Efficacy and Safety of Giredestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer

The primary objective of this study is to evaluate the **efficacy** of GDC-9545 combined with palbociclib compared with letrozole combined with palbociclib, specifically focusing on progression-free survival (PFS) in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer. This is clinically relevant as PFS is a critical endpoint in assessing the effectiveness of cancer therapies, providing insights into how long a treatment can delay disease progression.

Secondary objectives include:

• Evaluating the efficacy of GDC-9545 combined with palbociclib compared with letrozole combined with palbociclib based on overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and time to confirmed deterioration (TTCD) in various health aspects such as pain level, physical functioning, role functioning, global health status, and quality of life.
• Assessing the safety of GDC-9545 combined with palbociclib compared with letrozole combined with palbociclib.
• Characterizing the pharmacokinetic (PK) profile of GDC-9545 when administered with palbociclib, with or without an LHRH agonist.
• Characterizing the PK profile of palbociclib when administered with GDC-9545 or letrozole, with or without an LHRH agonist.

The clinical trial involves a total of **982 participants** diagnosed with **estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer**. The study population includes both **female and male 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 the requirement for premenopausal or perimenopausal women and men to receive approved LHRH agonist therapy throughout the study. The trial population comprises individuals with locally advanced or metastatic adenocarcinoma of the breast, who have not received prior systemic anti-cancer therapy for their advanced disease. Participants must have a documented ER-positive and HER2-negative tumor, with measurable disease as per RECIST v.1.1 or bone-only disease with at least one predominantly lytic bone lesion. The general health status of participants is indicated by an Eastern Cooperative Oncology Group Performance Status of 0-1. The trial also includes a vulnerable population, reflecting the careful consideration of ethical standards in participant selection.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, multicenter study** to evaluate the efficacy and safety of **Giredestrant** combined with **Palbociclib** compared to **Letrozole** combined with Palbociclib in patients with **estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer**. The primary objective is to assess progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and duration of response (DOR), among others. The trial is expected to run from January 18, 2021, to March 31, 2027, with a maximum treatment period of 82 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented ER-positive and HER2-negative tumor status, and no prior systemic anti-cancer therapy for advanced disease. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of disease progression and adverse events. The end-of-study visit will conclude the participant's involvement, with final evaluations of treatment outcomes and any long-term effects.

The expected length of participant involvement is up to 82 weeks, contingent upon disease progression and tolerability of the treatment regimen. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any protocol deviations that compromise the integrity of the trial. The study will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **Giredestrant**, an experimental medication identified by the product name RO7197597. This medication is provided in the form of a hard capsule and is administered orally. The maximum daily dose is 30 mg, with a total maximum dose of 75 mg over a treatment period of 82 days. Giredestrant is a small molecule of chemical origin, developed by F. Hoffmann-La Roche Ltd. The active substance, Giredestrant, is also known by the synonyms GDC-9545 and RG-6171.

In addition to the experimental treatment, the study includes a **placebo** for Giredestrant, which is relabeled for clinical trial use. The placebo is used to maintain blinding and does not contain any active substance. It is administered in a manner consistent with the experimental medication to ensure the integrity of the study design.

The trial also involves the administration of **Palbociclib**, marketed under the name IBRANCE, available in 75 mg, 100 mg, and 125 mg hard capsules. Palbociclib is administered orally with a maximum daily dose of 125 mg and a total maximum dose of 312 mg over the same 82-day treatment period. This comparator treatment is a chemical substance provided by Pfizer Europe MA EEIG and is relabeled for clinical trial use.

Another comparator treatment in the study is **Letrozole**, marketed as Femara® 2.5 mg film-coated tablets. Letrozole is administered orally with a maximum daily dose of 2.5 mg and a total maximum dose of 6.2 g over the treatment period. This medication is a small molecule of chemical origin, provided by Novartis Pharma GmbH, and is also relabeled for clinical trial use to maintain blinding.

A **placebo** for Letrozole is included in the study, similarly relabeled for clinical trial use. This placebo is used to ensure blinding and does not contain any active substance. It is administered in a manner consistent with Letrozole to maintain the study's integrity.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. This endpoint will evaluate the time from randomization to the first occurrence of disease progression or death from any cause. Secondary efficacy endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR). Additionally, time to confirmed deterioration (TTCD) in various parameters such as pain level, pain presence and interference, physical functioning (PF), role functioning (RF), and global health status (GHS) and quality-of-life (QoL) will be evaluated. The incidence and severity of adverse events will also be monitored, with severity determined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE v5.0). Changes from baseline in targeted vital signs and plasma concentrations of GDC-9545 and palbociclib at specified timepoints will be measured.