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.

PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis.

This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0-1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system-interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 [two-sided]), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting.

Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1-40·3) for olaparib plus abiraterone and 36·5 months (33·8-40·3) for placebo plus abiraterone. Median overall survival was 42·1 months (95% CI 38·4-not reached) with olaparib plus abiraterone and 34·7 months (31·0-39·3) with placebo plus abiraterone (hazard ratio 0·81, 95% CI 0·67-1·00; p=0·054). The most common grade 3-4 adverse event was anaemia reported in 64 (16%) of 398 patients in the olaparib plus abiraterone and 13 (3%) of 396 patients in the placebo plus abiraterone group. Serious adverse events were reported in 161 (40%) in the olaparib plus abiraterone group and 126 (32%) in the placebo plus abiraterone group. One death in the placebo plus abiraterone group, from interstitial lung disease, was considered treatment related.

Overall survival was not significantly different between treatment groups at this final prespecified analysis.

Supported by AstraZeneca and Merck Sharp & Dohme.

The Lancet. Oncology. 2023 Sep 12 [Epub ahead of print]

Fred Saad, Noel W Clarke, Mototsugu Oya, Neal Shore, Giuseppe Procopio, João Daniel Guedes, Cagatay Arslan, Niven Mehra, Francis Parnis, Emma Brown, Friederike Schlürmann, Jae Young Joung, Mikio Sugimoto, Oliver Sartor, Yu-Zhen Liu, Christian Poehlein, Laura Barker, Paula Michelle Del Rosario, Andrew J Armstrong

Centre Hospitalier de l'Université de Montréal, Montreal, Canada. Electronic address: ., The Christie and Salford Royal Hospital NHS Foundation Trusts and University of Manchester, Manchester, UK. Electronic address: ., Keio University School of Medicine, Tokyo, Japan., Carolina Urologic Research Center, Myrtle Beach, SC, USA., Programma Prostata Fondazione Istituto Nazionale Tumori Milano, Milan, Italy., Hospital de Base de São José do Rio Preto, São José do Rio Preto, Brazil., Izmir Economy University Medical Point Hospital, Karsiyaka, Izmir, Turkey., Radboud Universitair Medisch Centrum, Nijmegen, Netherlands., Ashford Cancer Centre Research, Adelaide, Australia., University Hospital Southampton, Southampton, UK., CHI de Cornouaille, Quimper, France., National Cancer Center, Goyang, South Korea., Kagawa University Hospital, Kagawa, Japan., Mayo Clinic, Rochester, MN, USA., Precision Medicine, Oncology R&D, AstraZeneca, Cambridge, UK., Merck & Co, Rahway, NJ, USA., Global Medicines Development, Oncology R&D, AstraZeneca, Cambridge, UK., Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University, Durham, NC, USA.