Abstract Purpose: We had previously reported on the safety and the recommended phase 2 dose (RP2D) of olaparib in combination with the PI3Kα-specific inhibitor alpelisib in patients with high-grade serous ovarian cancer as studied in a phase 1b trial (NCT01623349). Here, we report on the breast cancer cohort from that study. Patients and Methods: Eligible patients had recurrent triple-negative breast cancer (TNBC) or recurrent breast cancer of any subtype with a germline BRCA mutation and were enrolled to a dose-escalation or -expansion cohort. After definition of the RP2D, secondary end points included safety and objective response rate (ORR). Exploratory analyses were performed using circulating-free DNA (cfDNA). Results: Seventeen patients with TNBC were enrolled with a median of three prior lines of chemotherapy. The most common treatment-related grade 3–4 adverse events were hyperglycemia (18%) and rash (12%). The ORR was 18% (23% for patients treated at the RP2D) and 59% had disease control. The median duration of response was 7.4 months. Analysis of cfDNA tumor fractions (TFx) revealed that patients with TFx < 15% after completion of the first cycle had a longer progression-free survival compared with those with TFx ≥ 15% (6.0 vs. 0.9 months; P = 0.0001). Conclusions: Alpelisib in combination with olaparib is tolerable in patients with pre-treated TNBC, with evidence of activity in non-BRCA carriers. cfDNA provided important prognostic information. Results highlight potential synergistic use of a PI3K inhibitor to sensitize HR-proficient (BRCA wild-type) TNBC to PARP inhibition and suggest the potential to expand the use of PARP inhibition beyond BRCA-mutant tumors.