OBJECTIVES: CDK4/6i inhibitors have significantly impacted the treatment of HR+/HER2– mBC, improving progression-free survival (PFS) and, in some cases, overall survival (OS) compared to aromatase inhibitors (AIs) or fulvestrant alone. However, there is limited real-world (RWE) evidence regarding the efficacy of fulvestrant monotherapy after progression on AI+CDK4/6i.

METHODS: This retrospective study analysed data from the nationwide Flatiron Health electronic health record (EHR)-derived database to identify HR+/HER2– mBC patients who received fulvestrant monotherapy following progression on AI+CDK4/6i between January 1, 2011, and January 31, 2021. The study assessed real-world PFS (rwPFS), overall real-world survival (rwOS), time to discontinuation (rwTTD) using Kaplan-Meier methods. Patients were followed up from the date of fulvestrant treatment until their date of death, if available, or other outcome-specific events.

RESULTS: In this study, 179 patients with HR+/HER2– mBC were treated with fulvestrant monotherapy after progression on AI+CDK4/6i. Of these, 152 patients transitioned immediately to fulvestrant following AI+CDK4/6i. The median rwPFS was 3.8 months (95% CI 3.6–4.5), median rwTTD was 3.6 months (95% CI 3.0–4.3), and median rwOS was 20.2 months (95% CI 14.8–22.7). There were no significant differences between outcomes in patients with de-novo mBC compared to those with early-stage disease nor between patients receiving fulvestrant as immediate subsequent therapy versus at any time after progression on AI+CDK4/6i.

CONCLUSIONS: This evidence highlights unfavorable outcomes with fulvestrant monotherapy following AI+CDK4/6i treatment in HR+/HER2– mBC, consistent with recent clinical trial findings. However, the median rwPFS was longer than that reported in trials exclusively enrolling CDK4/6i pre-treated mBC patients (VERONICA 1.9 months; EMERALD 1.9 months), possibly due to differences in scanning frequencies and patient population selection between clinical trials and real-world data. Flatiron cohort included a higher proportion of patients with de-novo metastatic disease and a lower proportion of mBC with liver metastases.