Elacestrant for Treating ER+/HER2- Breast Cancer Patients With ctDNA Relapse (TREAT ctDNA)

Inclusion Criteria:

• ctDNA screening phase
• Female or male patients with histologically confirmed ER positive (regardless ofPR), HER2 negative breast cancer, according to local pathologist:
• ER-positive defined as ≥ 10% of cells staining positive for ER
• HER2-negative defined as a score of 0, 1+ by immunohistochemistry (IHC) or anegative in situ hybridization (ISH) based on single-probe average HER2 copynumber, as per American Society of Clinical Oncology guidelines
• Elevated risk of recurrence after definitive treatment for early breast cancer,defined as either:
• Stage IIB or stage III disease according to the 8th edition of the UICC TNMclassification and completion of adjuvant chemotherapy, OR
• Completion of at least 4 cycles of neoadjuvant chemotherapy and residualtumour at surgery of ≥ 1cm (≥ypT1c) or axillary node + (ypN+)
• Pre- or postmenopausal status (for female patients).
• Age ≥18 years
• Patients must have received at least 2 years and up to 7 years of ET
• Previous adjuvant CDK4/6 inhibitor or PARP-inhibitor treatment is allowed ifcompleted at least 12 months before registration
• Patients with multifocal tumours are allowed provided all foci are biopsied andare ER-positive and HER2-negative as defined above
• Available FFPE tumour block from the baseline biopsy or from surgical specimen orat least 10 slides of 10μm and a tumour cellularity of at least 25%. For patientswith multifocal tumours, FFPE block or slides from the largest focus is required.
• Written informed consent must be given according to ICH/GCP, and national/localregulations.
• Randomised phase
• ctDNA positive according to the Signatera ctDNA assay
• Absence of locoregional and/or metastatic disease, as investigated by:
• Mammogram (unilateral in case of mastectomy; not required in patients havingundergone bilateral mastectomy)
• CT thorax and abdomen/pelvis with IV contrast. In case of anycontra-indications (medical or regulatory): CT thorax without contrast + MRIabdomen/pelvis.
• Technetium-99m bone scintigraphy
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
• Adequate organ function
• Women of childbearing potential (WOCBP) must have a negative highly sensitiveserum or urine pregnancy test within 3 days prior to randomisation.

Exclusion Criteria:

• ctDNA screening phase
• Suspected recurrent disease or known conflicts with the inclusion and exclusioncriteria for the randomised trial
• Prior treatment with any SERD or investigational ER antagonist
• Previous history of invasive breast cancer
• Previous history of any other malignancy within the last 5 years, except foradequately treated basal cell or squamous cell skin cancer, or carcinoma in situof the cervix . Patients who have been disease free for more than 5 years withlow risk of relapse are allowed
• Bilateral breast cancer
• Participation in another clinical study, with the exception of the SURVIVE studyNote: patients participating in interventional studies may participate once theyenter the follow-up period of the study
• Randomised phase
• Any unresolved toxic effect of prior therapies or surgical procedures of Grade ≥ 2 according to Common Terminology Criteria of Adverse Events (CTCAE) v5.0, withthe exception of alopecia, peripheral neuropathy and other toxicities notconsidered a safety risk for the participant at investigator's discretion
• Unable or unwilling to avoid prescription medications, over-the-countermedications, dietary/herbal supplements, and/or foods that are moderate/stronginhibitors or inducers of CYP3A4 activity
• Known difficulty in tolerating oral medications or conditions which would impairabsorption of oral medications
• Any of the following cardiovascular disorders within 3 months before enrolment:
• Child-Pugh Score greater than Class A
• Uncontrolled significant active infections (≥ grade 3 according to CTCAE version 5), including active hepatitis B virus (HBV), hepatitis C virus (HCV) or humanimmunodeficiency Virus (HIV)
• Coagulopathy or any history of coagulopathy within the past 6 months, includinghistory of deep vein thrombosis or pulmonary embolism