The emergence of positive data from trials like PATINA creates a dilemma for oncologists treating patients who are already stable on an older maintenance therapy. The consensus suggests not altering a successful regimen to avoid disrupting patient stability, revealing a cautious approach to integrating new evidence into established care.

While platinum chemotherapy is considered the standard treatment after a patient progresses on a first-line ADC-IO combination, experts admit this is a standard "based on nothing." There is no clinical trial data to prove its efficacy in this specific setting; it serves only as a placeholder for new clinical trials.

Unlike immunotherapy, where re-challenge after progression is dubious, there is an emerging clinical practice of re-challenging patients with the same antibody-drug conjugate (ADC), such as enfortumab vedotin (EV), after a treatment break forced by toxicity. Anecdotally, patients are showing great responses, highlighting a key area for prospective data generation.

An advisory panel split 50/50 on a two-year immunotherapy regimen but voted 7-to-1 for a one-year drug with similar efficacy. This reveals that for adjuvant therapies in non-metastatic cancer, halving the treatment duration and toxicity exposure can decisively shift the risk/benefit calculation in favor of approval.

When a highly effective therapy like EV Pembro was approved for 'cisplatin ineligible' patients, the definition of 'ineligible' became very elastic in practice. This demonstrates that when a new treatment is seen as transformative, clinicians find ways to qualify patients, putting pressure on established guidelines.

The anticipated approval of the highly effective EV-Pembro combination in the perioperative setting will create a new clinical challenge. When these patients eventually relapse years later, clinicians will face a dilemma: re-challenge with the same potent regimen that worked before or switch to older, likely less effective chemotherapies.

Current bladder cancer trials often fail to differentiate between patients with primary resistance (never responded) versus acquired resistance (responded, then progressed). Adopting this distinction, common in lung cancer research, could help identify patient subgroups more likely to benefit from immunotherapy re-challenge and refine trial eligibility criteria.

For patients who previously received immunotherapy (IO), a recurrence more than 12 months after completing treatment makes re-challenging with an IO agent a reasonable option. The likelihood of benefit is lower if the recurrence is within 6-12 months and minimal if under 6 months.

Despite data from kidney cancer showing immunotherapy re-challenge is often ineffective, oncologists admit to using it in urothelial cancer. This highlights a clinical conflict where the desire to use a powerful drug class outweighs the lack of supporting evidence, especially in specific, confusing patient scenarios.