New England Section of the American Urological Association

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The PROSPER Trial: Prostate-Specific Antigen (PSA)- and Chemotherapy-Related Endpoints in Patients With Nonmetastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide
Joseph W. Kim, MD1, Cora N. Sternberg, MD2, David Penson, MD3, Neal Shore, MD4, Fred Saad, MD5, Jennifer Sugg, MD6, Joyce Steinberg, MD6, Katharina Modelska, MD7, Maha Hussain, MD8
1Yale Cancer Center, New Haven, CT; 2Weill Cornell Medicine, New York, NY; 3Vanderbilt University, Nashville, TN; 4Carolina Urologic Research Center, Myrtle Beach, SC; 5University of Montreal Hospital Centre (CHUM), Montreal, QC, QC, Canada, 6Astellas Pharma, Inc., Northbrook, IL; 7Pfizer Inc., San Francisco, CA; 8Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL

Introduction/Background: Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) are at high risk of developing metastatic CRPC (mCRPC). In previous clinical trials, enzalutamide improved overall survival and radiographic progression-free survival in men with mCRPC. The phase 3 PROSPER trial was designed with a primary endpoint of metastasis-free survival (MFS).
Methods/Materials: PROSPER is a randomized, double-blind, placebo-controlled, phase 3 multinational study (NCT02003924) in patients with asymptomatic nmCRPC, PSA doubling time ≤ 10 months and PSA ≥ 2 ng/mL at screening. Patients were randomized 2:1 to enzalutamide 160 mg/day or placebo. The primary endpoint was MFS. Secondary endpoints included time to PSA progression, time to first use of new antineoplastic therapy, overall survival, time to first use of cytotoxic chemotherapy, chemotherapy-free disease-specific survival (CFDS), chemotherapy-free survival (CFS), and safety.
Results: In 1401 patients, baseline characteristics were well balanced between treatment arms (Table). Enzalutamide significantly reduced the risk of metastasis or death (hazard ratio [HR], 0.29; P < .0001), time to PSA progression (HR, 0.07; P < .0001), and time to first use of new antineoplastic therapy (HR, 0.21; P < .0001) vs placebo. Enzalutamide treatment also significantly delayed the time to first use of cytotoxic chemotherapy, and prolonged CFDS, and CFS (Table). A significantly greater proportion of patients receiving enzalutamide than those receiving placebo had confirmed PSA responses of a ≥ 50% decline, of a ≥ 90% decline, and a decline to undetectable levels below the limit of quantification (Table). Median treatment duration was 18.4 vs 11.1 months with enzalutamide vs placebo, respectively. Adverse events (AEs) were higher with enzalutamide than with placebo (any grade, 87% vs 77%; grade ≥ 3, 31% vs 23%; serious, 24% vs 18%, respectively); 10% vs 8% of men receiving enzalutamide vs placebo, respectively, experienced an AE that caused treatment discontinuation.
Conclusions: For patients with nmCRPC and a rapidly rising PSA, enzalutamide resulted in a clinically meaningful and statistically significant reduction in developing mCRPC, as well as an increase in time to PSA progression and time to first use of new antineoplastic therapy (including chemotherapy), CFDS, and CFS. PSA responses were significantly greater in patients receiving enzalutamide than in those receiving placebo. AEs were generally consistent with the established safety profile of enzalutamide.
Baseline CharacteristicEnzalutamide + ADT (n = 933)Placebo + ADT (n = 468)
Age, median, y7473
PSA doubling time < 6 mo, no. (%)715 (76.6)361 (77.1)
Serum PSA, ng/mL11.110.2
Endpoint
Patients with baseline PSA values, no. (%)933 (100)467 (99.8)
Patients with ≥ 1 postbaseline assessment, no. (%)887 (95.1)439 (93.8)
Confirmed PSA response ≥ 50%, no. (%)712 (76.3)11 (2.4)
P value< .0001
Confirmed PSA response ≥ 90%, no. (%)522 (55.9)2 (0.4)
P value< .0001
Confirmed PSA response to undetectable level, no. (%)90 (9.6)0
P value< .0001
Time to first use of cytotoxic chemotherapy, median (95% CI), moNR (38.1-NR)39.7 (38.9-41.3)
HR (95% CI)0.38 (0.28-0.51)
P value< .0001
CFDS, median (95% CI), mo39.6 (37.7-NR)38.9 (30.9-41.3)
HR (95% CI)0.40 (0.31-0.52)
P value< .0001
CFS, median (95% CI), mo38.1 (37.7-NR)34.0 (30.3-39.7)
HR (95% CI)0.50 (0.40-0.64)
P value< .0001
Abbreviations: ADT, androgen deprivation therapy; CI, confidence interval; NR, not reached.


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