Inavolisib: a second-generation PI3Kα inhibitor in HR+/HER2-negative breast cancer

INTRODUCTION: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype, yet resistance to therapy remains a major clinical challenge. Up to 40% of patients carry PIK3CA mutations that activate PI3K/AKT/mTOR signaling and drive relapse, highlighting the need for more selective and tolerable targeted therapies. AREAS COVERED: This review summarizes the pharmacology, development, and therapeutic role of inavolisib, a next-generation, PI3Kα-selective inhibitor with dual inhibitory and degradation activity against mutant p110α. Preclinical studies demonstrate improved isoform selectivity versus earlier agents, reducing off-target toxicity while maintaining potent pathway suppression. In the phase III INAVO120 trial, adding inavolisib to palbociclib and fulvestrant nearly doubled progression-free survival and extended overall survival by seven months versus standard therapy. Safety data indicates a manageable profile, with hyperglycemia and stomatitis as the most common adverse events. Additional phase III trials are testing inavolisib in CDK4/6 inhibitor-resistant disease and HER2-positive settings, as well as in novel combinations. EXPERT OPINION: Inavolisib offers a significant advance for PIK3CA-mutated HR+/HER2-negative breast cancer by pairing potent PI3Kα selectivity with degradation of mutant p110α. Its clinical activity and improved tolerability position it as a strong candidate for future therapeutic strategies and evolving precision-oncology applications.