Ribociclib-based combination endocrine therapy in elderly and frail patients: key issues of efficacy, safety, and drug interactions requiring the attention of an oncologist

This review presents the findings of the most consequential large-scale randomized controlled trials and real-world practice studies on combination endocrine therapy with ribociclib in elderly patients with advanced HR-positive, HER2-negative breast cancer. Phase 3 and 3b randomized clinical trials (MONALEESA-2, MONALEESA-3, and CompLEEment-1) have consistently demonstrated that endocrine therapy combined with ribociclib confers a significant advantage over endocrine monotherapy in reducing the risks of disease recurrence and death—not only in older patients overall, but also in frail individuals with an ECOG performance status of 2 or higher. Particular emphasis is placed on the safety profile of ribociclib, with special attention to adverse events of special interest that demand enhanced monitoring throughout treatment. The phase 4 RibOB clinical trial has, for the first time, shown that three months of combination endocrine therapy with ribociclib modulates the immune system in elderly patients, potentially correcting age-related immunodeficiency by expanding the population of naïve T and B cells while reducing the memory cell compartment. A dedicated section examines two independent FDA pooled analyses evaluating the efficacy and safety of combination endocrine therapy in older adults (aged ≥70 years and ≥75 years) enrolled in three major randomized trials (PALOMA-2, MONALEESA-2, and MONARCH-3). This is complemented by a detailed review of cardiovascular toxicity associated with CDK4/6 inhibitors, as reported to the FDA Adverse Event Reporting System in routine clinical practice. The review also addresses clinically relevant drug–drug interactions that warrant careful consideration during CDK4/6 inhibitor therapy, and provides a practical clinical algorithm for managing concomitant use of CYP3A4 inhibitors or inducers when such co-administration becomes necessary.