Clinical outcomes of everolimus plus exemestane versus fulvestrant in patients with metastatic breast cancer after progression on cyclin-dependent kinase 4/6 inhibitors

Cyclin-dependent kinase (CDK) 4/6 inhibitors are commonly used in patients with hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) metastatic breast cancer. However, there is a lack of established standard treatment recommendations for second-line therapy after the failure of CDK4/6 inhibitors. This study aimed to compare the effectiveness of everolimus plus exemestane with that of fulvestrant as second-line therapy for HR+/HER2- metastatic breast cancer after progression on treatment with CDK4/6 inhibitors. A retrospective cohort study was conducted using Korean Health Insurance Review and Assessment claims data from 2016 to 2023. Patients with HR+/HER2- breast cancer who progressed on a CDK4/6 inhibitor were categorized into two cohorts based on their second-line therapy: everolimus plus exemestane or fulvestrant. We used inverse probability of treatment weighting to adjust for confounders. Overall survival (OS) and time to next treatment (TTNT) were estimated using the Kaplan–Meier method. Multivariate Cox regression analysis was used to assess the impact of everolimus plus exemestane compared with fulvestrant on OS and TTNT. The study cohort included 314 patients treated with everolimus plus exemestane and 316 patients treated with fulvestrant. Everolimus plus exemestane was associated with a longer TTNT compared with fulvestrant (median TTNT, 6.7 months vs. 4.6 months; p-value, 0.02). This difference remained significant after adjustment for measured confounders (hazard ratio, 1.25; 95% confidence interval [CI], 1.06–1.47). However, no statistically significant difference in OS was observed between the two cohorts (hazard ratio, 1.09; 95% CI, 0.87–1.36). This study suggests that everolimus plus exemestane may be associated with longer TTNT than fulvestrant as second-line therapy in patients with HR+/HER2- metastatic breast cancer following progression on CDK4/6 inhibitor plus aromatase inhibitor; however, because TTNT is a surrogate endpoint and no statistically significant difference in OS was observed, these findings should be interpreted cautiously.