Elacestrant + Everolimus in Patients ER+/HER2-, ESR1mut, Advanced Breast Cancer Progressing to ET and CDK4/6i.

Inclusion Criteria:

Patients will be included in the study only if they meet ALL of the following criteria:

1. Patient must be capable to understand the purpose of the study and have signedwritten informed consent form (ICF) prior to beginning specific protocol procedures.

2. Female or male patients ≥ 18 years of age at the time of signing ICF.

3. Pre- or perimenopausal women, who do not meet the criteria for post-menopausalstatus (defined in continuation) and men must be concurrently receiving a LHRHanalogue for at least 28 days (if shorter, post-menopausal levels of serumestradiol/follicle-stimulating hormone [FSH] must be confirmed analytically) priorto study randomization and are planning to continue LHRH agonist treatment duringthe study. Post-menopausal women as defined by any of the following criteria:

4. Age ≥ 60 years;

5. Age < 60 years and cessation of regular menses for at least 12 consecutivemonths with no alternative pathological or physiological cause; and serumestradiol and/or FSH levels within the laboratory's reference range forpost-menopausal females;

6. Documented bilateral surgical oophorectomy.

7. Histologically- or cytologically proven diagnosis of adenocarcinoma of the breastwith evidence of either unresectable locally recurrent or metastatic diseaseconfirmed by computerized tomography (CT) scan or magnetic resonance imaging (MRI)that is not amenable to resection with curative intent.

8. Documentation of ER[+] (≥10% positive stained cells) and HER2[-] (0-1+ byimmunohistochemistry [IHC] or 2+ and negative by in situ hybridization [ISH] test)tumor according to the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as per local assessment.ER[+]/HER2[-] status should be confirmed in metastatic setting, with exception ofpatients with bone and lung only disease.

9. Patients with ESR1 mutational status will be determined before patient randomizationusing Guardant360 CDx (Guardant Health) test. Note: Patients with previously determined ESR1 mutation using appropriatelyvalidated tests (Guardant360 CDx [Guardant Health], FoundationOne CDx, FoundationOneLiquid [Foundation Medicine Inc]) will be eligible for inclusion. This localdetermination can be performed either in blood or tumor samples.

10. Radiological or objective evidence of disease progression on prior treatment with aCDK4/6 inhibitor in combination with endocrine therapy for advanced disease after atleast 6 months of treatment. Patients receiving CDK4/6 inhibitor-based therapy inthe adjuvant setting are also eligible provided that disease progression isconfirmed after at least 12 months of treatment but no more than 12 months followingCDK4/6 inhibitor treatment completion in this scenario.

11. Patients must have previously received at least one and no more than two lines ofendocrine therapy for ABC. Progression during or within 12 months of adjuvantendocrine therapy is considered as a line of endocrine therapy for advanced disease.

12. No prior elacestrant or other investigational SERDs, proteolysis targeting chimera (PROTAC), complete estrogen receptor antagonist (CERAN), or novel SERM, and/orPI3K/AKT/mTOR inhibitors, including everolimus, for advanced disease are permitted. Note: Fulvestrant is permitted if treatment was completed administered at least 28days before randomization.

13. No prior chemotherapy for advanced disease is allowed.

14. Evidence of measurable disease as per Response Evaluation Criteria in Solid Tumorsversion 1.1 (RECIST v.1.1), or non-measurable, but evaluable, disease, includingbone-only disease with at least one lytic or mixed lytic-blastic bone lesion.

15. Willingness and ability to provide the most recently available formalin-fixedparaffin-embedded (FFPE) tumor tissue or block. If a newly obtained baseline biopsyof an accessible tumor lesion is not possible to be obtained prior randomization, anarchival tissue sample will be accepted.

16. Fasting serum cholesterol ≤ 300 mg/dL or 7.75 mmol/L and fasting triglycerides ≤ 2.5times the upper limit of normal (x ULN).

17. Adequate bone marrow and organ function:

18. Hematological (without platelet, red blood cell transfusion, and/or granulocytecolony-stimulating factor support within seven days before randomization):absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100.0 x109/L;and hemoglobin ≥ 9.0 g/dL.

19. Hepatic: Serum albumin ≥ 2.5 g/dL; total serum bilirubin < 1.5 x ULN except forpatients with Gilbert's syndrome who may be included if the total serumbilirubin is ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN; alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 3 x ULN in patients with liver and/or bone metastases);aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 x ULN (≤ 3 xULN in patients with liver metastases).

20. Renal: Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50mL/min as calculated by Cockcroft- Gault equation.

21. Coagulation: International normalized ratio (INR) ≤ 1.5 x ULN, unless that thepatient meets the exception described in the exclusion criteria 16.

22. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 asdetermined by the National Cancer Institute (NCI)-Common Terminology Criteria forAdverse Events (CTCAE) v.5.0 (except for toxicities not considered a safety risk forthe patient at Investigator's discretion). Note: Patients with grade 2 alopecia are allowed.

23. Women of childbearing potential who are sexually active with a non-sterilized malepartner must have a negative serum pregnancy test within 7 days beforerandomization. In addition, they agree to use one highly effective method of birthcontrol 28 days prior to start of treatment until 120 days after the last dose ofstudy treatments. Female patients must refrain from egg cell donation andbreastfeeding during this same time period.

