Contrary to concerns about tolerating Enfortumab Vedotin (EV) after major surgery, 80% of muscle-invasive bladder cancer patients who began the adjuvant phase in the KEYNOTE B15 trial successfully completed it. This suggests the regimen is more manageable post-cystectomy than anticipated.

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.

A major diagnostic challenge in bladder-sparing therapy for T4 tumors is the "fibrotic scar." When a large tumor responds to therapy, it leaves behind fibrotic tissue that is indistinguishable from residual cancer on an MRI, making it nearly impossible to confirm a true complete response.

Remarkable pathologic response rates from just 3-4 cycles of neoadjuvant EV-Pembro are creating divergent research questions. Future trials will explore whether some patients could benefit from more cycles (escalation) while high-responders might be able to skip cystectomy entirely (de-escalation).

With therapies like Enfortumab Vedotin + Pembrolizumab (EVPembro) inducing a pathological complete response (PathCR) in 60% of patients, many undergo radical cystectomies only to find no residual cancer. This success rate is driving trials for bladder-sparing approaches like active surveillance.

Professor Powles predicts a significant shift in bladder cancer treatment. High pathological complete response rates with neoadjuvant EV Pembro may allow responders, identified by imaging and circulating tumor DNA, to safely avoid radical cystectomy, a life-altering surgery that may become unnecessary for many.

While powerful drugs effectively shrink tumors, the response pattern can be a "splatter" rather than a uniform deflation. This creates a significant surgical challenge, making it difficult to define clear margins for breast-conserving surgery and potentially necessitating a more extensive operation despite a good therapeutic response.

With pathologic complete response rates approaching 67% in patients completing neoadjuvant EV-Pembro, a majority of cystectomies are now removing cancer-free bladders. This creates an ethical and clinical imperative to rapidly launch prospective trials to validate bladder preservation strategies and avoid overtreatment.

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.