Ulrich L, et al. - For managing advanced HER2 positive breast cancer, internationally agreed standards of care include dual blockade with the monoclonal antibodies, trastuzumab and pertuzumab, added to first-line taxane chemotherapy and second-line therapy with the antibody–drug conjugate, T-DM1. However, for patients for third-line therapy and beyond, options were of modest efficacy or limited by toxicity, until recently. For this space, the outcomes of trials of two exciting new agents were presented in 2019. A third-generation HER2 tyrosine kinase inhibitor, tucatinib, amalgamates the efficacy of the second-generation drug, neratinib, with a more manageable toxicity profile and has become a nover standard of care after T-DM1, in combination with capecitabine and trastuzumab. In heavily pre-treated patients, remarkable efficacy was demonstrated by the antibody–drug conjugate, trastuzumab deruxtecan; it was provided accelerated approval in the United States, whilst confirmatory phase 3 trials are completed.