A Phase 3 Randomized Trial of Endocrine Therapy Versus Radiation Therapy in Women Aged ≥70 with Luminal A-like Early Stage Breast Cancer

The primary objective of this study is to determine the **IBTR** (Ipsilateral Breast Tumor Recurrence) rate of exclusive radiation therapy (RT) compared to exclusive endocrine therapy (ET) following breast-conserving surgery (BCS) in low-risk early-stage breast cancer patients aged 70 years and older. Additionally, the study aims to assess patient-reported outcomes on health-related quality of life (HRQoL) using the QLQ-C30 and module BR45 questionnaires, comparing exclusive RT to exclusive ET in the same patient population. These objectives are clinically relevant as they address the efficacy and quality of life implications of treatment modalities in a specific demographic, potentially guiding therapeutic decisions in elderly patients with luminal A-like early-stage breast cancer.

Secondary objectives include evaluating the safety profile by assessing the number and grade of participants with reported adverse events (AEs), analyzing individual scales from the QLQ-C30 and module QLQ-BR45 scores, and measuring patient-reported outcomes on HRQoL using the ELD14 questionnaire. The study also aims to assess the rate of cosmesis, local recurrence rate (LRR), contralateral breast cancer (CBC), distant metastasis (DM) rate, breast cancer-specific survival (BCSS), and overall survival (OS). These secondary objectives provide a comprehensive evaluation of the treatment's impact on patient safety, quality of life, and long-term outcomes.

The clinical trial focuses on a study population consisting exclusively of **female** participants aged 70 years and older, diagnosed with **breast cancer**. The participants are characterized by a histologically proven invasive adenocarcinoma of the breast, specifically at the pathological T1 stage, with postoperative negative surgical margins and a clinical and pathological N0 stage. The trial targets individuals with luminal A-like biology, defined by ER and PgR positivity, HER2 negativity, and low Ki67 levels. Participants have undergone breast-conserving surgery, with or without sentinel node biopsy. The trial does not include a vulnerable population, and the sponsor has not provided the total number of participants. The selection criteria emphasize a low-risk early breast cancer profile, ensuring a homogenous study group for evaluating the trial's objectives.

The clinical trial is designed as a **randomized**, phase 3 study to evaluate the efficacy of exclusive endocrine therapy compared to radiation therapy in women aged 70 years or older with luminal A-like early-stage **breast cancer**. The trial employs a **double-blind** methodology to ensure unbiased results, with participants randomly assigned to receive either hormone therapy or radiation therapy. The study is expected to span approximately eight years, with an estimated end date in February 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histologically proven invasive adenocarcinoma, and specific tumor characteristics. Following successful screening, participants will be enrolled and randomized into one of the treatment arms. Follow-up visits are scheduled at baseline, 3, 6, 12, 24 months, and annually up to 5 years to monitor treatment efficacy and safety, as well as to assess patient-reported outcomes and quality of life using the QLQ-C30 and BR45 questionnaires. The end-of-study visit will occur at the conclusion of the trial to gather final data on primary and secondary endpoints, including the rate of ipsilateral breast tumor recurrence (IBTR) and health-related quality of life (HRQoL).

The expected length of participant involvement is up to 5 years, with conditions for early termination including withdrawal of consent, significant adverse events, or disease progression. The trial aims to provide comprehensive data on the comparative effectiveness of endocrine therapy versus radiation therapy, contributing valuable insights into treatment strategies for older women with early-stage breast cancer.

The clinical trial involves the administration of several **hormone therapy** medications, each with specific dosing regimens and administration routes. **Exemestane** is utilized in this study as an oral medication with a pharmaceutical form coded as PHF00009MIG. The maximum daily dose is 25 mg, administered once daily. The treatment period for exemestane is set for a maximum of 60 days. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.

**Anastrozole** is another experimental medication used in this trial. It is also administered orally, with a pharmaceutical form coded as PHF00009MIG. The maximum daily dose for anastrozole is 1 mg, taken once daily. The treatment duration is limited to 60 days, and participant compliance is closely monitored to maintain the integrity of the study.

**Tamoxifen** is included in the trial as an oral medication, with a pharmaceutical form coded as PHF00082MIG. The maximum daily dose is 20 mg, with a total allowable dose of 40 mg per day if required. The treatment period for tamoxifen is also set for a maximum of 60 days. Adherence to the dosing schedule is essential, and compliance is tracked throughout the study.

**Letrozole** is the final experimental medication in this trial, administered orally with a pharmaceutical form coded as PHF00082MIG. The maximum daily dose is 2.5 mg, taken once daily. The treatment period is capped at 60 days, and participant compliance is monitored to ensure accurate data collection and analysis.

All medications in this trial are of chemical origin and are not formulated for pediatric use. The study does not involve any orphan drug designations. Each medication is classified under hormone therapy, and the trial aims to evaluate their efficacy and safety in the context of the study objectives. Compliance monitoring is a critical component of the trial to ensure that participants adhere to the prescribed dosing regimens.

Efficacy in the clinical trial titled "ExclUsive endocRine therapy Or radiation theraPy for women aged ≥70 years with luminal A-like early stage breast cancer (EUROPA): a randomized phase 3 trial" will be assessed using several primary and secondary endpoints. The primary endpoints include the **IBTR** (Ipsilateral Breast Tumor Recurrence) rate at 5 years and patient-reported outcomes on health-related quality of life (HRQoL) measured by the global quality of life score (QLQ-C30) using the Global Health Status (GHS) at 24 months. Secondary endpoints encompass the LRR (Locoregional Recurrence) rate, CBC (Contralateral Breast Cancer) rate, DM (Distant Metastasis) rate, BCSS (Breast Cancer-Specific Survival), and OS (Overall Survival) at 5 years. Safety will be evaluated by the number and grade of participants with reported adverse events (AEs) at 5 years.

Additional assessments include individual scales from QLQ-C30 and QLQ-BR45 scores at baseline, 3, 6, 12, 24 months, and 5 years, as well as the rate of cosmesis assessment grade at the same timepoints. The PROMs HRQoL will also be measured by the ELD14 questionnaire (optional) at baseline, 12, 24 months, and 5 years. These efficacy parameters will be collected and analyzed at specified intervals to determine the comparative effectiveness of exclusive radiation therapy versus exclusive endocrine therapy in the specified patient population.