Alpelisib for the treatment of -mutated, hormone receptor-positive, HER2-negative metastatic breast cancer.

: Two-thirds of advanced breast cancers are hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-). Gene mutations in , encoding the PI3K catalytic subunit alpha of phosphatidyl-inositol 3-kinase (PI3K), are a frequent event in this population and are implicated in hormone therapy resistance. Alpelisib is a PI3K-alpha inhibitor and is the first PI3K inhibitor approved, in association with fulvestrant, by the FDA and EMA, based on improved progression-free survival (PFS) versus fulvestrant alone in a randomized phase III trial in HR+/HER2-, -mutated tumors following progression on/after HT.: The scientific rationale, preclinical development, pharmacokinetics, and clinical efficacy/safety of alpelisib-fulvestrant are summarized. The role of alpelisib in the clinical setting is discussed, referencing current therapeutic options and clinical challenges associated with alpelisib's safety profile.: Alpelisib is an option for patients with HR+/HER2-, -mutated tumors whose disease progressed during/after aromatase inhibitor treatment. The PFS benefit appears clinically significant over fulvestrant alone, with a 7.9 months, non-significant, improvement in overall survival. Its safety profile requires strict patient selection, mainly based on baseline glycemic status, and close monitoring.