Profound defects.

Top Line: A sizable portion of men with metastatic, castrate resistant prostate cancer (mCRPC) have defects in their tumor’s homologous recombination DNA repair pathway.

The Study: Such defects make tumors sensitive to the effects of PARP inhibitors. In the PROfound trial, men with mCRPC with mutations in DNA repair genes who progressed on enzalutamide or abiraterone were randomized to receive either the physician’s choice of enzalutamide or abiraterone (basically a switch) or the PARP inhibitor olaparib. Roughly two-thirds had also received prior taxane therapy. Among all men screened for the trial, 28% had eligible DNA repair defects. The most frequent were BRCA2 (19%), CDK12 (13%), and ATM (9%). There were two study cohorts: those with mutations in BRCA1, BRCA2, or ATM, and then those with mutations in other DNA repair pathway genes. Among the 245 men in the first cohort, olaparib resulted in a 33% objective response rate and significantly doubled the primary endpoint of radiographic progression-free survival (PFS) from 3.6 → 7.4 months. An interim analysis of median overall survival was encouraging (15 → 19 months), if not significant. PFS was also significantly prolonged in the overall cohort, but the magnitude was smaller, suggesting much of the improvement was driven by the primary cohort.

TBL: Olaparib prolongs disease control in men with progressive mCRPC and mutations in BRCA1, BRCA2, or ATM. | de Bono, N Engl J Med 2020