New Intravesical Agents for BCG-Unresponsive High-Risk Non-Muscle Invasive Bladder Cancer

BACKGROUND: With the exception of the FDA-approved valrubicin and pembrolizumab, there are no standard second-line treaments for BCG-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC). OBJECTIVES: To provide a systematic review of the novel intravesically administered therapeutic agents for the salvage treatment of BCG-unresponsive NMIBC. METHODS: Online search of the PubMed, EMBASE and Web of Science databases was performed. The endpoints of this review were to evaluate the efficacy of the agents in terms of complete response rates (CR) and durability of CR, overall survival, recurrence-free survival and cancer-specific survival and to report on their toxicity profile. A search on Clinicaltrials.gov was performed to identify ongoing clinical trials. RESULTS: 14 studies were included in this review. The critical clinical need for the development of an effective, safe and durable intravesical drug for the salvage treatment of high-risk NMIBC seems to be met mainly by intravesical gene therapy; in fact, data support the FDA-approved nadofaragene firadenovec as a potentially important therapeutic advancement in this context. Promising results are also being obtained by the combination of N-803/BCG and by innovative drug delivery systems. CONCLUSIONS: Considering the plethora of novel intravesical treatments that have completed phase II evaluation, one can reasonably expect that clinicians will soon have at their disposal new agents and treatment options for BCG-unresponsive NMIBC. In the near future, it will be up to the urologist to identify, for each specific patient, the right agent to use, based on safety, results and cost-effectiveness.