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.

Despite the perception that cisplatin-ineligible patients have worse disease biology, the pathologic complete response rates to neoadjuvant EV Pembro were nearly identical (56-57%) in both cis-ineligible (KEYNOTE-905) and cis-eligible (KEYNOTE-B15) trials. This suggests the regimen's high efficacy may overcome underlying biological differences.

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.

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.

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.

Expert consensus shows a major paradigm shift: perioperative systemic therapy (like EV-Pembro, scoring 2.9) is the undisputed standard for muscle-invasive bladder cancer. Approaches starting with cystectomy alone now score below 1.8, formally branding them as inferior options.

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.