gms | German Medical Science

Introduction: The median overall survival for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) is short after failure of new hormonal agent (NHA) (abiraterone (AA) or enzalutamide (enz)). Available agents may offer limited therapeutic benefit, but no molecularly stratified treatment has yet been approved. A sizable percentage of pts with mCRPC has loss of function aberrations in genes involved in homologous recombination repair (HRR) in tumor tissue, such as BRCA1/2 and ATM. These aberrations can confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition. A Phase II study indicated that the oral PARP inhibitor olaparib (Lynparza) had antitumor activity in 33% of mCRPC pts who had progressed after NHA and chemotherapy, with a strikingly higher composite response rate in pts with a deleterious HRR gene aberration (HRRa) (88%; 14/16) vs pts without a HRRa (6%; 2/33) (Mateo et al. 2015). The PROfound study evaluates olaparib efficacy and safety versus physician’s choice of either abi or enz, in pts with mCRPC and a HRRa (NCT02987543).

Methods: Multinational, phase III study randomizing mCRPC pts progressed on NHA treatment, to olaparib vs. AA or ENZ (2:1). Depending on HRRa in one of 15 genes, as confirmed by an HRR Assay (Foundation Medicine, Inc.), pts will be assigned to Cohort A (n~240, BRCA1/2 or ATM) or B (n~100, other). Treatment continued until radiographic progression (as assessed by blinded independent central review) or lack of treatment tolerability. The primary endpoint of radiographic progression-free survival (rPFS) will be assessed in Cohort A using RECIST 1.1 and PCWG3 criteria. Secondary endpoints include confirmed objective response rate, time to pain progression, overall survival (Cohort A) and rPFS (cohorts combined). Recruitment is ongoing at 11 sites in Germany.