Highlights
- Pembrolizumab added to enzalutamide and ADT did not improve radiographic progression-free or overall survival in mHSPC patients.
- Pembrolizumab combination led to higher rates of grade ≥3 and serious adverse events compared to placebo.
- Rash was notably more common with pembrolizumab addition.
- KEYNOTE-991 was stopped early for futility, impacting future immunotherapy strategies for mHSPC.
Study Background and Disease Burden
Metastatic hormone-sensitive prostate cancer (mHSPC) remains a significant clinical challenge. Despite advances with androgen deprivation therapy (ADT) and next-generation hormonal agents like enzalutamide, most patients progress to castration-resistant prostate cancer (CRPC) within five years. The high morbidity and mortality associated with mHSPC highlight unmet needs for effective, durable treatment options. Immunotherapy, particularly PD-1 inhibitors such as pembrolizumab, has transformed management in other solid tumors. Early-phase studies suggested possible synergy between immunotherapy and hormonal agents in prostate cancer, prompting investigation in large randomized trials.
Study Design
KEYNOTE-991 (NCT04585203) was a randomized, double-blind, phase III clinical trial evaluating the efficacy and safety of pembrolizumab in combination with enzalutamide and ADT versus placebo plus enzalutamide and ADT in patients with mHSPC. Eligible participants were adults (≥18 years) with newly diagnosed, next-generation hormonal agent-naive mHSPC. Patients were randomized 1:1 to receive intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) or placebo, alongside oral enzalutamide (160 mg daily) and continuous ADT. The primary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS); safety was a key secondary endpoint.
Key Findings
From March 2020 to August 2021, 1,251 patients were enrolled—626 to the pembrolizumab group and 625 to the placebo group. At the first interim analysis (median follow-up 21.1 months), the results were disappointing for pembrolizumab:
- Radiographic progression-free survival (rPFS): Median rPFS was not reached in either arm, but there was no significant difference. The hazard ratio (HR) for progression or death was 1.20 (95% CI 0.96-1.49; P = 0.9467), indicating a non-significant trend toward worse outcomes with pembrolizumab.
- Overall survival (OS): Median OS was not reached in both arms. HR for death was 1.16 (95% CI 0.88-1.53). OS was not formally tested due to the trial’s multiplicity strategy and early stopping for futility.
- Safety: Pembrolizumab addition resulted in substantially more grade ≥3 adverse events (61.9% vs. 38.1%), and serious adverse events (40.3% vs. 23.2%) compared to placebo. The rate of any-grade rash was also higher in the pembrolizumab group (25.1% vs. 9.3%). Other immune-related events were not detailed in the interim analysis, but overall safety signals were concerning.
The trial was stopped early due to futility, as predefined efficacy thresholds were not met, and safety concerns compounded the lack of benefit.
Expert Commentary
The KEYNOTE-991 results are pivotal in guiding the future use of immunotherapy in mHSPC. While PD-1 blockade has revolutionized treatment in multiple cancers, prostate cancer appears to be less immunogenic, and the addition of pembrolizumab does not confer a survival advantage when layered with potent hormonal manipulation. The notably higher incidence of serious adverse events, particularly immune-related toxicities, underscores the need for careful patient selection and highlights a potentially unfavorable risk-benefit profile in this setting.
Current guidelines (e.g., NCCN, EAU) continue to recommend ADT in combination with next-generation AR-targeted agents, but do not endorse immunotherapy for unselected mHSPC outside clinical trials. Ongoing research into biomarkers of response, such as mismatch repair deficiency or high microsatellite instability, may eventually identify subgroups who benefit from checkpoint inhibitors. For now, the KEYNOTE-991 findings caution against routine adoption of pembrolizumab in this population.
Conclusion
KEYNOTE-991 demonstrates that the addition of pembrolizumab to enzalutamide and ADT does not improve progression-free or overall survival in metastatic hormone-sensitive prostate cancer, and is associated with a higher risk of serious adverse events. These results signal a need to recalibrate immunotherapy strategies in mHSPC, focusing on better patient stratification and alternative approaches. The study underscores the importance of large, randomized trials in assessing clinical benefit and safety for new therapeutic combinations.
References
1. Gratzke C, Özgüroğlu M, Peer A, Sendur MAN, Retz M, Goh JC, Loidl W, Jayram G, Byun SS, Kwak C, Kwiatkowski M, Manneh Kopp R, Limón JCV, Penagos JFE, De Giorgi U, da Trindade KM, Niu C, Liu Y, Poehlein CH, Piulats JM. Pembrolizumab plus enzalutamide and androgen deprivation therapy versus placebo plus enzalutamide and androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: the randomized, double-blind, phase III KEYNOTE-991 study. Ann Oncol. 2025 Aug;36(8):964-975. doi: 10.1016/j.annonc.2025.05.008. PMID: 40383194.
2. National Comprehensive Cancer Network. NCCN Guidelines: Prostate Cancer. Version 1.2024.
3. European Association of Urology. Prostate Cancer Guidelines 2024.