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Abiraterone plus Olaparib in Metastatic Castration-Resistant Prostate Cancer
Abiraterone and enzalutamide are widely used as initial therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) both in those managed with androgen deprivation therapy (ADT) alone and in those given docetaxel intensification in the hormone-sensitive metastatic setting. A phase 3 trial of the poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) inhibitor olaparib demonstrated improvement in both progression-free (PFS) and overall survival (OS) in men with BRCA 1/2 and ATM mutations. A randomized phase 2 study of the combination of abiraterone and olaparib demonstrated provocative activity.
Now, in a double-blind, industry-sponsored phase 3 study, nearly 800 men with mCRPC who had not received prior systemic therapy were randomized to abiraterone (1000 mg once daily) plus either olaparib (300 mg twice daily) or placebo. Patients were randomized irrespective of their homologous recombination repair gene mutation (HRRm) status, which was determined after enrollment using tumor tissue and circulating tumor DNA.
HRRm was present in 29% of patients and not present in 69%; status was unknown in 9%. Twenty-four percent of patients had received prior docetaxel treatment. At the first planned primary analysis, median imaging-based PFS — the primary endpoint — was significantly longer in the olaparib arm than in the placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; P<0.001). Data for OS — a key secondary endpoint — were immature.
The most common adverse events were anemia, fatigue, and nausea, with grade ≥3 anemia in 15.1% of patients in the olaparib arm compared to 3.3% in the placebo arm. Pulmonary embolism was experienced by 6.5% in the olaparib arm compared with 1.8% in the placebo arm.
These intriguing results suggest a potential benefit from the addition of olaparib to abiraterone therapy in men with previously untreated mCRPC — irrespective of HRRm status. Prior to adoption of this approach, several critical issues need further clarity, including effect on overall survival; discrepancy with results from the MAGNITUDE study (J Clin Oncol 2022; 40 [Suppl. 6]: Abstract 12); and applicability of the findings to patients with progression on prior treatment with an androgen receptor inhibitor as part of ADT intensification for hormone-sensitive metastatic disease. Ongoing trials testing different PARP/androgen receptor inhibitor combinations (e.g., TALAPRO-2 and CASPAR), may provide some clarity.
Clarke NW et al.
Title: Abiraterone and olaparib for metastatic castration-resistant prostate cancer.
Source: NEJM Evid 2022 Jun 3; [e-pub]. (Abstract/FREE Full Text)