CDK4/6 Inhibitors: Existing and Emerging Differences.

The cyclin-dependent kinase (CDK)4/6 inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced/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 (eBC) are discordant, with sustained improvement in invasive disease-free survival demonstrated for abemaciclib but not other CDK4/6 inhibitors to date. We review non-clinical 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 to 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.