This is an international, multi-center, randomised, open label, superiority phase III trial of elacestrant vs standard endocrine therapy in patients with ER+/HER2- breast cancer and ctDNA relapse.

During the ctDNA screening phase, patients will be tested at different timepoints to detect the presence of ctDNA in their blood.

Patients who are found to be ctDNA-positive and have no evidence of distant metastasis, will be randomised 1:1 between standard endocrine treatment (the same they were receiving when tested ctDNA positive) versus elacestrant, provided they meet all eligibility criteria. After completion of the protocol treatment period, treatment will be left at the discretion of the treating physician.

International, multi-center, randomised, open label, superiority phase III trial of elacestrant vs standard endocrine therapy in patients with ER+/HER2- breast cancer and ctDNA relapse.

1. ctDNA screening phase: After verification of the eligibility criteria for screening, patients will enter the ctDNA screening phase of the study in which plasma samples will be collected and tested with ctDNA assay to detect the presence of ctDNA. The test will be performed every 6 months from study entry until the end of accrual (approximately 5.7 years). During the screening phase, patients will be treated with standard adjuvant endocrine therapy [either tamoxifen or an aromatase inhibitor (exemestane, anastrozole or letrozole)] and followed-up as per standard of care. The outcome of the serial ctDNA assessments performed during the screening phase will be disclosed to investigators.

   Patients who are found to be ctDNA-negative at the end of the screening period will not be followed further in this study.

   Patients who are found to be ctDNA-positive at one of the screening time points will undergo an imaging work-up to assess the presence of distant metastases.

   Patients for whom the imaging work-up confirms no evidence of distant metastases or locoregional recurrence will be eligible for the randomised phase of the study provided they meet all other eligibility criteria. Patients for whom the imaging work-up shows evidence of distant metastases or locoregional recurrence will be excluded.

2. Randomised trial:

Patients will be randomised 1:1 within 4 weeks from the date of ctDNA detection (i.e., the date on which the results of the test are received) between standard endocrine treatment (the same they were receiving when tested ctDNA positive) versus elacestrant.

In the absence of a withdrawal criteria, treatment in both arms will be administered for:

• For patients on ET between 1 to 5 years (12 to 60 months) at the time of randomisation: 2 to 6 years (allowing for 7 years of ET at the end of the study treatment).
• For patients on ET between 5 to 7.5 years (60 to 90 months) at the time of randomisation: 2 years.

After completion of the protocol treatment period, treatment will be left at the discretion of the treating physician.

Patients in both arms will undergo intensive follow-up with ctDNA tests at week 4 and week 16 after randomisation and every 16 weeks thereafter for a maximum of 3 years (36 months or 156 weeks) to assess ctDNA kinetics. In addition, the occurrence of distant metastases, locoregional recurrences and second cancers will be assessed via yearly mammograms and bone scans and 16-weekly CT scans thorax/abdomen for a maximum of 3 years after randomisation. Afterwards, follow-up will continue as per standard of care. All randomised patients will be followed-up until 3 years after the enrolment of the last patient.

End of study:

End of study occurs when all the following criteria have been satisfied:

All patients have completed their end of study visit. If a patient discontinues the follow-up due to withdrawal of consent, loss to follow-up, or death, the end of study participation is defined as the time point when one of these events occurred The trial is mature for all analyses defined in the protocol and the database has been cleaned and frozen for these analyses.

Inclusion Criteria:

1. ctDNA screening phase:

   Main inclusion criteria:

   • Female (both pre- and postmenopausal) or male patients with histologically confirmed 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 Allred proportion score ≥3
   • HER2-negative defined as a score of 0, 1+ by immunohistochemistry (IHC) or a negative in situ hybridization (ISH) based on single-probe average HER2 copy number, as per American Society of Clinical Oncology guidelines
   • Intermediate to high risk of recurrence after definitive treatment for early breast 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 high risk, Prosigna score >40 or EPclin risk score >=4.0.
   • Negative axillary lymph nodes (stage pN0) and tumour size ≥ 2 cm and either
   • Histologic grade 3 a or/and
   • Ki67≥20% and/or
   • High genomic risk defined as Oncotype Dx Recurrence Score >=26, Mammaprint high risk, Prosigna score >60 or EPclin risk score >=4.0. FOR PATIENTS TREATED WITH NEOADJUVANT

   SYSTEMIC TREATMENT FOLLOWED BY SURGERY:

   • Patient may have received neoadjuvant endocrine therapy or neoadjuvant chemotherapy provided that:
   • The initial tumour and/or the tumour after surgery meet the criteria above defined for patients treated with primary surgery or the initial tumour was staged as cT4anyN and
   • There is no pathological complete response, defined as no invasive disease in the 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 and planned to continue adjuvant ET during ctDNA screening phase
   • Previous adjuvant CDK4/6 inhibitor or PARP-inhibitor treatment is allowed provided it is completed
   • Invasive multicentric / multifocal disease is allowed provided that all the tested foci are ER+ HER2-. A sample from the highest-risk one, according to the investigator decision based on the size and grade, should be sent to Natera to build the patient ctDNA assay.
   • Available tumour sample from resected or biopsied tissue, with a tumour content of ≥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 unstained slides at 5 μm each), PLUS one contiguous H&E slide. Minimum total tissue thickness must be 60μm OR
   • FFPE tissue block with 25mm2 minimum surface area
   • Written informed consent must be given according to ICH/GCP, and national/local regulations.

   Main exclusion criteria:

   • Suspected recurrent disease or known conflicts with the inclusion and exclusion criteria 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 for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
   • Previous history of bone marrow and/or organ transplant
   • Bilateral invasive breast cancer
   • Participation in another clinical study, with the exception of the SURVIVE study and observational (non-interventional) and non-drug intervention clinical studies. Note: patients participating in interventional studies may participate once they enter the follow-up period of the study
   • Blood transfusion within 3 months prior to registration or during the screening.

2. Randomised trial:

Main inclusion criteria:

• ctDNA positive according to the Signatera ctDNA assay (main study ctDNA test) or other ctDNA assay approved for diagnostic purposes.
• Patients must meet the eligibility criteria for the screening phase, with the exception 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, as investigated by:
• Mammogram (unilateral in case of mastectomy; not required in patients having undergone bilateral mastectomy) NOTE: if local investigator plans to use MRIs instead 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 serum or urine pregnancy test within 7 days prior to randomisation.

Main exclusion criteria:

• Any unresolved toxic effect of prior therapies or surgical procedures of Grade ≥ 2 according to Common Terminology Criteria of Adverse Events (CTCAE) v5.0, with the exception of alopecia, peripheral neuropathy and other toxicities not considered a safety risk for the participant at investigator's discretion
• Unable or unwilling to avoid over-the-counter medications, dietary/herbal supplements, and/or foods that are moderate/strong inhibitors or inducers of CYP3A4 activity
• Known difficulty in tolerating oral medications or conditions which would impair absorption 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
• CTCAE version 5.0 grade 3 or 4 dyslipidemia at the time of screening, defined as cholesterol>400 mg/dL or >10.34 mmol/L and/or triglycerides>500 mg/dL or >5.7 mmol/L.
• 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 human immunodeficiency Virus (HIV)
• Coagulopathy or any history of coagulopathy within the past 6 months, including history of deep vein thrombosis or pulmonary embolism