Dharmesh Gopalakrishnan, Vadim S Koshkin, Moshe C Ornstein, Athanasios Papatsoris, Petros Grivas

Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor. Since the peak incidence of bladder cancer is in the eighth decade of life and beyond, medical comorbidities may often limit the use of chemotherapy. Immune checkpoint inhibitors with their favorable toxicity profiles and notable antitumor activity have ushered in a new era in the treatment of advanced urothelial cancer (UC) with five agents targeting the PD-1/PD-L1 pathway being recently approved by the US Food and Drug administration. A plethora of clinical trials are ongoing in diverse disease settings, employing agents targeting PD-1/PD-L1 and related immune checkpoint pathways. While reactivating anti-tumor immunity, these agents may lead to a unique constellation of immune-related adverse events, which may warrant discontinuation of therapy and potential use of immunosuppression. Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials and retrospective registries. At the era of precision molecular medicine, and since patients do not respond uniformly to these agents, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. This review discusses current updates and future directions of immunotherapy in advanced UC.