HER2-Positive Urothelial Carcinoma: Current Evidence on Targeted Agents and Immunotherapy-Based Combinations

Despite the introduction of immunotherapy and antibody–drug conjugates (ADCs), 5-year survival rates for advanced urothelial cancer (UC) remain unsatisfactory. Modest results with conventional systemic treatments have prompted the need for tailored therapies that exploit actionable mutations, such as those involving the human epidermal growth factor receptor (HER)-2 proto-oncogene, which plays a key role in regulating cell growth, differentiation, and survival. HER2-positive UC accounts for 13–25% of all locally advanced/metastatic UC. HER2 overexpression in UC varies widely by tumour stage and is usually a late phenomenon associated with poorer prognosis. Given the crucial biological role of HER2 in UC and the proven activity of anti-HER2 drugs in other solid tumours (e.g. breast and gastric cancer), in this comprehensive review, we analyse clinical trials using HER2-targeting strategies in HER2-positive metastatic UC. Clinical trials of anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors in UC have shown limited efficacy. On the other hand, HER2-targeted ADCs such as trastuzumab deruxtecan and disitamab vedotin have shown encouraging results. However, the most interesting data come from the combination of HER2-targeted ADCs with immunotherapy because of the synergistic action of the two drugs: HER2-directed ADCs, with their cytotoxic effect, lead to the release of cancer antigens, enhancing the anti-tumour immune response, which is boosted by the immune checkpoint inhibitor. Moreover, this combination strategy may also offer some advantages in rewiring the tumour microenvironment, favouring an anti-cancer immune response. ADC and immune checkpoint inhibitor combinations are supported by solid preclinical evidence and are emerging as novel and promising tailored therapeutic approaches for advanced UC.