Background: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) has demonstrated improvement in overall survival for patients with metastatic triple negative breast cancer (mTNBC). Despite great interest in enhancing efficacy of ADCs using combination therapy, there are no approved regimens. Preclinical data suggest that SG synergizes with Poly ADP-ribose polymerase inhibitors (PARPi) to induce DNA damage and cell death. Though the phase 1b study demonstrated intolerable myelosuppression with simultaneous dosing, tolerability was improved with sequential administration of SG and the PARPi talazoparib (Bardia AACR 2022). Here we report clinical outcomes from the phase II dose expansion cohort (NCT04039230). Methods: In a single-arm phase II study, adult patients with measurable mTNBC (per ASCO/CAP guidelines) were eligible. Starting dose was SG at 10mg/kg on days 1 and 8 with talazoparib 1mg on days 15-21. Growth factor (G-CSF) prophylaxis was required. The primary endpoint was the confirmed Objective Response Rate (ORR) calculated per RECIST v1.1 and secondary endpoints included progression-free survival (PFS) and overall survival (OS). The Clinical Benefit Rate (CBR) at 6 months was also measured. Results: From June 2021 to March 2023, 26 patients were enrolled. The median age was 54 (range, 35 to 81). Patients received a median of 2 prior therapy lines for metastatic disease (range, 0 to 7). 6/26 patients remain on treatment at time of data cutoff. Median PFS was 6.2 months (95% CI, 3.7 to 12.8), and median OS was 18.0 months (95% CI, 10.7 to not evaluable). The confirmed ORR was 30.1% (95% CI, 14 to 52) and the CBR at 6 months was 53.8% (95% CI, 33 to 73). Serious adverse events (AEs) were seen in 10 (38.5%) of patients; in 7 (26.9%) serious AEs were treatment related. The most common treatment related AEs were anemia (92.3%), neutropenia (88.5%), nausea (84.6%) fatigue (80.7%), and thrombocytopenia (65.3%). Grade ≥3 neutropenia and anemia were seen in 80.7% and 34.6% of cases, respectively. One or more dose reductions were required in 58.0% of patients. One patient with a germline BRCA mutation was treated for 625 days before disease progression. Updated biomarker and survival data will be presented at the meeting. Conclusions: In this single-arm phase II study, SG in combination with talazoparib was feasible and demonstrated preliminary evidence of efficacy. A randomized clinical trial is needed to determine if the SG-PARPi combination is superior to SG monotherapy. Clinical trial information: NCT04039230.