Efficacy and Safety of Culmerciclib Plus Aromatase Inhibitors in a Response-Adapted Neoadjuvant Strategy for Highly Proliferative ER-Positive/HER2-Negative Breast Cancer

This is a prospective, response-adapted, phase II study designed to evaluate an individualized neoadjuvant treatment strategy based on culmerciclib in combination with aromatase inhibitors in patients with highly proliferative ER-positive/HER2-negative early breast cancer. The study incorporates an adaptive treatment algorithm guided by on-treatment assessment of tumor response, with the aim of optimizing therapeutic efficacy while minimizing unnecessary treatment exposure. All eligible patients initially receive neoadjuvant treatment with culmerciclib plus endocrine therapy according to the study protocol. Following completion of a predefined initial treatment phase, tumor response is assessed using biological and clinical evaluation methods. Patients who achieve an adequate response continue the same neoadjuvant regimen to complete the planned course of therapy. In contrast, patients demonstrating a suboptimal response are transitioned to alternative treatment strategies prior to surgery. Subsequent treatment selection and management are conducted according to protocol-defined principles and investigator assessment. This response-adapted strategy is intended to address the clinical heterogeneity of endocrine sensitivity in ER-positive/HER2-negative breast cancer. By tailoring treatment intensity according to early response, the study seeks to maximize therapeutic benefit in responsive patients while facilitating timely treatment modification for those less likely to benefit from the initial regimen. Primary and secondary objectives include evaluation of clinical efficacy, safety and tolerability of the response-adapted neoadjuvant strategy, and the feasibility of treatment modification based on early response assessment. Exploratory analyses will investigate potential biomarkers associated with treatment response and resistance, with the goal of informing future individualized treatment approaches.