In this week’s VJOncology podcast, we will be joined by Rupert Bartsch, MD, Medical University of Vienna, Vienna, Austria, as he outlines current and emerging strategies for managing HER2-positive metastatic breast cancer after antibody–drug conjugate (ADC) therapy, with a focus on trastuzumab deruxtecan (T-DXd). He discusses the use of tucatinib-based regimens, mechanisms of resistance to agents such as trastuzumab emtansine (T-DM1), and approaches to treating brain metastases, drawing on evidence from trials. The importance of individualized treatment is highlighted, particularly in hormone receptor–positive disease, where CDK4/6 inhibitors may provide added benefit.