Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors: existing and emerging differences

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced or metastatic breast cancer, based on randomized trials showing improved progression-free survival for all 3 drugs and overall survival for ribociclib and abemaciclib. Results in early breast cancer are discordant, with sustained improvement in invasive disease-free survival demonstrated for abemaciclib but not other CDK4/6 inhibitors to date. We review nonclinical studies exploring mechanistic differences between the drugs, the impact of continuous dosing on treatment effect, and translational research into potential resistance mechanisms and prognostic and predictive markers. We focus particularly on how emerging findings may help us understand similarities and differences between the available CDK4/6 inhibitors. Even at late-stage clinical development, there remains much to learn about how agents in this class exert their varying effects.

Automated summary

CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have become standard-of-care therapy for hormone receptor-positive advanced or metastatic breast cancer, with improved progression-free survival and overall survival demonstrated in randomized trials. However, the results in early breast cancer are inconsistent. This review focuses on nonclinical studies investigating mechanistic differences, the impact of continuous dosing, and translational research into resistance mechanisms and prognostic markers, aiming to understand the similarities and differences between available CDK4/6 inhibitors.