As reported in the Journal of Clinical Oncology by Emmanuel S. Antonarakis, MD, and colleagues, the phase III KEYLYNK-010 trial has shown no improvement in survival outcomes with pembrolizumab/olaparib vs a next-generation hormonal agent (abiraterone or enzalutamide) in previously treated patients with biomarker-unselected metastatic castration-resistant prostate cancer. The trial was stopped for futility at the second interim analysis.

Emmanuel S. Antonarakis, MD

Study Details

In the open-label trial, 793 patients from sites in six regions whose disease progressed on or after treatment with abiraterone or enzalutamide (but not both) and docetaxel were randomly assigned 2:1 between May 2019 and July 2021 to receive pembrolizumab/olaparib (n = 529) or a next-generation hormonal agent (n = 264). Next-generation hormonal agents consisted of abiraterone at 1,000 mg once daily plus 5 mg of prednisone/prednisolone twice daily in patients who had received prior enzalutamide (44.5%), or enzalutamide at 160 mg once daily in patients who had received prior abiraterone (54.2%). Pembrolizumab was given at 200 mg every 3 weeks (for ≤ 35 cycles) and olaparib at 300 mg twice daily. The dual primary endpoints were radiographic progression–free survival on blinded independent central review and overall survival.

Survival Outcomes

Median time from random assignment to data cutoff in January 2022 for second interim analysis was 18.7 months (range = 6.1–31.7 months). Median radiographic progression–free survival was 4.4 months (95% confidence interval [CI] = 4.2–6.0 months) in the pembrolizumab/olaparib group vs 4.2 months (95% CI = 4.0–6.1 months) in the next-generation hormonal agent group (hazard ratio [HR] = 1.02, 95% CI = 0.82–1.25, P = .55). Median overall survival was 15.8 months (95% CI = 14.6–17.0 months) in the pembrolizumab/olaparib group vs 14.6 months (95% CI = 12.6–17.3 months) in the next-generation hormonal agent group (HR = 0.94, 95% CI = 0.77–1.14, P = .26).

Median time to first subsequent treatment was 7.2 months (95% CI = 6.7–8.1 months) in the pembrolizumab/olaparib group vs 5.7 months (95% CI = 5.0–7.1 months) in the next-generation hormonal agent group (HR = 0.86, 95% CI = 0.71–1.03). Objective response was observed in 16.8% vs 5.9% of patients.

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 34.6% of patients in the pembrolizumab/olaparib group vs 9.0% of the next-generation hormonal agent group; the most common were anemia (19.6%) and fatigue (3.0%) in the pembrolizumab/olaparib group and hypertension (2.3%) in the next-generation hormonal agent group. Treatment-related death occurred in four patients (0.8%) in the pembrolizumab/olaparib group, due to immune-mediated hepatitis, pneumonia, craniocerebral injury, and renal failure in one patient each. No treatment-related deaths were observed in the next-generation hormonal agent group.  

The investigators concluded, “Pembrolizumab plus olaparib did not significantly improve radiographic progression-free survival or overall survival vs next-generation hormonal agent[s] in participants with biomarker-unselected, heavily pretreated metastatic castration-resistant prostate cancer. The study was stopped for futility. No new safety signals occurred.”

Dr. Antonarakis, of the University of Minnesota Masonic Cancer Center, Minneapolis, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.