DESTINY-Breast04, or DB04, was one of the most important and practice-changing trials to be presented at ASCO 2022. DB04 enrolled patients who had unresectable or metastatic breast cancer that was considered resistant to endocrine treatment, and who had received 1 or 2 prior lines of chemotherapy treatment. Importantly, these patients had disease that was considered “HER2-Low”, a new classification of breast cancer as defined by specific molecular testing criteria. The trial was designed to determine whether treatment with trastuzumab-deruxtecan, or T-DXd, was superior to using the physician’s choice of chemotherapy in this group of patients. The trial enrolled 540 patients, the vast majority of whom had hormone receptor-positive, or HR+, disease. The results of DB04 showed that the patients who were treated with T-DXd survived almost twice as long without a recurrence of their breast cancer as compared to those treated with chemotherapy, and these results were similar when looking at both the HR+ patients as well as the entire patient population. Patients on T-DXd in DB04 also survived more than 6 months longer as compared to those treated with chemotherapy, and this was seen in both the HR+ patients and the entire patient population. In addition, about three-times as many patients in the T-DXd group responded to the treatment with shrinkage of their tumors as compared to those on chemotherapy. Important toxicities of T-DXd observed in DB04 included interstitial lung disease (ILD) and pneumonitis; in most cases these events were not severe, but some deaths did occur as a result. Although infrequent, some cardiac toxicities, including left ventricular dysfunction and cardiac failure, also occurred in the trial, in accordance with previous results for this type of therapy. While it is not clear yet whether “HER2-Low” breast cancer is biologically different than HER2-positive or HER2-negative breast cancer, the results of DB04 clearly establish T-DXd as a treatment option for patients with this subtype of breast cancer, which, by this new molecular designation, is estimated to represent approximately half of all patients with metastatic disease.