Treatment of recurrent nonmuscle-invasive bladder cancer (NMIBC) after intravesical Bacillus Calmette Guérin (BCG) remains challenging. Although the standard of care is radical cystectomy, many patients are unsuitable for surgery due to their advanced age and/or frailty, or simply refuse to undergo the procedure. The development of bladder sparing agents in this disease space has been hampered by the heterogeneity in the patient population, poor definition of disease states, a lack of appropriate control arms, and consensus on trial endpoints. High-risk NMIBCs show a greater propensity for disease recurrence and/or progression to muscle-invasive tumors, even after optimal BCG immunotherapy. NMIBC requires a better risk stratification due to clinical and molecular heterogeneity also in BCG responsiveness, which poses a major challenge for clinical decision-making. Genitourinary cancers are the most likely responsive to immunotherapy; however, about 20–30% of bladder cancers have unfavorable to very unfavorable prognoses.