The phase III KEYNOTE-921 study did not meet the predefined criteria for superiority of pembrolizumab plus docetaxel versus placebo plus docetaxel for the dual primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with disease progression after or intolerance to androgen receptor pathway inhibitor (ARPI).
Outcomes were also consistent between the two treatments across prespecified subgroups, and across secondary efficacy endpoints. The current standard-of-care (SoC) remains unchanged according to Dr. Daniel P. Petrylak of the Yale Cancer Center in New Haven, CT, US and colleagues, who published the findings on 5 March 2025 in the JCO.
Taxane chemotherapy is a key treatment option for patients with mCRPC following disease progression after a second-generation ARPI. The authors wrote in the background that immune checkpoint inhibitors (ICIs) have shown nominal antitumour activity in advanced prostate cancer, although no checkpoint inhibitor-based combination has yet been identified as superior to the SoC in a randomised trial setting for mCRPC.
Pembrolizumab demonstrated durable antitumour activity and an acceptable safety profile as monotherapy for patients with mCRPC previously treated with docetaxel and abiraterone and/or enzalutamide in Cohorts 1-3 of the KEYNOTE-199 study. In Cohort B of the phase Ib/II KEYNOTE-365 study, pembrolizumab plus docetaxel in patients with mCRPC previously treated with abiraterone or enzalutamide showed an objective response rate and PSA response that warranted further investigation in a randomised setting. The safety profile of this combination was consistent with the known profiles of each individual agent.
The KEYNOTE-921 study was designed to evaluate pembrolizumab or placebo plus docetaxel as a treatment for mCRPC after previous ARPI therapy. Adults with mCRPC who progressed after androgen-deprivation therapy and one ARPI were randomly assigned 1:1 to pembrolizumab or placebo plus docetaxel with concomitant prednisone. Dual primary endpoints were rPFS by blinded independent central review per Prostate Cancer Working Group 3–modified RECIST 1.1 criteria and OS. Safety was a secondary endpoint.
Between 30 May 2019 and 17 June 2021, 515 patients were randomly assigned to pembrolizumab plus docetaxel and 515 to placebo plus docetaxel. Median time from random assignment to data cut-off date on 20 June 2022 at final analysis was 22.7 months (range 12.1-36.7). At first interim analysis with data cut-off date on 27 September 2021, median rPFS was 8.6 months (95% confidence interval [CI] 8.3 to 10.2) with pembrolizumab plus docetaxel versus 8.3 months (95% CI 8.2 to 8.5) with placebo plus docetaxel (hazard ratio [HR] 0.85, 95% CI 0.71 to 1.01; p = 0.03). At final analysis, median OS was 19.6 months (95% CI 18.2 to 20.9) versus 19.0 months (95% CI 17.9 to 20.9), respectively (HR 0.92, 95% CI 0.78 to 1.09; p = 0.17).
In the pembrolizumab plus docetaxel group, median OS in patients with PD-L1-positive mCRPC was similar to that observed for the entire intention-to-treat (ITT) population. In the placebo plus docetaxel group, median OS in patients with PD-L1-positive mCRPC appeared shorter than that observed for the entire ITT population.
The addition of pembrolizumab to docetaxel generally did not result in a notable increase in any-cause adverse events, treatment-related adverse events (TRAEs), or treatment-related deaths, with the exception of any-cause and immune-mediated pneumonitis. No new safety signals were observed for this combination.
Grade ≥3 TRAEs occurred in 43.2% of patients who received pembrolizumab plus docetaxel and 36.6% of patients who received placebo plus docetaxel. Two and seven patients, respectively, died due to a TRAE. Pneumonitis was the most common immune-mediated adverse event (7.0% versus 3.1%).
Although no direct comparisons can be made between KEYNOTE-921 and the CheckMate 9KD study, results for the pembrolizumab plus docetaxel regimen in KEYNOTE-921 were in line with reported efficacy and safety outcomes for nivolumab plus docetaxel in the subgroup of patients who had received one or two previous ARPI therapies. Taxane chemotherapy is unable to sensitise prostate cancer to ICis, resulting in another negative trial with immunotherapy in prostate cancer. The authors commented that new efficacious therapeutic options for mCRPC remain an unmet need.
In an accompanied editorial article, Dr. Susan F. Slovin of the Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center in New York, NY, US wrote that it is another in a long line of combination trials of ICIs in prostate cancer including pembrolizumab, nivolumab, anti-CTLA-4 plus nivolumab, and atezolizumab with a variety of life-prolonging approved agents in either the hormone-resistant or hormone-sensitive setting. With all these agents and trials, which were primarily hypothesis-driven, no definitive rPFS or OS benefits have been achieved, only suggestions of potential gain which raises the question why do we keep doing costly phase II and phase III trials with these agents.
The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ.
References
- Petrylak DP, Ratta R, Matsubara N, et al. Pembrolizumab Plus Docetaxel Versus Docetaxel for Previously Treated Metastatic Castration-Resistant Prostate Cancer: The Randomized, Double-Blind, Phase III KEYNOTE-921 Trial. JCO; Published online 5 March 2025. DOI: https://doi.org/10.1200/JCO-24-01283
- Slovin SF. Immune Checkpoint Combos in Metastatic Castration-Resistant Prostate Cancer: Where Are We Going, What Are We Doing, and Why? JCO; Published online 13 March 2025. DOI: https://doi.org/10.1200/JCO-24-02402