As reported in The Lancet Oncology by Fred Saad, MD, of the Centre Hospitalier de l’Université de Montréal, and colleagues, the final prespecified overall survival analysis of the phase III PROpel trial has shown 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.¹

Fred Saad, MD

Offering perspective on these results, Dr. Saad told The ASCO Post: “There was a 7.4-month improvement in overall survival with olaparib plus abiraterone vs abiraterone alone—although not statistically significant, this is the largest advantage reported to date for metastatic castration resistant prostate cancer, and this is especially impressive given a life-prolonging control arm. As for the BRCA-mutated subgroup, there was a 71% reduction in the risk of death, with confidence intervals below 1.”

Primary analyses of radiographic progression–free survival from 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. These analyses also supported 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.

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 included the site of metastases and previous use of docetaxel at the 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. At primary analysis, median radiographic progression–free survival was 24.8 months in the olaparib group vs 16.6 months in the control group (hazard ratio [HR] = 0.66, P < .001) in the intention-to-treat population.

Overall Survival

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 and 36.5 months (IQR = 33.8–40.3 months) in the control group. Median overall survival was 42.1 months (95% confidence interval [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). Median overall survival 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. These treatments were most commonly cytotoxic chemotherapy (31% vs 42%) and next-generation hormonal agents (17% vs 19%).

At the time of analysis, the median time to 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 second 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 in the olaparib group vs 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); 0.74 (95% CI = 0.52–1.05) for other metastasis (129 vs 128 patients); 0.76 (95% CI = 0.52–1.11) with docetaxel treatment (95 vs 94 patients); and 0.85 (95% CI = 0.67–1.07) without 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 mutation (47 vs 38 patients) and 0.91 (95% CI = 0.73–1.13) among those without BRCA mutation (343 vs 350 patients). For HRR mutation status, hazard ratios were 0.66 (95% CI = 0.45–0.95) among patients with HRR mutation (111 vs 115 patients) and 0.89 (95% CI = 0.70–1.14) among those without HRR mutation (279 vs 273 patients).

Adverse Events

Grade ≥ 3 adverse events occurred in 56% of the olaparib group vs 43% of the control group. The most common grade 3 or 4 adverse event in the olaparib group was anemia (16% vs 3% in the control group). Grade 3 or 4 embolic and thrombotic venous adverse events were reported in 8% vs 3% of patients, respectively. Serious adverse events occurred in 40% vs 32%, most commonly anemia (6%) in the olaparib group. Adverse events led to discontinuation of olaparib in 17% of patients and placebo in 9%. Adverse events led to death in 7% vs 5% of patients; one death in the control group, from interstitial lung disease, was considered related to treatment.

The investigators concluded: “Overall survival was not significantly different between treatment groups at this final prespecified analysis.” 

DISCLOSURE: The study was funded by AstraZeneca and Merck Sharp & Dohme. For full disclosures of the study authors, visit thelancet.com.

REFERENCE

1. Saad F, Clarke NW, Oya M, et al: Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): Final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol 24:1094-1108, 2023.