Abstract
INTRODUCTION: This study aims to evaluate the clinical efficacy and safety profiles of various cyclin-dependent kinase 4/6 inhibitors(CDK4/6i) when administered alongside endocrine therapy (ET) in individuals diagnosed with advanced or metastatic breast cancer characterized by hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-negative (HER2-) status. A network meta-analysis approach was employed to systematically compare these therapeutic combinations. METHODS: A systematic literature search was executed across four biomedical databases (Web of Science, PubMed, Cochrane Library and Embase), followed by a Bayesian network meta-analysis implemented through R statistical software. Progression-free survival (PFS) served as the primary efficacy endpoint, with treatment effects expressed as hazard ratios (HR) and accompanying 95% confidence intervals (CI). Secondary endpoints encompassed overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: The study included 24 articles, comprising 15,602 patients and involving 12 treatment options. There were significant differences in PFS among certain CDK4/6i + ET combinations. Notably, the most effective combination therapy in terms of PFS might be abemaciclib plus aromatase inhibitors(AI), showing significant differences relative to palbociclib plus fulvestrant (HR = 2.01; 95% CI: 1.32–2.93), abemaciclib plus fulvestrant (HR = 2.68; 95% CI: 1.52–4.36), ribociclib plus fulvestrant (HR = 2.75; 95% CI: 1.54–4.83), while ribociclib plus AI was second, showing significant differences relative to ribociclib plus fulvestrant (HR = 0.38; 95% CI: 0.21–0.7), abemaciclib plus fulvestrant (HR = 0.39; 95% CI: 0.23–0.72), palbociclib plus fulvestrant (HR = 1.92; 95% CI: 1.20–2.92). Meanwhile, the SUCRA ranking diagram indicated that abemaciclib plus AI and palbociclib plus AI regimens might show the most favorable results in PFS and OS. In terms of safety, there was no statistically significant difference in adverse events (AEs) among different CDK4/6i combinations. CONCLUSIONS: The research results indicate that in the treatment of advanced or metastatic breast cancer with HR + /HER2- phenotype, CDK4/6 inhibitors combined with endocrine therapy is superior to endocrine monotherapy. Among the evaluated treatment options, abemaciclib plus aromatase inhibitors appear to be potentially recommended regimens. Therefore, clinical decision-making should be personalized based on comprehensive consideration of individual patient factors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-025-14841-2.