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Advancing mHSPC Care: Bridging Research and Practice - A Letter from UroToday's mHSPC Center of Excellence Editor-in-Chief, Neeraj Agarwal, MD, FASCO

Welcome to UroToday’s Center of Excellence on metastatic hormone-sensitive prostate cancer (mHSPC). I am honored to serve as its new editor. This multimedia Center helps audiences in the United States and worldwide stay abreast of clinical trials, real-world studies, biomarker data, regulatory approvals, and expert perspectives on this challenging, dynamic disease and treatment landscape. As therapies for patients with mHSPC evolve, real-world practice has lagged behind. Indeed, five years after the regulatory approvals of novel androgen receptor pathway inhibitors (ARPIs) for treating mHSPC, data suggest that less than half of patients are receiving them in the metastatic hormone-sensitive setting. In this editorial, I cover key data and approvals in mHSPC, what we know about real-world treatment patterns, and how we can narrow gaps between data and practice.


In the United States, the National Cancer Institute estimates that at least 8% of all prostate cancer cases are metastatic when first diagnosed (ie, de novo or synchronous mHSPC),1 and this proportion is higher in regions where prostate-specific antigen (PSA) screening is not routine and thus patients are more likely to be diagnosed only after they become symptomatic.2-4

A decade ago, the standard of care for mHSPC was androgen deprivation therapy (ADT) administered alone or with a first-generation nonsteroidal antiandrogen (NSAA); treatment intensification was reserved for patients with metastatic castration-resistant disease.5 This approach did not avert dismal outcomes—historical cohort studies show that as recently as 2005-2008, more than 55% of patients with newly diagnosed mHSPC died of prostate cancer within five years.6

A decade ago, this status quo was upended by the results of the phase 3 randomized CHAARTED trial, the first major clinical trial to demonstrate a significant overall survival (OS) benefit from upfront treatment intensification in patients with mHSPC. In this study, the addition of 6 cycles of docetaxel to ADT significantly prolonged median OS compared with ADT alone in patients with synchronous high-volume mHSPC (defined as the presence of > 4 bone metastases, with >1 beyond the vertebral bodies and pelvis, and/or visceral metastases).7,8 Subsequently, in the randomized phase 3 STAMPEDE trial, the addition of docetaxel to ADT significantly improved OS compared with ADT alone in patients with both low and high-burden disease.9 These findings heralded a new era in which large randomized phase 3 trials such as LATITUDE, STAMPEDE (Arm G), TITAN, ENZAMET, and ARCHES demonstrated that adding a next-generation ARPI (abiraterone, apalutamide, or enzalutamide) to ADT significantly improved OS in patients with mHSPC compared with conventional treatment.10-14 These findings and resulting regulatory approvals provided clinicians and patients with multiple options for upfront doublet therapy. While head-to-head trials of ARPIs are lacking, findings from individual trials suggest that adding an ARPI to ADT reduces the overall risk of death by as much as 30-40% compared with ADT alone.10-14

Building on these findings, the PEACE-1, ARASENS, and ENZAMET trials demonstrated significant improvements in OS among patients with mHSPC who received triplet regimens comprised of an ARPI (abiraterone, enzalutamide, or darolutamide), ADT, and docetaxel, as compared with a doublet regimen of ADT plus docetaxel.15-18 Benefits were observed across subgroups stratified by disease volume, although patients with synchronous, high-volume mHSPC appeared to benefit the most from triplet regimens.19-21 Triplets were not compared with doublets of ADT plus an ARPI, so these trials did not clarify which approach is superior for which patients. Nonetheless, these trials provide indisputable support for the use of upfront treatment intensification for most patients with mHSPC. There is no longer a role for ADT alone in treating mHSPC apart from exceptional cases, such as when life expectancy is less than two years. There is also no role for ADT plus docetaxel, given the superiority of triplet regimens compared to ADT plus docetaxel doublet therapy. Accordingly, treatment intensification is recommended by current prostate cancer treatment guidelines from groups such as the National Comprehensive Cancer Center (NCCN), the European Association of Urology (EAU), and the European Society for Molecular Oncology (ESMO).22-24

