Medical Imaging to Re-evaluate Elacestrant Clinical Usage (IRENA)

Inclusion Criteria:

1. Age ≥ 18 years old
2. ECOG performance status ≤ 1
3. Must have histologically or cytologically confirmed diagnosis of breast cancer with evidence of locally advanced disease not amenable to therapy with curative intent or metastatic disease not amenable to curative therapy.
4. Documentation of ER-positive (≥10% positive stained cells) and HER2 negative (0-1+ by immunohistochemistry [IHC] or 2+ and negative by in situ hybridization [ISH] test) advanced or metastatic breast cancer according to the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as per local assessment. ER-positive/HER2-negative status should be confirmed in metastatic setting, with exception of patients with bone and lung only disease, where this might not possible.
5. Must be appropriate candidates for endocrine monotherapy.

6. Must have previously received no more than 1 line of endocrine therapy:

   • a) Radiological or objective evidence of disease progression on prior treatment with a CDK4/6 inhibitor in combination with endocrine therapy (either an aromatase inhibitor or fulvestrant) for advanced disease after at least 12 months of treatment.
   • b) Patients receiving CDK4/6 inhibitor-based therapy in the adjuvant setting are also eligible provided that disease progression is confirmed after finishing treatment with CDK4/6 inhibitor but no more than 12 months following CDK4/6 inhibitor treatment completion in this scenario, this will count as 1 line of ET for mBC.
7. ESR1 mutation not detected, test performed after ET plus CDK4/6 inhibitor. This local determination will be performed in blood using a validated assay.

8. No contraindications to perform 18F-FES-PET/CT.

   - a) Patients will not be selected when treated with SERMs or SERDs ≤ 5 weeks prior to inclusion as these drugs interfere with the accessibility of the ER.

9. Life expectancy ≥ 6 months.

10. At screening FDG-PET/CT at least two "target" lesions are required to fulfil the following criteria:

    • a) anatomically transaxial diameter ≥ 1.5 cm AND
    • b) metabolically assessable with a maximum standard uptake value corrected for lean body mass (SUVmax) ≥ 1.5 x SUVmean + 2 standard deviations (SD) of the liver measured in a 3-cm-diameter spherical volume of interest (VOI) in normal liver parenchyma.
    • c) In case of suspected liver metastasis, a lesion should have a SUVmax ≥ 2 x SUVmean + 3 SD of the blood pool measured in a 1 cm-diameter VOI within descending thoracic aorta. Lesions pre-treated with irradiation are not eligible for consideration as "target" lesions.

11. Female participants must be post-menopausal women, defined by 1 of the following criteria:

    • a) Prior bilateral oophorectomy (≥ 28 days prior to Day 1 of treatment).
    • b) Age ≥ 60 years with amenorrhea ≥ 1 year since last menses.
    • c) Age < 60 years: i. Cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; OR ii. serum oestradiol and/or FSH levels within the laboratory's reference range for post-menopausal females
    • d) Pre- or perimenopausal women, who do not meet the criteria for post-menopausal status must be concurrently receiving a LHRH analogue (goserelin), as per standard of care, for at least 28 days (if shorter, post-menopausal levels of serum oestradiol/FSH must be confirmed analytically) prior to study enrolment and are planning to continue LHRH agonist treatment during the study.
12. Resolution of all toxic effects of prior therapies or surgical procedures to Grade ≤ 1 (except for toxicities not considered a safety risk for the patient at Investigator's discretion).

13. Adequate organ function as defined below:

    • a) Haematologic function: i. Absolute neutrophil count ≥ 1.0 x 109/L. ii. Platelet count ≥ 75 x 109/L. iii. Haemoglobin ≥ 9.0 g/dL.
    • b) Renal function: i. Estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or creatinine. clearance calculated by Cockcroft-Gault equation ≥ 30 mL/min.
    • c) Hepatic function i. Alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN; in the presence of liver metastases, ALT ≤ 5x ULN).

    ii. Total bilirubin ≤ ULN or total bilirubin ≤ 1.5x ULN with direct bilirubin ≤ ULN of the laboratory in participants with documented Gilbert's Syndrome.

