The discussion focuses on treatment selection for patients with hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2− mBC) who progress after CDK4/6 inhibitor-based therapy, with particular attention to biomarker-negative and PI3K/AKT/mTOR pathway-altered disease. Dr. Mayer explains that patients without an actionable biomarker remain an important area of clinical need and describes how treatment decisions can incorporate the duration of prior CDK4/6 inhibitor benefit, potential resistance mechanisms, disease burden, pace of progression, and treatment goals. Options discussed include switching to another CDK4/6 inhibitor, everolimus-based therapy, and the emerging role of gedatolisib, particularly for patients in whom greater disease control or response may be desirable. The panel then turns to patients with PI3K/AKT/mTOR pathway alterations, comparing capivasertib, alpelisib, and everolimus. Dr. Mayer describes capivasertib plus fulvestrant as a preferred approach in appropriate patients, while highlighting the significant hyperglycemia associated with alpelisib. Emerging VIKTORIA-1 data supporting gedatolisib-based regimens are also discussed, including the potential advantages of comprehensive pathway inhibition.
