Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial.

PARP inhibitors are approved for treating advanced prostate cancers (APC) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed TOPARP-B phase II clinical trial samples, evaluating whole-exome and low-pass whole-genome sequencing and IHC and IF assays evaluating and RAD51 foci (testing homologous recombination repair function). germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous deletion. Biallelic, but not monoallelic, deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by IHC was associated with a better outcome. RAD51 foci loss identified tumors with biallelic and alterations while most - and -altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous deletion are exceptional responders; biallelic loss and loss of ATM IHC expression associated with clinical benefit. SIGNIFICANCE: Not all APCs with DNA repair defects derive similar benefit from PARP inhibition. Most benefit was seen among patients with homozygous deletions, biallelic loss of , and loss of ATM protein. Loss of RAD51 foci, evaluating homologous recombination repair function, was found primarily in tumors with biallelic and alterations..