Considerations for emulations of randomized controlled trials using real-world data: learnings from an emulation of MONALEESA-2

This study attempted to emulate the MONALEESA-2 randomized controlled trial, which found a survival benefit associated with ribociclib plus letrozole for women with advanced breast cancer, using a linked electronic health records and claims database of 132,406 real-world patients. After applying the original trial's entry criteria, the resulting sample of 3,912 patients revealed stark demographic differences between trial participants and real-world patients: trial participants were younger, more commonly had liver or lung metastases, and had lower comorbidity burdens. Critically, the team was unable to replicate the trial's survival benefit in the real-world setting, with all hazard ratios exceeding 1.

These findings highlight a fundamental tension in evidence-based medicine: the patients who enroll in clinical trials often look quite different from those who ultimately receive a therapy in routine care, and that gap can significantly affect whether trial findings translate to real-world outcomes. The study reinforces both the limitations and the indispensable value of real-world data, which remains essential for characterizing patients in routine practice and answering the practical questions that arise after new therapies receive regulatory approval.