During the consensus meeting, patient advocates successfully argued for a highly robust definition of "event-free survival." The final definition counts not just cancer recurrence, but also the need for any additional standard-of-care treatment—including intravesical therapy—as an "event," reflecting the patient's perspective on what constitutes a successful outcome.
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The consensus for "event-free survival" (EFS) in bladder-sparing trials is now highly inclusive, counting even high-grade superficial (non-muscle invasive) relapses as events. This is a deliberately conservative choice to maximize patient safety and preempt the risk of these relapses leading to metastasis.
Experts caution that the new consensus definition of cCR, combining imaging and cystoscopy, is for clinical trials only. Applying it prematurely in routine practice could harm patients, as its correlation with true pathologic response is still being validated with modern therapies.
Despite strong data favoring pre-surgical systemic therapy, a surgeon argues that many patients will continue to undergo surgery first. This is due to real-world factors like surgeons being the point of diagnosis, urgent symptoms requiring rapid intervention, and patient preferences to have the tumor removed immediately.
Historically, bladder-sparing options were primarily for patients unfit for radical cystectomy. Now, with advances in surgical techniques and perioperative care, fewer patients are deemed truly ineligible for surgery. This shift means new bladder-sparing strategies are being developed for a much broader patient population.
The trial's 57.1% pathologic complete response (pCR) rate is deceptively conservative. It categorized patients who responded well but declined surgery as non-responders, suggesting the treatment's true biological efficacy is even higher than the already impressive reported figure.
The FDA's critique of both CREST and Potomac trials highlights that while event-free survival (EFS) endpoints were met, the lack of improvement in overall survival or prevention of muscle-invasive disease makes the risk/benefit profile questionable for an early-stage cancer, where treatment-related harm is a primary concern.
While circulating tumor DNA (ctDNA) is a powerful prognostic marker, it is not yet part of the formal "clinical complete response" definition for bladder-sparing trials. Experts lack data on its ability to predict the superficial, non-muscle invasive relapses common in this setting.
The success of new treatments like immunotherapy and ADCs leads to more patients achieving a deep response. This high efficacy makes patients question the necessity of a radical cystectomy, a life-altering surgery, creating an urgent need for data-driven, bladder-sparing protocols.
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.
An expert oncologist identified a pathological complete response (pCR) rate over 50% as the benchmark that would fundamentally alter treatment. The EV Pembro trial's 57% pCR rate crossed this threshold, forcing a shift from a surgery-centric model toward bladder preservation strategies and systemic therapy.