Metastatic urothelial cancer is generally associated with poor outcomes. In the first-line setting, platinum-based chemotherapy is the standard of care but resistance rapidly develops and the vast majority of patients ultimately experience disease progression. Despite several decades of clinical drug development focused on the treatment of platinum-resistant metastatic urothelial cancer, as of late 2015 there are no standard therapies approved by the US FDA in this setting. However, preliminary results from a series of recent trials exploring innovative approaches forecast a ‘sea change’ in the management of this difficult to treat malignancy. Herein, we review new approaches for the management of patients with metastatic urothelial cancer focused on three key therapeutic target areas: recurrent somatic alterations, the tumor neovasculature and tumor-associated immune escape.
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