Cyclin-Dependent 4/6 Kinase Inhibitors for Treatment of HER2-Positive Breast Cancer: 2026 Update.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; palbociclib, ribociclib, abemaciclib, dalpiciclib) combined with endocrine therapy (ET) were a major advance in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) worldwide. Notably, clinical activity has also been observed in HR+HER2-positive (HER2+) MBC, with significant progression-free survival (PFS) benefits. Cyclin-dependent kinases 4/6 (CDK4/6) are downstream of HER2 and pathways driving resistance to HER2-targeted therapies. However, clinical development of CDK4/6i in HER2+ MBC slowed, given the advent of highly effective tyrosine-kinase inhibitors (TKIs) (i.e., tucatinib) and antibody-drug conjugates (ADCs) (i.e., trastuzumab deruxtecan), which currently dominate the treatment armamentarium. The observation that luminal disease defined by a predictive analysis of microarray 50 (PAM50) was independently associated with a significantly longer PFS versus nonluminal disease was important, with researchers inferring that intrinsic molecular subtypes could be used to identify patients most suitable for ET + CDK4/6i + HER2-targeted treatment. Subsequently, the phase III PATINA trial (which included patients with 1L HR+HER2+ MBC, treated with palbociclib vs. placebo with maintenance ET+ H[P]) noted a striking PFS improvement of >15 months in the palbociclib arm, renewing interest in CDK4/6i-based treatments for HR+HER2+ MBC. Herein, we review the development of CDK4/6i in HER2+ BC, discussing current challenges and potential future directions.