Inclusion Criteria:

1. Patient has signed the informed consent before all study specific activities are
conducted.

2. Women or men aged ≥18 years (or the minimum age of consent in accordance with the
local law), at the time of informed consent signature. Female patients may be either
postmenopausal, premenopausal, or perimenopausal.

-Postmenopausal status is defined by:

1. Age ≥60 years

2. Age <60 years and amenorrhea for 12 or more months (in the absence of
chemotherapy, tamoxifen, toremifene, or ovarian suppression) or a
follicle-stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40
pg/mL (140 pmol/L) or in postmenopausal ranges per local reference ranges

3. Documentation of prior surgical sterilization (i.e., bilateral tubal ligation,
total hysterectomy, or bilateral oophorectomy, at least 1 month before first dose
of trial therapy).

- Premenopausal and perimenopausal women and men must be concurrently
receiving a luteinizing hormone-releasing hormone (LHRH) agonist initiated
at least 4 weeks before the start of trial therapy and are planning to
continue LHRH agonist treatment during the study.

- For perimenopausal women to be considered of non-childbearing potential, FSH
levels must be > 40 mIU/ml.

3. Histopathologically or cytologically confirmed ER+, HER2-, breast cancer, per local
laboratory, as per the American Society of Clinical Oncology (ASCO)/College of
American Pathologists(CAP) guidelines (Allison et al, 2020, Wolff et al, 2018).Note:
In the context of this trial, ER status will be considered positive if ≥ 10% of tumor
cells demonstrate positive nuclear staining by immunohistochemistry.

4. At least one measurable lesion as per RECIST version 1.1 or a mainly lytic bone
lesion.

Note: Patients with stable brain or subdural metastases are allowed if the
patient has completed local therapy and was on a stable or decreasing dose of
corticosteroids at baseline for management of brain metastasis for at least 4 weeks
before starting treatment in this study. The dose must be ≤ 2.0 mg/day of dexamethasone
or equivalent. Any signs (e.g., radiologic) or symptoms of brain metastases must be
stable for at least 4 weeks before starting study treatment.

5. ECOG performance status of 0 or 1.

6. Patient has adequate bone marrow and organ function, as defined by the following
laboratory values:

1. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L

2. Platelets ≥ 100 × 10^9/L

3. Hemoglobin ≥ 9.0 g/dL

4. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE
grade ≤1

5. Cockcroft-Gault based creatinine clearance ≥50 mL/min.

Note:

? Creatinine clearance (male) = ([140-age in years] × weight in kg)/ ([serum
creatinine in mg/dL] × 72)

? Creatinine clearance (female) = (0.85 × [140-age in years] × weight in kg)/
([serum creatinine in mg/dL] × 72)

6. Serum albumin ≥ 3.0 g/dL (≥ 30 g/L)

7. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) ≤ 3.0 × ULN. If the patient has liver metastases, ALT and
AST ≤ 5 × ULN

8. Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndrome who
may be included if the total serum bilirubin is ≤3.0 × ULN or direct bilirubin ≤
1.5 × ULN.

Exclusion Criteria:

1. Active or newly diagnosed CNS metastases, including meningeal carcinomatosis.

2. Patients with advanced, symptomatic visceral spread, that are at risk of
life-threatening complications in the short term, including massive uncontrolled
effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or liver
involvement > 50%.

3. Prior chemotherapy or elacestrant in the advanced/metastatic setting.

4. Patient has a concurrent malignancy or history of invasive malignancy within 3 years
of enrollment, with the exception of basal or squamous cell skin cancer, superficial
bladder cancer, or carcinoma in situ of the cervix that has completed curative
therapy.

5. Uncontrolled significant active infections. ? Patients with hepatitis B virus (HBV)
and/or hepatitis C virus (HCV) infection must have undetectable viral load during
screening.

? Patients known to be HIV+ are allowed as long as they have undetectable viral load
at baseline.

6. Documented pneumonitis/ILD prior to Cycle 1 Day 1.

7. Major surgery within 28 days before starting trial therapy.

8. Inability to take oral medications, refractory or chronic nausea, gastrointestinal
conditions (including significant gastric or bowel resection), history of
malabsorption syndrome, or any other uncontrolled gastrointestinal condition that
impact the absorption of the study drug.

9. Known intolerance to elacestrant or any of its excipients.

10. Females of childbearing potential who:

- Within 28 days before starting trial therapy, did not use a highly effective
method of contraception.

