Considerations for emulations of randomized controlled trials using real-world data: learnings from an emulation of MONALEESA-2
Publication: Journal of Comparative Effectiveness Research
Abstract
Aim: The eligibility criteria of randomized controlled trials can exclude groups of patients indicated for the therapy post-approval and the trial population may not be generalizable to routine care. We attempted to emulate the MONALEESA-2 trial of ribociclib plus letrozole for women with advanced breast cancer using real-world data (RWD) to assess the impact of modifying entry criteria of the trial, which found a survival benefit associated with ribociclib (hazard ratio [HR] = 0.76). Materials & methods: Post-menopausal women with recurrent or metastatic breast cancer were identified in a linked electronic health records-claims database. Treatment groups were ribociclib plus letrozole or letrozole without ribociclib (referred to as letrozole). Overall survival was compared between the two groups using Cox proportional hazards models with inverse probability of treatment weights and propensity score matching. Results: There were 132,406 patients who initiated ribociclib plus letrozole or letrozole from 13 March 2017 (ribociclib approval) to 30 September 2023. After applying trial entry criteria, the sample size was 3912 patients. Compared with real-world patients, trial participants tended to be younger (>50% were <65 years old compared with 38%) and more commonly had liver or lung metastases (>50% vs <15%). Among real-world patients, those treated with ribociclib plus letrozole had higher comorbidity scores (mean Elixhauser Comorbidity Index Score 15 vs 9) and were more likely to have metastatic disease burden than patients treated with letrozole (85% vs 45%). We were unable to emulate the trial findings; all HRs in this analysis were >1. Conclusion: Real-world patients may differ from those participating in randomized controlled trials. Along with data source limitations, such as missing clinical information or incomplete capture of mortality, this can impact the ability to emulate trials in RWD. However, RWD is key for describing patients in routine care and to answer relevant questions following the approval of new therapies.
Plain language summary
What is this article about?
Patients who are indicated for an approved therapy may have different demographic and health conditions than those who participated in the randomized controlled trials. To assess the potential impact of relaxing overly restrictive inclusion and exclusion criteria, we attempted to emulate the MONALEESA-2 randomized controlled trial evaluating overall survival of women with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer treated with ribociclib plus letrozole using real-world data (RWD).
What were the results?
The women meeting all the trial criteria in addition to a baseline observability requirement were a small proportion of those initiating ribociclib plus letrozole in the real world (3%). Trial patients were younger and had more liver or lung metastasis than real-world patients. In the RWD, there were also significant differences between women receiving ribociclib plus letrozole and women receiving letrozole without ribociclib, with those treated with ribociclib plus letrozole having more metastatic disease. We were unable to emulate the trial findings.
What do these results mean?
We could not assess the impact of relaxing trial inclusion and exclusion on the main findings for overall survival because the trial results could not be replicated in this RWD source. There are important considerations for conducting trial emulations, including differences in patient populations, data source limitations, and study design challenges. Ongoing research in RWD is needed after approval to understand drivers of treatment decisions and relevant questions beyond those addressed by the pivotal trial(s).
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Received: 10 April 2025
Accepted: 18 September 2025
Published online: 28 October 2025
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Considerations for emulations of randomized controlled trials using real-world data: learnings from an emulation of MONALEESA-2. (2025) Journal of Comparative Effectiveness Research. DOI: 10.57264/cer-2025-0026
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