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

Abstract

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 <i>ATM</i> and RAD51 foci (testing homologous recombination repair function). <i>BRCA1/2</i> germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous <i>BRCA2</i> deletion. Biallelic, but not monoallelic, <i>PALB2</i> 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 <i>BRCA</i> and <i>PALB2</i> alterations while most <i>ATM</i>- and <i>CDK12</i>-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous <i>BRCA2</i> deletion are exceptional responders; <i>PALB2</i> 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 <i>BRCA2</i> homozygous deletions, biallelic loss of <i>PALB2</i>, and loss of ATM protein. Loss of RAD51 foci, evaluating homologous recombination repair function, was found primarily in tumors with biallelic <i>BRCA1/2</i> and <i>PALB2</i> alterations.<i>This article is highlighted in the In This Issue feature, p. 2659</i>.