Despite significant advances and the approval of
immune checkpoint inhibitors, metastatic urothelial
carcinoma (mUC) is still very hard to treat and has poor outcomes. Deeper understanding of the molecular underpinnings of mUC has identified potential
biomarkers,
biologic drivers, and relevant
therapy targets. However, targeted
therapies in mUC have had significant challenges due to molecular heterogeneity, clonal evolution, and
genomic instability, and have not improved outcomes so far. Despite that, recent technological developments, clinical utilization of molecular biology, and discovery of new agents with preclinical and early clinical activity have signaled a new age of experimental
therapeutics in mUC. The more frequent use of next-generation sequencing of
tumor tissue and cell-free
circulating tumor DNA, combined with novel agents tested in clinical trials, provides promise. There is a plethora of agents being tested in mUC, including inhibitors of receptors and signaling pathways (e.g.,
fibroblast growth factor receptor, human
epidermal growth factor receptor,
phosphatidylinositol 3-kinase/AKT/mTOR pathway), angiogenesis (e.g.,
vascular endothelial growth factor and its receptors),
poly (ADP-ribose) polymerase (
PARP) inhibitors, immuno-oncology agents,
cytotoxic agents (e.g.,
chemotherapy,
antibody drug conjugates), and epigenetic modulators, among others. Two agents,
enfortumab-vedotin (
antibody drug conjugate) and
erdafitinib (
fibroblast growth factor receptor inhibitor), have breakthrough designation by the FDA, but are not approved as of March 2019. Novel combinations with various modalities and optimal sequencing of active
therapies are being investigated in clinical trials. More sophisticated patient selection, discovery and prospective validation of predictive (and prognostic)
biomarkers with clinical utility, and relevant clinical trial designs are important parameters in that context. Based on the above, there is high potential for targeted
therapies to be added in the growing armamentarium of mUC, and possibly
complement chemotherapy and immuno-oncology agents.