No statistically significant improvement in radiographic progression-free survival and overall survival was seen with pembrolizumab plus olaparib in metastatic castration-resistant prostate cancer.
The combination pembrolizumab (Keytruda) plus olaparib (Lynparza) did not reveal a significant improvement in radiographic progression-free survival (rPFS) and overall survival (OS) vs novel hormonal agents (NHA) in patients with molecularly unselected, previously treated metastatic castration-resistant prostate cancer (mCRPC), according to results from the phase 3 KEYLINK-010 trial (NCT03834519) presented at the 2022 European Society for Medical Oncology Congress.
At interim analysis 1 in the intent-to-treat (ITT) population, the median rPFS was 4.4 months (95% CI, 4.2-6.0) in the pembrolizumab plus olaparib group vs 4.2 months (95% CI, 4.0-6.1) in the NHA group (HR, 1.02; 95% CI, 0.82-1.25; P = .55). Moreover, the median OS at interim analysis 2 in the ITT population was 15.8 months (95% CI, 14.6-17.0) in the pembrolizumab plus olaparib group vs 14.6 months (95% CI, 12.6-17.3) in the NHA group (HR, 0.94; 95% CI, 0.77-1.14; P = .26).
“The study was stopped for futility after the second prespecified interim analysis based on guidance from the external data monitoring committee,” Evan Y. Yu, MD, clinical research director of Genitourinary Medical Oncology at Seattle Cancer Care Alliance, said during the presentation.
Patients were randomly assigned 2:1, with 529 patients being enrolled into the combination arm and 264 patients in the NHA arm. Those in the experimental arm received pembrolizumab at 200 mg every 3 weeks for 35 cycles or less plus olaparib at 300 mg twice a day, and the control group received abiraterone (Zytiga) at 1000 mg every day if they received prior enzalutamide (Xtandi) or enzalutamide at 160 mg each day if they received prior abiraterone. The co-primary end points were rPFS and OS, and secondary end points included time to first subsequent therapy, objective response rate, and safety.
Patients were eligible for the trial if they had cytologically confirmed mCRPC, progressive disease after receiving abiraterone or enzalutamide and docetaxel, an ECOG performance status of 0 or 1, and available tissue samples for biomarker testing. Stratification factors included having received prior abiraterone or enzalutamide or measurable disease at baseline.
Patients were heavily pretreated. In the pembrolizumab arm, 51.4% of patients had an ECOG performance status of 1 vs 47.3% in the NHA arm. Prior NHA treatment was equal between arms. Homologous recombination repair (HRR) status was assessed, with 26.1% vs 22.3% of patents in both respective arms having HRR mutations, 67.1% vs 65.5% having non-HRR mutations, and 6.8% vs 12.1% having unknown mutations. Additionally, BRCA mutations were present in 9.8% of those in the pembrolizumab plus olaparib group vs 9.1% in the NHA group, 83.4% vs 78.8% were non-BRCA mutated, and 6.8% vs 12.1% had unknown mutation status. PD-L1 expression of less than 1 was present in 69.0% of those in the combination arm vs 74.6% in the NHA arm, 24.0% vs 18.9% had an expression of 1 or more, and 7.0% vs 6.4% had a PD-L1 status that was not evaluable or unknown.
In the ITT population, the median time to first subsequent therapy was a 7.2 months (95% CI, 6.7-8.1) in the pembrolizumab plus olaparib arm vs 5.7 months (95% CI, 5.0-7.1) in the NHA arm (HR, 0.86; 95% CI, 0.71-1.03). A total of 51.4% of patients in the combination arm and 55.3% in the NHA arm received any subsequent therapy at the interim analysis. Subsequent therapies included cabazitaxel (37.2% vs 40.9%), enzalutamide (12.1% vs 0%), and radiopharmaceuticals (6.8% vs 9.5%) in the combination and NHA arms, respectively.
In the pembrolizumab plus olaparib arm, the ORR was 16.8% (95% CI, 12.3%-22.1%) vs 5.9% (95% CI, 2.4%-11.7%), and the disease control rate was 32.4% (95% CI, 26.5%-38.6%) vs 19.3% (95% CI, 12.7%-27.6%), respectively. A complete response was observed in 1.6% of patients in the pembrolizumab plus olaparib arm vs 0 in the NHA arm, with 15.2% vs 5.9% of patients experiencing a partial response.
Overall, grade 3 or higher adverse effects (AEs) occurred in 57.2% vs 39.5% of patients in the combination and NHA arms, respectively. Grade 3 or higher AEs leading to discontinuation occurred in 15.2% vs 3.5% of patients, respectively, with 4.0% vs 2.3% experiencing high-grade AEs leading to death.
Treatment-related AEs (TRAEs) of grade 3 or higher occurred in 34.6% of patients in the pembrolizumab plus olaparib arm vs 9.0% in the NHA arm, with 10.8% vs 1.6% experiencing high-grade TRAEs leading to discontinuation and 0.8% vs 0.0% leading to death. The most common TRAEs in the pembrolizumab plus olaparib arm vs the NHA arm, respectively, included anemia (46.0% vs 2.7%), nausea (35.6% vs 5.1%), fatigue (25.7% vs 16.4%), and decreased appetite (21.3% vs 4.7%).