Genomic alterations in DNA damage repair (DDR) genes other than 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- 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- DDR gene alteration ( = 49), ( = 15), ( = 12), and other DDR genes ( = 14). Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in 2/19 (10.5%) and 2/49 (4.1%), respectively, 0/10 (0%) and 1/15 (6.7%), respectively, or 1/9 (11.1%) and 2/12 (16.7%), respectively, including no radiographic or PSA responses in 11 patients with confirmed biallelic loss or 11 patients with germline mutations. Responses were observed in patients with alterations in the DDR genes , and . In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in , or . However, patients with alterations in other DDR-associated genes (e.g., ) may benefit from PARP inhibition. .