Faculty Collaboration Database

Pembrolizumab plus enzalutamide versus placebo plus enzalutamide for chemotherapy-naive metastatic castration-resistant prostate cancer: the randomized, double-blind, phase III KEYNOTE-641 study. Ann Oncol 2025 Aug;36(8):976-987

Date

05/19/2025

Pubmed ID

40383193

DOI

10.1016/j.annonc.2025.05.007

Scopus ID

2-s2.0-105008902157 (requires institutional sign-in at Scopus site)   17 Citations

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.

Author List

Graff JN, Burotto M, Fong PC, Pook DW, Zurawski B, Manneh Kopp R, Salinas J, Bylow KA, Kramer G, Ratta R, Kwiatkowski M, Retz M, Kwak C, Arranz Arija JA, Gurney H, Matsubara N, Villanueva L, Todenhöfer T, Liang LW, Todoric J, Imai K, Stenzl A, KEYNOTE-641 Investigators

Author

Kathryn A. Bylow MD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Benzamides
Double-Blind Method
Humans
Male
Middle Aged
Nitriles
Phenylthiohydantoin
Prostatic Neoplasms, Castration-Resistant