In the final overall survival analysis of the phase III PROSPER trial reported at the ASCO20 Virtual Scientific Program1 and published in The New England Journal of Medicine,2 Cora N. Sternberg, MD, and colleagues found that enzalutamide plus androgen-deprivation therapy (ADT) significantly improved overall survival vs placebo plus ADT in men with nonmetastatic castration-resistant prostate cancer.
Findings in the PROSPER trial supported the 2018 U.S. Food and Drug Administration approval of enzalutamide with continuing androgen-deprivation therapy in this setting on the basis of superior metastasis-free survival. At the time of primary analysis, with a median follow-up of 23 months, data on overall survival were immature, with 165 deaths having occurred (28% of 596 prespecified events for the final analysis). Median overall survival had not been reached in either group (hazard ratio [HR] for enzalutamide vs placebo = 0.80, 95% confidence interval [CI] = 0.58–1.09, P = .15).
Cora N. Sternberg, MD
The current analysis is the third prespecified interim analysis and final analysis of overall survival in the trial, performed after approximately 440 deaths had occurred. A P value of up to .021 was required for statistical significance.
In the double-blind trial, men with nonmetastatic castration-resistant disease—defined on the basis of imaging and a prostate-specific antigen (PSA) doubling time of up to 10 months—who were continuing to receive androgen-deprivation therapy were randomly assigned 2:1 between November 2013 and June 2017 to receive enzalutamide at 160 mg (n = 933) or placebo (n = 468) once daily until radiographic disease progression or unacceptable toxicity.
As of October 2019, a total of 288 patients (31%) in the enzalutamide group and 178 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% CI = 64.0 months to not reached) in the enzalutamide group and 56.3 months (95% CI = 54.4–63.0 months) in the placebo group (HR = 0.73, 95% CI = 0.61–0.89, P = .001); since the predefined boundary for significance was crossed, the analysis became the final analysis. An unplanned analysis indicated 3-year overall survival of 80% vs 73%. The benefit of enzalutamide was generally consistent across prespecified subgroups, with the potential exception of the small group of patients receiving bone-sparing agents.
The median time to first use of new antineoplastic therapy was 66.7 months vs 19.1 months (HR = 0.29, 95% CI = 0.25–0.35). A total of 87 patients in the placebo group crossed over to open-label enzalutamide after unblinding of the trial, with a median duration of enzalutamide treatment of 14.5 months after crossover. Excluding these patients, at least one subsequent antineoplastic treatment was received by 33% of the enzalutamide group and 56% (84% when including patients who crossed over) of the placebo group after discontinuation of study therapy. The most common treatments among those starting new treatment were abiraterone acetate (49% and 59%), docetaxel (60% and 47%), and enzalutamide (14% and 36%, not including patients who crossed over).
The median duration of study treatment was 33.9 months in the enzalutamide group and 14.2 months in the placebo group. The exposure-adjusted rate of grade ≥ 3 adverse events was 17 per 100 patient-years in the enzalutamide group vs 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported at the time of primary analysis, with the most frequent being fatigue and musculoskeletal events. Adverse events of special interest that occurred at an exposure-adjusted rate of at least 3 events/100 patient-years higher in the enzalutamide group were falls (9 vs 4 events/100 patient-years) and fractures (9 vs 5 events/100 patient-years). Cardiovascular adverse events were the most frequently reported adverse events leading to death during the entire trial, resulting in death in 14 vs 2 patients.
The investigators concluded: “Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide.”
Disclosure: Dr. Sternberg reported serving in a consulting or advisory role with Astellas Pharma, AstraZeneca, Bayer, Incyte, Medscape, Merck, MSD, Pfizer, Roche, Roche/Genentech, Sanofi/Genzyme, and UroToday.
1. Sternberg CN, Fizazi K, Saad F, et al: Final overall survival from PROSPER. ASCO20 Virtual Scientific Program. Abstract 5515.
2. Sternberg CN, Fizazi K, Saad F, et al: Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 382:2197-2206, 2020.