The B15 trial shows EV-Pembro is superior to chemotherapy in muscle-invasive bladder cancer. However, the true benchmark is now the Niagara study (chemo + durvalumab), which already beat chemo alone. The debate will focus on whether EV-Pembro offers a significant enough improvement to become the definitive standard over this new chemo-IO combination.

With highly active agents yielding 30% complete response rates, the immediate goal should be to cure more patients by exploring potent combinations upfront. While sequencing minimizes toxicity, an ambitious combination strategy, such as ADC doublets, offers the best chance to eradicate disease and should be prioritized in clinical trials.

Perioperative enfortumab vedotin-pembrolizumab (EV-Pembro) is surprisingly well-tolerated on a per-cycle basis compared to the traditional GEMSYS chemotherapy regimen. This challenges preconceived notions about the toxicity of this powerful combination, though cumulative toxicity over longer durations remains a key factor.

Historically, aggressive variants like micropapillary went directly to surgery. However, recent data suggests these patients do poorly due to micrometastatic disease. The trend is now to give neoadjuvant EV-Pembro to treat systemic disease, even with limited specific evidence.

While KEYNOTE-905 showed dramatic survival benefits with neoadjuvant plus adjuvant EV-pembrolizumab, its design makes it impossible to isolate the benefit of each phase. The high (57%) pathologic complete response after neoadjuvant therapy alone suggests many patients may be overtreated with adjuvant cycles, risking unnecessary long-term toxicity like neuropathy.

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 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.