As neoadjuvant enfortumab vedotin plus pembrolizumab (EVP) achieves high pathologic complete response rates in MIBC, a critical question emerges: is adjuvant EVP necessary for everyone? Continuing treatment in patients who are already cancer-free post-surgery may offer no extra benefit while increasing toxicity.

In real-world practice, oncologists are granting treatment breaks, or 'holidays,' to metastatic bladder cancer patients who achieve major responses on enfortumab vedotin-pembrolizumab. This practice, driven by toxicity management and quality of life concerns, is common despite the lack of formal trial data to guide the optimal duration or timing of discontinuation.

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.

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.

Clinicians are pragmatically using novel drug combinations based on safety and early efficacy data from Phase 1b/2 trials like ELEVATE. This practice circumvents the impossibility of running Phase 3 trials for every permutation and is reportedly being covered by insurers, accelerating patient access to new options.

The demonstrated superiority of the enfortumab vedotin (EV) and pembrolizumab combination over platinum chemotherapy has effectively made the Galski criteria, used for determining cisplatin eligibility, irrelevant. This marks a major paradigm shift in how frontline bladder cancer is approached, moving beyond platinum-based decisions.

In cisplatin-ineligible muscle-invasive bladder cancer, neoadjuvant enfortumab vedotin plus pembrolizumab demonstrated a 57% pathologic complete response rate in the KEYNOTE-905 trial. This is an unprecedented result, significantly higher than any previously studied regimen and signals a major shift in perioperative treatment.

A key lesson in bladder cancer is that patient attrition is rapid between lines of therapy; many who relapse from localized disease never receive effective later-line treatments. This reality provides a strong rationale for moving the most effective therapies, like EV-pembrolizumab, to earlier settings to maximize the number of patients who can benefit.

The success of EV-Pembro in perioperative trials has established it as a foundational treatment. The emerging clinical philosophy is to initiate EV-Pembro for a wide spectrum of muscle-invasive disease and then decide on subsequent steps, like surgery, based on the patient's response, marking a major strategic shift.