Pembrolizumab plus enzalutamide versus placebo plus enzalutamide for chemotherapy-naive metastatic castration-resistant prostate cancer: the randomized, double-blind, phase III KEYNOTE-641 study
Mené sur 1 244 patients atteints d'un cancer de la prostate résistant à la castration et de stade métastatique (durée médiane : 27,6 mois), cet essai randomisé de phase III évalue l'efficacité, du point de vue de la survie globale et de la survie sans progression, et la toxicité de l'ajout du pembrolizumab à l'enzalutamide
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 PCWG-modified RECIST v1.1 by blinded independent central review. Safety was a secondary end point.
Results: 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.
Conclusion: 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 , résumé, 2025