Cisplatin-based neoadjuvant chemotherapy has been the standard of care in muscle-invasive bladder cancer (MIBC) for nearly 25 years. Its integration into clinical practice was driven by improvements in survival compared with surgery alone. However, despite this benefit, outcomes have plateaued, and the field has seen relatively few practice-changing advances in this setting.
At the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, SurvivorNet was on site as new data were presented that may reshape the treatment of MIBC. During a featured session, Dr Matthew D. Galsky, of the Icahn School of Medicine at Mount Sinai, shared results from the phase 3 KEYNOTE-B15 trial evaluating perioperative enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda).
Following the presentation, SurvivorNet spoke with several genitourinary oncology specialists to better understand how these findings fit into an already evolving treatment landscape — and what they may mean for clinical practice in the years ahead.
“It hasn’t been that long since bladder cancer was almost an orphan disease. With cisplatin being the most important [therapy] in the entire modern history of bladder cancer.” – Dr Elizabeth Wulff, Associate Professor and Medical Oncologist at the University of Kansas Health System, told SurvivorNet.
“And the data that has come out of this trial is truly practice changing because of its impact on disease-free survival.”
Dr Wulff points that this combination is not new to clinicians treating bladder cancer. In fact, it has already transformed outcomes in the metastatic setting.
“Enfortumab vedotin and pembrolizumab has been a treatment available to patients with advanced bladder cancer for a few years,” says Dr Dr Wulff. “Following EV-302, it was shown to be a practice-changing treatment for advanced disease.”
What makes these data particularly compelling is the consistency of benefit across disease states. In metastatic disease, the combination improved survival. Now, in earlier-stage muscle-invasive bladder cancer, it is showing the ability to both improve cancer control and extend survival.
As Dr Wulff noted, this represents a major conceptual shift:
“We’ve taken something that has improved survival as well as cancer control for patients with metastatic disease and now moved it into the curative intent setting with incredible success.”
This transition — from palliative to curative-intent therapy — is a critical milestone. Historically, many of the most effective systemic therapies in oncology were first developed for advanced disease, with gradual movement into earlier lines of treatment.
“The data most recently presented has shown that enfortumab vedotin and pembrolizumab reduces the risk of recurrence and improves overall survival.”
When asked directly whether the new regimen could supplant cisplatin, Dr Wulff did not hesitate.
“I think that the EV-304 or KEYNOTE-B15 data of perioperative enfortumab vedotin and pembrolizumab is immediately actionable and practice changing. Yes.”
A More Cautious View: Interpreting the Data in Modern Practice
While many experts view the KEYNOTE-B15 results as practice-changing, not everyone is ready to immediately replace cisplatin-based chemotherapy. In a separate interview with SurvivorNet, Dr. Sarah Psutka, a urologic oncologist at Fred Hutchinson Cancer Center, emphasized the importance of interpreting these findings in the context of current clinical practice.
She noted that the trial compared perioperative enfortumab vedotin plus pembrolizumab to neoadjuvant chemotherapy alone — without routine adjuvant therapy in the control arm.
“This was a study comparing treatment around the time of surgery,” she explained. “But in modern practice, many patients (particularly those with residual disease) are considered for additional therapy after surgery.”
In fact, only a small number of patients in the chemotherapy arm received adjuvant treatment, raising questions about whether the control group reflects contemporary standards.
At the same time, the investigational arm involved a more intensive approach, with treatment given both before surgery and for up to a year afterward. “This is a lot more therapy,” Dr. Psutka noted.
She also highlighted the broader context: cisplatin, while effective, is not an option for many patients. Because bladder cancer predominantly affects older individuals, often with comorbidities, up to half of patients are ineligible for cisplatin due to kidney function, neuropathy, or other factors.
The availability of enfortumab vedotin plus pembrolizumab in both cisplatin-eligible and ineligible populations represents an important advance. However, Dr. Psutka cautioned that further research is needed.
“These findings provide a compelling rationale for more rigorously designed comparative trials,” she said.
From a clinical perspective, her comments underscore a key point: while the data are highly encouraging, integrating this regimen into practice will require careful consideration of evolving standards, patient selection, and treatment sequencing.
KEYNOTE-B15: Redefining Care in Cisplatin-Eligible Patients
The phase 3 KEYNOTE-B15 trial enrolled 808 patients with MIBC who were eligible for cisplatin-based chemotherapy and radical cystectomy. Patients were randomized to receive perioperative enfortumab vedotin plus pembrolizumab (both before and after surgery) or standard neoadjuvant gemcitabine plus cisplatin followed by surgery.
The trial met its primary endpoint, demonstrating a significant improvement in event-free survival (EFS). Median EFS was not reached in the enfortumab vedotin–pembrolizumab arm, compared with 48.5 months in the chemotherapy arm (hazard ratio [HR] 0.53; 95% CI, 0.41–0.70; P < .0001). At 24 months, EFS rates were 79.4% with the combination versus 66.2% with chemotherapy.
Overall survival (OS) was also significantly improved, with a 35% reduction in the risk of death (HR 0.65; 95% CI, 0.48–0.89). At 24 months, OS rates were approximately 86.9% to 89.6% in the experimental arm, compared with about 81% in the control group.
Pathologic complete response (pCR) rates were notably higher with the combination therapy. A pCR was achieved in 55.8% of patients treated with enfortumab vedotin plus pembrolizumab, compared with 32.5% of those receiving cisplatin-based chemotherapy — an absolute difference of more than 20%.
These results are particularly striking in the context of historical data, marking the first time that a non-platinum regimen has demonstrated superiority over cisplatin-based neoadjuvant therapy in MIBC.
SurvivorNet Perspective: Balancing Enthusiasm With Clinical Nuance
From a broader perspective, the emergence of enfortumab vedotin plus pembrolizumab represents a major advance in bladder cancer care. The magnitude and consistency of benefit seen across KEYNOTE-B15 are difficult to ignore, and many clinicians view the regimen as practice-changing.
At the same time, as SurvivorNet heard in discussions with experts at ASCO GU, the transition from clinical trial results to real-world practice is rarely straightforward.
Ultimately, the field may be moving toward a new paradigm in which perioperative systemic therapy is tailored based on patient characteristics, disease risk, and emerging biomarkers. Enfortumab vedotin plus pembrolizumab is likely to play a central role in that evolution — but ongoing studies and clinical experience will help determine exactly how it is best used.
