Background: RP12146 is an orally bioavailable, potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and PARP 2. Pre-clinically, 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. The first-in-human of RP12146 as a single agent is underway to determine the safety, pharmacokinetics and anti-tumor activity. Methods: The phase I/Ib study was designed as two-part study. Phase I was a dose escalation, 3+3 design, MTD determination study and would enroll pts who have tumors which are known to harbour DNA repair deficiencies. Phase Ib is dose expansion at the MTD/ optimal dose and would enroll thirty-six pts (12 pts each of advanced/metastatic ovarian cancer (OC), breast cancer (BC), and castration-resistant Prostate cancer (mCRPC) having a confirmed deleterious HRR mutation. RP12146 was administered orally in a 28-days cycles until disease progression. Safety were the primary outcome and the investigator-assessed ORR, CBR and PFS assessed using RECIST v1.1, are the secondary outcomes. Predictive biomarker analysis included inhibition of PARP enzyme as measured by gH2AX levels in PMBCs. Results: As of 31-Jan-2023, 9 pts in the dose escalation at 3 dose levels (100 mg QD, 200mg BID and 400 mg BID) and 13 pts (with 5 CHEK2, 4 BRCA2, 2 ATM, 1 CDK12, and 1 RAD51C mutations) in dose expansion have been enrolled. No DLTs were reported in dose escalation. The dose of 400mg BID was considered for dose expansion. Out of 22 pts enrolled, 13 pts had PC, 3 pts had OC, and 2 pts had BC. Most of the related AEs reported were mild in severity except one event of Grade 3 anaemia which resolved, and patient continues to be on therapy. None of the pts developed related SAEs or discontinued due to an AE. Eleven patients (50%) in the expansion group continue to be on RP12146 treatment. RP12146 exhibited rapid absorption achieving maximum concentrations in 1 hr, with an elimination half-life of ~ 4 hrs. Out of the 7 efficacy evaluable PC patients, 5pts showed stable disease and 2pts showed progressive disease. Out of 3 OC pts, 2 pts showed stable disease, and one pt had progressive disease. Among two BC pts, one showed stable disease and the other had progressive disease. Overall, out of 16 efficacy evaluable patients, 8 patients (50%) showed stable disease. Conclusions: RP12146 showed a differentiated safety profile so far with limited hematological toxicities reported as compared to the first-generation PARP inhibitors. Updated safety and efficacy data will be provided at the time of presentation. Clinical trial information: NCT05002868.