The success of neoadjuvant immunotherapy trials like Niagara and those with EV-Pembro means most patients will receive immune therapy before surgery. This fundamentally shifts the clinical landscape, making the question of starting adjuvant immunotherapy less relevant as perioperative treatment becomes the standard.

The transformative efficacy of EV-Pembro has ushered in a new, aggressive treatment philosophy for both muscle-invasive and metastatic bladder cancer. The approach is to administer the combination upfront to gain rapid disease control, and only then make subsequent decisions about surgery, radiation, or further therapy.

The practice-changing Keynote B15 trial showed strong efficacy for neoadjuvant EV-Pembro. However, about half of patients discontinued treatment due to side effects. This creates a clinical paradox: patients who complete the full regimen may be over-treated, while those who stop early due to toxicity may be under-treated, complicating patient management and counseling.

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.

Historically, aggressive variants like micropapillary went directly to surgery. However, recent data suggests these patients do poorly due to micrometastatic disease. The trend is now to give neoadjuvant EV-Pembro to treat systemic disease, even with limited specific evidence.

A critical warning for clinicians: data showing that ctDNA-negative patients can skip *adjuvant* therapy (InVigor011) should not be extrapolated to the *neoadjuvant* setting. Stopping the post-operative portion of a perioperative EV-Pembro regimen based on a negative ctDNA result is unsupported by data and risks under-treating patients.

New bladder-sparing trials mandate nine cycles of EV-Pembro to replicate the conditions of successful surgical trials. This conservative approach ignores that patient response is front-loaded while toxicity is back-loaded, likely overtreating many patients to ensure comparable efficacy.

Giving EV Pembro perioperatively for muscle-invasive bladder cancer provides the best chance for a cure. Waiting to use it in the first-line metastatic setting is a major gamble, as many patients relapse and may not get a second chance at effective therapy. The consensus is to use the best treatment upfront.

Despite the temptation to shorten therapy for patients with good responses or toxicity, Professor Powles warns against deviating from the rigorous trial protocols that produced exceptional survival outcomes. He argues that de-escalation should be explored only within formal research studies to avoid compromising hard-won patient cures.