A PHASE III, RANDOMIZED, OPEN-LABEL STUDY EVALUATING THE EFFICACY AND SAFETY OF GIREDESTRANT IN COMBINATION WITH PHESGO VERSUS PHESGO AFTER INDUCTION THERAPY WITH PHESGO+TAXANE IN PATIENTS WITH PREVIOUSLY UNTREATED HER2-POSITIVE, ESTROGEN RECEPTOR-POSITIVE LOCALLY-ADVANCED OR METASTATIC BREAST CANCER

The primary objective of this study is to evaluate the **efficacy** of Phesgo in combination with giredestrant compared to Phesgo alone, based on **progression-free survival (PFS)** in patients with previously untreated HER2-positive, estrogen receptor-positive locally-advanced or metastatic breast cancer. This is clinically relevant as progression-free survival is a critical endpoint in assessing the effectiveness of cancer therapies, indicating the length of time during and after treatment that a patient lives with the disease without it worsening.

Secondary objectives include:

• Evaluating the efficacy of Phesgo plus giredestrant compared with Phesgo based on overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and quality of life (QoL) as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).
• Assessing the safety of Phesgo plus giredestrant compared with Phesgo.

The clinical trial involves a total of **704 participants** diagnosed with **locally-advanced unresectable or metastatic breast cancer (MBC)**. The study population includes both **females and males** aged 18 years and older, regardless of menopausal status. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of adenocarcinoma of the breast with metastatic or locally-advanced disease that is not amenable to curative resection. The trial includes individuals with at least one measurable lesion or non-measurable disease evaluable according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Participants must have a disease-free interval from the completion of adjuvant or neoadjuvant systemic nonhormonal treatment to recurrence of at least six months. The general health status of participants is assessed with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, and a left ventricular ejection fraction (LVEF) of at least 50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA). The trial population includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase III**, randomized, open-label study designed to evaluate the efficacy and safety of **giredestrant** in combination with Phesgo compared to Phesgo alone in patients with previously untreated HER2-positive, estrogen receptor-positive locally-advanced or metastatic breast cancer. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), health-related quality of life (HRQoL), and the incidence and severity of adverse events. The trial is expected to conclude by March 2027, with recruitment having commenced in July 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and performance status. Following randomization, participants will receive induction therapy with Phesgo and a taxane, after which they will be assigned to either the combination therapy group or the Phesgo alone group. Study visits will occur regularly to monitor treatment response, adverse events, and overall health status. The end-of-study visit will mark the conclusion of the participant's involvement, which is anticipated to last up to 72 weeks, depending on the treatment arm and individual response.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will adhere to rigorous scientific and ethical standards, ensuring that data collection and analysis are conducted with precision and integrity. The study's design and methodology are structured to provide robust evidence on the comparative effectiveness of the treatment regimens, contributing valuable insights into the management of this specific breast cancer subtype.

The clinical trial involves the administration of several experimental and non-experimental medications. **Giredestrant**, also known as RO7197597, is an investigational medicinal product of chemical origin. It is provided in a hard capsule form and administered orally. The maximum daily dose is 30 mg, with a total maximum dose of 11,340 mg over a treatment period of 54 weeks. This compound is a small molecule designed to target specific pathways in cancer treatment.

**Phesgo**, a combination of **trastuzumab** and **pertuzumab**, is administered as a solution for injection. It is available in two formulations: 600 mg/600 mg and 1200 mg/600 mg. The maximum daily dose for the 600 mg/600 mg formulation is 1200 mg, with a total maximum dose of 26,400 mg over 72 weeks. For the 1200 mg/600 mg formulation, the maximum daily dose is 1800 mg, with a total maximum dose of 3600 mg over the same period. This combination is used as a standard-of-care therapy in HER2-positive breast cancer.

**Anastrozole** is a nonsteroidal aromatase inhibitor provided in an oral pharmaceutical form. The maximum daily dose is 1 mg, with a total maximum dose of 378 mg over 54 weeks. It is used as a comparator treatment in the study.

**Paclitaxel** is a taxoid antineoplastic agent administered via infusion. The maximum daily dose is 80 mg/m², with a total maximum dose of 1920 mg/m² over 24 weeks. It is used in combination with Phesgo during the induction phase of the trial.

**Exemestane** is another nonsteroidal aromatase inhibitor, administered orally. The maximum daily dose is 25 mg, with a total maximum dose of 9450 mg over 54 weeks. It serves as a comparator treatment in the study.

**Letrozole**, also a nonsteroidal aromatase inhibitor, is administered orally. The maximum daily dose is 2.5 mg, with a total maximum dose of 945 mg over 54 weeks. It is used as a comparator treatment in the study.

**Tamoxifen** is a non-steroidal, triphenylethylene-based drug that acts as an estrogen receptor modulator. It is administered orally with a maximum daily dose of 20 mg and a total maximum dose of 7560 mg over 54 weeks. It is used as a comparator treatment in the study.

**Anhydrous Docetaxel** is a taxoid antineoplastic agent administered via infusion. The maximum daily dose is 100 mg/m², with a total maximum dose of 775 mg/m² over 24 weeks. It is used in combination with Phesgo during the induction phase of the trial.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy of Phesgo in combination with giredestrant compared to Phesgo alone, based on progression-free survival in patients with previously untreated HER2-positive, estrogen receptor-positive locally-advanced or metastatic breast cancer.

The efficacy of the clinical trial will be assessed primarily through **progression-free survival (PFS)**, which is defined as the time from randomization to the first occurrence of disease progression or death from any cause, as determined by the investigator according to RECIST version 1.1. Secondary efficacy endpoints include **overall survival (OS)**, defined as the time from randomization to death from any cause, and **objective response rate (ORR)**, which is the proportion of participants with a complete response (CR) or partial response (PR) on two consecutive occasions at least four weeks apart. Additionally, **duration of response (DOR)**, **clinical benefit rate (CBR)**, and changes in health-related quality of life (HRQoL) will be evaluated. The HRQoL will be assessed using the Functional and GHS/QoL scales of the EORTC QLQ-C30.

The efficacy parameters will be measured and collected at various timepoints throughout the trial, with assessments conducted according to the RECIST v1.1 criteria. The analysis will involve comparing the efficacy of giredestrant in combination with Phesgo versus Phesgo alone after induction therapy with Phesgo and a taxane in patients with previously untreated HER2-positive, estrogen receptor-positive locally-advanced or metastatic breast cancer. The trial is designed to provide a comprehensive evaluation of the treatment's impact on disease progression and patient quality of life.