However, are data and guidelines recommending ADT intensification being translated widely into real-world practice? Multiple large retrospective studies indicate otherwise. In a study of 1,560 patients with mHSPC from the United States (n=239) and five European countries (n=1,321), the use of guideline-recommended ADT intensification with an ARPI or taxane chemotherapy rose during 2019-2020 relative to 2016-2018 but remained low—fully 39% of patients in the later time period did not receive intensification.25 In a large study from Ontario, Canada, less than 13% of patients aged 66 years and older with mHSPC received treatment intensification; use of abiraterone rose after LATITUDE results were reported, but the absolute increase was only 2.5% (from 0.5% to 3.0%).26 In a large study of the Optum claims database, which includes both commercially insured and Medicare Advantage patients, only 30% of patients with mHSPC received upfront doublet therapy during 2014-2019 and less than 2% received a triplet regimen, while more than 50% of patients received ADT alone—including more than half of those with visceral metastases.27 Another study of more than 35,000 Medicare patients with mHSPC showed that as recently as 2018, only 22% of non-Hispanic White patients received ADT intensification, and this percentage was even lower in Black patients (16%), who are at greater risk for aggressive disease.28,29 Furthermore, data presented in 2024 show that underutilization persists. At ASCO GU 2024, we learned that in a large study of the Flatiron EHR database, only approximately 34% of patients with newly diagnosed mCRPC had received an ARPI in the hormone-sensitive disease setting.30 In a large study of more than 10,000 privately insured US patients with mHSPC, the use of treatment intensification rose linearly over time, but at the end of the study (2023), more than a third of patients were only prescribed ADT.31

Researchers have sought to parse contributors to the underutilization of treatment intensification in patients with mHSPC. In a large study of insurance claims during 2014-2019, upfront treatment intensification was underutilized by both urologists and medical oncologists, even when patients had visceral metastases.32 In a recent survey of 65 oncologists and 42 urologists, reasons for not prescribing an upfront ARPI included perceptions/concerns regarding drug tolerability (38%), lack of effect on OS (31%), lack of reimbursement (26%), patient financial constraints (20%), and sequencing of ARPIs earlier versus later in the disease trajectory (21%).33 Currently, we are conducting qualitative interviews of physicians to better understand their reasons for underutilization of treatment intensification in patients with advanced prostate cancer. Without such understanding, our ability to effect practice-level change will be limited.

Medical oncologists and urologists both face barriers to staying abreast of data and guideline changes—urologists often have a large surgical caseload, while medical oncologists may treat scores of different cancer types and subtypes, leaving little time to keep up with treatment changes in a subset of patients with metastatic prostate cancer. Nonetheless, physician concerns about tolerability, clinical outcomes, and timing of treatment initiation point to the need for greater education and awareness of clinical data. Pragmatic strategies to achieve this include digital media campaigns (eg, via X/Twitter), low-cost or free hybrid conferences and webinars, and incorporating AI-based decision-making tools into the EHR—while ensuring that relevant data are provided to explain rationales for treatment algorithms. Patients and caregivers, too, need better access to data on treatment intensification through mechanisms such as open access, patient-friendly publications and presentations, and websites designed exclusively for patients and families.

As the results of the 2022 clinician survey indicate, financial toxicity poses a formidable barrier to wider adoption of treatment intensification. In a recent study of private insurance data, one year of ADT monotherapy accrued out-of-pocket costs of $165, compared with $4,236 in out-of-pocket costs for one year of ARPI therapy.34 Black race, older age (65-74 years) and lower household income were associated with significantly higher out-of-pocket costs for these drugs, underscoring the need for interventions that reach financially vulnerable groups of patients with mHSPC and help them gain access to guideline-recommended therapies. The Inflation Reduction Act, which was passed in 2022, takes steps toward this goal by lowering prescription drug prices in Medicare through price negotiation with manufacturers, implementing a hard cap on annual out-of-pocket prescription drug costs in Medicare (the cap will be $2,000 in 2025), and continuing lower health insurance premiums through HealthCare.gov and state-based insurance marketplaces.

