Phase 3 Randomized Study of Elacestrant Versus Standard Endocrine Therapy in Node-Positive, ER-Positive, HER2-Negative Early Breast Cancer with High Recurrence Risk

The primary objective of this study is to evaluate the efficacy of **elacestrant** relative to standard endocrine therapy in terms of invasive breast cancer-free survival (IBCFS) in participants with node-positive, estrogen receptor-positive, HER2-negative early breast cancer with a high risk of recurrence. This objective is clinically relevant as it aims to determine whether elacestrant can provide a more effective treatment option for this specific patient population, potentially improving long-term outcomes and reducing the risk of cancer recurrence.

Secondary objectives include: - Evaluating the efficacy of elacestrant relative to standard of care (SoC) in terms of distant relapse-free survival (DRFS), overall survival (OS), and invasive disease-free survival (IDFS). - Characterizing the safety of elacestrant in the trial patient population. - Evaluating the effect of elacestrant relative to SoC on patient-reported outcomes (PROs). - Characterizing elacestrant steady-state pharmacokinetics (PK) and exposure-response relationships (efficacy and safety) in a subset of participants enrolled in the elacestrant arm at United States clinical sites.

The clinical trial involves a total of **2458 participants** diagnosed with **node-positive, estrogen receptor-positive, HER2-negative, early breast cancer** with a high risk of recurrence. The study population includes both male and female subjects, with age categories ranging from 18 to 64 years. Participants were selected based on specific inclusion criteria, including a histopathologically or cytologically confirmed diagnosis of ER-positive (≥ 10% by immunohistochemistry), HER2-negative breast cancer, and having received 24 to 60 months of endocrine therapy. The trial also considers vulnerable populations. Participants' general health status is characterized by the absence of recurrence or distant metastases, as per local laboratory standards. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection process ensures that participants have completed or discontinued prior treatments involving CDK4/6 inhibitors or poly ADP-ribose polymerase inhibitors, if applicable.

The clinical trial is designed to evaluate the efficacy of **elacestrant** compared to standard endocrine therapy in participants with node-positive, estrogen receptor-positive, HER2-negative early breast cancer with a high risk of recurrence. This is a global, multicenter, randomized, open-label Phase 3 study. The trial will involve the administration of **elacestrant** and comparator drugs, including **exemestane**, **anastrozole**, **letrozole**, and **tamoxifen**, all in the form of film-coated tablets taken orally. The maximum treatment period for participants is 60 months, with a maximum daily dose of 345 mg for **elacestrant**.

The trial will commence with a screening visit to confirm eligibility based on histopathological or cytological criteria, ensuring participants have received prior endocrine therapy. Randomization will follow, assigning participants to either the test or comparator group. The primary endpoint is invasive breast cancer-free survival (IBCFS), with secondary endpoints including distant recurrence-free survival (DRFS), overall survival (OS), and incidence of adverse events. Participants will undergo regular follow-up visits to monitor these endpoints, assess adverse events, and evaluate changes in quality of life using the EORTC QLQ-C30 and QLQ-BR42 questionnaires.

The trial is expected to conclude by June 2032, with recruitment starting in February 2025. Participants will be involved for the duration of the treatment period unless early termination is warranted due to adverse events, withdrawal of consent, or protocol non-compliance. The study aims to provide comprehensive data on the efficacy and safety of **elacestrant** in comparison to standard therapies, contributing valuable insights into treatment options for this specific breast cancer subtype.

The clinical trial involves the administration of **Elacestrant**, an experimental medication, which is provided in the form of a film-coated tablet. The active substance, **Elacestrant**, is a chemically derived tetrahydronaphthalene compound. The maximum daily dose is 345 mg, with a total maximum dose of 629,970 mg over a treatment period of 60 days. The medication is administered orally, and the trial includes repackaging and relabeling of the product. Participant compliance is monitored to ensure adherence to the dosing schedule.

**Exemestane** is used as a comparator treatment in the study. It is an irreversible, steroidal aromatase inhibitor, also provided as a film-coated tablet. The maximum daily dose for Exemestane is 25 mg, with a total maximum dose of 45,650 mg over the 60-day treatment period. This medication is also administered orally, with similar repackaging and relabeling processes as Elacestrant.

Another comparator in the trial is **Anastrozole**, a potent and highly selective non-steroidal aromatase inhibitor. It is administered in the form of a film-coated tablet, with a maximum daily dose of 1 mg and a total maximum dose of 1,826 mg over the treatment period. The administration route is oral, and the product undergoes repackaging and relabeling.

**Letrozole** serves as an additional comparator treatment. It is a non-steroidal aromatase inhibitor, provided as a film-coated tablet. The maximum daily dose is 2.5 mg, with a total maximum dose of 4,565 mg over the 60-day period. Letrozole is administered orally, with repackaging and relabeling included in the trial protocol.

**Tamoxifen** is also included as a comparator treatment. It is a non-steroidal, triphenylethylene-based drug, available in film-coated tablet form. The maximum daily dose is 20 mg, with a total maximum dose of 36,520 mg over the treatment period. The administration is oral, and the product is subject to repackaging and relabeling.

The efficacy of the investigational product **elacestrant** will be assessed in a Phase III clinical trial comparing it to standard endocrine therapy in participants with node-positive, estrogen receptor-positive, HER2-negative early breast cancer at high risk of recurrence. The primary endpoint for evaluating efficacy is Invasive Breast Cancer-Free Survival (IBCFS), defined as the time from randomization to the first occurrence of ipsilateral invasive breast tumor recurrence, local/regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause.

Secondary endpoints include Distant Recurrence-Free Survival (DRFS), Overall Survival (OS), and Invasive Disease-Free Survival (IDFS). These endpoints will measure the time from randomization to distant recurrence or death, death from any cause, and the first occurrence of local or regional recurrence, contralateral recurrence, second primary non-breast invasive cancer, distant recurrence, or death, respectively. Additionally, adverse events, treatment-emergent adverse events, and serious adverse events will be monitored, along with changes in clinical laboratory values and vital sign measurements.

Patient-reported outcomes will be assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Breast Cancer module (EORTC QLQ-BR42). Changes from baseline in global health status, physical functioning, and endocrine therapy symptoms will be evaluated at 6 and 12 months and annually thereafter. The Question 168 of the EORTC Question Library will assess changes in side effects and tolerability. Pharmacokinetic parameters of elacestrant and exposure-response analyses between elacestrant pharmacokinetics and efficacy/safety endpoints will also be conducted.