Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study.

Abstract

Genomic alterations in DNA damage repair (DDR) genes other than <i>BRCA</i> may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-<i>BRCA</i> DDR gene alterations. TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline). TRITON2 enrolled 78 patients with a non-<i>BRCA</i> DDR gene alteration [<i>ATM</i> (<i>n</i> = 49), <i>CDK12</i> (<i>n</i> = 15), <i>CHEK2</i> (<i>n</i> = 12), and other DDR genes (<i>n</i> = 14)]. Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in <i>ATM</i> [2/19 (10.5%) and 2/49 (4.1%), respectively], <i>CDK12</i> [0/10 (0%) and 1/15 (6.7%), respectively], or <i>CHEK2</i> [1/9 (11.1%) and 2/12 (16.7%), respectively], including no radiographic or PSA responses in 11 patients with confirmed biallelic <i>ATM</i> loss or 11 patients with <i>ATM</i> germline mutations. Responses were observed in patients with alterations in the DDR genes <i>PALB2, FANCA, BRIP1</i>, and <i>RAD51B</i>. In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in <i>ATM, CDK12</i>, or <i>CHEK2</i>. However, patients with alterations in other DDR-associated genes (e.g., <i>PALB2</i>) may benefit from PARP inhibition.<i>See related commentary by Sokolova et al., p. 2439</i>.