Descend into the PARPicular.

Top Line: A subset of prostate cancers are driven by defects in DNA damage repair (DRR), which includes BRCA mutations.

The Study: That proportion is enriched among men with metastatic, castrate resistant prostate cancer (mCRPC). As we’ve seen in ovarian cancer, DRR can lead to sensitivity to PARP inhibition due to an overwhelming buildup of sublethal DNA damage that becomes lethal in cells with DRR. TOPARP is a series of phase 2 trials that adapt at each step based on the results of the prior sub-trial. In TOPARP-A, olaparib was associated with anti-tumor activity in patients with defects in DRR. TOPARP-B was a confirmatory phase 2 study of a larger cohort of men with mCRPC who had next-generation sequencing (NGS) to look for deleterious tumor mutations in DRR genes. Of note, they had to have had at least one prior taxane, and roughly 90% had prior abiraterone and/or enzalutamide. Of the 711 men who underwent NGS, nearly a quarter had a DRR mutation, but ultimately only 14% were eligible for study treatment. Among the DRR  mutations, 31% were in BRCA2 and 21% were in ATM or CDK12. The primary endpoint of tumor response was defined as 1) a radiographic response, 2) a 50% decrease in PSA from baseline, and/or 3) diminution of circulating tumor cells. That last criterion was the one most commonly met. Overall, 54% of men who received olaparib 400 mg BID and 39% who received 300 mg BID had a response. Median progression-free survival was just shy of 6 months. Among the different DRR mutations, olaparib activity appeared greatest in those with germ line or somatic BRCA mutations.

TBL: The PARP inhibitor olaparib has a >50% response rate among men with taxane-treated mCRPC and defects in DNA damage repair, particularly those with BRCA mutations. | Mateo, Lancet Oncol 2019