Post CDK4/6 inhibitors: Novel targeted combinations based on SERDs in HR⁺/HER2^- advanced breast cancer

The addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy has redefined the treatment paradigm for HR-positive, HER2-negative (HR⁺/HER2^-) advanced breast cancer, with clear survival gains. However, resistance is almost inevitable and remains the central barrier to durable benefit. Selective estrogen receptor degraders (SERDs) have therefore moved from a later-line option to a core component of post-progression strategies aimed at targeting ESR1 mutations and estrogen receptor (ER) pathway reactivation. Notably, oral SERDs differ substantially in ER occupancy, degradation potency, and pharmacokinetic behavior, and these differences appear to translate into distinct efficacy and toxicity profiles across studies. This review summarizes recent progress in SERD-based therapeutic strategies, with a focus on post-CDK4/6 inhibitor sequencing and biomarker-driven combination approaches. Particular attention is given to rational combinations with PI3Kα and AKT inhibitors, HER2-directed tyrosine kinase inhibitors, and emerging targets such as FGFR, CDK2, and CDK7, as well as the growing role of liquid biopsy in guiding treatment adaptation. Together, these developments position SERD-centered strategies as a key framework for advancing mechanism-informed, precision treatment in HR⁺/HER2^- advanced breast cancer.