EORTC 2129-BCG: Elacestrant for treating ER+/HER2- breast cancer patients with ctDNA relapse (TREAT ctDNA)

The primary objective of this study is to evaluate whether **elacestrant** can delay the occurrence of distant metastasis or death when compared to standard endocrine therapy in patients with ER+/HER2- **breast cancer** who have experienced a ctDNA relapse. This is clinically relevant as it aims to improve the prognosis and management of patients with early breast cancer by potentially offering a more effective treatment option that could extend survival and delay disease progression.

Secondary objectives include:

• Evaluating invasive disease-free survival (iDFS), relapse-free survival (RFS), and overall survival (OS) between the two treatment arms.
• Characterizing the safety and tolerability of the two treatment arms.
• Establishing the patient-reported tolerability profile in each treatment arm.
• Comparing the patient-reported benefit between the two treatment arms.

The clinical trial involves a total of **10 participants** diagnosed with **breast cancer**, specifically ER+/HER2- subtype, who have experienced a ctDNA-relapse. The study population includes both **female** (pre- and postmenopausal) and **male** patients, with an age range starting from **18 years** and above. Participants were selected based on their histologically confirmed ER-positive and HER2-negative status, as per the American Society of Clinical Oncology guidelines. The trial includes individuals who have completed adjuvant chemotherapy or neoadjuvant chemotherapy with specific residual tumor criteria. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial also considers lifestyle factors such as the continuation of adjuvant endocrine therapy during the ctDNA screening phase. The study population is not limited to a specific gender, and both vulnerable and non-vulnerable populations are included. The selection criteria ensure that participants have adequate organ function and, for women of childbearing potential, a negative pregnancy test prior to randomization. The trial aims to evaluate the efficacy of elacestrant in delaying distant metastasis or death compared to standard endocrine therapy.

The clinical trial is designed to evaluate the efficacy of **elacestrant** in delaying the occurrence of distant metastasis or death in patients with ER+/HER2- breast cancer who have experienced a ctDNA relapse. This is a randomized, open-label, phase III trial comparing elacestrant with standard endocrine therapy. The trial is expected to run until May 2032, with recruitment starting in November 2023. Participants will be involved for a maximum treatment period of 104 weeks, depending on their assigned treatment group.

The trial includes several key phases and visits. Initially, a ctDNA screening phase will determine eligibility based on specific criteria, including histologically confirmed ER-positive, HER2-negative breast cancer, and elevated risk of recurrence. Eligible participants will then proceed to the randomization phase, where they will be assigned to either the elacestrant group or the standard endocrine therapy group. The primary endpoint is distant metastasis-free survival, with secondary endpoints including invasive disease-free survival, relapse-free survival, overall survival, and safety assessments.

Study visits are structured to monitor participants' health and treatment efficacy. The inclusion visit involves comprehensive screening to confirm eligibility. Follow-up visits will occur regularly to assess treatment response, monitor for adverse events, and ensure compliance with the study protocol. The end-of-study visit will conclude the participant's involvement, with a final assessment of their health status and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. Additionally, any significant protocol deviations or non-compliance may result in early termination from the study. The trial aims to provide valuable insights into the potential benefits of elacestrant in managing ER+/HER2- breast cancer with ctDNA relapse, contributing to the advancement of treatment options for this patient population.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Elacestrant** is the primary investigational drug, administered in the form of a film-coated tablet. The maximum daily dose is 400 mg, with a total maximum dose of 291,200 mg over a treatment period of 104 weeks. The route of administration is oral. Elacestrant is of chemical origin and is used to evaluate its efficacy in delaying the occurrence of distant metastasis or death in ER+/HER2- breast cancer patients with ctDNA relapse.

**Tamoxifen** is used as a comparator treatment in the trial. It is also administered as a film-coated tablet with a maximum daily dose of 20 mg and a total maximum dose of 14,560 mg over 104 weeks. The administration route is oral, and it is of chemical origin. Tamoxifen serves as a standard endocrine therapy in the study.

**Anastrozole** is another comparator treatment, provided in a film-coated tablet form. The maximum daily dose is 1 mg, with a total maximum dose of 728 mg over the same treatment period of 104 weeks. It is administered orally and is of chemical origin, serving as a standard endocrine therapy.

**Exemestane** is included as a comparator, administered as a coated tablet. The maximum daily dose is 25 mg, with a total maximum dose of 18,200 mg over 104 weeks. The route of administration is oral, and it is of chemical origin, used as part of the standard endocrine therapy.

**Letrozole** is also used as a comparator treatment, available in a film-coated tablet form. The maximum daily dose is 2.5 mg, with a total maximum dose of 1,820 mg over 104 weeks. It is administered orally and is of chemical origin, included as a standard endocrine therapy.

**Leuprorelin**, **Goserelin**, and **Triptorelin** are used as auxiliary treatments in the trial. Leuprorelin is administered intramuscularly with a total maximum dose of 3.75 mg over 24 weeks. Goserelin is administered subcutaneously with a total maximum dose of 3.6 mg over 24 weeks. Triptorelin is administered intramuscularly with a total maximum dose of 3.75 mg over 24 weeks. These auxiliary treatments are of protein origin and are used to support the primary and comparator treatments in the trial.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Distant Metastasis Free Survival (DMFS)**, which is defined as the time from randomization until the first occurrence of distant metastatic recurrence or death from any cause. Secondary endpoints include Invasive Disease-Free Survival (iDFS) rate, Relapse-Free Survival (RFS) rate, Overall Survival rate, and safety assessments. These secondary endpoints will be evaluated according to the STEEP criteria, which include locoregional recurrence, distant metastasis, invasive contralateral breast cancer, invasive non-breast second cancers, and deaths from any cause as events. Safety will be monitored through adverse events, serious adverse events, and laboratory abnormalities graded according to CTCAE version 5.0. Additionally, patient-reported outcomes will be measured using the QLQ-C30, QLQ-BR45, and EORTC IL198 to assess tolerability and benefit.