Testing Olaparib Either Alone or in Combination With Atezolizumab in BRCA Mutant Non-HER2-positive Breast Cancer

PRIMARY OBJECTIVE: I. To compare the progression free survival (PFS) between two study arms, i.e., olaparib monotherapy (arm 1) and olaparib + atezolizumab in combination (arm 2) based on normal Response Evaluation Criteria in Solid Tumors (RECIST) criteria in patients with locally advanced or metastatic non-HER2-positive breast cancer harboring homologous deoxyribonucleic acid (DNA) repair (HDR) through BRCA 1/2 mutation. SECONDARY OBJECTIVES: I. To compare the progression free survival (PFS) between the two study arms based on immune response criteria. II. To compare the time to treatment failure (TTF) between the two study arms based on immune response criteria and normal RECIST. III. To compare the overall response rate (ORR) between the two study arms based on immune response criteria and normal RECIST. IV. To compare the duration of response (DoR) between the two study arms based on immune response criteria and normal RECIST. V. Determine the changes in extent of mutational burden in BRCA 1/2 mutated tumors at baseline and at progression. VI. Evaluate and characterize changes in the extent of PD-L1 expression and tumor immune infiltrates. VII. Retrospectively evaluate tumors with limited immune infiltrate (e.g. "non-inflamed") to determine if PARPi increased immune infiltration. VIII. Determine the immune-related best overall response (irBOR) of olaparib in combination with atezolizumab in locally advanced or metastatic non-HER2+ breast cancer harboring HDR through BRCA 1/2 mutation. EXPLORATORY OBJECTIVES: I. Evaluate changes in candidate neoantigen profiles and immune/inflammation signatures using DNA and ribonucleic acid (RNA)-sequencing in serial tumor biopsies. II. Evaluate and characterize circulating tumor DNA (ctDNA) and immune parameters in blood. III. Test the hypothesis that DNA repair status affects the tumor-immune interaction. IV. Characterize mechanism of action of the PARP inhibitor olaparib. V. To explore the inclusion of patient reported symptomatic adverse events. VI. To use anti-Kynurenine antibodies for immunohistochemistry (IHC) as well as unbiased metabolome studies on plasma to understand the metabolic consequences of PARP-inhibition and their effects on immune infiltrates. VII. To explore pharmacodynamic transcriptional changes induced by treatment in different immune cell populations and with high resolution in single cell RNA sequencing of peripheral blood mononuclear cell (PBMC) preparations. This will also be used to study changes in specific T-cell clonotypes. VIII. To examine increased mitotic errors during response that are surveilled by the innate immune system. IX. To test whether mutations or expression changes in genes tied to DNA repair regulation arise during acquired resistance and can be discerned by comparative genomics of pre- and at- progression biopsies. X. To examine whether biomarker development tied to mitotic errors will be of future utility in predicting PARPi response. XI. To test DNA methylation relationship to resistance mechanism and RNA sequencing (seq). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive olaparib orally (PO) twice daily (BID) on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross-over to Arm II. Patients undergo an x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI), bone scan, and/or positron emission tomography (PET) scan as well as a biopsy and blood sample collection throughout the trial. Patients may also undergo a bone marrow aspiration and biopsy on study. ARM II: Patients receive olaparib as in Arm I and atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, CT scan, MRI, bone scan, and/or PET scan as well as a biopsy and blood sample collection throughout the trial. Patients may also undergo a bone marrow aspiration and biopsy on study. After completion of study treatment, patients are followed up at 30 days. Patients who come off treatment for reasons other than disease progression are followed every 4-8 weeks.