Background: RP12146 is an orally bioavailable, potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and PARP 2. RP1246 demonstrated anti-proliferative activity in both BRCA and non-BRCA mutant cancer cell lines of different tumor types as well as in xenograft models. In combination with abiraterone, RP12146 synergistically inhibited cell growth in both androgen-dependent (VCAP, LNCaP) and androgen-independent (C4-2) metastatic prostate cancer cell lines, signifying the role of RP12146 in this indication. Methods: The phase I/Ib study was designed as a two-part study in patients with advanced/metastatic solid tumors who received at least one prior therapy in a metastatic setting. Phase I was a 3+3, dose escalation for the determination of MTD and enrolled pts with tumors harboring DNA repair mechanism impairments. Phase Ib was a multiple tumor type expansion phase to delineate the anti-tumor activity of RP12146 at the MTD/optimal dose. Twelve patients with metastatic castration-resistant prostate cancer (mCRPC) having deleterious HRR mutation were enrolled in one of the expansion cohorts. RP12146 was given orally in a 28-day cycle until disease progression. Results: A total of 14 mCRPC pts [(2 pts without HRR mutation in dose escalation at 200mg BID and 400 mg BID) and 12 pts with deleterious HRR mutation in dose expansion at 400 mg BID] were enrolled in the study. In pts with HRR mutation, 5 pts had CHEK2 mutations, 3 pts each had ATM and BRCA2 mutations and 1 pt had a CDK12 mutation. As of 13 Sept 2023, the median duration of treatment was 3.8+ months. RP12146 was well tolerated with the majority of the reported TEAEs being mild to moderate in severity. There was no DLT reported. Related Grade 3 AE was limited to a single event of anemia which was resolved. There were no dose reductions due to TEAEs related to RP12146. None of the pts developed related SAEs or discontinued due to an AE. Out of 14 enrolled mCRPC patients, 5 pts with HRR mutation had at least one measurable lesion at baseline. Out of these 5 pts, one pt (gBRCA2/CHEK2) showed complete response and 2 pts (gCHEK2) showed stable disease with an ORR (overall response rate) of 20%. One patient (gBRCA2) with elevated PSA (no measurable lesion) at baseline showed a PSA response (>50% PSA reduction). Three patients with BRCA2 mutations showed good disease control and continue to be on therapy. The median duration of treatment in these BRCA2 mutated patients was 8.6 (8.36-9.53+) months. Conclusions: RP12146 has shown a differentiated safety profile so far in patients with mCRPC, with limited hematological toxicities as compared to the first-generation PARP inhibitors. Encouraging activity was seen in mCRPC patients with BRCA2 mutation. Updated safety and efficacy data will be provided at the time of presentation. Clinical trial information: NCT05002868.