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

Inclusion Criteria:

• Adult females, pre/peri-menopausal and/or post-menopausal, and adult males

• Histologically or cytologically documented diagnosis of HR-positive, HER2-negativebreast cancer

• Advanced breast cancer with either locally advanced disease not amenable to curativetreatment 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 uncontrolledinfections

• Refractory nausea and vomiting, chronic GI disease, inability to swallow theformulated product, or previous significant bowel resection

• History of another primary malignancy

• Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anti-cancer therapyexcluding alopecia

• Spinal cord compression, brain metastases, carcinomatous meningitis, orleptomeningeal 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 therapyfor non-cancer-related conditions

• Major surgical procedure or significant traumatic injury within 4 weeks of the firstdose 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 withwide field of radiation or to more than 30% of the bone marrow within 4 weeks beforethe first dose of study treatment

• Prior treatment with systemic anti-cancer therapy for locoregionally recurrent ormetastatic disease is not permitted, apart from treatment with ET up to 28 daysbefore 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) andphenytoin.

• 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 breastcancer:

1. Disease progression ≤ 84 days following the last dose of neo-adjuvant oradjuvant chemotherapy

2. Disease progression ≤ 1 year (365 days) from the last dose of treatment with aPARPi and/or platinum agent for early breast cancer

3. Disease progression ≤ 1 year (365 days) from the last dose with a CDK4/6i inthe adjuvant setting

4. Disease progression ≤ 1 year (365 days) from the last dose of an oral SERDincluding camizestrant.