Abstract

Background: Established first- and second-line standard-of-care treatment options (abiraterone, enzalutamide, taxane chemotherapy) are available for patients with metastatic castration-resistant prostate cancer (mCRPC), but almost all patients experience subsequent disease progression. The randomized, double-blind, phase III KEYNOTE-641 study evaluated pembrolizumab plus enzalutamide versus placebo plus enzalutamide in participants with chemotherapy-naive mCRPC. Patients and methods: Eligible participants were males aged ?18 years with confirmed mCRPC and no prior chemotherapy except docetaxel in the hormone-sensitive setting. Prior abiraterone treatment was permitted. Participants were randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo intravenously once every 3 weeks for ?35 cycles plus enzalutamide 160 mg orally daily. Dual primary end points were overall survival (OS) and radiographic progression-free survival (rPFS) per Prostate Cancer Clinical Trials Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review. Safety was a secondary end point. Results: Between 21 August 2019, and 10 June 2022, 1244 participants were randomly assigned to pembrolizumab plus enzalutamide (n = 621) or placebo plus enzalutamide (n = 623). At the data cut-off date (12 December 2022), median follow-up was 27.6 months (range, 6.1-39.8 months). Primary end points of OS [median, 24.7 versus 27.3 months; hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.88-1.22, P = 0.66] and rPFS (median, 10.4 versus 9.0 months; HR 0.98, 95% CI 0.84-1.14, P = 0.41) with pembrolizumab plus enzalutamide versus placebo plus enzalutamide were not met. The prespecified boundary for futility for OS was crossed, and the study was stopped. Grade ?3 treatment-related adverse events occurred in 192 of 615 participants (31.2%) with one or more doses of pembrolizumab plus enzalutamide and in 67 of 620 participants (10.8%) with one or more doses of placebo plus enzalutamide. Seventy-one (11.5%) and 21 (3.4%) participants, respectively, discontinued study treatment due to treatment-related adverse events. Conclusion: Adding pembrolizumab to enzalutamide did not improve efficacy outcomes for participants with chemotherapy-naive mCRPC. Additional toxicity was observed with the combination regimen. © 2025 Merck & Co., Inc., Rahway, NJ, USA and its affiliates, The Author(s)