Abstract: - Background: HER2 receptor expression is associated with poor prognosis across a wide variety of cancers including breast cancer, biliary tract cancer, and urothelial cancers amongst others. Despite this, HER2 targeted therapy such as trastuzumab has proven to improve clinical outcomes amongst patients. Furthermore, trastuzumab combination drugs have demonstrated even better outcomes amongst patients with various HER2 positive malignancies. - Case: A 61 year-old man with a diagnosis of stage IV cancer was initially started on atezolizumab but experienced disease progression 2 years later as evidenced by a CT chest/abdomen/pelvis with contrast. The patient was then treated with pembrolizumab with an excellent response until four years later where the patient’s urothelial cancer progressed further. The patient was then started on gemcitabine/carboplatin and transitioned to trastuzumab emtansine plus atezolizumab until a CT chest/abdomen/pelvis showed disease progression one year later. The patient was then transitioned to enfortumab vedotin for one cycle before starting trastuzumab deruxtecan for four cycles with a CT chest/abdomen/pelvis performed on 12/21/2022 after the fourth trastuzumab deruxtecan cycle showing a partial response. - Conclusion: Trastuzumab deruxtecan is approved in the USA to treat unresectable or metastatic HER2-positive breast cancer in adults who have received two or more prior anti-HER2-based regimens in the metastatic setting. While there are promising trials underway that describe clinical utility of trastuzumab deruxtecan in various different HER2 positive malignancies, more evidence is needed. In our patient’s case, trastuzumab deruxtecan led to a durable response with stabilization of his stage IV urothelial cancer despite progression on a variety of different first line chemotherapy agents typically used in metastatic urothelial cancer. - Keywords: urothelial cancer, HER2 positive, ERBB2 positive, trastuzumab deruxtecan, durable anticancer