Editor's Note: The 2026 Congress of the European Society for Medical Oncology (ESMO) featured several important advances in urothelial carcinoma (UC). Nectin-4-targeted therapy continued to attract considerable attention, with 34 studies related to enfortumab vedotin presented, covering long-term follow-up of first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC), evidence of benefit across patient subgroups with different characteristics, and prospective investigations of perioperative treatment and bladder preservation in muscle-invasive bladder cancer (MIBC).These studies do more than extend the use of the same treatment across different disease stages. They address two distinct clinical questions. In la/mUC, how can long-term follow-up and subgroup evidence help clinicians identify the optimal first-line treatment window and ensure standardized patient management? In MIBC, how can perioperative studies, circulating tumor DNA (ctDNA) analyses, health-related quality-of-life (HRQoL) assessments, and bladder-preservation trials help explore future treatment pathways that remain to be validated? Together, these studies emphasize comprehensive management throughout the disease course while extending research into earlier disease stages and exploring the possibility of cure.
In this article, Oncology Frontier – UroStream reviews the series of studies on enfortumab vedotin presented at this year’s ESMO Congress, covering long-term first-line benefits in advanced UC, more detailed analyses of patient subgroups, and perioperative and bladder-preservation strategies in MIBC.
First-Line Treatment for Advanced Disease: Sustained Long-Term Benefits and Broader Evidence Across Patient Populations
For patients with la/mUC, first-line treatment is an important starting point that influences subsequent disease control and long-term outcomes. The EV-302 study established enfortumab vedotin combination therapy as a first-line standard of care. At 3.5 years of follow-up, median overall survival (OS) reached 33.6 months in the enfortumab vedotin combination group, compared with 15.9 months in the chemotherapy group (HR=0.53). The 3.5-year OS rates were 44.0% and 24.6%, respectively. Previously reported data also showed a complete response (CR) rate as high as 41.1% in the Asian subgroup.
Notably, among patients who ultimately achieved CR with enfortumab vedotin combination therapy, approximately two-thirds initially had a partial response (PR) and subsequently converted to CR during continued treatment. This suggests that an early assessment showing PR does not necessarily indicate that the maximum treatment response has been reached. For patients whose disease has not progressed and whose adverse events remain manageable, standardized response assessments and adverse-event management are essential. Clinicians should avoid prematurely dismissing the possibility of further benefit simply because CR has not been achieved at an early assessment.
Following the establishment of first-line survival benefits in EV-302, subgroup analyses presented at this year’s ESMO Congress further demonstrated that patients with different disease characteristics, ages, and comorbidities generally experienced benefit consistent with that observed in the overall population.
Updated subgroup analyses (Abstracts 4760P and 4761P) showed that the enfortumab vedotin combination regimen demonstrated benefits consistent with those in the overall population among patients with different disease characteristics, including liver or other visceral metastases, as well as older patients aged 75 years or above and patients with underlying conditions such as diabetes and renal impairment. No new safety signals emerged. The overall consistency of benefit across disease characteristics, age groups, and comorbidity subgroups further supports the value of enfortumab vedotin combination therapy as a first-line option for a broad population of patients with la/mUC.
In addition, real-world data from the French EVOLVE 3 study provided complementary evidence of the regimen’s benefits in routine clinical practice. The EV-103 study, which has one of the longest follow-up periods among studies in this setting, further confirmed durable responses and survival benefits in patients ineligible for cisplatin (Abstract 4740RO), supporting a favorable long-term benefit–risk profile.
Taken together, these long-term follow-up and subgroup findings further strengthen the evidence supporting enfortumab vedotin combination therapy in first-line la/mUC and provide additional insights into long-term outcomes across different patient characteristics. The ESMO data suggest that patients may benefit from this standard treatment even when their clinical characteristics are complex. Going forward, standardized response assessments, effective adverse-event management, and appropriate dose adjustments will remain important to help eligible patients maintain treatment continuity and maximize long-term benefit.
