Recent updates in HER2-positive metastatic breast cancer highlight evolving first-line strategies and maintenance approaches. The DESTINY-Breast09 trial demonstrated impressive progression-free survival with trastuzumab deruxtecan plus pertuzumab as first-line therapy. Meanwhile, the PATINA trial and HER2CLIMB-05 explored maintenance strategies using palbociclib or tucatinib following induction therapy. Drs. Reshma Mahtani, Heather McArthur, and Anne O’Dea discuss how these emerging data create new sequencing questions as therapies increasingly move into earlier treatment settings.