A pharmacokinetic evaluation of alpelisib for the treatment of HR+, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer

Introduction: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30-40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease. Areas covered: This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of alpelisib, a PI3K inhibitor indicated in HR+/HER2 - PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions. Expert opinion: Following results of the SOLAR-1 trial, alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 - PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought.

Automated summary

PIK3CA mutations are associated with endocrine resistance in breast cancer, and PI3K inhibitors offer new therapeutic options for HR+/HER2- PIK3CA-mutated breast cancer. Alpelisib, the first approved PI3K inhibitor in this context, showed improved progression-free survival in clinical trials, but the decision to use it should consider its side effects and benefits carefully. Identification of patients who will benefit the most from PI3K inhibitors remains a key focus in current research.