Efficacy and Safety of Giredestrant vs. Fulvestrant with CDK4/6 Inhibitor in ER+ HER2- Advanced Breast Cancer Resistant to Endocrine Therapy

The primary objective of this study is to evaluate the **efficacy** of giredestrant compared with fulvestrant in the ESR1 mutation detected (ESR1m) subgroup and full analysis set (FAS) on the basis of progression-free survival (PFS). This is clinically relevant as progression-free survival is a critical endpoint in assessing the effectiveness of treatments for estrogen receptor-positive, HER2-negative advanced breast cancer, particularly in patients with resistance to prior adjuvant endocrine therapy.

Secondary objectives include:

• To evaluate the **safety** of giredestrant compared with fulvestrant.
• To assess the efficacy of giredestrant compared with fulvestrant based on PFS in the ESR1 no mutation detected (ESR1nmd) subgroup, and based on overall survival (OS), confirmed objective response rate (cORR), duration of response (DOR), clinical benefit rate (CBR), time to chemotherapy (TTCtx), time to confirmed deterioration (TTCD) in pain severity, presence and interference, TTCD in physical functioning (PF), role functioning (RF), and global health status/quality of life (GHS/QoL) in the ESR1m and ESR1nmd subgroups and in the FAS.

The clinical trial involves a total of **757 participants** diagnosed with **estrogen receptor (ER)-positive, HER2-negative advanced breast cancer**. 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 specific criteria, including confirmed ESR1 mutation status and resistance to prior standard adjuvant endocrine therapy. The trial population is characterized by a general health status that allows for an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1, indicating fully active individuals or those restricted in physically strenuous activity but ambulatory. The study also includes a vulnerable population, reflecting the advanced nature of the disease. Lifestyle considerations such as diet and physical activity were not specified by the sponsor. The selection process ensured that participants had locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent, with documented ER+ HER2- status. The trial aims to evaluate the efficacy of giredestrant compared with fulvestrant, focusing on progression-free survival in the ESR1 mutation detected subgroup and the full analysis set.

The clinical trial is designed to evaluate the efficacy and safety of **giredestrant** compared with **fulvestrant**, both in combination with a **CDK4/6 inhibitor**, in patients with **estrogen receptor-positive, HER2-negative advanced breast cancer** who have shown resistance to prior adjuvant endocrine therapy. This is a Phase III, randomized, open-label study. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), clinical objective response rate (cORR), duration of response (DOR), and clinical benefit rate (CBR), among others. The trial is expected to start recruitment on December 30, 2023, and conclude by December 30, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed ESR1 mutation status, resistance to prior standard adjuvant endocrine therapy, and measurable disease as per RECIST v1.1. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events, with assessments conducted according to the trial protocol. The end-of-study visit will mark the completion of the participant's involvement in the trial, which is anticipated to last up to 60 months, depending on individual response and disease progression.

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 to ensure the validity and reliability of the data collected. The study will be conducted in compliance with Good Clinical Practice (GCP) guidelines and applicable regulatory requirements.

The clinical trial involves the administration of several experimental and comparator medications. **Giredestrant**, also known as RO7197597, is a selective estrogen receptor degrader (SERD) provided in the form of hard capsules. The maximum daily dose is 30 mg, with a total dose not exceeding 41 g over a 60-day treatment period. The medication is administered orally.

**Fulvestrant**, marketed as Faslodex, is a competitive estrogen receptor antagonist available as a solution for injection. The maximum daily dose is 500 mg, with a total dose of 33 g over the treatment period. It is administered via intramuscular use.

**Palbociclib**, marketed under the name IBRANCE, is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6. It is available in film-coated tablet form with dosages of 75 mg, 100 mg, and 125 mg. The maximum daily dose is 125 mg, with a total dose of 171 g over 60 days. Administration is oral.

**Ribociclib**, marketed as Kisqali, is another selective inhibitor of CDK 4 and 6, provided in film-coated tablet form with a dosage of 200 mg. The maximum daily dose is 600 mg, with a total dose of 822 g over the treatment period. It is administered orally.

**Abemaciclib**, marketed as Verzenios, is a potent and selective inhibitor of CDK 4 and 6. It is available in film-coated tablet form with dosages of 50 mg, 100 mg, and 150 mg. The maximum daily dose is 300 mg, with a total dose of 548 g over 60 days. Administration is oral.

**Leuprorelin**, a synthetic nonapeptide agonist, is provided in a pharmaceutical form identified as PHF00231MIG. The maximum daily dose is 3.75 mg, with a total dose of 248 mg over the treatment period. It is administered via intramuscular use.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these medications in patients with estrogen receptor-positive, HER2-negative advanced breast cancer resistant to prior adjuvant endocrine therapy.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause during the study, whichever occurs first. This primary endpoint will be evaluated in both the ESR1 mutation detected (ESR1m) subgroup and the full analysis set (FAS).

Secondary efficacy endpoints include several parameters: PFS in the ESR1 non-mutation detected (ESR1nmd) subgroup, Overall Survival (OS), which is the time from randomization to death from any cause, and the confirmed Objective Response Rate (cORR), defined as 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) will be measured from the first occurrence of a documented objective response to disease progression or death. Clinical Benefit Rate (CBR) will be assessed as the proportion of participants with stable disease for at least 24 weeks or a CR or PR. Time to Chemotherapy (TTCtx) and Time to Confirmed Deterioration (TTCD) in various parameters such as pain severity, pain presence and interference, physical functioning, role functioning, and global health status/quality of life (GHS/QoL) will also be evaluated.

The incidence and severity of adverse events will be monitored, with severity determined according to NCI CTCAE v5.0. Changes from baseline in selected vital signs and clinical laboratory test results will also be recorded. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, ensuring a comprehensive assessment of the treatment's impact on patients with estrogen receptor-positive, HER2-negative advanced breast cancer resistant to prior adjuvant endocrine therapy.