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Background: Poly-ADP ribose polymerase inhibitors (PARPi) work by impairing DNA damage repair and have demonstrated activity in patients with BRCAmt breast cancer. Their mechanism of action leads to high mutational burden and increased neoantigens suggesting tumors exposed to PARPi may have increased response to immunotherapy. Preclinical and phase I/II trials have shown evidence of antitumor effect of PARPi + PD-L1 inhibition. In this study, we assessed the efficacy of the PARPi olaparib as monotherapy vs. in combination with PD-L1 inhibitor atezolizumab in patients with BRCAmt advanced breast cancer. Methods: A multicenter, randomized, open-label, phase II study was conducted. Patients were enrolled at 20 sites in the US. Patients were allowed prior hormone or chemotherapy and randomized to receive olaparib 300 mg twice daily (O) +/- atezolizumab 1200 mg IV every 21 days (O+A) until disease progression or intolerable side effect. Patients with progression on O were allowed to crossover to O+A arm. The primary endpoint was comparison of progression free survival (PFS) between arms. Overall survival (OS) was also assessed. Safety and activity analyses were done in patients who received at least one dose of study treatment. Serial tumor biopsies were collected at baseline, 6 weeks, and progression to evaluate the effect of therapy on tumor infiltrating lymphocyte populations, whole exome DNA sequencing, and correlate with outcome to assess predictive value. Enrollment has completed and the study is ongoing. The trial is registered with ClinicalTrials.gov, NCT02849496. Results: 78 patients with BRCAmt advanced breast cancer were enrolled between 5/3/2018 and 3/17/2022 and available for analysis. Groups were generally well matched on baseline characteristics. PFS was 7.0 months (95% CI 5.5-11.5) in O arm and 7.67 months (95% CI 5.6-10) in O+A arm (p=0.92). Median OS was 26.5 months (95% CI 19.2- NR) in O arm and 22.4 months (95% CI 16.6-31.3) in O+A arm (p=0.3). In triple negative breast cancer (TNBC) subgroup (n=23), there was no significant difference in PFS (p=0.92) or OS (p=0.6). Treatment was generally well tolerated with expected side effects, with O+A group experiencing more adverse events of all grades. Analysis of tumor samples from serial biopsies will be presented separately. Conclusion: Olaparib or combination olaparib + atezolizumab resulted in clinically meaningful PFS in both treatment arms. Addition of atezolizumab did not significantly increase PFS. Treatment in both arms was generally well tolerated with expected side effects based on prior drug profiles. This is the first randomized trial to show that the addition of immunotherapy (atezolizumab) to PARPi (olaparib) in patients with advanced BRCAmt breast cancer does not add to therapeutic response but carries with it additional toxicities. Citation Format: Kristina A. Fanucci, Mary Jo Pilat, Derek Shyr, Yu Shyr, Scott A. Boerner, Diane Durecki, Anne Noonan, Vandana Abramson, Cesar Santa-Maria, Hyo Han, Rita Nanda, Elizabeth Claire Dees, Haeseong Park, Saundra Buys, Namrata Peswani, Helen Chew, Hadeel Assad, Gerburg Wulf, Angelique Richardson, Meghna S. Trivedi, Adam Brufsky, James Abbruzzese, Anosheh Afghahi, Elad Sharon, Kurt Schalper, Patricia LoRusso. Olaparib +/- atezolizumab in patients with BRCA-mutated (BRCAmt) locally advanced unresectable or metastatic (advanced) breast cancer: an open-label, multicenter, randomized phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT145.