells systemically.¹⁶² These are currently under investigation in the advanced, CRPC stages of prostate cancer, but they are likely to move up in clinical trials to mHSPC, biochemical recurrence, and possibly even as neoadjuvant therapy for high-risk localized disease. The durability of these treatments is being evaluated in multiple prospective clinical studies. This is 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).

Biomarkers and other systemic therapies

Given the dramatic increase in available therapies for advanced prostate cancer over the past 10 years, there is a renewed urgency to identify predictive biomarkers that can guide treatment selection. A number of promising molecular approaches continue to be investigated, but as of yet there is no assay that has been prospectively demonstrated to lead to improved oncologic outcomes.

Currently, the most promising markers are the expression levels of AR-V7 and the identification of germline or somatic alterations in DDR genes such as BRCA1, BRCA2, and ATM. The potential value for assessing these markers stems from the possibility that they can serve as predictive—rather than solely prognostic—biomarkers. That is, there is substantial evidence that these tests might predict differential response to specific systemic therapies, with the implication that pairing these tests with changes in treatment selection could lead to improved long-term outcomes. For AR-V7, the initial seminal study by Antonarakis and colleagues showed that high expression of AR-V7 in CTCs was associated with rapid disease progression in men with mCRPC starting enzalutamide or abiraterone acetate.¹⁶³ Other studies have confirmed these findings using different platforms for measuring AR-V7 expression in circulation and also showed that patients with high AR-V7 expression may still respond well to chemotherapy.^164-167 Two CLIA-certified laboratory developed tests are currently commercially available, and the PROPHECY trial prospectively validated these tests in an mCRPC population while also showing that some discrepancies exist in test results between these two assays.¹⁶⁸ Importantly, the vast majority of patients were AR-V7-negative by both assays.

The potential importance of germline and somatic tumor testing, covered in guideline statements 13 and 26, largely surrounds their promise for predicting response to PARP inhibitors such as olaparib, rucaparib, niraparib, veliparib, and talozaparib. Because PARP inhibitors target the DNA replication machinery, tumors with deficiencies in homologous recombination repair (e.g., because of BRCA1, BRCA2 mutations) are uniquely sensitive to PARP inhibition, a phenomenon termed synthetic lethality. In the TOPARP-A trial, heavily-treated mCRPC patients treated with olaparib were much more likely to respond in the setting of a DDR alteration.³⁹ The response rate was 88% in biomarker positive patients and 6% in biomarker negative patients. From a biomarker standpoint, it is important to note that circulating cell-free DNA may be a future alternative approach for identifying these DDR alterations, and subsequent reversion mutations could be identified after disease progression.¹⁶⁹ In the TOPARP-B study, which assessed 92 patients with DDR aberrations treated with olaparib, 44 patients (48%) demonstrated a confirmed response by imaging, PSA, or CTC criteria.¹⁷⁰ Results of multiple prospective RCTs assessing PARP inhibitors in mCRPC patients with DDR alterations are pending.

In addition to PARP inhibitors, immunotherapies have also emerged as a key therapeutic modality in a large number of solid tumors. Aside from sipuleucil-T, these treatments have generally shown less efficacy in advanced prostate cancer compared to other malignancies, in part related to the relatively low tumor mutational burden of most prostate cancers.¹⁷¹ However, as described in guideline statement 34, there is likely to be a subset of prostate cancer patients who are uniquely sensitive to immunotherapy— particularly those patients who have tumors that have a high mutational burden (MSI-high).¹⁷² Ongoing trials continue to explore whether immune checkpoint inhibitors, vaccine-based therapies, or oncolytic viruses may have broader utility in men with advanced prostate cancer.

Unmet needs

While dramatic recent advances have been made, there are many unmet needs in prostate cancer management. Personalized care with predictive markers for treatment selection based on tumor and host biology have not yet been achieved. There has been movement toward identification of prognostic markers and identification of molecular markers based on immunohistochemistry and use of genomic signatures, but these have yet to yield predictive results. A recent example of prognostic ability is the finding that patients with combined defects in tumor suppressor genes (P53, Rb, PTEN) demonstrated improved responses to cabazitaxel plus carboplatin versus cabazitaxel alone in CRPC.¹⁷³ Further prospective phase III trials are planned to evaluate the predictive ability of this combined defect for treatment selection. As we move forward as a field, we need to focus on the biologic make-up of tumors and how these can be better leveraged to identify treatment options for patients.

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