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

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.


Eligibility Criteria:
Inclusion Criteria:

* ctDNA screening phase

  * Female 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
    * 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
  * 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 TNM classification and completion of adjuvant chemotherapy, OR
    * Completion of at least 4 cycles of neoadjuvant chemotherapy and residual tumour 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 if completed at least 12 months before registration
  * Patients with multifocal tumours are allowed provided all foci are biopsied and are ER-positive and HER2-negative as defined above
  * Available FFPE tumour block from the baseline biopsy or from surgical specimen or at least 10 slides of 10μm and a tumour cellularity of at least 25%. For patients with multifocal tumours, FFPE block or slides from the largest focus is required.
  * Written informed consent must be given according to ICH/GCP, and national/local regulations.
* 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 having undergone bilateral mastectomy)
    * 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 3 days prior to randomisation.

Exclusion Criteria:

* ctDNA screening phase

  * 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 of the cervix . Patients who have been disease free for more than 5 years with low risk of relapse are allowed
  * Bilateral breast cancer
  * Participation in another clinical study, with the exception of the SURVIVE study Note: patients participating in interventional studies may participate once they enter 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, 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 prescription medications, 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:
  * 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