Background: mCRPC is a molecularly heterogenous disease. Tumours in a sizable proportion of patients with mCRPC harbour loss-of-function mutations in genes involved in HRR (eg BRCA1, BRCA2 and ATM). HRRm have been associated with increased sensitivity to the PARP inhibitor olaparib in mCRPC. The PROfound study (NCT02987543) evaluates olaparib efficacy and safety versus either enzalutamide or abiraterone acetate, in mCRPC patients with a HRRm.
Methods: PROfound is a randomized, open-label, Phase III study in men with mCRPC, for whom prior new hormonal agent treatment for metastatic prostate cancer and/or CRPC had failed. Eligible patients had a qualifying tumour HRRm in one of 15 genes, prospectively and centrally determined in tumour tissue using an investigational next-generation sequencing test (Foundation Medicine, Inc.). Two cohorts were enrolled: Cohort A (n=245) included patients with mutations in BRCA1, BRCA2 or ATM; Cohort B included patients with a mutation in 12 other HRR genes (n=142). Patients were randomized (2:1) to olaparib tablets (300 mg bid) or physician’s choice of either enzalutamide (160 mg orally od) or abiraterone acetate (1000 mg orally od + 5 mg bid prednisone). Treatment continued until radiographic progression (assessed by blinded independent central review or lack of treatment tolerability. The primary endpoint of radiographic progression-free survival (rPFS) in Cohort A was assessed by BICR using RECIST 1.1 and PCWG3 criteria and analysed via stratified log-rank test.
Expected results: rPFS will be reported for Cohort A, as well as confirmed objective response rate in Cohort A, rPFS in Cohorts A+B, time to pain progression in Cohort A, overall survival and a safety summary.
Expected conclusions: The PROfound study will demonstrate whether olaparib monotherapy leads to a clinically meaningful benefit in rPFS compared with enzalutamide or abiraterone acetate, for patients with mCRPC and HRRm who had failed prior treatment with a new hormonal agent.