24. Male participants with a female partner of childbearing potential must be surgicallysterile or using a highly effective method of contraception 28 days prior totreatment until 120 days after the last dose of study treatments to preventpregnancy in a partner. Male participants must not donate or bank sperm during thissame time period. Not engaging in heterosexual activity (sexual abstinence) for theduration of the study and 120 days after the last dose of study treatments is anacceptable practice if this is the preferred usual lifestyle of the participant.

25. ECOG performance status of 0-1.

26. Minimum life expectancy of ≥ 12 weeks at screening.

Exclusion Criteria:

Any patient meeting ANY of the following criteria will be excluded from the study:

1. Inability to comply with study and follow-up procedures.

2. Formal contraindication to endocrine therapy defined as visceral crisis and/orrapidly or symptomatic progressive visceral disease.

3. Current participation in another therapeutic clinical trial.

4. Treatment with approved or investigational cancer therapy within 14 days prior torandomization except for fulvestrant that must be administered completed at least 28days before randomization.

5. Known active uncontrolled or symptomatic central nervous system (CNS) metastasesand/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema,and/or progressive growth. Patients with a history of CNS metastases are eligible ifthey have been previously treated with local therapy, are clinically stable, and offanticonvulsants and steroids for at least 14 days before randomization.

6. Intact uterus with a history of endometrial intraepithelial neoplasia (atypicalendometrial hyperplasia or higher-grade lesion).

7. Concurrent malignancy or malignancy within three years before randomization with theexception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stageI uterine cancer. For other cancers considered to have a low risk of recurrence,discussion with the Medical Monitor is required.

8. Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances.

9. History of malabsorption syndrome or other condition that would interfere withenteral absorption (ongoing gastrointestinal obstruction/motility disorder,malabsorption syndrome, or prior gastric bypass) or results in the inability orunwillingness to swallow pills.

10. Palliative radiotherapy with a limited field of radiation within two weeks or withwide field of radiation or to more than 30% of the bone marrow within four weeksprior to randomization.

11. Major surgical procedure or significant traumatic injury within 14 days beforerandomization or anticipation of need for major surgery within the course of thestudy treatment.

12. Clinically relevant cardiovascular/cerebrovascular disease and/or cardiacdysfunction or conduction abnormalities including, but not confined, to any of thefollowing: a. Symptomatic pericarditis, unstable angina pectoris, documented myocardialinfarction, coronary/peripheral artery bypass graft, symptomatic cardiac heartfailure (CHF) (New York Heart Association [NYHA] Class II-IV), or cerebrovascularaccident including transient ischemic attack within six months before studyrandomization.

13. Concurrent uncontrolled atrial fibrillation, other ongoing cardiac dysrhythmiasgrade ≥ 2 as determined by NCI-CTCAE v.5.0, or prolonged QT Interval Corrected byFridericia's formula ([QTcF] > 480 msec).

14. Clinically severe pulmonary compromise resulting from intercurrent pulmonaryillnesses including, but not limited, to any of the following:

15. Massive lung metastatic involvement (e.g., pleural effusion, lymphangiticcarcinomatosis, etc.).

16. Any underlying pulmonary disorder (e.g., severe asthma, severe chronicobstructive pulmonary disease [COPD], restrictive lung disease, postCoronavirus disease (COVID-19) pulmonary fibrosis, etc.).

17. Any autoimmune, connective tissue, or inflammatory disorders with pulmonaryinvolvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis,etc.).

18. Prior pneumonectomy.

19. History of non-infectious interstitial lung disease (ILD)/pneumonitis that requiredsteroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannotbe ruled out by imaging at screening.

20. Coagulopathy or any history of coagulopathy within six months before studyenrollment, including history of deep vein thrombosis or pulmonary embolism.However, patients with the following conditions will be allowed to participate:

21. Adequately treated catheter-related venous thrombosis occurring more than 28days prior to randomization.

22. Treatment with an anticoagulant (e.g., warfarin or heparin) for a thromboticevent occurring more than six months before randomization, or for an otherwisestable and allowed medical condition (e.g., well controlled atrialfibrillation), provided dose and coagulation parameters (as defined by localstandard of care) are stable for at least 28 days prior to randomization.

23. Concomitant treatment with immunosuppressive agents or chronic corticosteroids usebefore randomization with the following exceptions: topical applications, inhaledsprays, eye drops, mouthwash, or local injections are allowed. Patients on stablelow dose of corticosteroids ( ≤ 10 mg/day of prednisone or equivalent) for at leasttwo weeks before randomization are also permitted.

24. Unable or unwilling to avoid prescription medications, over-the-counter medications,dietary/herbal supplements (e.g., St. John's wort), and/or foods (e.g., grapefruit,pomelos, star fruit, Seville oranges and their juices) that are moderate/stronginhibitors or inducers of CYP3A4 activity. Participation will be allowed if themedication, supplements, and/or foods are discontinued for at least five half-livesor 14 days (whichever is shorter) prior to randomization and for the duration of thestudy.

25. Pregnant or lactating women or patients not willing to apply highly effectivecontraception as defined in the protocol.

26. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBVinfection (defined as having a negative hepatitis B surface antibody [HBsAg] testand a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBVDNA test) are eligible. Patients positive for HCV antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV RNA. Any other activeuncontrolled infection at the time of screening is not allowed.

27. Known substance abuse or any other concurrent severe and/or uncontrolled psychiatricor medical condition that would, in the Investigator's judgment, contraindicatepatient participation.