This is a global, Phase 3, randomized, open-label study evaluating BGB-43395 in combination with letrozole compared with investigator’s choice of CDK4/6i in combination with letrozole in patients with HR+/HER2- advanced or metastatic breast cancer who have not received prior systemic therapy for advanced or metastatic disease. Participants are randomized in a 1:1 ratio to receive either BGB-43395 plus letrozole (Arm A) or investigator’s choice of CDK4/6i (abemaciclib, palbociclib, or ribociclib) plus letrozole (Arm B). Randomization is stratified by the presence of visceral metastasis (yes versus no), de novo metastatic diagnosis (yes versus no), and investigator’s choice of CDK4/6i. The primary endpoint is progression-free survival (PFS) as assessed by blinded independent central review (BICR). Secondary endpoints include overall survival (OS; key), objective response rate (ORR) as assessed by BICR, duration of response (DoR) as assessed by BICR, progression-free survival as assessed by the investigator, clinical benefit rate (CBR), time to response (TTR), safety and tolerability, patient-reported outcomes (PROs) assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and progression-free survival 2 (PFS2). Exploratory endpoints include additional patient-reported outcomes assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire and Patient Global Impression scales, pharmacokinetic and pharmacodynamic assessments, and evaluation of other biomarkers.