Key Clinical Summary
- A study examines methodological approaches used in major real-world (RW) studies assessing overall survival (OS) with CDK4/6 inhibitors for HR+/HER2– metastatic breast cancer.
- Authors highlight persistent challenges—temporal bias, short follow-up, small and imbalanced cohorts—that complicate comparisons with randomized controlled trials (RCTs).
- Findings reinforce the need for cautious interpretation of RW OS estimates and emphasize that RWE cannot replace RCT data for determining survival benefit.
A study examines how methodological limitations shape the interpretation of real-world evidence (RWE) comparing overall survival outcomes among cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in metastatic breast cancer. Although CDK4/6 inhibitors are now standard first-line therapy for HR+/HER2– disease, uncertainty remains regarding how real-world OS compares with randomized trial findings. The authors evaluate major RW studies to clarify alignment—and divergence—between RWE and RCTs.
Study Findings
Numerous RCTs have demonstrated variable OS outcomes among available CDK4/6 inhibitors. Ribociclib showed statistically significant OS improvement across three MONALEESA trials, while abemaciclib achieved significance in MONARCH 2 but not MONARCH 3. Palbociclib did not reach OS significance in PALOMA-2 or PALOMA-3. These mixed findings have elevated interest in whether RW studies can clarify comparative effectiveness.
However, the study notes substantial methodological constraints in key RW analyses. The largest, P-VERIFY, evaluated 6831 palbociclib-, 1036 abemaciclib-, and 1279 ribociclib-treated patients but reported no OS differences. Follow-up varied widely—33 months (palbociclib), 21 months (abemaciclib), and only 16 months (ribociclib)—creating staggered entry bias. Nearly 44% of ribociclib users initiated therapy in 2023, compared with <10% for palbociclib. Resulting discrepancies in calendar time, event rates, and censoring (54.7% for palbociclib vs 74.4% for ribociclib) likely biased hazard ratios toward null. Kaplan–Meier curves showed delayed separation, suggesting insufficient informative follow-up.
Other RW studies showed similar issues. A UK cohort (n = 544) reported comparable OS across agents, though small sample sizes for ribociclib (n = 38) and abemaciclib (n = 33) limited power. The German prospective OPAL registry also found no significant differences, with only ~33% OS events at analysis.
More robust outcomes emerged in studies with longer follow-up and more balanced cohorts. PALMARES-2, encompassing up to 1408 ribociclib and 1392 palbociclib patients with OS follow-up up to 67 months, demonstrated an OS benefit for ribociclib (HR 0.75) and improved real-world PFS for both ribociclib and abemaciclib versus palbociclib. A Danish database study likewise showed prolonged PFS with abemaciclib and ribociclib and longer median OS with ribociclib. Still, each study reported limitations—including temporal imbalance, evolving prescribing patterns, and differences in event rates.
Clinical Implications
For clinicians, the commentary underscores the complexity of relying on RWE to guide treatment decisions in metastatic breast cancer. While RWE complements RCTs by capturing outcomes in broader, more heterogeneous patient populations, these datasets are vulnerable to confounding, differential follow-up, and temporal bias. CDK4/6 inhibitors have distinct OS profiles in RCTs, and RW studies—particularly those with short follow-up—cannot reliably confirm or refute survival benefits observed in controlled settings.
The authors emphasize that RWE is hypothesis-generating unless methodological rigor is sufficient to support confirmatory conclusions. Regulatory agencies have outlined conditions under which RWE can inform population-level decisions, but only when study design adequately accounts for biases. For CDK4/6 inhibitors, the commentary reinforces that OS claims cannot be based on RWE alone when RCTs fail to show significance.
Conclusion
The commentary highlights persistent methodological challenges in RW comparisons of CDK4/6 inhibitors and urges cautious interpretation of OS results. Longer follow-up, balanced cohorts, and multiple endpoints are essential to strengthening RWE and improving its alignment with RCT-based evidence.
Reference
Sammons S, Yardley DA, Sharma P, et al. Investigating real-world evidence and reported survival outcomes of CDK4/6 inhibitors in HR+/HER2- advanced breast cancer. Oncol Ther. Published online November 14, 2025. doi:10.1007/s40487-025-00394-8
