As reported by Fred Saad, MD, and colleagues in The Lancet Oncology, the final prespecified overall survival analysis of the phase III PROpel trial showed no significant benefit with the addition of first-line olaparib to abiraterone in patients with metastatic castration-resistant prostate cancer unselected for homologous recombination repair (HRR) mutation status.
The trial supported the December 2022 European approval of olaparib in combination with abiraterone and prednisone or prednisolone in patients with metastatic castration-resistant prostate cancer for whom chemotherapy is not clinically indicated and the May 2023 U.S. Food and Drug Administration approval of the combination in patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer.
Fred Saad, MD
Study Details
In the double-blind trial, 796 patients from sites in 17 countries were randomly assigned between October 2018 and March 2020 to receive abiraterone at 1,000 mg once daily with prednisone or prednisolone plus either olaparib at 300 mg twice daily (n = 399) or placebo (n = 397). Treatment continued until investigator-assessed radiographic progressive disease or unacceptable toxicity. Stratification factors were the site of metastases and previous receipt of docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression–free survival was the primary endpoint; overall survival was a key secondary endpoint, with a prespecified significance threshold of .0377 in the intention-to-treat population.
Key Findings
At primary analysis in the intention-to-treat population, investigator-assessed median radiographic progression–free survival was 24.8 months (95% confidence interval [CI] = 20.5–27.6 months) in the olaparib group vs 16.6 months (95% CI = 13.9–19.2 months) in the control group (hazard ratio [HR] = 0.66, 95% CI = 0.54–0.81, P < .001).
Median follow-up for overall survival in patients with censored data was 36.6 months (interquartile range [IQR] = 34.1–40.3 months) in the olaparib group vs 36.5 months (IQR = 33.8–40.3 months) in the control group. Median overall survival was 42.1 months (95% CI = 38.4 months to not reached) in the olaparib group vs 34.7 months (95% CI = 31.0–39.3 months) in the control group (HR = 0.81, 95% CI = 0.67–1.00, P = .054). Rates at 2 and 3 years were 70% (95% CI = 65.4%–74.4%) vs 67% (95% CI = 60.5%–67.0%) and 57% (95% CI = 51.7%–61.7%) vs 50% (95% CI = 44.3%–54.5%).
A total of 45% of patients in the olaparib group vs 54% of patients in the control group received subsequent therapy, most commonly cytotoxic chemotherapy (31% vs 42%) and next-generation hormonal agents (17% vs 19%). At the time of analysis, the median time to receipt of first subsequent therapy or death was 24.6 months (95% CI = 21.1–28.5 months) in the olaparib group vs 19.4 months (95% CI = 17.0–21.1 months) in the control group (HR = 0.76, 95% CI = 0.64–0.90). The median time to subsequent disease progression or death was not reached in the olaparib group or the control group (events in 26% vs 32% of patients; HR = 0.76, 95% CI = 0.59–0.99).
For stratification factors, hazard ratios for overall survival for the olaparib group vs the control group were 0.85 (95% CI = 0.64–1.13) for bone-alone metastasis (217 vs 217 patients), 0.89 (95% CI = 0.53–1.51) for visceral metastasis (53 vs 52 patients), and 0.74 (95% CI = 0.52–1.05) for other metastasis (129 vs 128 patients); the hazard ratios were 0.76 (95% CI = 0.52–1.11) for docetaxel treatment (95 vs 94 patients) and 0.85 (95% CI = 0.67–1.07) for no docetaxel treatment (304 vs 303 patients) at the metastatic hormone-sensitive stage.
Hazard ratios were 0.29 (95% CI = 0.14–0.56) among patients with BRCA-mutated status (47 vs 38 patients) and 0.91 (95% CI = 0.73–1.13) among those with non–BRCA-mutated status (343 vs 350 patients).
The investigators concluded: “Overall survival was not significantly different between treatment groups at this final prespecified analysis.”
Dr. Saad, of Centre Hospitalier de l’Université de Montréal, and Noel Clarke, ChM, of the Christie and Salford Royal Hospital NHS Foundation Trusts and the University of Manchester, are the corresponding authors of The Lancet Oncology article.
Disclosure: The study was funded by AstraZeneca and Merck Sharp & Dohme. For full disclosures of the study authors, visit thelancet.com.
