ELACESTRANT in Women and Men With CDK4/6 Inhibitor-Naive Estrogen Receptor Positive, HER-2 Negative Metastatic Breast Cancer Study

Inclusion Criteria:

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

2. Women or men aged ≥18 years (or the minimum age of consent as per local law), at thetime of informed consent signature. Female patients may be either postmenopausal orpremenopausal/perimenopausal.

3. Premenopausal or perimenopausal women and men must be concurrently given aluteinizing hormone-releasing hormone (LHRH) agonist starting at least 4 weeksbefore the start of trial therapy and is planning to continue LHRH during thestudy.

4. For perimenopausal women to be considered of non-childbearing potential,follicle-stimulating hormone (FSH) levels must be >40 milli-international unitsper milliliter (mIU/mL).

5. Documentation of histopathologically or cytologically confirmed ER+, HER2-breastcancer, per local laboratory, as per the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Note: In the context ofthis trial, ER status will be considered positive if ≥10% of tumor cells demonstratepositive nuclear staining by immunohistochemistry.

6. Radiological disease progression during or after the most recent therapy in theadvanced/metastatic setting

7. Patient has received at least one (and up to two) prior hormonal therapy in theadvanced/metastatic setting.

8. Patients with disease relapse while on adjuvant endocrine therapy after the 2 firstyears, or with disease relapse within 12 months of completing adjuvant endocrinetherapy are allowed (i.e., patients with secondary-resistant breast cancer accordingto the 5th European School of Oncology (ESO)-European Society for Medical Oncology (ESMO) international consensus guidelines for advanced breast cancer, Cardoso et al 2020). This therapy will be considered as first line treatment for eligibilitypurposes.

9. At least one measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or a mainly lytic bone lesion for bone only disease.

10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

11. Patient has adequate bone marrow and organ function, as defined by the followinglaboratory values:

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

13. Platelets ≥100 × 10^9/L

14. Hemoglobin ≥9.0 grams(g)/deciliter(dL)

15. Potassium, sodium, calcium (corrected for serum albumin) and magnesium, CommonTerminology Criteria for Adverse Events (CTCAE) v5.0 grade ≤1. Note: Correctedcalcium for serum albumin must be calculated manually by the site using thePayne formula: Corrected calcium (milligrams [mg]/dL) = measured total calcium (mg/dL) + 0.8 (Normal albumin [g/dL] - serum albumin [g/dL]), where normalalbumin is usually defaulted to 4.0 g/dL.

16. Cockcroft-Gault based creatinine clearance ≥50 milliliters per minute (mL/min).Note: Creatinine clearance (male) = ([140-age in years] × weight in kilograms [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)

17. Serum albumin ≥3.0 g/dL (≥30 g/L)

18. In absence of liver metastases, alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤3.0 × upper limit of normal (ULN). If the patient hasliver metastases, ALT and AST ≤5 × ULN

19. If the patient has liver metastases, ALT, and AST ≤5.0 × ULN

20. Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndromewho may be included if the total serum bilirubin is ≤3.0 × ULN or directbilirubin ≤ 1.5 × ULN. Note: Laboratory assessments may be repeated during theScreening Phase after supplementation or transfusions (a single red blood cellstransfusion is allowed once during the screening period).

Exclusion Criteria:

1. Active or newly diagnosed central nervous system (CNS) metastases, includingmeningeal carcinomatosis.

2. Patients with advanced, symptomatic visceral crisis who are at risk oflife-threatening complications in the short term, including massive uncontrolledeffusions (peritoneal, pleural, pericardial) and liver involvement of >50%.

3. Prior chemotherapy, elacestrant, or CDK4/6i in the advanced/metastatic setting.

4. Patients with only disease relapse while on the first 2 years of adjuvant endocrinetherapy i.e., patients with primary endocrine resistance, are not eligible.

5. Patient has a concurrent malignancy or history of invasive malignancy within 3 yearsof enrollment, with the exception of basal or squamous cell skin cancer, superficialbladder cancer, or carcinoma in situ of the cervix that has completed curativetreatment.

6. Uncontrolled significant active infections.

7. Patients with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infectionmust have undetectable viral load during screening.

8. Patients known to be human immunodeficiency virus (HIV)+ are allowed as long asthey have undetectable viral load at baseline.

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

10. Systemic radiotherapy within 14 days before starting trial therapy, or centralnervous system (CNS) radiotherapy within 28 days before starting trial therapy.Inability to take oral medication, refractory or chronic nausea, gastrointestinalcondition (including significant gastric or bowel resection), history ofmalabsorption syndrome, or any other uncontrolled gastrointestinal condition thatmay impact the absorption of study drug.

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

12. Females of childbearing potential who do not agree to use a highly effective methodof contraception and to abstain from donating/freezing ova within 28 days of thefirst dose of study treatment through 120 days after the last dose of studytreatment. Highly effective non-hormonal methods of contraception should be used.

13. Men who do not agree to abstain from donating/freezing sperm, or to use a highlyeffective method of contraception within 28 days of the first dose of studytreatment through 120 days after the last dose of study treatment. For subjects (whohave not undergone vasectomy) with female partners of childbearing potential, thesubject and his partner must use highly effective methods of contraception.

14. Females who are pregnant or breastfeeding. Females should not get pregnant duringstudy treatment and for 120 days after last dose of study treatment. Females shouldnot breastfeed during administration of elacestrant and for 1 week after receivingthe last dose.

15. Patient is currently receiving or received any of the following medications prior tofirst dose of trial therapy:

16. Investigational anti-cancer therapy within 14 days (28 days in case ofanticancer antibody-based treatments) or 5 half-lives, whichever is shorter.

17. Fulvestrant treatment (last injection) <42 days before first dose of studydrug.

18. Any other endocrine therapy <14 days before first dose of study drug.

19. Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4within 14 days or 5 half-lives, whichever is shorter.

20. Herbal preparations/medications within 7 days. These include, but are notlimited to, St. John's wort, kava, ephedra (ma huang), gingko biloba,dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.

21. Any severe medical or psychiatric condition that in the opinion of theinvestigator(s) would preclude the patient's participation in a clinical study