The progression of HR+/HER2- metastatic breast cancer after treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) poses significant therapeutic challenges. Endocrine therapy (ET) remains a cornerstone of subsequent treatment, but its effectiveness depends on a nuanced understanding of clinical and genomic factors that drive therapy selection. For example, the duration of response to prior CDK4/6i therapy strongly predicts sensitivity to subsequent ET. Patients with prolonged responses to first-line therapy may benefit most from additional endocrine strategies, whereas those with rapid cancer progression often require alternative approaches. Clinical parameters such as disease burden, visceral involvement, and comorbidities also guide treatment decisions. Low-burden, indolent disease favors continued ET, whereas aggressive progression may necessitate the addition of targeted agents or a shift to chemotherapy. Genomic profiling via liquid or tissue biopsy should be integral to identifying actionable mutations and ensuring timely, individualized intervention. Molecular parameters, such as ESR1 mutations and PI3K pathway alterations, can predict therapeutic response, thus guiding treatment selection. This review underscores the importance of a personalized, evidence-based approach to the selection of endocrine-based therapy post-CDK4/6i failure, leveraging clinical insights and molecular diagnostics to optimize patient outcomes.
