Role of Targeted Therapies in Management of Metastatic Urothelial Cancer in the Era of Immunotherapy
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.
KeywordsUrothelial carcinoma Bladder cancer Precision oncology Targeted therapeutics Biologic therapies Biomarkers
Compliance with Ethical Standards
Conflict of Interest
Petros Grivas has received research funding (paid to Cleveland Clinic Foundation for conduction of clinical trials) from Genentech, Bayer, Merck & Co., Mirati Therapeutics, OncoGenex Pharmaceuticals, Pfizer, and AstraZeneca; has received research funding (paid to the University of Washington for conduction of clinical trials) from Pfizer, Clovis Oncology, Bavarian Nordic, and Immunomedics; has received compensation from Genentech, Dendreon, Bayer, Merck & Co., Pfizer, Bristol-Myers Squibb, Exelixis, AstraZeneca, Biocept, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Driver, Inc., QED Therapeutics, Heron Therapeutics, and Janssen; and has participated in educational, unbranded, non-product-related speaker’s program (after providing direct input for content of slides) sponsored by Genentech and Bristol-Myers Squibb.
Evan Y. Yu has received research funding from Bayer, Dendreon, Merck, and Seattle Genetics and has received compensation from Amgen, AstraZeneca, Bayer, Churchill Pharmaceuticals, Dendreon, EMD Serono, Incyte Corporation, Janssen, Merck, Pharmacyclics, QED Therapeutics, Tolmar, Inc., and Seattle Genetics for service as a consultant.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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