(UroToday.com) The 2023 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Julie Graff discussing results of the phase 3 KEYNOTE-641 trial assessing pembrolizumab + enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC).
Patients with mCRPC with progressive disease during second generation hormonal agent therapy typically receive chemotherapy as next line of therapy. Thus, additional therapies are needed in this setting. Pembrolizumab + enzalutamide had antitumor activity in pretreated mCRPC in early phase studies. As such, the KEYNOTE-641 trial evaluated pembrolizumab + enzalutamide vs placebo + enzalutamide in patients with chemotherapy-naïve mCRPC patients with or without prior abiraterone.
Eligible patients were male, aged ≥18 years, had ECOG performance status ≤1, had confirmed mCRPC with no prior chemotherapy except docetaxel in the hormone-sensitive setting, and had intolerance to or progressive disease during prior abiraterone or no prior abiraterone. Patients were randomized 1:1 to pembrolizumab 200 mg or placebo IV Q3W for ≤35 cycles + enzalutamide 160 mg orally daily. The trial design for KEYNOTE-641 is as follows:
Dual primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS) per PCWG-modified RECIST 1.1 by blinded independent central review. Time to initiation of first subsequent anticancer therapy was a key secondary endpoint, as well as safety/tolerability. From a statistical perspective, the first prespecified interim analysis was conducted after ~510 OS events and ~6 months after enrollment completion. The median time from randomization to data cutoff date (December 12, 2022) was 27.6 months (range: 6.1-39.8). The overall type I error rate was strongly controlled at 2.5% (one-sided) across OS and rPFS.
There were 1,244 patients enrolled between August 21, 2019, and June 10, 2022 (n = 621 to pembrolizumab + enzalutamide; n = 623 to placebo + enzalutamide). The baseline characteristics for this trial are as follows:
Overall, 60.9% of all patients had prior abiraterone and 29.1% had prior docetaxel, which was balanced between the arms. The primary endpoint of rPFS (median 10.4 months with pembrolizumab + enzalutamide vs 9.0 months with placebo + enzalutamide; HR 0.98, 95% CI 0.84−1.14) was not reached, with no appreciable benefit noted in the subgroup analyses:
Additionally, the dual primary endpoint of OS (median 24.7 months vs 27.3 months; HR 1.04, 95% CI 0.88−1.22) was also not met, with no appreciable benefit noted in the subgroup analyses:
Thus, the prespecified boundary for futility for OS was crossed and the study was stopped. The median time to initiation of the first subsequent anticancer therapy was 13.2 months vs 12.6 months, respectively (HR 0.95, 95% CI 0.83−1.09):
Numerically, there were more complete responses in the pembrolizumab + enzalutamide arm (7.4%) versus the placebo + enzalutamide arm (2.7%). Any-grade and grade ≥3 treatment-related adverse events occurred in 77.9% and 31.2% of 615 patients with ≥1 dose pembrolizumab + enzalutamide and 61.6% and 10.8% of 620 patients with ≥1 dose placebo + enzalutamide. There were three treatment-related deaths occurred with pembrolizumab + enzalutamide and none with placebo + enzalutamide.
Dr. Graff concluded her presentation discussing results of the phase 3 KEYNOTE-641 trial assessing pembrolizumab + enzalutamide for patients with mCRPC with the following take-home points:
- The randomized phase 3 KEYNOTE-641 trial was stopped for OS futility at the first interim analysis
- The addition of pembrolizumab to enzalutamide in patients with chemotherapy-naïve mCRPC with or without prior abiraterone did not improve rPFS or OS versus enzalutamide
- Pembrolizumab + enzalutamide was associated with more treatment related grade >= 3 and serious adverse events leading to treatment discontinuation
- A modest number of complete responses occurred and future studies should focus on patient selection and the identification of predictive markers of response
Presented by: Julie N. Graff, MD, Oregon Health & Science University, Portland, OR
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.