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.

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