In addition, Congress should pass the Help Ensure Lower Patient (HELP) Co-pays Act, which would prevent insurers from excluding the value of manufacturer coupons or other direct support when calculating a patient’s deductible or annual out-of-pocket maximum cost. In past rulemaking, the Centers for Medicare & Medicaid Services (CMS) proposed that insurers be allowed to use these Accumulator Adjustment Programs (AAPs) if a coupon is used for a brand-name drug for which a generic is available. In essence, the HELP Co-Pays Act would ensure that any amount paid by or on behalf of a patient reduces their total out-of-pocket costs. In February 2023, this bill was referred to the House Subcommittee on Health, where it has stalled.35 However, in January 2024, three House sponsors of the bill successfully pressured the Biden administration to stop trying to keep copay assistance from counting toward a patient’s deductible and out-of-pocket maximum in most instances.36 In addition, at least 19 states and Puerto Rico have taken steps to ban or limit the use of AAPs. Passing the HELP Co-Pays Act would help protect most privately insured patients.

We should also reduce prior authorization burdens, which create diagnostic and treatment delays, stop some patients from receiving guideline-recommended cancer treatments, and increase out-of-pocket costs. The Improving Seniors’ Timely Access to Care Act would require insurers to comply with standards for electronic prior authorizations, bar Medicare Advantage plans from using proprietary payer portals, and implement vigorous transparency standards, such as requiring insurers to report how they use prior authorizations and statistics on approvals and denials. Although this bill previously was not taken up by the US Senate, it was updated to reduce fiscal impact while retaining key patient protection measures and reintroduced in June 2024.37 If passed, the legislation would require the federal Health IT office and CMS to report to Congress on the use of prior authorizations in Medicare Advantage, define “real-time decisions” for “routinely approved services,” make CMS responsible for implementing real-time prior authorization processes, and give the federal government the authority to enforce these processes and mandate tighter insurer decision timelines.

Personalization of treatment intensification is another way to help guideline-recommended mHSPC regimens reach more patients while simultaneously supporting quality of life, curbing individual clinical and financial toxicities, and conserving healthcare resources. To that end, researchers are working to identify response-based criteria that can guide decisions at both a prognostic and a predictive level and develop de-intensification strategies for patients with favorable risk profiles. One of the most studied assessment criteria is PSA response after the start of systemic therapy. In subgroup analyses of LATITUDE, TITAN, and ARASENS, deep, rapid, durable PSA responses were associated with improved OS and time to progression.38-40 Currently, the phase 2 A-DREAM trial is assessing systemic treatment (ADT and ARPI) cessation at 18–24 months in patients who reach PSA <0.2 ng/ml.41 In addition, the phase 3 EORTC-2238 GUCG De-escalate) trial is comparing intermittent versus continuous ARPI (abiraterone, enzalutamide, apalutamide, or darolutamide) plus ADT in patients with mHSPC who achieve a PSA <0.2 ng/mL during the first 6–12 months of therapy; this trial addresses several pragmatic questions and should substantially help inform this topic.42 In another phase 3 trial (LIBERTAS), patients receive both ADT and apalutamide for 6 months, after which patients with PSA < 0.2 ng/mL are randomized to intermittent versus continuous ADT (both arms continue apalutamide); co-primary endpoints evaluate rPFS and hot flash severity.43

Many other biomarkers for treatment selection are of interest. For example, the presence of an SPOP mutation may warrant avoiding docetaxel, while PTEN/RB1/TP53 loss may merit its inclusion in treatment.44,45 Currently, the TALAPRO-3, AMPLITUDE, CAPItello-281, and PSMAddition trials are evaluating molecular or imaging biomarker-directed intensification strategies, including ADT plus an APRI plus a PARP inhibitor in patients with relevant DDR and HRR gene alterations, or 177-Lu-PSMA-607 in patients with PSMA-positive disease as identified by a PSMA PET/CT scan.46-49 These studies will report primary results late this year or in 2025. If positive, they will advance us toward a future in which individualized testing such as comprehensive genomic profiling (CGP) becomes the norm—whereas today CGP is performed in a minority of patients with advanced prostate cancer.50

