Inclusion Criteria:
- Female (assigned at birth), greater than or equal to (>=) 18 years old, and able to provide informed consent
- Histologically confirmed metastatic or locally advanced breast cancer
- Postmenopausal status defined by surgical or natural menopause, or ovarian suppression with a GnRH agonist
- Prior therapy including
1. Must have received at least one endocrine therapy in the metastatic setting.
2. Must have received at least one cyclin-dependent kinase (CDK) 4/6i, either in the adjuvant and/or metastatic setting.
3. For Part 1 and Part 2 Cohorts 2A, 2B, 2C, and 2D: Participants may have received up to two prior distinct cytotoxic regimens (for example, taxanes, antibody-drug conjugates (ADCs), etc.) in the metastatic setting, unless discussed and approved by the medical monitor.
4. For Part 2 Cohort 2E: Participants must have received more than two prior distinct cytotoxic regimens (for example, taxanes, ADCs, etc.) in the metastatic setting.
- Radiologic disease progression on the most recent therapy
- Patients must have disease evaluable per response evaluation criteria in solid tumors (RECIST) v1.1
1. For Part 1 and Part 2B, 2C, and 2E: Participants may have either evaluable or measurable disease per RECIST v1.1.
2. For Part 2 Cohort 2A: Participants should have measurable soft tissue disease per RECIST v1.1.
3. For Part 2 Cohort 2D: Participants should have evaluable but not measurable disease.
- Willingness to provide baseline and on-treatment tumor biopsies, unless not feasible or medically appropriate
- For Part 1 and Part 2 (all cohorts):
1. Participants must have documented >=10% ER staining and human epidermal growth factor receptor 2 (HER2) negative (per american society of clinical oncology \[ASCO\] college of american pathologists \[CAP\] guidelines) on the most recent tumor biopsy sample obtained.
2. For Part 2 Cohort 2B: Participants must have recent estrogen receptor 1 gene (ESR1) wild type from tumor or circulating tumor deoxy ribonucleic acid (ctDNA) testing performed after the most recent endocrine therapy prior to enrollment.
3. For Part 2 Cohort 2C: Participants must have ESR1 mutation detected from tumor or ctDNA testing performed prior to enrollment.
- Eastern cooperative oncology group (ECOG) performance status 0-1 and life expectancy of at least 3 months
- Adequate organ function Recovery from prior therapy-related toxicities to Grade <=1 (except alopecia; neuropathy and endocrinopathies <=Grade 2)
- Ability to swallow oral medication and comply with study procedures
- Stable dose (>=30 days) of bisphosphonates or denosumab, if applicable
Exclusion Criteria:
- Participants with Inflammatory breast cancer or leptomeningeal disease or brain metastases, with the exception of patients with definitively treated brain metastases that are clinically stable and asymptomatic for >2 weeks and who are off or receiving low-dose corticosteroid treatment (<=10 mg prednisone or equivalent) for at least 2 weeks prior to start of study treatment.
- Recent major bleeding or uncontrolled bleeding disorder
- Ongoing corticosteroid use >10 mg/day (prednisone equivalent)
- Recent anticancer or investigational therapy within 14 days (28 days for fulvestrant)
- Untreated or unstable spinal cord compression
- Significant cardiovascular disease within 6 months or ongoing uncontrolled cardiac conditions
- Active or uncontrolled infection (controlled HIV or treated hepatitis C allowed)
- Uncontrolled renal, pancreatic, or liver disease (excluding stable conditions such as Gilbert's syndrome or liver metastases)
- Another malignancy requiring treatment within 2 years (except low-risk, curatively treated cancers)
- Major surgery within 28 days
- Any condition that may interfere with safety or study compliance
- Pregnancy or breastfeeding