This is a Phase 1/2 dose escalation and cohort expansion study and will assess the safety, tolerability and anti-tumor activity of ARV-471 alone and in combination with palbociclib (IBRANCE®) in patients with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) locally advanced or metastatic breast cancer, who have received prior hormonal therapy and chemotherapy in the locally advanced/metastatic setting.
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Inclusion Criteria: Part A, Part B, and Part C: * Patients at least 18 years of age at the time of signing the informed consent. * Patients must have histologically or cytologically confirmed ER+ and HER2- advanced breast cancer for which standard curative therapy is no longer effective or does not exist. * Patients must have measurable or non-measurable disease by RECIST criteria (version1.1), with radiologic tumor assessments performed within 28 days of the first dose of therapy. * Patients must be willing to undergo a core biopsy of accessible tumor within 4 weeks prior to the initiation of study treatment and a follow-up biopsy on treatment for ER immunohistochemistry (IHC) testing and pharmacodynamics (PD) studies. (Patients without accessible tumor tissue may be eligible after discussion with the Medical Monitor.) * Women must be postmenopausal due to surgical or natural menopause. Part A: \- Patients must have received at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or advanced/metastatic) a CDK4/6 inhibitor and up to 3 prior regimens of cytotoxic chemotherapy in the locally advanced or metastatic setting. Part B: * Patients must have received at least 1 prior endocrine regimen for a minimum of 6 months in the locally advanced or metastatic setting; if more than 1 prior endocrine regimen has been administered, only one of the regimens must have been administered for a minimum of 6 months in the locally advanced or metastatic setting * Patients must have received a CDK4/6 inhibitor * Patients must have received up to 1 prior regimen of cytotoxic chemotherapy in the locally advanced or metastatic setting * Women must be postmenopausal due to surgical or natural menopause. Part C: * Patients must have received at least one prior endocrine regimen. * Patients must have received no more than two prior chemotherapy regimens for advanced disease. * Women must be postmenopausal due to surgical or natural menopause. Exclusion Criteria: Part A, Part B, and Part C: * Patients with known symptomatic brain metastases requiring steroids (above physiologic replacement doses). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to first dose of study drug, have discontinued high-dose corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable as judged by the Investigator. * Receipt of prior anti-cancer or other investigational therapy within 14 days prior to the first administration of study drug. * Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to \>25% of the bone marrow. Palliative radiation for the alleviation of pain due to bone metastasis will be allowed during the study.