• Pre- or postmenopausal.

• Postmenopausal women are defined as:

‣ ≥60 years of age with no vaginal bleeding over the prior year, or

‣ \<60 years with premature menopause or premature ovarian failure manifest itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards, or

‣ surgical menopause with bilateral oophorectomy. Note: premenopausal women who meet all of the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy.

• If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide histological or cytological confirmation of ER+ and HER2- disease as assessed by a local laboratory, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue obtained at the time of the original diagnosis must confirm that the subject's cancer is ER+ and HER2-.

• Locally advanced or metastatic breast cancer with radiological or clinical evidence of progression on an AI in combination with a CDK 4/6 inhibitor for advanced breast cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or progression after at least 12 months of treatment in the metastatic setting).

• Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1) or non-measurable lesions.

• At least one or more of the following point ESR1 mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood (plasma) or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. The ctDNA sample collection must be obtained within 30 days prior to randomization to determine eligibility and baseline. Note: a prior genomic test confirming that the subject has an ESR1 mutation can be used to determine eligibility; however, an ESR1 sample must also be collected within 30 days of randomization.

• Subjects who have not received cytotoxic chemotherapy or those who have received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial and/or no more than one chemotherapy regimen for metastatic breast cancer. Subjects must be free of all chemotherapy acute toxicity excluding alopecia and Grade II peripheral neuropathy before study entry.

• ECOG performance score of 0 or 1.

• Adequate organ function as shown by:

∙ absolute neutrophil count (ANC) \>/=1,500 cells/mm3

‣ platelet count ≤100,000 cells/mm3

‣ hemoglobin \>/=9.0 g/dl

‣ ALT and AST levels ≤2.5 upper limit of normal (ULN) or ≤5 in the presence of visceral metastasis

‣ total serum bilirubin ≤1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert Syndrome)

‣ alkaline phosphatase level ≤ 2.5 X ULN

‣ creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula

‣ International normalized ratio (INR), activated partial thromboplastin (aPTT), or partial thromboplastin time (PTT) \<2.0 X ULN.

• Able to swallow tablets.

⁃ Able to understand and voluntarily sign a written informed consent before any screening procedures.