Key clinical point: In patients with metastatic castration-resistant prostate cancer (CRPC) having BRCA1/2 or ATM mutations and who progressed during enzalutamide/abiraterone treatment, olaparib significantly prolonged radiographic progression-free survival (PFS) compared with either enzalutamide or abiraterone.

Major finding: The olaparib group vs control group had a significantly prolonged median radiographic PFS in patients with BRCA1/2 or ATM mutations (7.4 vs 3.6 months; hazard ratio, 0.34; P less than .001). Grade ≥3 adverse event rates higher in the olaparib group than in the control group.

Study details: In phase 3 PROfound trial, 387 patients with metastatic CRPC who had progressed during enzalutamide or abiraterone treatment and were randomly assigned to receive olaparib or enzalutamide/abiraterone plus prednisone (control group).

Disclosures: The study was funded by AstraZeneca and Merck Sharp & Dohme. The authors declared relationships with one or more pharmaceutical companies.

Commentary

"It is recognized that a significant minority of prostate tumors harbor genetic alterations in genes involving DNA damage repair. The best recognized include BRCA1 and BRCA2, but several others are also postulated to be important for prostate cancer biology. Detection of alterations in these genes has been hypothesized to be associated with increased susceptibility to treatment with PARP inhibitors. In the PROfound study, patients with tumors (containing alterations in 1 of 15 prespecified genes) that progressed while undergoing treatment with enzalutamide or abiraterone were randomized to olaparib or a different hormonal agent (enzalutamide or abiraterone). In two separate cohorts (tumors with BRCA1, BRCA2, or ATM alterations or 1 of 15 alterations), an improvement in progression-free and overall survival was identified. Further analysis of the effects of specific gene alterations on outcomes is underway. This is a significant finding that results in a new option for select prostate cancer patients."

Mark Klein, MD