PROpel Analysis Identifies rPFS Benefit With the Addition of Olaparib to Abiraterone in Non-BRCA-Mutated mCRPC

A post hoc exploratory analysis of the phase 3 PROpel trial, published in European Urology Oncology, reports efficacy, safety, and health-related quality of life (HRQoL) outcomes for olaparib plus abiraterone with prednisone/prednisolone versus placebo plus abiraterone with prednisone/prednisolone in the subgroup of patients with metastatic castration-resistant prostate cancer (mCRPC) who do not harbor BRCA1 or BRCA2 mutations (non-BRCAm). This analysis was conducted to inform benefit-risk decision-making for a patient population where the role of poly(ADP-ribose) polymerase (PARP) inhibitor combination therapy has remained uncertain.

In the non-BRCAm subgroup of 693 patients, olaparib plus abiraterone was associated with an improvement in radiographic progression-free survival (rPFS) compared with placebo plus abiraterone, though no significant overall survival (OS) benefit was observed. The authors caution that all analyses in this subgroup were post hoc and exploratory, were not powered for statistical significance, and should be interpreted accordingly.

Study Design

PROpel randomly assigned patients in a 1:1 ratio at 126 centers in 17 countries. Biomarker testing using tumor tissue (FoundationOne CDx) and circulating tumor DNA (FoundationOne Liquid CDx) were used to classify patients by BRCA mutational status. Non-BRCAm was defined as at least one negative BRCAm result and no positive BRCAm result from either test. All efficacy, safety, and quality of life analyses in the non-BRCAm subgroup reported in this publication were post hoc and exploratory.

Results and Safety

In the non-BRCAm subgroup, median investigator-assessed rPFS was 24.1 months with olaparib plus abiraterone versus 19.0 months with placebo plus abiraterone (HR 0.76, 95% CI 0.61–0.94), a difference of 5.1 months. A sensitivity analysis by blinded independent central review (BICR) showed a larger numerical separation, with a median of 27.6 months with olaparib versus 16.6 months with placebo (HR 0.72, 95% CI 0.58–0.90). Median OS at the final prespecified analysis was 39.6 months versus 38.0 months (HR 0.91, 95% CI 0.73–1.13), indicating no meaningful difference between study arms. Additional efficacy analyses also favored the PARP combination treatment, in which PSA₅₀ response rates were 79% versus 71%, ORRs were 56% versus 50%, median time to PSA progression was 22 versus 13 months (HR 0.7, 95% CI 0.6–0.8), median TFCC was 30 versus 23 months (HR 0.8, 95% CI 0.7–1.0), and median TFST was 24 versus 19.9 months (HR 0.8, 95% CI 0.7–1.0). No significant difference in the change in Functional Assessment of Cancer Therapy–Prostate (FACT-P) total score from baseline was observed between arms (–6.3 vs –5.3; difference in least squares means –1.0, 95% CI –3.6 to 1.6), indicating no meaningful detriment to HRQoL with the addition of olaparib.

The safety profile in the non-BRCAm subgroup was consistent with that of the overall biomarker-unselected population and the known toxicities of each individual agent. Anaemia was the most frequently reported adverse event, occurring in 51% of patients in the olaparib plus abiraterone arm versus 17% in the placebo plus abiraterone arm, in which grade 3–4 anaemia was reported by 17% and 3.1% of patients, respectively. Fatigue or asthenia occurred among more olaparib recipients (39% versus 32%), as did nausea (31% versus 15%) compared with placebo recipients, respectively. Serious adverse events were reported in 42% of patients receiving olaparib plus abiraterone and 32% receiving placebo plus abiraterone. Discontinuation of olaparib or placebo due to an adverse event occurred in 18% and 8.0% of patients, respectively. Death due to an adverse event occurred in 7.0% of the olaparib study arm compared with 4.9% of the placebo study arm. No new safety signals were identified in this subgroup.

Clinical Context

The PROpel trial was the first phase 3 study to demonstrate a statistically significant rPFS benefit for a PARP inhibitor combined with a next-generation hormonal agent in biomarker-unselected first-line mCRPC. Regulatory changes since the original publication of PROpel have varied. The combination of olaparib and abiraterone received approval in the European Union regardless of biomarker status, while US approval is restricted to patients with mCRPC and deleterious or suspected deleterious BRCA1/2 mutations. The present analysis directly addresses the non-BRCAm population, among whom the benefit of olaparib plus abiraterone has been less clearly defined. The non-BRCAm subgroup is biologically heterogeneous, encompassing patients with other HRR gene mutations, including ATM, which may account for the partial sensitivity to PARP inhibition in some tumors.

Findings from two other phase 3 trials provide additional context. In the MAGNITUDE trial, a prespecified futility analysis in the non-HRRm cohort showed no benefit for niraparib plus abiraterone, leading to early cohort closure. In TALAPRO-2, a trend toward rPFS and survival benefit with talazoparib plus enzalutamide was observed in non-HRRm and non-BRCAm subgroups, directionally consistent but not identical findings to those reported in PROpel. The authors note that differences in testing methodologies and subgroup definitions limit direct cross-trial comparisons. They also emphasize that the post hoc, exploratory nature of the non-BRCAm analyses in PROpel mean that these results should inform but not determine clinical decision-making, and that refined biomarker strategies to prospectively identify potential responders remains an unmet clinical need.

Sources

• European Urology Oncology. Mehra N, et al. “Efficacy and Safety of Olaparib plus Abiraterone Versus Placebo plus Abiraterone in the Non-BRCA Mutation Subgroup of Patients with Metastatic Castration-resistant Prostate Cancer in the PROpel Trial.” Original research. 2026. View source.