Investigating the impact of adding olaparib, or olaparib and durvalumab together, to standard chemotherapy before surgery in young, pre-menopausal women with HER2-negative breast cancer.

ACTRN 12623000657628

Brief Summary

This study aims to find out if adding the medications olaparib, or olaparib + durvalumab together, to standard chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells given to premenopausal women with HR-positive, HER2-negative, HRD-positive breast cancera disease where abnormal cells split without control and spread to other nearby body tissue and/or organs before surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence will do a better job of controlling the cancer.

Intervention/Treatment

• Drug: Olaparib.
• Drug: Durvalumab.
• Drug: Paclitaxel.

Inclusion Criteria

PRE-SCREENING:
For inclusion in pre-screening for the study, participants must fulfil all the following criteria:

1. Has provided written, informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment. to participate in pre-screening for the study.
2. Female aged >= 18 to <= 44 years at the time of breast cancer diagnosisthe process of identifying a disease based on signs and symptoms, patient history and medical test results.
3. Premenopausal as defined as the presence of at least one ovary at the time of diagnosis of breast cancer.
4. Histologically confirmed ER-positive and HER2-negative early breast cancer by local assessment:
   • ER-positive is defined as >= 1% of tumoura tissue mass that forms from groups of unhealthy cells nuclei positive for ER via IHC analysis [CAP Guidelines 2020].
   • HER2-negative is defined as a negative ISH test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative ISH result is also required [CAP Guidelines 2018].
   • PR may be positive or negative.
5. High disease burden defined as either:
   • cT1c-T2, cN1-cN3
     OR
   • cT3-T4a-c, cN0-cN3.
     Note: multicentric tumours are allowed with at least 1 tumour >= 10 mm at diagnosis. Tumour in each quadrant needs to be confirmed to be hormonea chemical substance produced by glands in the endocrine system that regulates various functions in the body receptor-positive and HER2-negative breast cancer as per Pre-screening Eligibility Criteria 4.
     Note: Inflammatory breast cancer is allowed.
6. High riskthe possibility that something bad will happen as defined by either:
   • Age < 35 years at diagnosis OR
   • Age 35 – 44 years at diagnosis and gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells 3 tumour by local pathologista doctor who specialises in the study and diagnosis of disease through the examination and testing of body tissue assessment OR
   • Age 35-44 years at diagnosis and tumour Ki67 >= 20% by local pathologist assessment.
7. Planned to complete or has completed a maximum of 1 cycle of neoadjuvant treatment that starts with 4 cycles of standard anthracycline-based chemotherapy.
8. Two FFPE tumour blocks or 10 slides comprising the largest available tumour tissuea group of cells that work together to perform a function (area and cellularity) from a new biopsyremoval of a section of tissue to analyse for cancer cells or previously taken biopsy will be used for assessment of homologous recombination deficiency (HRD) status, as well as for correlative research. If deemed inadequate for the SOPHiA DDM (TM) assay by the test laboratory, other archival blocks can be assessed provided they were obtained within 12 months of pre-screening consent.

RANDOMISATION
In addition to the above listed pre-screening inclusion criteria, participants must fulfil all of the following criteria before randomisation:

1. Has provided written, informed consent to participate in the study.
2. Confirmed HRD-positive status evaluated by SOPHiA DDM(TM) HRD NGS assay.
   Note: HRD-positive status is defined as having a Genomic Instability Index (GII) of > 0 and/or identification of a predicted loss of function germline or tumour mutation in one of the following homologous recombination repair genes (BRCA1, BRCA2, PALB2, RAD51C, RAD51D) as determined by the SOPHiA DDM(TM) HRD NGS assay.
3. Has completed at least 3 cycles of anthracycline-based neoadjuvant chemotherapy.
4. Has an Eastern Cooperative Oncologythe study, diagnosis and treatment of cancer Group (ECOG) performance status of 0 or 1.
5. Body weight >30 kg.
6. Adequate organ function within 28 days before the start of study treatment, as defined by:
   • Haemogoblin >= 10 g/dL
     Note: Prior red bloodthe red bodily fluid that transports oxygen and other nutrients around the body cell transfusion is permitted but must not occur within 28 days before randomisation.
   • Plateletssmall disc-shaped blood cells that clump together to form clots to stop bleeding >= 100 x 10^9/L
     Note: Prior platelet transfusion is permitted for treatment of chemotherapy-related thrombocytopaenia
   • Absolute neutrophil count >= 1.5 x 10^9/L.
   • Creatinine <= 1.5 x ULN or serum creatinine clearance >= 50 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance.
   • Total bilirubin <= 1.5x ULN (Total bilirubin must be < 4 x ULN for patients with Gilbert’s Syndrome).
   • AST and ALT <= 2.5x ULN.
   • International normalised ration (INR)a blood test that measures how quickly your blood clots/ Prothrombin time (PT) <= 1.5 ULN unless participant is receiving anticoagulantmedication used to prevent or reduce blood clots; also known as blood thinners therapy. The participant is eligible as long as the INR, PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants.
7. Negative urine or serum pregnancy test within 28 days of the first dosethe amount of medication taken of study treatment and confirmed before Day 1 (-5 days) of study treatment for Women of Childbearing Potential (WOCBP).
8. WOCBP must agree to use a highly effective method of contraception from the signing of informed consent until 9 months after the last dose of study treatment. WOCBP are defined as a premenopausal woman who has NOT had either documented hysterectomycomplete or partial removal of the uterus, documented bilateralaffecting both sides salpingectomyremoval of one (unilateral) or both (bilateral) fallopian tubes.
9. Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with BCT and the Study Chair.