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

Inclusion Criteria:

1. ctDNA screening phase: Main inclusion criteria:

• Female (both pre- and postmenopausal) or male patients with histologicallyconfirmed ER positive (regardless of PR), HER2 negative breast cancer, according to local pathologist:

• ER-positive defined as ≥ 10% of cells staining positive for ER or Allredproportion score ≥3

• 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

• Intermediate to high risk of recurrence after definitive treatment for earlybreast cancer, defined as: FOR PATIENTS TREATED WITH PRIMARY SURGERY:

• Any patient with ≥ 4 positive axillary lymph nodes (stage pN2-3).

• 1-3 positive axillary lymph nodes (stage pN1) and either:

• Tumour size ≥ 5 cm or/and

• Histologic grade 3 or/and

• Ki67≥20% or/and

• High genomic risk defined as Oncotype Dx Recurrence Score >=26, Mammaprint highrisk, Prosigna score >40 or EPclin risk score >=4.0.

• Negative axillary lymph nodes (stage pN0) and tumour size ≥ 5 cm and either

• Histologic grade 3 a or/and

• Ki67≥20% and/or

• High genomic risk defined as Oncotype Dx Recurrence Score >=26, Mammaprint highrisk, Prosigna score >60 or EPclin risk score >=4.0. FOR PATIENTS TREATED WITHNEOADJUVANT SYSTEMIC TREATMENT FOLLOWED BY SURGERY:

• Patient may have received neoadjuvant endocrine therapy or neoadjuvantchemotherapy provided that:

• The initial tumour and/or the tumour after surgery meet the criteria abovedefined for patients treated with primary surgery or the initial tumour wasstaged as cT4anyN and

• There is no pathological complete response, defined as no invasive disease inthe breast and axilla (ypT0/is ypN0).

• Age ≥18 years

• Patients must have received at least 1 year and up to 7.5 years of ET andplanned to continue adjuvant ET during ctDNA screening phase

• Previous adjuvant CDK4/6 inhibitor or PARP-inhibitor treatment is allowedprovided it is completed

• Invasive multicentric / multifocal disease is allowed provided that all thetested foci are ER+ HER2-. A sample from the highest-risk one, according to theinvestigator decision based on the size and grade, should be sent to Natera tobuild the patient ctDNA assay.

• Available tumour sample from resected or biopsied tissue, with a tumour contentof ≥20% (30% preferred) either before or after macro dissection (if performed)and a cell viability of a minimum 100 cells.

• Core Needle Biopsies (CNB): recommended minimum of four (4) cores per block

• Fine Needle Aspirates (FNA) are not accepted

• The following sample types are acceptable:

• 6-10 unstained slides (charged and unbaked) of 10μm each (or 12-19 unstainedslides at 5 μm each), PLUS one contiguous H&E slide. Minimum total tissuethickness must be 60μm OR

• FFPE tissue block with 25mm2 minimum surface area

• Written informed consent must be given according to ICH/GCP, and national/localregulations.

Main exclusion criteria:

• 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 insitu.

• Previous history of bone marrow and/or organ transplant

• Bilateral breast cancer

• Participation in another clinical study, with the exception of the SURVIVEstudy and observational (non-interventional) and non-drug intervention clinicalstudies. Note: patients participating in interventional studies may participateonce they enter the follow-up period of the study

• Blood transfusion within 3 months prior to registration or during thescreening.

2. Randomised trial:

Main inclusion criteria:

• ctDNA positive according to the Signatera ctDNA assay (main study ctDNA test) orother ctDNA assay approved for diagnostic purposes.

• Patients must meet the eligibility criteria for the screening phase, with theexception of the tissue sample requirements.

• Patients must receive adjuvant ET at the time of the ctDNA positive test

• Absence of locoregional and/or metastatic disease and/or new malignancy, asinvestigated by:

• Mammogram (unilateral in case of mastectomy; not required in patients havingundergone bilateral mastectomy) NOTE: if local investigator plans to use MRIsinstead of mammograms during the study, MRI will have to be performed at baseline.

• CT thorax and abdomen/pelvis with IV contrast. In case of any contra-indications (medical or regulatory): CT thorax without contrast + MRI abdomen/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 sensitive serumor urine pregnancy test within 7 days prior to randomisation.

Main exclusion criteria:

• Any unresolved toxic effect of prior therapies or surgical procedures of Grade ≥ 2according to Common Terminology Criteria of Adverse Events (CTCAE) v5.0, with theexception of alopecia, peripheral neuropathy and other toxicities not considered asafety risk for the participant at investigator's discretion

• Unable or unwilling to avoid over-the-counter medications, dietary/herbalsupplements, and/or foods that are moderate/strong inhibitors or inducers of CYP3A4activity

• 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:

• myocardial infarction

• stroke

• severe/unstable angina

• symptomatic cardiac arrhythmia

• prolonged QTcF ≥ Grade 3 (i.e., > 500 msec)

• heart failure ≥ Class III as defined by the New York Heart Association (NYHA)guidelines

• 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