Current and Emerging Strategies to Treat Urothelial Carcinoma

SIMPLE SUMMARY: Urothelial cell carcinoma (UCC) is the ninth most common cancer worldwide and in the US the fourth most common cancer, with ~82,000 new cases (~62,000 men) diagnosed annually leading to ~17,000 deaths/year (~12,000 men). While early-stage cases exhibit more favorable outcomes, the emergence of drug resistance and distant metastasis reduces median overall survival (OS) to 12–15 months. The development of modern genetic and molecular assays to detect high-risk mutations has improved the detection of high-risk disease. Recently, immune therapies have been developed; these demonstrate markedly improved OS rates compared to treatment with chemotherapy alone. However, challenges persist and there remains an urgent, unmet need to develop and advance novel molecular and therapeutic strategies that prevent or overcome drug resistance, to improve patient outcome. Here, we provide an overview of the etiology, diagnostic approach and emerging therapeutic strategies for improving UCC patient quality of life and OS. ABSTRACT: Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more commonly observed in men than women. The most important risk factor for developing BC is tobacco smoking, which accounts for ~50% of cases, followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC remains generally incurable and is associated with intrinsic and acquired drug and immune resistance. UCC is lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and a high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss therapies to improve UCC management and how comprehensive tumor profiling can identify actionable biomarkers and eventually fulfill the promise of precision medicine for UCC patients.