Adjuvant CDK4/6 inhibitors in breast cancer: Interpreting trial design, evidence, and uncertainty

• Published in: Cancer treatment reviews Vol. 136; p. 102944
• Main Author: Niraula, Saroj
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.05.2025
• Subjects: Abemaciclib; Adjuvant; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cdk; Cdk 4/6; Chemotherapy, Adjuvant; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Female; Financial toxicity; Humans; MonarchE; NATALEE; Palbociclib; PALLAS; Penelope-B; Protein Kinase Inhibitors - therapeutic use; Research Design; Ribociclib; Financial toxicity; Abemaciclib; NATALEE; Palbociclib; Ribociclib; PALLAS; Adjuvant; Breast cancer; Cdk; Cdk 4/6; MonarchE; Penelope-B
• ISSN: 0305-7372; 1532-1967; 1532-1967
• DOI: 10.1016/j.ctrv.2025.102944

•Adjuvant CDK4/6 trials (NATALEE, monarchE) show iDFS benefit; OS not seen, QoL maintained.•Variations in risk selection, design, and censoring complicate interpretation.•iDFS may seem meaningful but lacks OS surrogacy in ER+ breast cancer and is highly design-sensitive.•Preliminary evidence suggests early use may promote resistance and reduce later benefit.•Without OS or QoL gain, broad use warrants caution due to cost, toxicity, and competing needs. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the treatment landscape for metastatic hormone receptor–positive, HER2-negative breast cancer by improving progression-free and Overall Survival (OS). In the adjuvant context, however, results have been discordant and remain immature. The PALLAS and PENELOPE-B trials of palbociclib reported no benefit, while monarchE and NATALEE demonstrated improvements in invasive disease-free survival (iDFS) with abemaciclib and ribociclib, respectively, leading to regulatory approvals despite no demonstrated OS benefit yet. It remains possible that adjuvant CDK4/6 inhibition provides meaningful long-term benefit, but that has not been demonstrated. Concerns related to trial design: risk-enrichment, open-label conduct, high treatment-discontinuation rates, and potential informative censoring complicate interpretation. Although iDFS is a recognized intermediate endpoint with potential psychological validity, it is subject to bias in collection and communication, and has not been validated as a surrogate for OS in this setting. Moreover, early inhibition of CDK4/6 may induce resistance and compromise subsequent efficacy. Reported quality-of-life outcomes were preserved, not improved, which holds limited value considering added toxicity, inconvenience, and cost in a largely curable population. If even half of eligible patients are treated, estimated annual costs in the United States would exceed $7 billion. As these agents are incorporated into clinical guidelines, it is critical to clarify whether they improve long-term outcomes, delay recurrence without affecting survival, or cause unintended harm. Impulse to intervene early is understandable, but emerging data must be carefully assessed to ensure adjuvant CDK4/6 inhibition offers meaningful benefit to patients and health systems.