Background: Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. This Phase 1 trial evaluates the tolerability, dose limiting toxicities (DLT) and efficacy of, the PARP inhibitor, talazoparib, in combination with carboplatin in patients with or without DNA repair mutations. We hypothesize that talazoparib may overcome carboplatin resistance but induce greater toxicity in patients with DNA repair defects. Methods: Talazoparib and carboplatin pharmacokinetics (PK), safety and anti-tumor activity were evaluated in a 3+3 dose escalation design. Genetic testing, PK, pharmacodynamic effects (PD), and alternate dose modeling were evaluated to better understand the interaction of carboplatin and talazoparib. Results: 24 patients were enrolled in 4 cohorts and treated with talazoparib 0.75 or 0.1 mg/day and carboplatin AUC 1 or 1.5 for 3/3 or 2/3 weeks. Tumor types included: breast, prostate, cholangiocarcinoma, ovarian, bladder and adenoid cystic carcinoma. DLTs were fatigue and thrombocytopenia; other grade 3/4 toxicities included fatigue (13%), neutropenia (33%), thrombocytopenia (33%), and anemia (58%). Post cycle 1 heme toxicities required dose delays/reductions in almost all patients. One complete response occurred in a germline BRCA1 (gBRCA1) breast cancer patient and two partial responses (PR) occurred in gBRCA2 patients (breast and bladder cancer); 11 patients (pts) had stable disease (SD) for ≥ 3 months, 5 pts are not yet evaluable. Thrombocytopenia (11.4% vs. 1.1% P < 0.001) and neutropenia (9.1% vs. 3.8% P < 0.001) were significantly more common in gBRCA carriers. PK modeling suggested that monthly carboplatin dosing in patients with DNA repair defects and every other week dosing in non-carriers may be more tolerable for PARPi and carboplatin combinations. Conclusions: Mutation carriers in BRCA or DNA repair genes responded better to the combination and responses were in prior progression on PARPi and carboplatin, but the combination caused increased heme toxicity in gBRCA or other DNA repair mutations. Less frequent carboplatin dosing may be required when given with PARPi in germ line mutation carriers. Clinical trial information: NCT02358200