Post-CDK4/6 inhibitor therapy in HR+/HER2– advanced breast cancer: expanding options and persisting uncertainties

Endocrine treatment in combination with CDK4/6 inhibitors represents the mainstay of first-line palliative treatment in HR+/HER2– breast cancer. The treatment landscape after progression on CDK4/6 inhibitors has evolved into a complex and rapidly evolving field, driven by novel endocrine and targeted agents, new combination therapies, and increasing implementation of biomarker-directed approaches. Recent randomized trials have shown that new therapeutic strategies significantly prolong progression-free survival in this setting, with some treatments reaching notable numerical improvements. Translating these options into routine clinical practice remains challenging due to heterogeneous trial designs, lack of head-to-head comparisons, suboptimal comparator treatments, and limited overall survival data. While the increasing implementation of biomarkers holds the potential for more personalized treatments, their clinical utility depends on their mechanistic and contextual biological relevance, methodological reliability of detection, and proven predictive value in clinical trials. Based on the current evidence, optimal treatment selection and sequencing in the post-CDK4/6 inhibitor setting remain insufficiently defined, and optimization of biomarker-guided treatment requires further mechanistic understanding and methodological refinement. This narrative review provides an overview of the most recent randomized clinical trial evidence shaping current clinical practice and discusses persistent uncertainties regarding its implementation in routine care.