The combination of the PARP inhibitor olaparib and abiraterone offered improved efficacy in patients with metastatic castration-resistant prostate cancer, but at what cost?
The combination of the PARP inhibitor olaparib and the androgen receptor pathway inhibitor abiraterone offered improved efficacy over abiraterone alone in patients with metastatic castration-resistant prostate cancer (CRPC), according to a new trial. However, the combination did result in more toxicity than abiraterone monotherapy.
In the past, research has shown improved responses to PARP inhibition in patients carrying a homologous recombination repair (HRR) mutation. “Preclinical data have indicated synergy between olaparib and drugs that affect the androgen receptor pathway, regardless of HRR mutation status,” wrote study authors led by Noel Clarke, ChM, of the Christie and Salford Royal Hospitals in Manchester, in the United Kingdom.
The new study was a double-blind, randomized, placebo-controlled phase II trial comparing the combination of olaparib and abiraterone (71 patients) with abiraterone alone (71 patients) in patients with metastatic CRPC. The results were published in Lancet Oncology.
The median age of the patients in the combination group was 70 years, and was 67 years in the placebo-plus-abiraterone group; most patients were white (94% in both groups), and almost all patients had an ECOG performance status score of 0 or 1. Approximately half of the patients had bone metastases only; 15% and 14%, respectively, had HRR mutations.
The median radiographic progression–free survival (rPFS) was 13.8 months with olaparib and abiraterone, compared with 8.2 months with placebo and abiraterone, for a hazard ratio of 0.65 (95% CI, 0.44–0.97; P = .034).
The investigators conducted a prespecified subgroup analysis based on HRR mutation status. Of 21 patients with HRR mutations, 8 of 11 in the olaparib group (73%) had radiographic progression or died, compared with 7 of 10 (70%) in the placebo group. Of the 35 patients with confirmed wild-type HRR, 53% in the olaparib group and 85% in the placebo group had progression or died.
Among those with measurable disease at baseline, there was no difference between the groups with regard to objective response rate (27% vs 32%).
In the olaparib group, 93% of patients experienced at least one adverse event, compared with 80% of placebo-plus-abiraterone patients. Grade 3 or higher adverse events were more common with olaparib, reported in 54% of patients compared with 28% with placebo. Grade 3 or higher adverse events that were more common with olaparib included anemia, pneumonia, and myocardial infarction.
“Although patients given olaparib had more adverse events than did those who received placebo, median treatment duration was longer for patients treated with olaparib, and combined therapy did not lead to a decline in health-related quality of life,” the authors wrote. “Our data provide evidence of clinical benefit for men with metastatic castration-resistant prostate cancer given olaparib in combination with abiraterone compared with abiraterone alone, and indicate that this combination could potentially benefit patients, regardless of HRR mutation status.”