Perioperative Treatment: Moving Therapeutic Exploration Earlier and Deepening the Evidence Base
Unlike la/mUC, treatment of MIBC places particular emphasis on balancing the opportunity for cure, recurrence-risk reduction, surgical outcomes, and long-term quality of life. Positive results from EV-303 and EV-304 indicate that research into enfortumab vedotin combination therapy is expanding into the earlier-stage perioperative setting for MIBC. The two studies investigate perioperative treatment strategies in cisplatin-ineligible and cisplatin-eligible populations, respectively, providing a new evidence base for further evaluation of enfortumab vedotin combination therapy in earlier-stage disease.
Updates presented at this year’s ESMO Congress further enriched the understanding of the potential value of perioperative treatment.
First, a post hoc analysis of the ITT3 population in EV-303 (Abstract 4733O) provided additional data from patients randomized concurrently. Among patients randomized concurrently to the three study groups, the efficacy results for the enfortumab vedotin combination regimen were consistent with the direction of the primary study analysis compared with the control group.
Second, ctDNA analyses and HRQoL assessments from EV-304 broadened the scope of evidence relevant to precision treatment and comprehensive disease management. With efficacy already established, the ctDNA analysis (Abstract 4734O) showed that ctDNA positivity was associated with a poor prognosis. However, the enfortumab vedotin combination regimen demonstrated better event-free survival (EFS) outcomes than chemotherapy regardless of ctDNA status before neoadjuvant treatment or after surgery. The proportion of patients achieving ctDNA clearance was also higher in the enfortumab vedotin combination group, and patients who achieved clearance had better outcomes.
Regarding quality of life, the HRQoL analysis (Abstract 4738RO) found no clinically meaningful differences between the two groups across the HRQoL domains assessed at postoperative Week 42. These findings provide complementary patient-reported outcome data to help characterize the overall clinical value of perioperative enfortumab vedotin combination therapy.
These updates deepen the multidimensional understanding of perioperative treatment. Post hoc analyses help characterize efficacy and safety in specific study populations; ctDNA analyses explore associations between minimal residual disease status, recurrence risk, and treatment endpoints; and HRQoL analyses examine whether intensified perioperative treatment affects patient-reported outcomes.
All these findings must be interpreted within the context of their respective study designs and levels of evidence. At present, ctDNA should not be described as an established routine tool for independently guiding treatment intensification or de-intensification. Perioperative research is expanding beyond efficacy validation to encompass patient-reported outcomes, biomarkers, and comprehensive management throughout the treatment course.
Bladder Preservation: Prospective Exploration of Organ-Sparing Strategies
In MIBC, preserving the bladder as much as possible while maintaining tumor control is an important area of ongoing research. EV-209 and EV-309, both presented at this year’s ESMO Congress, are Trial in Progress studies that further explore the potential role of enfortumab vedotin combination therapy in bladder-preservation strategies.
EV-209 (Abstract 4769TiP) and EV-309 (Abstract 4770TiP) are both ongoing studies without efficacy results available at this stage.
EV-209 is a Phase II, single-arm proof-of-concept study planning to enroll 240 patients. It aims to evaluate the efficacy of bladder preservation with enfortumab vedotin combination therapy in patients with MIBC who are eligible for, but unwilling to undergo, radical cystectomy.
EV-309 is a Phase III randomized controlled study planning to enroll approximately 390 patients. It is the first Phase III randomized study in a bladder-preservation setting to directly compare enfortumab vedotin combination therapy with standard concurrent chemoradiotherapy (cCRT).
Although efficacy results are not yet available, the designs of these studies convey an important message: research into enfortumab vedotin in MIBC is extending beyond the perioperative setting into organ preservation, a particularly challenging clinical context.
Conclusion
Long-term follow-up from EV-302 further reinforces the first-line survival benefits of enfortumab vedotin combination therapy across a broad population of patients with la/mUC. Subgroup analyses, long-term follow-up, and real-world studies presented at this year’s ESMO Congress continue to strengthen this core body of evidence from different perspectives.
Meanwhile, studies including EV-303, EV-304, EV-209, and EV-309 are exploring the potential value of enfortumab vedotin combination therapy in perioperative MIBC treatment and bladder-preservation strategies.
Overall, from the continued accumulation of long-term first-line and patient-subgroup evidence in la/mUC to prospective investigations of perioperative treatment and bladder preservation in MIBC, research on enfortumab vedotin is addressing a broader range of disease stages and clinical questions in UC, continuously expanding the evidence base for comprehensive management throughout the disease course.
