Background/Objectives: CDK4/6i and ET improve outcomes in HR-positive, HER2-negative breast cancer, but their benefits differ between early-stage (EBC) and metastatic disease (MBC). We aimed to compare the efficacy and toxicity of CDK4/6i plus ET versus ET alone across these disease settings. Methods: We conducted a meta-analysis of phase III randomized trials identified through MEDLINE, EMBASE, and Web of Science up to 1 October 2025. Twenty-two trials (18 MBC, n = 6364; 4 EBC, n = 17,741) met the inclusion criteria. Two reviewers extracted data and assessed risk of bias. The study followed PRISMA 2020 guidelines (PROSPERO: CRD420251132302). Outcomes included overall survival (OS), progression-free survival (PFS), invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), response rates, treatment discontinuation (TDR), dose reductions (DRR), and grade 3–4 adverse events. Results: In MBC, CDK4/6i improved OS (HR: 0.78, 95% CI: 0.72–0.85) and PFS (HR: 0.53, 95% CI: 0.50–0.56) and increased objective response, clinical benefit, and disease control rates along with TDR, DRR, and grade 3–4 adverse events. In EBC, iDFS improved, whereas OS (HR: 0.92, 95% CI: 0.75–1.12; p = 0.40) and DRFS did not. TDR, DRR, and grade 3–4 adverse events were increased. Conclusions: CDK4/6i confer significant OS and PFS benefits in MBC, supporting first-line use. In EBC, no OS benefit was observed, and toxicity was increased, underscoring the need for individualized risk–benefit assessment. Longer follow-up is warranted to clarify survival outcomes.
Dhanoa et al. (Sun,) studied this question.