BGB-43395 Plus Letrozole Versus CDK4/6i Plus Letrozole for Patients With Advanced or Metastatic HR+/HER2- Breast Cancer Who Have Not Received Prior Treatment for Advanced or Metastatic Disease

• BGB-43395 (Drug): Administered orally.
• Letrozole (Drug): Administered orally.
• Abemaciclib (Drug): Administered orally.
• Palbociclib (Drug): Administered orally.
• Ribociclib (Drug): Administered orally.

Primary outcomes

• Progression-Free Survival (PFS) Determined by Blinded Independent Central Review (BICR) [Up to approximately 4 years]: PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Secondary outcomes

• Overall Survival (OS) [Up to approximately 11 years]: OS is defined as the time from the date of randomization until the date of death due to any cause.
• Overall Response Rate (ORR) [Up to approximately 4 years]: ORR is defined as the percentage of participants who had a complete response (CR) or partial response (PR), as assessed by BICR per RECIST v1.1.
• Duration of Response (DOR) [Up to approximately 4 years]: DOR is defined as the time from the first occurrence of a documented objective response to the time of disease progression or death from any cause, whichever occurs first, as assessed by BICR per RECIST v1.1.
• PFS Determined by Investigator [Up to approximately 4 years]: PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Clinical Benefit Rate (CBR) [Up to approximately 4 years]: CBR is defined as the percentage of participants who have a CR, PR, or stable disease maintained for ≥ 24 weeks after randomization (without subsequent anticancer treatment) per RECIST v1.1 .
• Time to Response (TTR) [Up to approximately 4 years]: TTR is defined as the time from treatment initiation to the first response confirmed by BICR per RECIST v1.1.
• Number of Participants with Adverse Events (AEs) [From first dose of study drug up to 30 days after last dose, up to approximately 11 years]: Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including laboratory values, vital signs, physical examination findings, and electrocardiogram results.
• Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC)-Item Library (IL)454. [Baseline and up to approximately 4 years]: The EORTC-IL454 is a questionnaire that asks participants to rate their breast cancer symptoms and the impact of breast cancer on their quality of life (QoL). The EORTC-IL454 is an EORTC Item Library-derived scale set constructed using items from the validated EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) (a core measure of health-related QoL in cancer patients) and the QLQ-BR23 (its breast cancer-specific module) The EORTC-IL454 contains 26 questions, each answered on a 4-point scale (1 = Not at all; 4 = Very much), and includes 2 functional scales (physical functioning and role functioning), 2 symptom scales (Nausea/Vomiting and Diarrhea), and 1 Global Health Status (GHS)/Quality of Life (QoL) scale, 7 systemic side effects scales, 3 arm symptom scales, and 4 breast-specific symptom scales. The recall period is the past 7 days. Higher scores in GHS and functional scales and lower scores in symptom scales indicate better QoL.
• Progression-Free Survival 2 (PFS2) [Up to approximately 4 years]: PFS2 is defined as the time from randomization until progression on the next line of treatment (ie, first subsequent therapy), as assessed by the investigator, or death due to any cause, whichever occurs first.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Participants must be at least 18 years of age or the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the informed consent.
* Participants with histologically confirmed locally advanced or metastatic HR+ HER2- breast cancer.
* Participants must have a stable Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1.
* Adequate organ function.

Exclusion Criteria:

* Participants who have received prior systemic treatment in the advanced or metastatic setting.
* Participants who have received prior treatment with any selective cyclin-dependent kinase 4 (CDK4) or cyclin-dependent kinase 2 (CDK2) targeting agent, or any other investigational anticancer drug in any disease setting, except for prior investigational or approved SERDs in the adjuvant setting, provided that disease recurrence occurred more than 12 months after the last dose of endocrine-based therapy.
* Participants with active leptomeningeal disease or uncontrolled, untreated brain metastasis.

Note: Other protocol-defined inclusion/exclusion criteria may apply.

106 more sites not listed.

• Study Director, Study director, BeOne Medicines

NIH grants: 2025