Precision Endocrine-Based Combinations After CDK4/6 Inhibitor Progression in HR-Positive Metastatic Breast Cancer

CDK4/6 inhibitors combined with endocrine therapy (ET) has significantly improved progression-free (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), HER2-negative breast cancer, however, most patients ultimately develop acquired resistance and experience disease progression. Historically, this transition marked the point at which chemotherapy was initiated; however, advances in molecular profiling and drug development have fundamentally altered this paradigm.Resistance to endocrine therapy is mediated by distinct and therapeutically actionable mechanisms, most notably ESR1 mutations, activation of the PI3K/AKT/mTOR signaling pathway, and cell-cycle deregulation. These insights have led to the development of a new generation of targeted endocrine therapies that restore or prolong endocrine sensitivity. Oral selective estrogen receptor degraders (SERDs), particularly elacestrant and imlunestrant, have demonstrated clinically meaningful efficacy in patients with ESR1-mutant tumors progressing after CDK4/6 inhibitors. Additionally, targeted inhibitors of the PI3K and AKT pathways, such as alpelisib and capivasertib, when combined with appropriate endocrine backbones, have been shown to overcome resistance mechanisms.The emergence of circulating tumor DNA (ctDNA) testing has further refined therapeutic decision-making by enabling real-time detection of resistance mutations and guiding directed treatment selection. Several prospective trials have demonstrated that molecularly guided switching of endocrine therapy can delay clinical progression and extend disease control, highlighting a shift toward precision-based, adaptive strategies.Collectively, these advances support a new treatment paradigm in which endocrine-based combinations remain the preferred approach after progression, delaying the need for chemotherapy while maintaining efficacy and quality of life. This review summarizes the biology of endocrine resistance, evaluates current targeted endocrine therapies, and provides a practical framework for biomarker-driven sequencing in patients with HR+/HER2- advanced breast cancer following progression on prior endocrine therapy.