    - d) Chemistry i. Potassium, sodium, calcium (corrected for albumin), magnesium, and phosphorus NCI CTCAE v6.0 Grade ≤ 1. If screening assessments are abnormal, chemistry assessments may be repeated up to 2 times; participants may receive appropriate supplementation or treatment (e.g., for hypercalcemia) prior to re-assessment e) Coagulation i. International normalized ratio (INR) ≤ 1.5

14. Subject is willing and able to comply with the protocol for the duration of the study including treatment and scheduled visits and examinations.

15. Signed Informed Consent Form (ICF) obtained prior to any study related procedure.

    Inclusion criterion applicable to FRANCE only:

16. Affiliated to the French Social Security System (applicable only to participants treated in France)

Exclusion Criteria:

1. Prior treatment with elacestrant, or an investigational SERD or ER antagonist.
2. Prior chemotherapy for advanced or metastatic disease.

3. Prior anti-cancer or investigational drug treatment within the following windows:

   • a) Fulvestrant treatment (last injection) < 5 weeks before first dose of study drug.
   • b) Any other endocrine therapy < 14 days before first dose of study drug.
   • c) Chemotherapy or other anti-cancer therapy < 21 days before first dose of study drug.
   • d) Any investigational anti-cancer drug therapy < 28 days or 5 half-lives (whichever is shorter) before the first dose of study drug.
4. Radiation therapy (other than CNS directed) within 14 days before the first dose of study drug. CNS directed radiation therapy within 28 days before the first dose of study drug.
5. Active or newly diagnosed CNS metastases, including meningeal carcinomatosis. Note: Patients with stable brain or subdural metastases are allowed if the subject has completed local therapy and was on a stable or decreasing dose of corticosteroids at pre-study treatment period baseline for management of brain metastasis for at least 4 weeks before starting treatment in this study. Any signs (e.g., radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. If anticonvulsant medication is required, participants must be stable on a non-enzyme inducing anticonvulsant regimen (Appendix 1).
6. Participants 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%.
7. Intact uterus with a history of endometrial intraepithelial neoplasia (atypical endometrial hyperplasia or higher-grade lesion).
8. Diagnosis of any other malignancy within 5 years before enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or second primary breast cancer.
9. Any of the following within 6 months before enrolment: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE v6.0 Grade ≥2, prolonged QTcF ≥ Grade 2 (i.e., > 480 msec), uncontrolled atrial fibrillation of any grade, coronary/peripheral artery bypass graft, heart failure ≥ Class II as defined by the New York Heart Association guidelines, or cerebrovascular accident including transient ischemic attack.

10. Coagulopathy or any history of coagulopathy within the past 6 months, including history of deep vein thrombosis or pulmonary embolism. However, participants with the following conditions will be allowed to participate:

    • a) Adequately treated catheter-related venous thrombosis occurring > 28 days prior to the first dose of study drug.
    • b) Treatment with an anticoagulant, e.g., warfarin or heparin, for a thrombotic event occurring > 6 months before enrolment, or for an otherwise stable and allowed medical condition (e.g., well controlled atrial fibrillation), provided dose and coagulation parameters (as defined by local standard of care) are stable for at least 28 days prior to the first dose of study drug and provided that an AI would be an appropriate therapy for the subject.
11. Known difficulty in tolerating oral medications or conditions which would impair absorption of oral medications such as: uncontrolled nausea or vomiting (i.e., CTCAE ≥ Grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motility disorder, malabsorption syndrome, or prior gastric bypass.
12. 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/strong inhibitors or inducers of CYP3A4 activity (Appendix 1). Participation will be allowed if the medication, supplements, and/or foods are discontinued for at least 5 half-lives or 14 days (whichever is longer) prior to initiation of study treatment study enrolment and for the duration of the study.
13. Major surgery < 28 days before the first dose of study drug
14. Pregnant and/or lactating women, or intending to become pregnant during the study.
15. Women of childbearing potential refusing to use 1 highly effective method of contraception prior study entry, during the course of the study and at least 120 days after the last administration of study treatment.
16. Men with childbearing potential partner refusing to use condom during the course of this study and for at least 120 days after the last administration of the study treatment.
17. Participant with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator's opinion, may interfere with completion of the study.

18. Known hypersensitivity reactions to the study drugs or to any excipients.

    Exclusion criterion applicable to FRANCE ONLY:

19. Vulnerable persons according to the article L.1121-6 of the "Code de la Santé Publique" (CSP), adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the CSP.