Efficacy and Safety of Giredestrant Plus Everolimus Versus Endocrine Therapy Plus Everolimus in ER-Positive, HER2-Negative Advanced Breast Cancer

The primary objective of this study is to evaluate the **efficacy** of giredestrant plus everolimus compared with the physician's choice of endocrine therapy plus everolimus in patients with estrogen receptor 1 mutant (ESR1m) subpopulation and in the intent-to-treat (ITT) population. This evaluation is based on investigator-assessed progression-free survival (PFS), which is clinically relevant as it measures the length of time during and after treatment that a patient lives with the disease without it getting worse.

Secondary objectives include:

• Evaluating the efficacy of giredestrant plus everolimus compared with the physician’s choice of endocrine therapy plus everolimus in the ESR1m subpopulation and the ITT population based on overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), time to confirmed deterioration (TTCD) in pain severity, TTCD in pain presence and interference, TTCD in Physical Functioning (PF), TTCD in Role Functioning (RF), and TTCD in health-related quality of life (HRQoL).
• Evaluating the safety of giredestrant plus everolimus compared with the physician’s choice of endocrine therapy plus everolimus.
• Characterizing the giredestrant pharmacokinetic (PK) profile when given in combination with everolimus.

The clinical trial involves a total of **308 participants** diagnosed with **Estrogen Receptor (ER)-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer** who have previously been treated with a CDK4/6 inhibitor and endocrine therapy. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on their ability to provide a blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) ESR1 mutation status determination and must have measurable disease as defined per RECIST v.1.1 or evaluable bone metastases. The trial population includes individuals with a documented ER-positive tumor and HER2-negative status, as assessed locally. The study also considers vulnerable populations, ensuring that all acute toxic effects of prior anti-cancer therapy or surgical procedures have resolved to NCI CTCAE v5.0 Grade ≤ 1. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **giredestrant** plus **everolimus** compared with the physician's choice of endocrine therapy plus **everolimus** in patients with **estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer**. This is a Phase III, randomized, open-label, multicenter study. The trial aims to assess progression-free survival (PFS) in both the ESR1 mutant subpopulation and the intent-to-treat (ITT) population. The study is expected to commence recruitment on October 30, 2023, and conclude by June 30, 2026, with a maximum treatment period of 42 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented **estrogen receptor-positive** and **HER2-negative** tumor status, and the ability to provide a blood sample for ESR1 mutation status determination. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of PFS, overall survival (OS), objective response rate (ORR), and duration of response (DOR). The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 42 days, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will utilize oral administration of investigational medicinal products, with **giredestrant** and **everolimus** being the primary agents under investigation. The study will adhere to rigorous scientific standards, ensuring that all data collected is reliable and valid for assessing the primary and secondary endpoints.

The clinical trial involves the administration of several investigational medicinal products. **Giredestrant**, marketed as RO7197597, is provided in the form of a hard capsule. The active substance, giredestrant, is a chemical compound administered orally. The maximum daily dose is 30 mg, with a total dose not exceeding 37.47 g over a treatment period of 42 days. This investigational product is relabeled for clinical trial use and is classified as an investigational medicinal product (IMP) of chemical origin.

**Everolimus** is utilized in multiple formulations, including Afinitor and Everolimus Zentiva, available in tablet form. The active substance, everolimus, is administered orally with a maximum daily dose of 10 mg and a total dose limit of 12.49 g over 42 days. Everolimus is relabeled for clinical trial use and is also classified as an IMP of chemical origin. The trial includes various dosages, such as 2.5 mg, 5 mg, and 10 mg tablets, provided by manufacturers like Novartis Europharm Limited and Zentiva Pharma GmbH.

**Exemestane** is another investigational product used in the trial, available as MEXABREST and Exemestan STADA® in film-coated tablet form. The active substance, exemestane, is administered orally with a maximum daily dose of 25 mg and a total dose limit of 31.22 g over 42 days. This product is relabeled for clinical trial use and is classified as an IMP of chemical origin. It is provided by manufacturers such as Accord Healthcare S.L.U. and STADAPHARM GmbH.

**Tamoxifen Citrate**, marketed as Tamoxifen 20 PCH, is provided in tablet form. The active substance, tamoxifen citrate, is administered orally with a maximum daily dose of 20 mg and a total dose limit of 24.98 g over 42 days. This product is relabeled for clinical trial use and is classified as an IMP of chemical origin, provided by TEVA B.V.

**Fulvestrant**, marketed as Faslodex, is provided as a solution for injection. The active substance, fulvestrant, is administered intramuscularly with a maximum daily dose of 500 mg and a total dose limit of 22.5 g over 42 days. This product is relabeled for clinical trial use and is classified as an IMP of chemical origin, provided by AstraZeneca AB.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the efficacy and safety of these investigational products in patients with estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)** in both the estrogen receptor 1 mutant subpopulation (ESR1m subpopulation) and the intent-to-treat (ITT) population. PFS 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 the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).

Secondary efficacy endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR). ORR is defined as the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions at least four weeks apart. DOR is the time from the first occurrence of a documented objective response to disease progression or death. CBR is defined as the proportion of patients with stable disease for at least 24 weeks or a CR or PR on two consecutive occasions at least four weeks apart. These assessments will also be determined by the investigator according to RECIST v1.1.

Additional secondary endpoints include time to confirmed deterioration (TTCD) in pain severity, pain presence and interference, physical functioning (PF), role functioning (RF), and health-related quality of life (HRQoL). These will be measured using the Brief Pain Inventory-Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 Questionnaire (QLQ-C30). Changes in targeted vital signs and clinical laboratory test results, as well as plasma concentration of giredestrant at specified timepoints, will also be evaluated.