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 ofcontraception

• Histologically confirmed, newly diagnosed, primary, operable, nonmetastatic invasivebreast 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 fromlocal 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 ofstudy treatment.

• Participant must be willing to have any leftover tumour tissue/FFPE from thediagnostic biopsy submitted for research purposes, if available.

Exclusion Criteria:

• Any evidence of other diseases (such as severe or uncontrolled systemic diseases oractive, uncontrolled infections, including but not limited to, uncontrolledventricular arrhythmia, uncontrolled hypertension, recent [within 3 months]myocardial infarction, uncontrolled major seizure disorder, renal transplant, activebleeding diseases, unstable spinal cord compression, superior vena cava syndrome,extensive interstitial bilateral lung disease on High Resolution Computed Tomographyscan

• Refractory nausea and vomiting, chronic gastrointestinal disease likely to interferewith absorption of the study medication, inability to swallow the formulated product

• History of another primary malignancy except for malignancy treated with curativeintent with no known active disease for ≥5 years before the first dose of studyintervention and of low potential risk for recurrence

• Participants with MDS or AML

• For higher risk (Cohort B) participants only: Active or prior documented autoimmuneor inflammatory disorders (including inflammatory bowel disease [eg, colitis orCrohn's disease], diverticulitis [with the exception of diverticulosis], systemiclupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, andautoimmune myocarditis

• Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virussurface antigen or hepatitis B virus core antibody

• Known to have tested positive for human immunodeficiency virus unless currently oneffective 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 oruncontrolled atrial fibrillation despite treatment, or asymptomatic sustainedventricular tachycardia

• Participant must not have had any prior treatment for the current breast cancer,including surgery, chemotherapy, hormonal therapy, radiation, or experimentaltherapy

• 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-inhibitoryor co-stimulatory T-cell receptors

• Any concurrent anticancer treatment

• Major surgical procedure (excluding placement of vascular access, local surgery ofisolated lesions, or diagnostic staging) within 2 weeks of the first dose of studyintervention

• For higher risk (Cohort B) participants only: Current or prior use ofimmunosuppressive medication within 14 days before the first dose of durvalumab.

• Concomitant use of:

• Known strong cytochrome P450 (CYP3A) inhibitors or moderate CYP3A inhibitorswithin 2 weeks prior to first dose of study intervention

• Known strong CYP3A inducers or moderate CYP3A inducers .The required washoutperiod prior to starting study therapy is 5 weeks for enzalutamide orphenobarbital and 3 weeks for other agents