Background Bladder cancer is the 10th most common cancer globally. The majority of bladder cancers are urothelial carcinomas (UCs), which, if locally advanced or metastatic, carry poor long-term prognosis. Cancer cells can evade the immune system by expressing the programmed cell death ligand 1 protein (PD-L1). Programmed cell death ligand 1 protein binds to programmed cell death protein 1 (PD-1) on T cells, inhibiting their antitumor action. Bladder tumor cells also overexpress nectin-4, a cell adhesion polypeptide that contributes to metastasis, worsening prognosis. Current platinum-based chemotherapy treatments are suboptimal. This review aimed to assess novel treatments for locally advanced or metastatic UC that specifically target PD-L1 or nectin-4, namely, the PD-1 inhibitor pembrolizumab and the anti–nectin-4 antibody-drug conjugate enfortumab vedotin (EV). Materials and methods Relevant English-language peer-reviewed articles and conference abstracts from the last 5 years were identified through MEDLINE and EMBASE database searches. A narrative review was performed, with key results outlined below. Results Pembrolizumab was demonstrated to be superior to chemotherapy as a second-line treatment for platinum-unresponsive participants in the KEYNOTE-045 trial, resulting in its Food and Drug Administration (FDA) approval. Enfortumab vedotin therapy resulted in superior outcomes compared with chemotherapy in the EV-301 trial, resulting in FDA approval for its use for patients with locally advanced or metastatic UC who had previously undergone treatment with platinum-based chemotherapy and PD-1/PD-L1 inhibitors. Positive preliminary results for pembrolizumab and EV combination therapy have led to FDA approval in patients with locally advanced or metastatic UC who are not eligible for platinum chemotherapy. Conclusions Pembrolizumab and EV represent novel treatment options for patients with locally advanced or metastatic UC with documented superior outcomes and tolerability as compared with standard chemotherapy.