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Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) is the most prevalent subtype of advanced breast cancer and is predominantly driven by estrogen receptor (ER) signaling. Endocrine therapy (ET) has become the backbone of first-line treatment; however, both intrinsic and acquired resistance limit long-term disease control. The introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has fundamentally reshaped the therapeutic landscape even in subsets of patients with aggressive or symptomatic visceral metastatic disease. Advances in molecular profiling have also enabled more precise, adaptive therapy. Circulating tumor DNA (ctDNA)-based liquid biopsy now allows real-time detection of emerging resistance mutations, particularly in ESR1. Additionally, patients with PIK3CA-mutated tumors who had progressed on or within 12 months of completing adjuvant ET and had no prior systemic therapy for metastatic disease had better treatment outcomes when treated with the PI3K inhibitor inavolisib in combination with palbociclib and fulvestrant. Together, these developments mark a shift from fixed treatment sequencing toward a more dynamic, biomarker-driven approach in first-line HR+/HER2- MBC. Integration of CDK4/6 inhibitors with next-generation endocrine agents and liquid biopsy-guided therapy offers the potential to delay resistance, improve survival outcomes, and individualize treatment.