alpelisib + buparlisib

Alpelisib + buparlisib is an investigational oral combination of two phosphatidylinositol 3-kinase inhibitors: alpelisib, a selective PI3K alpha inhibitor, and buparlisib, a pan–class I PI3K inhibitor. Both agents inhibit the PI3K/AKT signaling pathway involved in tumor growth and endocrine resistance in hormone receptor–positive, HER2-negative breast cancer. Alpelisib is approved in combination with fulvestrant for PIK3CA‑mutated HR-positive, HER2-negative advanced breast cancer, while buparlisib development has been limited by toxicity. This specific dual-PI3K-inhibitor combination does not have an approved indication; related clinical research evaluated each agent separately combined with tamoxifen plus goserelin in premenopausal HR-positive, HER2-negative advanced breast cancer, establishing recommended phase 2 doses and tolerability profiles for each within that triplet backbone. Preclinical studies also support synergy of each PI3K inhibitor with tamoxifen in ER-positive models via PI3K pathway suppression. These data contextualize the pharmacologic rationale for PI3K pathway blockade in HR-positive disease but do not establish clinical use of alpelisib plus buparlisib together in patients.[4][6][8][10][7][5]