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Aim: This review article summarizes the current clinical practice guidelines around disease definitions and risk stratifications, and the treatment of non-muscle-invasive bladder cancer (NMIBC). Recently completed and ongoing clinical trials of novel and investigational therapies in Bacillus Calmette-Guerin (BCG)-naive, BCG-recurrent, and BCG-unresponsive patient populations are also described, e.g., those involving immune checkpoint inhibitors, targeted therapies, other chemotherapy regimens, vaccines, and viral-or bacterial-based treatments. Finally, a brief overview of enhanced cystoscopy and drug delivery systems for the diagnosis and treatment of NMIBC is provided. Background: A global shortage of access to BCG is affecting the management of BCG-naive and BCG-recurrent/unresponsive NMIBC; hence, there is an urgent need to assist patients and urologists to enhance the treatment of this disease. Methods: Searches of ClinicalTrials.gov, PubMed, and Google Scholar were conducted. Published guidance and conference proceedings from major congresses were reviewed. Conclusion: Treatment strategies for NMIBC are generally consistent across guidelines. Several novel therapies have demonstrated promising antitumor activity in clinical trials, including in high-risk or BCG-unresponsive disease. The detection, diagnosis, surveillance, and treatment of NMIBC have also been improved through enhanced disease detection. (C) 2021 Pfizer Inc. and the Author(s). Elsevier Inc.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) – a selective, potent, oral IDO1 inhibitor – combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320