Non-metastatic castration-resistant prostate cancer (nmCRPC) affects at least 110,000 patients in the United States each year, comprises 1% to 2% of prostate cancers worldwide, and is a significant risk factor for progression to overt metastatic disease and cancer-related death.1,2 Amidst the many challenges of 2020, a bright spot has been the reporting of final overall survival (OS) data from the registrational SPARTAN, PROSPER, and ARAMIS trials, which confirm that for appropriately selected patients with high-risk nmCRPC, treatment with a next-generation androgen receptor (AR) inhibitor, whether apalutamide, enzalutamide, or darolutamide, significantly prolongs both metastasis-free survival (MFS) and overall survival (OS). It is remarkable that we now have three approved therapies for a disease state wherein, just three years ago, there was no level 1 evidence for an approved therapeutic. Herein, I will review the new efficacy and safety data and clinical implications for these recently approved nmCRPC agents.
In brief, the randomized, double-blind, dual-arm, Phase III SPARTAN (n=1,207), PROSPER (n=1,401), and ARAMIS (n=1,509) studies compared apalutamide, enzalutamide, and darolutamide, respectively, with placebo when added to conventional androgen-deprivation therapy (ADT) in men with high-risk nmCRPC, defined as 1) prostate-specific antigen (PSA) doubling time (DT) <10 months despite castrate levels of testosterone, and 2) the absence of detectable metastases on conventional imaging. In prior interim analyses, all three therapies were associated with clinically and statistically significant prolongations in the primary endpoint of MFS, leading to their FDA approvals in 2018 and 2019.3-5 This year, final analyses of the three trials (SPARTAN, PROSPER, ARAMIS) were reported at the 2020 ASCO Virtual Meeting and were subsequently published in first-tier peer-reviewed journals.6-8 In the final report of the SPARTAN trial, after a median follow-up of 52 months, median OS was 14 months longer in the apalutamide arm compared with the placebo arm (73.9 vs. 59.9 months, respectively; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64-0.96).7 In PROSPER (median follow-up, 42 months), median OS was 67.0 months in the enzalutamide arm and 56.3 months in the placebo arm (HR, 0.73; 95% CI, 0.61 to 0.89).8 In ARAMIS (median follow-up, 29 months), 3-year OS was 83% (95% CI, 80%-86%) in the darolutamide arm and 77% (95% CI, 72%-81%) in the placebo arm (HR, 0.69; 95% CI, 0.53-0.88).6 As in prior analyses, all three drugs also demonstrated significant benefits with regard to other key secondary endpoints, such as times to symptomatic progression, subsequent antineoplastic therapy, and first use of cytotoxic chemotherapy.
In all three trials, superior MFS and OS were observed in the active treatment arms even though placebo-arm patients were permitted to cross over and/or receive additional antineoplastic treatments upon progression, which supports the early initiation of these approved novel anti-androgen therapies for patients with high-risk nmCRPC. Importantly, none of these trials enrolled patients with PSA DTs >10 months; median PSA DTs in all three trials were approximately 6 months.3,4 For these patients with high-risk nmCRPC, the American Urological Association (AUG) strongly recommends the use of one of these three novel hormonal agents, while the National Comprehensive Cancer Network (NCCN) makes a similarly strong Category 1 recommendation.9,10
Although head-to-head comparisons of apalutamide, enzalutamide, and/or darolutamide for nmCRPC are unavailable, several indirect comparisons were published this year.11-14 Individually, such studies are of limited value, but consistencies in findings are worth considering as a supplemental source of information in cases where treatment selection may be challenging. Recent reviews cannot definitively state that one of the three approved nmCRPC agents will postpone progression more than another or have a greater impact upon survival; however, there may be differences in tolerability and safety profiles.11-14 Final results from the ARAMIS trial confirmed prior interim findings that darolutamide, compared with placebo, does not significantly increase the risk for hypertension, falls, seizures, cognitive impairment, or depressed-mood disorders.6 In contrast, in the final analysis of the SPARTAN trial, apalutamide was associated with an increased risk for rash, fatigue, fractures, hypertension, and ischemic cardiovascular events, while in the PROSPER trial, enzalutamide continued to be associated with increased rates of hypertension, fatigue, falls, and (much less commonly) cardiovascular death.7,8 Indirect comparisons also suggest (but cannot confirm) a favorable tolerability profile for darolutamide. The cardiovascular risk profiles of these agents are noteworthy because patients with nmCRPC already have been exposed to the adverse cardiovascular risks of conventional ADT. The apparently lower risk for central-nervous system effects with darolutamide may be attributed to its uniqueness in only minimally penetrating the blood-brain barrier. Regarding the relative efficacy of the three agents, longer follow-up, real-world studies, and direct comparisons should better differentiate outcomes.
In conclusion, the final results of the SPARTAN, PROSPER, and ARAMIS trials confirm the efficacy of these therapies for the management of high-risk nmCRPC. Safety profiles differ among agents and should be discussed during patient counseling to facilitate shared decision-making. Additional studies of apalutamide, enzalutamide, and darolutamide are ongoing or planned; for example, the Phase II ARACOG trial will directly compare the cognitive effects of enzalutamide and darolutamide in patients with non-metastatic or metastatic CRPC, and the Phase II DAROACT trial will compare the effects of enzalutamide and darolutamide on physical function, including balance and daily activity. Other planned trials will evaluate next-generation AR inhibitors in combination with antineoplastic drugs or consolidation radiotherapy. Hopefully, the results of these studies will build on the promising data reported in 2020 and will further optimize care for patients with advanced prostate cancer.
Written by: Neal Shore, MD, FACS, Medical Director of the Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina
References:
1. Scher, Howard I., Kirk Solo, Jason Valant, Mary B. Todd, and Maneesha Mehra. "Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model." PLoS One 10, no. 10 (2015): e0139440.
2. Shore, Neal D., Louisa Oliver, Irene Shui, Alicia Gayle, On Yee Wong, Jeri Kim, Sarah Payne, and Sameer R. Ghate. "Review of the real-world prevalence of mHSPC, nmCRPC, mCRPC, and gene alterations associated with HRR in prostate cancer (PC)." (2020): 229-229.
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4. Fizazi, Karim, Neal Shore, Teuvo L. Tammela, Albertas Ulys, Egils Vjaters, Sergey Polyakov, Mindaugas Jievaltas et al. "Darolutamide in nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 380, no. 13 (2019): 1235-1246.
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10. NCCN. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. Version 3.2020; November 18, 2020. https://www.nccn.org/professionals/physician_gls/pdf/prostate_blocks.pdf. Accessed December 11, 2020.
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13. Mori, Keiichiro, Hadi Mostafaei, Benjamin Pradere, Reza Sari Motlagh, Fahad Quhal, Ekaterina Laukhtina, Victor M. Schuettfort et al. "Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis." International journal of clinical oncology (2020): 1-9.
14. Kumar, Jatinder, SeyedBehzad Jazayeri, Shiva Gautam, Daniel Norez, Muhammad Umar Alam, Karthik Tanneru, Soroush Bazargani et al. "Comparative efficacy of apalutamidedarolutamide and enzalutamidefor treatment of nonmetastatic castrate-resistant prostate cancer: Asystematic review and network meta-analysis." In Urologic Oncology: Seminars and Original Investigations. Elsevier, 2020.