Cytotoxic chemotherapy has been the only systemic treatment of locally advanced 
and metastatic urothelial carcinoma for decades. Long-term survival remains 
stagnant around 12-14 months for patients with advanced disease who have 
progressed on or recurred after receiving first-line platinum-based 
chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma 
in all disease settings requires the development of novel treatments, especially 
for patients who failed on first-line chemotherapy. Since the discovery of 
intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive 
disease, there have not been any major breakthrough drugs that exploit the 
immune-sensitivity of bladder cancer until recently. Immune-checkpoint 
inhibitors targeting the programmed death 1/programmed death-ligand 1 
(PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways 
have shown significant anti-tumor activity, tolerable safety profiles and 
durable, long-term responses in clinical trials. Atezolizumab, avelumab, 
durvalumab, nivolumab and pembrolizumab are promising PD-1/PD-L1 blockade drugs 
under investigation that will redefine the standard of care for bladder cancer. 
CTLA-4 inhibitors are also under investigation in this setting. Atezolizumab, 
approved in May 2016, and nivolumab, approved in February 2017, are the first 
Food and Drug Administration (FDA)-approved immune-checkpoint inhibitors in 
bladder cancer for platinum-pretreated patients based on phase II data. On March 
16, 2017, results from the phase III trial KEYNOTE-045 demonstrated that 
survival was significantly longer in patients treated with pembrolizumab when 
compared with the standard second-line chemotherapy. Research into biomarkers 
such as PD-L1 expression, messenger RNA subtype, mutational and neoantigen load 
and gene signature expression will be crucial to determining why some patients 
respond to immunotherapy and others do not. This review article describes the 
advances in immunotherapy since the development of BCG, presents results from 
clinical trials investigating immune-checkpoint inhibitors and discusses 
biomarkers and prognostic factors associated with response to these new drugs.