- Do not agree to use a highly effective method of contraception throughout the
entire study period and for 28 days after trial therapy discontinuation

11. Men who do not agree to abstain from donating sperm, or to use a highly effective
method of contraception, during the course of the treatment period and for 120 days
thereafter.

12. Patient is currently receiving or received any of the following medications prior to
first dose of trial therapy:

? Investigational anti-cancer therapy within 14 days (28 days for anticancer antibody
based treatment) or 5 half-lives, whichever is shorter,

- Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4
within 14 days or 5 half-lives, whichever is shorter, (Refer to
http://medicine.iupui.edu/clinpharm/ddis/),

- Herbal preparations/medications within 7 days. These include, but are not limited
to, St. John's wort, kava, ephedra (ma huang), gingko biloba,
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng,

- Vaccination, including but not limited to vaccination against COVID-19, during
the 7 days prior to randomization.

13. Evidence of ongoing alcohol or drug abuse as assessed by the investigator.

Additional Eligibility for the Alpelisib Combination (Phase 1b and Arm A)

Inclusion:

1. PIK3CA mutation by local laboratory assessment.

2. One or two prior hormonal therapies in the metastatic setting, one of which was in
combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with alpelisib or any other PI3K inhibitor.

2. Type 1 diabetes or uncontrolled type 2 diabetes (fasting plasma glucose level of >140
mg/dL [7.7 mmol/L], or glycosylated hemoglobin [HbA1c] level of >6.4%).

3. Known intolerance to alpelisib or any of its excipients.

4. Patient is currently receiving or received drugs known to be a BCRP inhibitor within
14 days or 5 half-lives, whichever is shorter, prior to first dose of trial therapy.

5. Patient has ongoing osteonecrosis of the jaw from previous or concurrent treatment
with bisphosphonates or denosumab.

Additional Eligibility for the Everolimus Combination (Phase 1b and Arm B):

Inclusion Criuteria:

1. One or two prior hormonal therapies in the metastatic setting, one of which was in
combination with a CDK4/6 inhibitor.

Exclusion Criteria:

1. Prior therapy with everolimus.

2. Known intolerance to everolimus or any of its excipients.

Additional Eligibility for the Abemaciclib Combination (Arm C)

Inclusion Criteria:

1. One or two prior hormonal therapies in the metastatic setting, one of which was in
combination with a CDK4/6 inhibitor.

Exclusion Criteria:

1. Prior therapy with abemaciclib in the metastatic setting.

2. Known intolerance to abemaciclib or any of its excipients.

Additional Eligibility for the Ribociclib Combination (Phase 1b and Arm C)

Inclusion Criteria:

1. One or two prior hormonal therapies in the metastatic setting, one of which was in
combination with a CDK4/6 inhibitor.

Exclusion Criteria:

1. Prior therapy with ribociclib in the metastatic setting.

2. Known intolerance to ribociclib or any of its excipients.

3. Patient is currently receiving or received drugs known to prolong QT interval within
14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy.

Additional Eligibility for the Palbociclib Combination (Phase 1b)

Inclusion Criteria:

1. None.

Exclusion Criteria:

1. Prior therapy with palbociclib in the metastatic setting.

2. Known intolerance to palbociclib or any of its excipients

Additional Eligibility for the Palbociclib Combination (Arm D)

Inclusion Criteria:

1. One or two prior hormonal therapies in the metastatic setting.

Exclusion Criteria:

1. Prior therapy with a CDK4/6i in the metastatic setting.

2. Known intolerance to palbociclib or any of its excipients.

Additional Eligibility for the Abemaciclib Combination (Arm D)

Inclusion Criteria:

1. One or two prior hormonal therapies in the metastatic setting.

Exclusion Criteria:

1. Prior therapy with a CDK4/6i in the metastatic setting.

2. Known intolerance to abemaciclib or any of its excipients.

Additional Eligibility for Ribociclib Combination (Arm D)

Inclusion Criteria:

1. One or two prior hormonal therapies in the metastatic setting.

Exclusion Criteria:

1. Prior therapy with a CDK4/6i in the metastatic setting.

2. Known intolerance to ribociclib or any of its excipients.

3. Patient is currently receiving or received drugs known to prolong QT interval within
14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/17/22. Questions regarding updates should be directed to the study team contact.