Breast Cancer Clinical Trials

• Participants must have histologically confirmed estrogen receptor-positive (ER+), HER2- negative metastatic or locally recurrent unresectable (advanced) invasive breast cancer.

• ER and HER2 measurements should be performed according to institutional guidelines in a CLIA-approved setting. ER must be ≥ 10% on the most recent biopsy in which receptor testing was performed. Cutoff values for positive/negative HER2 staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines

• Participants must have standard of care testing documenting ESR1 mutation status. In patients without ESR1 mutation, this result must be from within 2 months.

‣ qualifying ESR1 mutations: E380Q, V422del, S436P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, D538G

• Women or men age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of capecitabine in combination with elacestrant participants \<18 years of age are excluded from this study

• Women must be postmenopausal, which is defined as any of the following:

‣ Age ≥ 60 years

⁃ Age \< 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range

⁃ Premenopausal women who have been on a GnRH agonist for at least three consecutive months prior to study entry are eligible. Women in this group MUST remain on the GnRH agonist for the duration of protocol treatment.

⁃ Status-post bilateral oophorectomy or total hysterectomy after adequate healing post-surgery

• Must have measurable or evaluable disease by RECIST 1.1. Must have progressed on at least one line of endocrine therapy in the metastatic setting or recurred on or within one year of adjuvant endocrine therapy

• Up to two prior endocrine therapies (with or without targeted treatment) are allowed in the advanced disease setting. If a patient recurred on or within one year of adjuvant endocrine therapy, it would be counted as one line of treatment.

• Prior CDK4/6 inhibition is required (in adjuvant or metastatic disease), unless a CDK4/6 inhibitor is contraindicated (CDK4/6 inhibitor in combination with endocrine treatment is considered as one line of endocrine treatment).

• Participants must have remained on a prior endocrine treatment alone or in combination with a CDK4/6 inhibitor in the metastatic setting without progression for at least 6 months prior to study entry. This regimen does not need to be the most recent regimen prior to study entry. If patients have progressed on adjuvant endocrine treatment and have not received treatment in the metastatic setting, they must have progressed after at least two years of adjuvant endocrine treatments.

• Prior alpelisib with endocrine treatment is allowed (considered as a line of endocrine treatment).

• Prior everolimus with endocrine treatment is allowed (considered a line of endocrine treatment).

• Prior capivasertib with endocrine treatment is allowed (considered a line of endocrine treatment)

• Prior fulvestrant is permitted. Prior elacestrant is NOT permitted, but prior other oral SERD is permitted.

• No prior chemotherapy regimen is allowed in the metastatic setting.

• Participants may have received radiotherapy for palliative purposes but must not be experiencing grade \>1 treatment-related toxicities at study entry and must have completed treatment \> 14 days prior to registration.

• ECOG PS 0-1

• Adequate hematological, liver, and kidney function, as defined below:

‣ Absolute neutrophil count \> 1,500/µL

⁃ Platelets \> 100,000/µL

⁃ Hemoglobin \> 9 g/dL (transfusion is allowed to meet this criterion) Total bilirubin \< 1.5 x institutional upper limit or normal (ULN) or \< 3 institutional ULN in the presence of documented Gilbert's syndrome

⁃ AST (SGOT)/ALT (SGPT) \< 2.5 x institutional ULN, or ≤ 5 institutional ULN for subjects with documented metastatic disease to the liver

⁃ Creatinine clearance \> 30 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN

• Women of childbearing age, women who are made postmenopausal through use of GNRH agonists, and men must agree to use adequate contraception for the duration of protocol treatment and for at least 6 months after the last dose of capecitabine.

• Premenopausal women must have a negative serum or urine pregnancy test. Pregnancy testing does not need to be pursued in female participants who are:

‣ Age \> 60 years; or

⁃ Age \< 60 with intact uterus and amenorrhea for 12 consecutive months or more AND estrogen (estradiol) and FSH levels are within postmenopausal range; or

⁃ Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation

• Participants must be able to swallow and retain oral medication.

• Ability to understand and the willingness to sign a written informed consent document.

• HIV-infected participants must have well-controlled HIV on ART, defined as:

∙ Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening.

‣ Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.

‣ It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months.

‣ Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study. The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates.

• Note: No HIV testing is required at screening unless mandated by local health Authority.

• Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load before allocation.

• Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

• Hepatitis B screening tests are not required unless:

• Known history of HBV infection

• As mandated by local health authority Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. Note: Participants must have completed curative antiviral therapy at least 4 weeks before allocation.

• Hepatitis C screening tests are not required unless:

• Known history of HCV infection

• As mandated by local health authority