Conclusions

Over the last decade, mHSPC treatment has undergone massive shifts. There is no longer a role for ADT alone in treating these patients except in exceptional cases such as when life expectancy is less than two years. There is also no longer a role for ADT plus docetaxel, given the superiority of triplet regimens comprised of docetaxel, ADT, and an ARPI. For most patients with mHSPC, doublets of ADT plus an ARPI are appropriate, but more aggressive treatment with triplets should be considered for patients with visceral metastases or other high-risk genomic or clinical features. Real-world clinician surveys and studies of treatment patterns reveal the need to bolster urologist and medical oncologist awareness of the benefits of guideline-recommended treatment regimens. Because these clinicians are very busy, accessible, time-efficient educational initiatives will be vital. Advocacy measures are underway to help curb financial toxicity to patients and enable greater access. Partnerships with patients, not only at the clinician level but through patient-friendly, freely accessible platforms, also can help improve awareness of treatment options and support shared decision-making. Research on prognostic and predictive biomarkers is paving the way for a future in which mHSPC treatment is personalized to maximize individual benefit. At the same time, the art of medicine is more important than ever—no biomarker panel can replace clinical experience and acumen.

Written by: Neeraj Agarwal, MD, FASCO, Professor of Medicine, Presidential Endowed Chair of Cancer Research, Huntsman Cancer Institute (HCI), University of Utah

References:

