Study of Neoadjuvant Olaparib Monotherapy and Olaparib and Durvalumab Combination in HER2 Negative BRCAm Breast Cancer

Inclusion Criteria

• Males or Females ≥18 years
• Minimum body weight of 30 kg
• Capable of giving signed informed consent.
• Male and Female participants of childbearing potential must use effective methods of contraception
• Histologically confirmed, newly diagnosed, primary, operable, nonmetastatic invasive breast cancer with the following characteristics: --ER-negative or ER-low defined as IHC nuclear staining ≤10%
• HER2-negative (not eligible for anti-HER2 therapy) defined as:
• IHC 0, 1+ without in situ hybridization OR
• In situ hybridization non-amplified with ratio less than 2.0 OR
• In situ hybridization average HER2 copy number < 6 signals/cells
• Clinical TNM staging (per AJCC 8th Edition) as follows:
• T1b (>5 mm but ≤10 mm), N0, no known metastases (M0 or MX); OR
• T1c (>10 mm but ≤20 mm), N0, no known metastases (M0 or MX); OR
• T1 (>1 mm but ≤20 mm), N1, no known metastases (M0 or MX); OR
• T2 (>20 mm but ≤50 mm), N0, no known metastases (M0 or MX).).
• Documented deleterious or suspected deleterious mutation in BRCA1 or BRCA2 from local BRCA testing using either a germline or tumour test.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Participants must have adequate organ and bone marrow function
• Participant must be willing to undergo a baseline research biopsy prior to start of study treatment.
• Participant must be willing to have any leftover tumour tissue/FFPE from the diagnostic biopsy submitted for research purposes, if available.

Exclusion Criteria

• Any evidence of other diseases (such as severe or uncontrolled systemic diseases or active, uncontrolled infections, including but not limited to, uncontrolled ventricular arrhythmia, uncontrolled hypertension, recent [within 3 months] myocardial infarction, uncontrolled major seizure disorder, renal transplant, active bleeding diseases, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography scan
• Refractory nausea and vomiting, chronic gastrointestinal disease likely to interfere with absorption of the study medication, inability to swallow the formulated product
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease for ≥5 years before the first dose of study intervention and of low potential risk for recurrence
• Participants with MDS or AML
• For higher risk (Cohort B) participants only: Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, and autoimmune myocarditis
• Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody
• Known to have tested positive for human immunodeficiency virus unless currently on effective anti-retroviral therapy with an undetectable viral load within 6 months
• History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia
• Participant must not have had any prior treatment for the current breast cancer, including surgery, chemotherapy, hormonal therapy, radiation, or experimental therapy
• For higher risk (Cohort B) participants only: Prior exposure to anti-PD1, anti-PD-L1, or anti-CTLA4 agents (ICIs); OR an agent directed to other co-inhibitory or co-stimulatory T-cell receptors
• Any concurrent anticancer treatment
• Major surgical procedure (excluding placement of vascular access, local surgery of isolated lesions, or diagnostic staging) within 2 weeks of the first dose of study intervention
• For higher risk (Cohort B) participants only: Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
• Concomitant use of:
• Known strong cytochrome P450 (CYP3A) inhibitors or moderate CYP3A inhibitors within 2 weeks prior to first dose of study intervention
• Known strong CYP3A inducers or moderate CYP3A inducers .The required washout period prior to starting study therapy is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents