saruparib (azd5305) plus camizestrant compared with cdk4/6 inhibitor plus endocrine therapy or plus camizestrant in hr-positive, her2-negative (ihc 0, 1+, 2+/ ish non-amplified), brca1, brca2, or palb2m advanced breast cancer

Conditions: Advanced Breast Cancer

Summary: the primary objective of the study is to measure efficacy of saruparib (azd5305) plus camizestrant compared with physician's choice cdk4/6i plus et in patients with brca1, brca2, or palb2m, hr-positive, her2-negative (defined as ihc 0, 1+, 2+/ ish non-amplified) advanced breast cancer

approximately 2,620 participants will be screened to achieve approximately 500 participants randomised to study intervention. participants will be randomised in a 2:2:1 ratio to one of the following intervention groups: * arm 1: saruparib (azd5305) plus camizestrant * arm 2: physician's choice cdk4/6i plus physician's choice et * arm 3: physician's choice cdk4/6i plus camizestrant treatment continues until bicr-confirmed disease progression, unacceptable toxicity occurs, or the participant withdraws consent.

Eligibility criteria:
inclusion criteria: * adult females, pre/peri-menopausal and/or post-menopausal, and adult males * histologically or cytologically documented diagnosis of hr-positive, her2-negative breast cancer * advanced breast cancer with either locally advanced disease not amenable to curative treatment or metastatic disease * ecog performance status of 0 or 1 with no deterioration over the previous 2 weeks * ffpe tumour tissue from each participant * documented germline tumour loss of function mutation in brca1, brca2, or palb2 * adequate organ and marrow function exclusion criteria: * participants with history of mds/aml or with features suggestive of mds/aml * participants with any known predisposition to bleeding * any history of persisting severe cytopenia * any evidence of severe or uncontrolled systemic diseases or active uncontrolled infections * refractory nausea and vomiting, chronic gi disease, inability to swallow the formulated product, or previous significant bowel resection * history of another primary malignancy * persistent toxicities (ctcae grade ≥ 2) caused by previous anti-cancer therapy excluding alopecia * spinal cord compression, brain metastases, carcinomatous meningitis, or leptomeningeal disease * evidence of active and uncontrolled hepatitis b and/or hepatitis c * evidence of active and uncontrolled hiv infection * active tuberculosis infection * cardiac criteria, including history of arrythmia and cardiovascular disease * concurrent exogenous reproductive hormone therapy or non-topical hormonal therapy for non-cancer-related conditions * major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study * palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study treatment * prior treatment with systemic anti-cancer therapy for locoregionally recurrent or metastatic disease is not permitted, apart from treatment with et up to 28 days before randomisation * prior treatment within 28 days with blood product support or growth factor support * any systemic concurrent anti-cancer treatment * concomitant use of the following types of medications or herbal supplements within 21 days or at least 5 half-lives of randomisation: 1. strong and moderate cyp3a4 inducers/inhibitors 2. sensitive cyp2b6 substrates 3. substrates of cyp2c9 and/or cyp2c19 which have a narrow therapeutic index, eg, warfarin (and other coumarin-derived vitamin k antagonist anticoagulants) and phenytoin. * concomitant use of drugs that are known to prolong qt and have a known risk of tdp * systemic use of atropine * the following exclusion criteria apply to treatments administered for early breast cancer: 1. disease progression ≤ 84 days following the last dose of neo-adjuvant or adjuvant chemotherapy 2. disease progression ≤ 1 year (365 days) from the last dose of treatment with a parpi and/or platinum agent for early breast cancer 3. disease progression ≤ 1 year (365 days) from the last dose with a cdk4/6i in the adjuvant setting 4. disease progression ≤ 1 year (365 days) from the last dose of an oral serd including camizestrant.