Bacillus Calmette–Guérin induction with or without maintenance is the gold standard therapy for intermediate-/high-risk non-muscle-invasive bladder cancer; however, one-third of patients treated with adequate bacillus Calmette–Guérin therapy do not achieve sufficient responses, and this is referred to as “bacillus Calmette–Guérin failure.” The term, bacillus Calmette–Guérin failure, is ambiguous and includes a very heterogeneous population of patients. By strictly focusing on patients who are unlikely to benefit from additional bacillus Calmette–Guérin therapy and who need to be treated with radical cystectomy, the new concept of “bacillus Calmette–Guérin unresponsive” was recently proposed, and might accelerate the development of novel therapeutic options for bacillus Calmette–Guérin-unresponsive disease. A promising therapeutic strategy for bacillus Calmette–Guérin-unresponsive disease is the blockade of the programmed cell death-1/programmed cell death-ligand 1 pathway, which is considered to be activated by bacillus Calmette–Guérin therapy. Several large clinical trials have been carried out to assess the potential of programmed cell death-1/programmed cell death-ligand 1 blockade in bacillus Calmette–Guérin-naïve high-risk non-muscle-invasive bladder cancer and bacillus Calmette–Guérin-unresponsive disease. Furthermore, clinical trials that are targeting bacillus Calmette–Guérin-unresponsive disease with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. The findings of these trials are awaited in order to establish appropriate bladder-sparing approaches for patients with bacillus Calmette–Guérin-unresponsive disease.
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