Outcome-specific differences between randomized trials and real-world studies of CDK4/6 inhibitors in hormone receptor-positive, HER2-negative advanced breast cancer: a meta-epidemiological analysis

Background Real-world evidence is increasingly interpreted alongside randomized clinical trial evidence in oncology, but reported outcomes may differ because of variation in patient selection, treatment composition, follow-up, ascertainment, documentation, and reporting. We examined whether outcomes differed between randomized trials and real-world studies of CDK4/6 inhibitors. Methods We searched PubMed, Embase, Cochrane CENTRAL, and Web of Science through December 2025 for phase 2/3 randomized trials and real-world cohort, registry, or postmarketing studies of CDK4/6 inhibitors plus endocrine therapy for first- or second-line treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Arm proportions were pooled separately using logit-transformed random-effects models, and between-source differences were assessed using mixed-effects meta-regression. Results Eighty-six studies were included: 31 randomized trials (40 arms; 7464 patients) and 55 real-world studies (101 cohorts; 30 858 patients). Real-world cohorts included older patients and greater first-line and palbociclib use. After aggregate-level mixed-effects meta-regression adjustment, the model-based objective response rate was higher in real-world cohorts than in trial arms (51.8% vs. 36.6%; P = .031). Laboratory-based adverse events did not differ significantly, whereas symptom-based adverse events were consistently lower in real-world cohorts. Adverse event-related discontinuation was similar (10.6% vs. 8.6%; P = .523), whereas AE-related dose reduction was higher in real-world cohorts (50.8% vs. 33.4%; P = .016). Conclusions Reported single-arm outcomes differed between randomized trials and real-world studies, with the largest differences observed for response and symptom-based adverse-event outcomes. These estimates should be interpreted according to endpoint definition, denominator construction, ascertainment, and reporting. Systematic review registration PROSPERO CRD420261397529.