CDK4/6 inhibitors combined with fulvestrant for the treatment of HR+/HER2–advanced or metastatic breast cancer: a Bayesian network meta-analysis

This study aimed to assess the efficacy and safety of different CDK4/6 inhibitors combined with fulvestrant in treating HR+/HER2– advanced or metastatic breast cancer, using a Bayesian network meta-analysis. A comprehensive search was conducted across major medical databases, including PubMed, Web of Science, Cochrane Library, and Embase, to identify randomized controlled trials (RCTs) investigating the combination of CDK4/6 inhibitors and fulvestrant for HR+/HER2– advanced or metastatic breast cancer. The search encompassed studies published from database inception to Sep 10, 2025. Relevant studies were screened, data extracted, and risk of bias evaluated. A Bayesian network meta-analysis was performed using R software (version 4.5.1). Ten randomized controlled trials involving seven CDK4/6 inhibitors combined with fulvestrant were included. All regimens significantly improved progression-free survival (PFS) versus placebo + fulvestrant, and tibremciclib + fulvestrant ranked first among all regimens (HR = 0.37, 95% CrI 0.27–0.52; SUCRA = 89.26%), followed by dalpiciclib (HR = 0.42) and lerociclib (HR = 0.45). Abemaciclib + fulvestrant and palbociclib + fulvestrant demonstrated favorable overall survival (OS) improvements (HR = 0.76 and 0.79, respectively), consistent with pivotal trial evidence. For objective response rate (ORR), tibremciclib + fulvestrant ranked highest (RR = 4.0, 95% CrI 1.2–15.0), while clinical benefit rate (CBR) and quality of life (QoL) showed no statistically significant improvement compared with placebo. In safety analyses, abemaciclib + fulvestrant was associated with higher overall adverse events (RR = 1.16, 95% CrI 1.02–1.34), and bireociclib, dalpiciclib, and lerociclib showed increased risks of grade 3–4 events. Bireociclib and abemaciclib regimens also had higher rates of serious adverse events and treatment discontinuation. All CDK4/6 inhibitors combined with fulvestrant significantly improve progression-free survival in HR+/HER2 − advanced breast cancer, with abemaciclib and palbociclib also showing overall survival benefits. Tibremciclib plus fulvestrant showed relatively higher efficacy, demonstrating moderately superior performance to other regimens, while abemaciclib plus fulvestrant was associated with a higher incidence of treatment-related adverse events. These findings confirm the class effect of CDK4/6 inhibition and highlight the need to balance efficacy with tolerability. Future biomarker-informed and real-world studies are warranted to optimize treatment sequencing and support personalized therapeutic decisions.