A Decade After Approval of the First CDK4/6 Inhibitor: A Look Back at Palbociclib's Journey from Discovery to Approval and What's Next in CDK Inhibition in Breast Cancer.

The initial approval of palbociclib in 2015 marked a major advancement in the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). As the first-in-class cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, palbociclib introduced a new therapeutic strategy for this disease subtype by targeting the CDK4/6:cyclin-D:Rb pathway to halt cell cycle progression from the G1 to the S phase. The PALOMA clinical trials demonstrated a significant improvement in progression-free survival for palbociclib in combination with endocrine therapy (ET), representing clinically meaningful and consistent progression-free survival benefits across all studies in patients with HR+/HER2- ABC. Although the PALOMA clinical trials did not demonstrate a statistically significant overall survival (OS; secondary endpoint) benefit for palbociclib combined with ET in HR+/HER2- ABC over ET monotherapy, several real-world studies have reported substantial OS improvements in diverse patient populations. Despite the significant improvement in clinical outcomes, there remain challenges, particularly regarding proposed resistance mechanisms such as RB1 loss and CDK2 activation, which may diminish the long-term effectiveness of CDK4/6 inhibitors. Moreover, although the toxicity profiles of CDK4/6 inhibitors, such as the risks of myelosuppression and gastrointestinal side effects, necessitate careful patient monitoring, there is an opportunity to refine their use and explore strategies for broader applicability. For these reasons, further research into next-generation CDK inhibitors and combination therapies are critical and ongoing. This review explores the discovery of CDK inhibitors, the development of palbociclib from preclinical studies to its global approval, and future drug development strategies to overcome resistance and enhance patient outcomes.