First-line treatment for locally advanced or metastatic urothelial carcinoma has changed rapidly with the introduction of enfortumab vedotin plus pembrolizumab. Platinum-based chemotherapy followed by avelumab maintenance remains an important comparator, but only patients who do not progress after chemotherapy can receive maintenance treatment.
On June 26, 2026, European Urology Oncology published an article entitled “Adjusted Comparison of First-line Enfortumab Vedotin Plus Pembrolizumab Versus Platinum-based Chemotherapy ± Avelumab Maintenance for the Treatment of Locally Advanced/Metastatic Urothelial Carcinoma.”
Authors: Ryan Dillon, Robert Jones, Aude Fléchon, Keith Chan, Alicia N. Pepper, Dylan McLoone, Sam Keeping, Jeroen P. Jansen, Allison Thompson, and Florence R. Wilson.
Bladder Cancer in 2026
According to the American Cancer Society, bladder cancer is more common in men than women. In the United States in 2026, about 84,530 new cases of bladder cancer are expected, including about 64,730 in men and 19,800 in women. About 17,870 deaths are expected, including about 12,640 in men and 5,230 in women.
Smoking remains the biggest risk factor for bladder cancer. In recent years, incidence rates have decreased by about 1% per year in both men and women, likely reflecting declines in smoking. Bladder cancer is the 10th leading cause of cancer death in the United States, and death rates have recently decreased by 1.4% per year since 2016.
Background
EV-302/KEYNOTE-A39 established enfortumab vedotin plus pembrolizumab as a first-line standard of care for patients with previously untreated locally advanced or metastatic urothelial carcinoma, showing improved progression-free survival and overall survival compared with platinum-based chemotherapy.
However, avelumab maintenance became available after EV-302 had already started and was potentially underused among patients without progression in the chemotherapy arm. The adjusted comparison evaluated whether the benefit of EV+P would remain when outcomes in the EV-302 chemotherapy arm were modeled as if patients without progression after platinum-based chemotherapy had received avelumab maintenance, as supported by JAVELIN Bladder 100.
A direct comparison is challenging because JAVELIN Bladder 100 enrolled only patients who had not progressed after platinum-based chemotherapy, whereas EV-302 randomized patients at the start of first-line treatment.
Read more about Enfortumab Vedotin (Padcev) on OncoDaily.
Study Design
This was a counterfactual modeling analysis using patient-level data from EV-302 and study-level data from JAVELIN Bladder 100. The analysis included EV-302 data from 886 patients and JAVELIN Bladder 100 data from 700 patients. Investigators created a hybrid platinum-based chemotherapy ± avelumab maintenance arm by applying the avelumab maintenance treatment effect from JAVELIN Bladder 100 to comparable EV-302 patients who had not progressed after a 22-week first-line treatment period.
This 22-week period represented six 3-week cycles of platinum-based chemotherapy plus a 4-week treatment-free interval. Patients who progressed during chemotherapy were kept in the chemotherapy group and were not considered eligible for avelumab maintenance.
The adjusted platinum-based chemotherapy with or without avelumab maintenance arm was then compared with the observed EV+P arm from EV-302.
Key Findings
EV+P remained favored over the adjusted platinum-based chemotherapy with or without avelumab maintenance comparator. For progression-free survival, the weighted average hazard ratio was 0.51, with a 95% confidence interval of 0.44 to 0.59. For overall survival, the weighted average hazard ratio was 0.64, with a 95% confidence interval of 0.49 to 0.86.
The benefit remained consistent across sensitivity analyses. When a longer 28-week first-line treatment period was used, the hazard ratio was 0.49 for progression-free survival and 0.63 for overall survival.
In a sensitivity analysis using investigator-assessed progression-free survival from EV-302, the hazard ratio was 0.63. In a scenario analysis pooling survival curves, EV+P also remained favored, with a hazard ratio of 0.63 for progression-free survival and 0.62 for overall survival.
Clinical Meaning
The analysis supports the role of EV+P as a preferred first-line standard in locally advanced or metastatic urothelial carcinoma, even when the chemotherapy comparator is adjusted to reflect broader use of avelumab maintenance.
This matters clinically because first-line treatment decisions are made before clinicians know whether a patient will respond to platinum-based chemotherapy and become eligible for maintenance treatment. EV+P can be started upfront, while avelumab maintenance is limited to patients who do not progress after chemotherapy.
EV-302 Updates at ASCO 2026
At ASCO 2026, Thomas Powles, MD, PhD, from Barts Cancer Centre, Queen Mary University of London, presented updated EV-302 findings with 3.5 years of follow-up. At a median follow-up of 42.8 months, median overall survival was 33.6 months with enfortumab vedotin plus pembrolizumab compared with 15.9 months with chemotherapy. The 42-month overall survival rate was 44.0% versus 24.6%, with a hazard ratio of 0.53.
The objective response rate was 67.5% with enfortumab vedotin plus pembrolizumab and 44.2% with chemotherapy. The complete response rate was also higher with the combination, at 30.4% versus 14.5%. Among patients with confirmed complete response in the EV+P arm, 66.2% first achieved partial response and later converted to complete response, showing that responses continued to deepen over time.
These longer-term EV-302 data provide clinical context for the adjusted comparison, showing that the benefit of EV+P remained durable with extended follow-up.
Read more about EV-302 at ASCO 2026: 3.5-Year Follow-Up on OncoDaily.
Avelumab Maintenance in Real-World Practice
Avelumab maintenance remains an important part of the treatment landscape for patients with advanced urothelial carcinoma who do not progress after platinum-based chemotherapy. A multicenter retrospective cohort study published in Cancers on March 6, 2025, titled “Avelumab Maintenance Therapy in Advanced Urothelial Carcinoma: Implications of Timing and Treatment Sequencing,” included 105 patients treated across 13 Portuguese centers.
In that real-world cohort, median progression-free survival from the start of avelumab was 9.8 months and median overall survival was 39.5 months. These data support the clinical relevance of avelumab maintenance after platinum-based chemotherapy, while also highlighting why comparisons with upfront EV+P must account for the fact that only patients without progression after chemotherapy can receive maintenance therapy.
Read more about Avelumab Maintenance Therapy in Advanced Urothelial Carcinoma on OncoDaily.
Limitations
This was not a randomized head-to-head trial of EV+P versus platinum-based chemotherapy followed by avelumab maintenance. The analysis assumed that all patients without progression after chemotherapy received avelumab maintenance, which may not reflect real-world treatment patterns.
The study focused on survival outcomes and did not evaluate comparative safety, tolerability, or later treatment sequencing. The study was funded by Astellas Pharma Inc. and Pfizer. Precision AQ, funded by the study sponsors, performed the analyses and provided editorial assistance.
Conclusion
In this adjusted comparison, first-line enfortumab vedotin plus pembrolizumab remained associated with more favorable progression-free and overall survival outcomes than platinum-based chemotherapy with or without avelumab maintenance in patients with locally advanced or metastatic urothelial carcinoma.
By applying the treatment benefit of avelumab maintenance from JAVELIN Bladder 100 to patients without progression in the EV-302 chemotherapy arm, the analysis addressed an important clinical question about how EV+P compares with a chemotherapy-based approach that includes maintenance therapy for patients without progression.
Although this was a modeling study rather than a randomized head-to-head trial, the results remained consistent across sensitivity analyses and support EV+P as a preferred first-line standard of care in this setting.
The full article is available in European Urology Oncology.
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