Hope Rugo, MD, FASCO, University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, discusses the latest opinions on the optimal sequencing of novel HER2-targeted therapies in metastatic HER2-positive breast cancer. Pertuzumab plus trastuzumab is widely used as the optimal first line treatment, often followed by trastuzumab emtansine. Where available, combined tucatinib, trastuzumab and capecitabine is an appealing approach after the second line setting. Trastuzumab deruxtecan is also an efficacious option for patients who have received two or more prior anti-HER2-based regimens in the metastatic setting. Margetuximab, an investigational Fc-engineered HER2 monoclonal antibody may be used as the next step. This interview took place during the 17th St. Gallen International Breast Cancer Conference.