Efficacy and Safety of Post-CDK4/6 Inhibitor Treatment Options for HR-Positive, HER2-Negative Advanced Breast Cancer: A Network Meta-Analysis of Randomized Controlled Trials

Purpose: In patients with HR-positive, HER2-negative advanced breast cancer who have progressed after CDK4/6 inhibitors, the optimal selection of subsequent therapies remains uncertain. This study employs a Bayesian network meta-analysis to evaluate the efficacy and safety of different treatment options. Methods: We conducted a comprehensive literature search in the PubMed, Embase, and Cochrane databases, as well as abstracts from the San Antonio Breast Cancer Symposium, European Society for Medical Oncology, and American Society of Clinical Oncology, covering the past five years, with the search cutoff date of April 1, 2025. Only randomized controlled trials were included in the final analysis. Our analysis focused on several key outcomes, including progression-free survival (PFS) in the overall population, PFS in the ESR1 mutations, PFS in those with PIK3CA mutations population, overall survival, objective response rate and the incidence of grade 3 or higher adverse events. Results: We identified a total of 7,860 publications, ultimately including 16 studies involving 2,972 patients, all of whom experienced disease progression following treatment with CDK4/6 inhibitors. mTOR inhibitors demonstrated superior PFS. Oral-SERD were preferred in ESR1-mutant patients (vs endocrine therapy: HR 0.66, 95% CI 0.44–0.99), while CDK4/6 inhibitor rechallenge showed benefit in PIK3CA-mutant cases (vs endocrine therapy: HR 0.56, 95% CI 0.32–0.98). SERM and oral-SERD achieved optimal efficacy-safety balance. Conclusion: Our findings demonstrate that mTOR inhibitors represent a viable therapeutic option for patients with good performance status, while Oral-SERD may be more suitable for elderly patients or those with multiple comorbidities. Future research should focus on addressing existing evidence gaps and optimizing therapeutic strategies to further improve long-term patient outcomes.