Abiraterone plus olaparib as a new first-line treatment option for patients with metastatic castration-resistant prostate cancer

A previous analysis of the phase III PROpel trial showed that the addition of olaparib to first-line abiraterone treatment significantly improves radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer. To get a clear view on whether such a positive effect also extends to overall survival, the final analysis of the overall survival and adverse event profile of this drug combination were presented.

The randomised, double-blind, phase III PROpel trial has previously achieved its primary endpoint by demonstrating a radiographic progression-free survival (rPFS) benefit for patients with metastatic castration-resistant prostate cancer  (mCRPC) when treated with abiraterone plus olaparib (ABI+OLA) compared to abiraterone plus placebo (ABI+PBO) in first-line. The sensitivity analysis based on a blinded, independent, central review was also consistent with these findings. During the primary rPFS analysis and subsequent interim analysis, a trend towards improved overall survival (OS) was observed. Now the pre-planned final OS and safety analysis of the PROpel trial has also been performed.

Study design

PROpel is a randomised, double-blind phase III trial of first-line therapy for patients with mCRPC eligible for abiraterone. Patients were prospectively assessed for homologous recombination repair mutation (HRRm) status using tumour tissue (FoundationOneCDx) and/or circulating tumor DNA (ctDNA; FoundationOneLiquid CDx) tests after randomisation 1:1 to OLA (300 mg twice daily [BID]) or placebo, and ABI (1,000 mg once daily) plus prednisone/prednisolone (5 mg BID). Treatment continued until radiographic disease progression, unacceptable toxicity or withdrawal of consent. Primary endpoint was rPFS and OS was a key secondary endpoint (2-sided boundary for significance 0.0377). Aggregate results from tumour tissue and ctDNA tests were used to assign patients to HRRm/BRCAm subgroups.

Results

In total, 399 patients were randomised to ABI+OLA and 397 patients to ABI+PBO. Baseline patient and disease characteristics were well balanced between study arms.  At the final pre-specified OS analysis, the median OS in the intention-to-treat (ITT) population was more than 7 months longer in the ABI+OLA arm as compared to the ABI+PBO arm (42.1 vs. 34.7 months, HR[95%CI]: 0.81[0.67-1.00], p= 0.0544). Results across subgroups were generally consistent with the ITT population. In addition, a trend towards OS benefit was observed across HRRm  (median NR vs. 28.5 months, HR[95%CI]: 0.66[0.45-0.95]) and non-HRRm subgroups (median 42.1 vs. 38.9 months, HR[95%CI]: 0.89[0.70-1.14]). In total, 44.9% of patients in the olaparib-arm and 54.2% of patients in the placebo-arm had a subsequent therapy. The median time to first subsequent therapy was 24.6 months for ABI+OLA and 19.4 months for ABI+PBO (HR[95%CI]: 0.76[0.64-0.90]). The most common first subsequent therapies were cytotoxic chemotherapy (N= 242) or hormonal therapy (N= 113). With longer treatment duration and follow-up, there were no new safety signals. Adverse events of grade ≥3 occurred in 55.8% of patients treated with ABI+OLA and in 43.2% of patients treated with ABI+PBO. Adverse events leading to olaparib discontinuation occurred in 17.3% of patients. Two cases of MDS/AML were reported in the olaparib and abiraterone arm. The incidence of new primary malignancies and pneumonitis were balanced between treatment arms. Health-related quality of life was similar between arms, indicating no detriment with the addition of olaparib.

Conclusion

PROpel met its primary endpoint demonstrating a statistically significant and clinically meaningful rPFS benefit in the ITT population of patients with mCRPC treated with abiraterone + olaparib vs. abiraterone + placebo. The OS trend observed with abiraterone + olaparib vs. abiraterone alone was sustained at the final pre-specified analysis. The rPFS and OS benefit was observed across subgroups. The safety profile remained consistent over time, with no new signals observed.

Reference

Clarke N, et al. Final overall survival (OS) in PROpel: Abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). Presented at ASCO GU 2023; Abstract LBA16.