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.

For aggressive diseases like muscle-invasive bladder cancer, where half of patients historically relapsed and died quickly, using transformative perioperative regimens that overtreat some patients is a reasonable strategy to achieve high cure rates (e.g., 60% pathologic complete response) for the overall group.

Achieving a pathologic complete response (path CR) in the bladder after neoadjuvant therapy is a marker of drug efficacy, not a signal to stop treatment. Because patients die from metastatic, not local, disease, a path CR should be seen as a reason to "double down" on the effective systemic therapy to eradicate micrometastases.

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.

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.

While promising, current ctDNA technology is not robust enough to justify stopping effective neoadjuvant systemic therapy in bladder cancer, even if a patient becomes ctDNA negative. Experts argue against using it to de-escalate treatment outside of a clinical trial due to the risk of undertreating a lethal disease.

Clinical Complete Response (cCR), assessed by imaging and biopsy, is the primary endpoint for avoiding surgery in new trials. However, these tools are known to be unreliable, potentially missing up to 25% of residual post-mucosal tumors and leading to undertreatment.

A notable trend is patients achieving a strong response to neoadjuvant therapy and then refusing definitive local treatment like cystectomy. Experts caution against this "off-study" approach, as it deviates from the curative backbone of care and undermines the ability to build an evidence base for bladder preservation strategies.

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.