Phase 3 trial of pembrolizumab for prostate cancer misses endpoints
SAN FRANCISCO — The addition of pembrolizumab to docetaxel failed to significantly extend survival for men with chemotherapy-naive metastatic castration-resistant prostate cancer, according to results of the randomized phase 3 KEYNOTE-921 trial.
Results showed slight numerical improvements in radiographic PFS and OS — the study’s key endpoints — with the experimental regimen, but neither difference reached statistical significance, findings presented at ASCO Genitourinary Cancers Symposium showed.
“It’s disappointing, but I’m glad that the hypothesis was tested because there was good rationale for doing it,” Daniel P. Petrylak, MD, professor of medicine and urology and chief of genitourinary oncology at Yale School of Medicine, as well as a HemOnc Today Editorial Board member, told Healio. “The phase 2 data for this combination showed a 19-month median survival — so that was a 6-month difference — and there was thought that maybe that was a real value, but clearly the control arm did better than people thought it would do.”
Background and methodology
Docetaxel is a treatment option for men with metastatic castration-resistant prostate cancer whose disease progresses on a next-generation hormonal agent. However, more effective treatments are urgently needed, according to study background.
Pembrolizumab (Keytruda, Merck) is an anti-PD-1 antibody that has been approved as monotherapy and as part of combination therapy for a variety of malignancies.
The double-blind KEYNOTE-921 trial assessed the efficacy and safety of pembrolizumab plus docetaxel for men with chemotherapy-naive metastatic castration-resistant prostate cancer. All 1,030 men included in the study either experienced disease progression after or exhibited intolerance to a next-generation hormonal therapy.
Researchers randomly assigned 515 men to pembrolizumab dosed at 200 mg every 3 weeks for approximately 2 years, plus docetaxel and prednisone. The other 515 men received placebo plus docetaxel and prednisone.
Men in the experimental group received a median 12 cycles (range, 1-35) of pembrolizumab and a median nine cycles (range, 1-12) of docetaxel. Men in the control group received a median 12 (range, 1-35) cycles of placebo and a median nine (range, 1-10) cycles of docetaxel.
Radiographic PFS and OS served as dual primary endpoints. Secondary endpoints included PSA response rate, time to start of first subsequent anticancer treatment, objective response rate and duration of response.
Results
Median follow-up was 22.7 months (range, 12.1-36.7).
Results showed a numerical improvement in median radiographic PFS in the pembrolizumab group (8.6 months vs. 8.3 months; HR = 0.85; 95% CI, 0.71-1.01) and median OS (19.6 months vs. 19 months; HR = 0.92; 95% CI, 0.78-1.09). However, neither difference reached statistical significance.
Grade 3 or higher treatment-related adverse events occurred among 43.2% of men assigned pembrolizumab and 36.6% of men assigned placebo.
Researchers reported two treatment-related deaths in the pembrolizumab group and seven in the placebo group.
The most frequent grade 3 or higher treatment-emergent adverse events by treatment group included pneumonitis in the pembrolizumab group (7%) and hypothyroidism in the placebo group (3.1%).
Next steps
Despite the negative trial outcome, researchers intend to continue exploring whether certain men with prostate cancer may benefit from pembrolizumab.
“We have tissue available that needs to be analyzed,” Petrylak told Healio. “We do see responders with pembrolizumab — not commonly, but you do see it — as a single agent, so there is something there.”
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Petrylak DP, et al. Abstract 19. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 16-18, 2023; San Francisco.
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