Immunotherapy for metastatic urothelial carcinoma: status quo and the future

The treatment paradigm of urothelial carcinoma has been revolutionized by the advent of multiple anti-programmed-cell death-1/ligand-1 (PD-1/PD-L1) antibodies. Significant improvements have been obtained in the locally advanced or metastatic stage, which was lacking of therapeutic standards. This review reports key findings from completed and ongoing clinical trials that highlight the potential of PD-1/PD-L1 blockade in this disease.

Anti-PD-1/PD-L1 monoclonal antibodies have shown efficacy and safety in patients with urothelial carcinoma, regardless of their prognostic features. Efficacy was similar across different compounds, with objective responses that approximate 20%, with some differences favoring PD-L1-expressing patients. Typically, responding patients have good chances of achieving durable response, but biomarkers predictive of therapeutic effect are lacking. To date, evidences from randomized studies are limited to the second-line, postplatinum therapy.

Despite the activity of PD-1/PD-L1 inhibitors is well established in metastatic urothelial carcinoma, multiple gray zones still exist regarding their optimal use in clinical practice. These uncertainties are related to patient and treatment-related criteria, to the optimal duration of treatment, including combination or sequence with standard chemotherapy. Special issues are represented by pseudoprogression or hyperprogression. Generally, enhanced predictive tools are needed and a myriad of further investigations are underway.