  1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Prostate cancer. Accessed August 20, 2024.  https://seer.cancer.gov/statfacts/html/prost.html
  2. Sayan M, Langoe A, Aynaci O, et al. Prostate cancer presentation and management in the Middle East. BMC Urol. 2024 Feb 9;24(1):35. doi: 10.1186/s12894-024-01427-6. 
  3. Sierra MS, Soerjomataram I, Forman D. Prostate cancer burden in Central and South America. Cancer Epidemiol. 2016;44 Suppl 1:S131-S140. doi:10.1016/j.canep.2016.06.010
  4. Baade PD, Yu XQ, Smith DP, et al. Geographic disparities in prostate cancer outcomes--review of international patterns. Asian Pac J Cancer Prev. 2015;16(3):1259-1275. doi:10.7314/apjcp.2015.16.3.1259
  5. Komura K, Sweeney CJ, Inamoto T, et al. Current treatment strategies for advanced prostate cancer. Int J Urol. 2018;25(3):220-231. doi: 10.1111/iju.13512.
  6. Helgstrand JT, Røder MA, Klemann N, et al. Trends in incidence and 5-year mortality in men with newly diagnosed, metastatic prostate cancer-A population-based analysis of 2 national cohorts. Cancer. 2018;124(14):2931-2938. doi:10.1002/cncr.31384
  7. Sweeney CJ, Chen YH, Carducci M, et al. chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747
  8. Kyriakopoulos CE, Chen YH, Carducci MA, 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(11):1080-1087. doi:10.1200/JCO.2017.75.3657
  9. Clarke NW, Ali A, Ingleby FC, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019;30(12):1992-2003. doi: 10.1093/annonc/mdz396. Erratum in: Ann Oncol. 2020 Mar;31(3):442. doi: 10.1016/j.annonc.2020.01.002.
  10. 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(5):686-700. doi:10.1016/S1470-2045(19)30082-8
  11. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3
  12. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307
  13. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799
  14. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(4):323-334. doi:10.1016/S1470-2045(23)00063-3
  15. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835
  16. 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(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1
  17. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115
  18. Hussain M, Fizazi K, Shore ND, et al. Metastatic hormone-sensitive prostate cancer and combination treatment outcomes: a review. JAMA Oncol. 2024;10(6):807-820. doi:10.1001/jamaoncol.2024.0591
  19. Bossi A, Foulon S, Maldonado X, et al. Prostate irradiation in men with de novo, low-volume, metastatic, castration-sensitive prostate cancer (mCSPC): Results of PEACE-1, a phase 3 randomized trial with a 2x2 design.J Clin Oncol. 2023:41:LBA5000. doi:10.1200/JCO.2023.41.17_suppl.LBA5000
  20. Hussain M, Tombal B, Saad S, 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(20):3595-3607.
  21. Davis ID, Martin AJ, Zielinski RR, et al. Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2022;40:LBA5004. doi: 10.1200/JCO.2022.40.17_suppl.LBA5004.
  22. European Association of Urology. Guidelines: Prostate Cancer. Chapter 6: Treatment. Available at:  https://uroweb.org/guidelines/prostate-cancer/chapter/treatment
  23. National Comprehensive Cancer Center. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2024—May 17, 2024. Accessed August 16, 2024.  https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
  24. Parker C, Castro E, Fizazi K, et al. ESMO Guidelines Committee. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(9):1119-1134. doi: 10.1016/j.annonc.2020.06.011.
  25. Barata PC, Leith A, Ribbands A, et al. Real-world treatment trends among patients with metastatic castration-sensitive prostate cancer: results from an international study. Oncologist. 2023;28(9):780-789. doi:10.1093/oncolo/oyad045
  26. Wallis CJD, Malone S, Cagiannos I, et al. Real-world use of androgen-deprivation therapy: intensification among older Canadian men with de novo metastatic prostate cancer. JNCI Cancer Spectr. 2021;5(6):pkab082. doi: 10.1093/jncics/pkab082.
  27. Swami U, Hong A, El-Chaar NN, et al., Real-world first-line (1L) treatment patterns in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in a U.S. health insurance database. J Clin Oncol. 2021;39:5072-5072. doi:10.1200/JCO.2021.39.15_suppl.5072
  28. Freedland SJ, Agarwal N, Ramaswamy K, et al. Real-world utilization of advanced therapies and racial disparity among patients with metastatic castration-sensitive prostate cancer (mCSPC): a Medicare database analysis. 2021;39:5073-5073. doi: 10.1200/JCO.2021.39.15_suppl.5073.
  29. Lillard JW Jr, Moses KA, Mahal BA, et al. Racial disparities in Black men with prostate cancer: a literature review. Cancer. 2022;128(21):3787-3795. doi: 10.1002/cncr.34433.
  30. Smyth EN, Whipple S, Guinter M, et al. Real-world treatment (Tx) sequences and time to discontinuation (rwTTD) in the first-line (1L) metastatic castration-resistant prostate cancer (mCRPC) setting. J Clin Oncol. 2024;42:55-55. doi:10.1200/JCO.2024.42.4_suppl.55
  31. Raval AD, Lunacsek O, Korn MJ, et al. Real-world intensification beyond androgen deprivation therapy (ADT) in metastatic hormone sensitive prostate cancer (mHSPC) in the United States 2017-2023: An administrative claims database study. J Clin Oncol. 2024;42:e17082-e17082. doi: 10.1200/JCO.2024.42.16_suppl.e17082.
