Background: The combination of an oral CDK4/6 inhibitor with endocrine therapy (ET) has become the standard first-line therapy for women with advanced HR+ HER2- breast cancer. In this context, the broadest clinical trial data are available for ribociclib, a highly selective CDK4/6 inhibitor, with three phase III trials (MONALEESA-2, -3 and -7) consistently showing a significant overall survival benefit compared to ET monotherapy regardless of treatment line, menopausal status or combination partner. However, de novo or acquired resistance to CDK4/6 inhibitors does occur and biomarkers predicting treatment response or providing information on resistance mechanisms are only beginning to be understood. Comprehensive identification and validation of biomarkers before and during ribociclib therapy is needed to better understand mechanisms leading to disease progression, which will be the first step towards developing novel therapies and optimizing treatment sequences. Methods: CAPTOR-BC (NCT054552213) is a single-arm, open-label phase IV study evaluating the combination of ribociclib and ET according to SmPC in the first-line treatment of HR+ HER2- advanced breast cancer to identify and validate molecular and non-molecular biomarkers predictive of drug response and resistance. First patient first visit occurred in October 2022 and at least 1000 patients across more than 75 sites in Germany will be enrolled until October 2025. Progression-free survival (PFS) and overall survival (OS) at 12 months are the co-primary endpoints, quality of life (QoL) and toxicity are secondary endpoints. Exploratively, a comprehensive multi-omics biomarker discovery and validation program is integrated into the study: Besides tumor tissue, liquid biopsies profiling circulating tumor (ct)DNA, ctRNA, whole blood RNA, proteins from serum and plasma, and circulating immune cells will be evaluated before, during and after treatment or upon progression to determine correlations with PFS, OS, QoL and adverse events. Clinical trial information: NCT05452213.