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.
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 PCWG-modified RECIST v1.1 by blinded independent central review. Safety was a secondary end point.
Between August 21, 2019, and June 10, 2022, 1244 participants were randomly assigned to pembrolizumab plus enzalutamide (n=621) or placebo plus enzalutamide (n=623). At the data cutoff date (December 12, 2022), median follow-up was 27.6 months (range, 6.1-39.8 months). Primary end points of OS (median, 24.7 vs 27.3 months; hazard ratio [HR], 1.04 [95% CI, 0.88-1.22]; P=0.66) and rPFS (median, 10.4 vs 9.0 months; HR, 0.98 [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 ≥1 dose of pembrolizumab plus enzalutamide and in 67 of 620 participants (10.8%) with ≥1 dose of placebo plus enzalutamide. Seventy-one (11.5%) and 21 (3.4%) participants, respectively, discontinued study treatment due to treatment-related adverse events.
Adding pembrolizumab to enzalutamide did not improve efficacy outcomes for participants with chemotherapy-naive mCRPC. Additional toxicity was observed with the combination regimen.
Annals of oncology : official journal of the European Society for Medical Oncology. 2025 May 16 [Epub ahead of print]
J N Graff, M Burotto, P C Fong, D W Pook, B Zurawski, R M Kopp, J Salinas, K A Bylow, G Kramer, R Ratta, M Kwiatkowski, M Retz, C Kwak, J A Arranz Arija, H Gurney, N Matsubara, L Villanueva, T Todenhöfer, L W Liang, J Todoric, K Imai, A Stenzl, KEYNOTE-641 Investigators
Oregon Health Sciences University, Portland, OR, USA. Electronic address: ., Bradford Hill, Santiago, Chile., Auckland City Hospital and University of Auckland, Auckland, New Zealand., Monash Health, Clayton, Australia., Centrum Onkologii im. Prof. Franciszka Łukaszczyka, Bydgoszcz, Poland., Sociedad de Oncología Y Hematología del Cesar S.A.S., Valledupar, Colombia., CEMAIC, Cordoba, Argentina., Medical College of Wisconsin, Milwaukee, WI, USA., Department of Urology, Medical University of Vienna, Vienna, Austria., Hopital Foch, Suresnes, France., Szpital Wojewódzki im. Mikołaja Kopernika, Koszalin, Poland., Rechts der Isar Medical Center, Technical University Munich, Munich, Germany., Seoul National University Hospital, Seoul, Republic of Korea., Hospital General Universitario Gregorio Marañon, Madrid, Spain., Macquarie University, Sydney, New South Wales, Australia., National Cancer Center Hospital East, Chiba, Japan., Fundación Arturo López Pérez, Santiago, Chile., Studienpraxis Urologie, Nürtingen, Germany., MSD China, Beijing, China., Merck & Co., Inc., Rahway, NJ, USA., Universitätsklinik für Urologie, Tübingen, Germany.