  32. Swami U, Hong A, El-Chaar NN, et al. The role of physician specialty in the underutilization of standard-of-care treatment intensification in patients with metastatic castration-sensitive prostate cancer. J Urol. 2023;209(6):1120-1131.
  33. Freedland SJ, Klaassen WA, Agarwal N, et al. Reasons for oncologist and urologist treatment choice in metastatic castration-sensitive prostate cancer (mCSPC): a physician survey linked to patient chart reviews in the United States. J Clin Oncol. 2022;40:5065-5065. doi: 10.1200/JCO.2022.40.16_suppl.506.
  34. Joyce DD, Sharma V, Jiang DH, et al. Out-of-pocket cost burden associated with contemporary management of advanced prostate cancer among commercially insured patients. J Urol. 2022;208(5):987-996. doi:10.1097/JU.0000000000002856
  35. gov. H.R.830 - HELP Copays Act. Accessed August 18, 2024.  https://www.congress.gov/bill/118th-congress/house-bill/830/text?s=2&r=26
  36. United States Representative Buddy Carter: Georgia’s 1st Press release: Carter, Barragán, Miller-Meeks successfully push Biden administration to protect patients’ access to life-saving medications. Accessed August 21, 2024.  https://buddycarter.house.gov/news/documentsingle.aspx?DocumentID=11604
  37. Advocacy update: June 14, 2024: Advocacy Update spotlight on reintroduced prior authorization bill. Accessed August 21, 2024.  https://www.ama-assn.org/health-care-advocacy/advocacy-update/june-14-2024-advocacy-update-spotlight-reintroduced-prior
  38. Saad F, Hussain MHA, Tombal B, et al. Deep and durable prostate-specific antigen response to darolutamide with androgen deprivation therapy and docetaxel, and association with clinical outcomes for patients with high- or low-volume metastatic hormone-sensitive prostate cancer: analyses of the randomized phase 3 ARASENS study. Eur Urol. 2024:S0302-2838(24)02264-4. doi: 10.1016/j.eururo.2024.03.036.
  39. Chowdhury S, Bjartell A, Agarwal N, et al. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Ann Oncol. 2023;34(5):477-485. doi:10.1016/j.annonc.2023.02.009
  40. Matsubara N, Chi KN, Özgüroğlu M, et al. Correlation of Prostate-specific Antigen Kinetics with Overall Survival and Radiological Progression-free Survival in Metastatic Castration-sensitive Prostate Cancer Treated with Abiraterone acetate plus prednisone or placebos added to androgen deprivation therapy: post hoc analysis of phase 3 LATITUDE study. Eur Urol. 2020;77(4):494-500. doi:10.1016/j.eururo.2019.11.021
  41. Choudhury AD, Heller G, Reimers MA, et al. A phase 2 trial of ADT interruption in patients responding exceptionally to AR-pathway inhibitor in metastatic hormone-sensitive prostate cancer (A-DREAM/Alliance A032101). J Clin Oncol. 2024;42: TPS5118-TPS5118.
  42. Grisay G, Turco F, Patrikidou A, et al. EORTC GUCG 2238 De-escalate: A pragmatic trial to revisit intermittent androgen-deprivation therapy in metastatic hormone-naïve prostate cancer in the era of new AR pathway inhibitors. J Clin Oncol. 2024;42: TPS232-TPS232.
  43. Azad A, Badillo MA, Dong Q, et al. Apalutamide (APA) plus intermittent versus continuous androgen-deprivation therapy (ADT) in participants (pts) with metastatic castration-sensitive prostate cancer (mCSPC): LIBERTAS phase 3 study design. J Clin Oncol. 2024;42:TPS236.
  44. Swami U, Graf RP, Nussenzveig RH, et al. SPOP mutations as a predictive biomarker for androgen receptor axis-targeted therapy in de novo metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2022;28(22):4917-4925. doi:10.1158/1078-0432.CCR-22-2228
  45. Velez MG, Kosiorek HE, Egan JB, McNatty AL, Riaz IB, Hwang SR, Stewart GA, Ho TH, Moore CN, Singh P, Sharpsten RK, Costello BA, Bryce AH. Differential impact of tumor suppressor gene (TP53, PTEN, RB1) alterations and treatment outcomes in metastatic, hormone-sensitive prostate cancer. Prostate Cancer Prostatic Dis. 2022 Sep;25(3):479-483. doi: 10.1038/s41391-021-00430-4. 
  46. Agarwal N, Saad F, Azad AA, et al. TALAPRO-3 clinical trial protocol: phase III study of talazoparib plus enzalutamide in metastatic castration-sensitive prostate cancer. Future Oncol. 2024;20(9):493-505. doi: 10.2217/fon-2023-0526.
  47. Rathkopf DE, Chi KN, Olmos D, et al. AMPLITUDE: A study of niraparib in combination with abiraterone acetate plus prednisone (AAP) versus AAP for the treatment of patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC).J Clin Oncol. 2021;39:TPS176-TPS176. doi: 10.1200/JCO.2021.39.6_suppl.TPS176
  48. Fizazi K, George DJ, De Santis M, et al. A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with de novo metastatic hormone-sensitive prostate cancer characterized by PTEN deficiency (CAPItello-281). J Clin Oncol. 2021;39:TPS178-TPS178. doi:10.1200/JCO.2021.39.6_suppl.TPS178
  49. Sartor AO, Tagawa ST, Saad F, et al. PSMAddition: A phase 3 trial to compare treatment with 177Lu-PSMA-617 plus standard of care (SOC) versus SOC alone in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol.2022;40: TPS210-TPS210. doi: 10.1200/JCO.2022.40.6_suppl.TPS210
  50. Hage Chehade C, Jo Y, Gebrael G, Tripathi N, et al. Trends and disparities in next-generation sequencing in metastatic prostate and urothelial cancers. JAMA Netw Open. 2024;7(7):e2423186. doi: 10.1001/jamanetworkopen.2024.23186.