Abstract: Background and Objectives: Endocrine therapy combined with CDK4/6 inhibitors are widely recognized as the standard first-line approach for treating hormone receptor-positive HER2-negative (HR+/HER2−) metastatic breast cancer (mBC). Nonetheless, potential pharmacokinetic interactions—particularly with proton pump inhibitors (PPIs)—have raised concerns about reduced drug bioavailability and compromised therapeutic efficacy. Materials and Methods: This retrospective analysis included 92 patients with HR+/HER2− mBC who received either ribociclib or palbociclib between 2019 and 2024 at a single tertiary care center. Patients were stratified according to whether they were concurrently using PPIs during CDK4/6 inhibitor treatment. The primary endpoint assessed was progression-free survival (PFS). The study population was dominated by ribociclib users, and the results primarily apply to ribociclib; the palbociclib analyses are descriptive only due to the very small numbers (n = 6). Results: The median PFS was significantly shorter in patients who received concomitant PPI therapy compared with those who did not (5.6 vs. 24.4 months; p < 0.001). Multivariable analysis identified PPI use, endocrine resistance, and the presence of three or more metastatic sites as independent predictors of reduced PFS. In the ribociclib-only cohort (n = 86), the association persisted (adjusted HR 6.36, 95% CI 3.02–13.37, p < 0.001). No notable differences in toxicity profiles were observed between the groups. Conclusions: In this ribociclib-dominant real-world cohort, concomitant PPI use was associated with shorter PFS, and the findings primarily apply to ribociclib. Given the potential for confounding by the indication/comorbidity inherent to retrospective studies, the results should be interpreted as associational. These data support the cautious use of non-essential PPIs during ribociclib therapy and underscore the need for prospective agent-specific pharmacokinetic studies.
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