Second-line therapies after CDK4/6 inhibitor failure in HR-positive/HER2-negative metastatic breast cancer patients: real-world data from the HERMIONE-13 study

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). However, treatment resistance and progression remain significant challenges, and optimal second-line strategies are not well defined. Materials and methods: HERMIONE-13 is a multicentre, observational study conducted across 18 Italian centres, including both retrospective and prospective cohorts. The study aimed to describe real-world second-line treatment patterns following progression on CDK4/6i and to identify factors influencing therapeutic decisions. Clinical outcomes, including real-world progression-free survival (rwPFS) and overall survival (OS), were also evaluated. Results: Among 254 assessable patients, 67.3% received chemotherapy (CHT) and 32.7% received ET ± targeted therapy (TT) as second-line treatment. The most common regimens included capecitabine and everolimus plus exemestane. Multivariable analysis showed that younger age, prior fulvestrant use, and shorter CDK4/6i duration were associated with CHT choice. Median rwPFS was 5.8 months for CHT and 5.3 months for ET ± TT. Median OS was longer in the ET ± TT group (3.8 versus 2.3 years). Metronomic CHT showed promising activity with a median rwPFS of 9.7 months. Conclusions: In the Italian real-world setting, CHT remains the predominant second-line choice after CDK4/6i failure, though ET ± TT may offer comparable or superior outcomes in selected patients. Treatment decisions are influenced by clinical history and patient characteristics. These findings underscore the need for personalized approaches and molecular profiling to guide post-CDK4/6i therapy in HR-positive/HER2-negative MBC.