A multicenter real-world analysis found that enfortumab vedotin maintained comparable efficacy in older patients with locally advanced or metastatic urothelial carcinoma, but patients aged 70 years or older had a significantly higher risk of severe toxicity.
The findings were published as an article in press in Clinical Genitourinary Cancer on September 2, 2026, under the title, “EVOLUTE: Enfortumab Vedotin in OLder patients with locally advanced/metastatic UroThElial carcinoma.”
Authors: Ilgın Akbıyık, Mathilde Cabart, Arnaud Pagès, Leticia Aptecar, Mathilde Cancel, Helen Boyle, Théophile Bertail, Loïc Mourey, Cedric Pobel, Yohann Loriot, Natacha Naoun, and Maxime Frélaut.
Why EVOLUTE Was Conducted
Enfortumab vedotin has become an established treatment option for advanced or metastatic urothelial carcinoma. However, evidence on its safety and effectiveness in older patients remains limited, particularly in real-world populations that may include patients with comorbidities, reduced performance status, or characteristics that are underrepresented in clinical trials.
Older adults make up a large proportion of patients with urothelial carcinoma, and treatment decisions in this population can be complex. The source article notes that older patients are frequently affected by frailty and comorbidities, which may increase the risk of adverse events. At the same time, pivotal clinical trials may not fully reflect the broader older population seen in routine oncology practice.
The EVOLUTE study was therefore designed to describe and compare the frequency, severity, and patterns of toxicity associated with enfortumab vedotin monotherapy in patients aged 70 years or older versus younger patients with locally advanced or metastatic urothelial carcinoma.
How the Study Was Designed
EVOLUTE was a multicenter retrospective cohort study conducted across 7 institutions in France. The study included patients who received at least one dose of enfortumab vedotin monotherapy as second-line or later treatment for advanced or metastatic urothelial cancer between July 2022 and October 2023.
Patients were divided into 2 age groups: those aged 70 years or older and those younger than 70 years. The 70-year threshold was predefined, as this cut-off is commonly used in geriatric oncology studies and is referenced in recommendations for geriatric assessment and management in older adults with cancer who are being considered for systemic anticancer treatment.
The study evaluated grade 3 or higher toxicity, dose reductions, dose interruptions, treatment discontinuations due to toxicity, progression-free survival, overall survival, and best radiological response. Radiological responses were assessed locally according to RECIST v1.1, and no central radiology review was performed. Adverse events were graded using CTCAE version 5.0.
Patient Population
A total of 99 patients were included. The median age was 71 years, with 52 patients aged 70 years or older and 47 patients younger than 70 years. Most patients were male, and more than half had an ECOG performance status of 0 or 1.
Baseline disease characteristics were generally balanced between the 2 age groups. However, recurrent disease was more frequent among older patients, while nonurothelial histology was more common among younger patients. Among patients aged 70 years or older, G8 screening was recorded as performed in 28 patients, but a numerical G8 score was available in only 7 patients.
Most patients started enfortumab vedotin at the standard dose of 1.25 mg/kg. Overall, 87.9% received the standard starting dose, while 12.1% started at a reduced dose below 1.25 mg/kg. Patients who began treatment at a reduced dose had a similar median age, ECOG performance status, and Charlson comorbidity index compared with those who started at the standard dose, but more often had renal impairment or pre-existing diabetes.
Regarding previous therapy, 83.8% of the total cohort had received platinum-based combination therapy for advanced disease, and 93.9% had received prior anti-PD-1 or anti-PD-L1 therapy for advanced disease.
Efficacy Outcomes
After a median follow-up of 24.6 months, median progression-free survival in the entire population was 5.7 months, and median overall survival was 10.3 months.
When outcomes were analyzed by age, there were no statistically significant survival differences between older and younger patients. Median progression-free survival was 6.3 months in patients aged 70 years or older compared with 3.1 months in patients younger than 70 years. Median overall survival was 11.6 months in the older group and 10.2 months in the younger group. These differences were not statistically significant.
The study also evaluated outcomes according to starting dose. Median progression-free survival was 6.0 months among patients who started at the standard dose and 4.6 months among those who started at a reduced dose. Median overall survival was 10.6 months in the standard-dose group and 9.6 months in the reduced-dose group. There was no statistically significant difference in efficacy between the 2 starting-dose groups.
Best radiological response showed a numerical trend toward higher response rates in the older group, although this did not reach statistical significance. Progressive disease was reported in 22.9% of evaluable older patients and 48.9% of evaluable younger patients. Six patients were not evaluable for radiological response.
Safety Findings
Toxicity was a central finding of EVOLUTE. In the overall cohort, 33.3% of patients experienced grade 3 or higher toxicity. Treatment modifications were common: 39.4% required dose reductions, 35.4% required dose interruptions, and 20.2% discontinued treatment because of toxicity. Toxicity-related hospitalization occurred in 19.2% of patients, and toxicity-related emergency consultation occurred in 13.1%.
Age had a significant impact on safety. Patients aged 70 years or older experienced higher rates of grade 3 or higher toxicity than younger patients, at 44.2% versus 21.3%. Treatment discontinuation due to toxicity was also substantially more frequent in the older cohort, at 34.6% compared with 4.3% in younger patients. Dose interruptions, hospitalizations due to toxicity, and emergency consultations due to toxicity were also significantly more frequent among older patients.
The most common grade 3 or higher toxicities in the total cohort were peripheral sensory neuropathy, skin toxicity, and anemia. Peripheral sensory neuropathy occurred in 9.1% of all patients, while skin toxicity and anemia each occurred in 5.1%.
Predictors of Severe Toxicity
In univariable analysis, age 70 years or older and recurrent advanced or metastatic urothelial carcinoma were associated with grade 3 or higher toxicity. In a post hoc analysis, each additional 5 years of age was associated with increased odds of grade 3 or higher toxicity. Starting enfortumab vedotin at a reduced dose was associated with a lower incidence of grade 3 or higher toxicity. None of the 12 patients who received an upfront reduced dose experienced grade 3 or higher toxicity, compared with 37.9% of those who started at the standard dose.
In the multivariable logistic regression model, age 70 years or older remained the only statistically significant independent predictor of grade 3 or higher toxicity. The adjusted odds ratio was 2.63, with a 95% confidence interval of 1.05 to 6.58.
Because no grade 3 or higher toxicity events occurred in the reduced-dose group, the starting dose could not be estimated in the conventional multivariable model. A Firth penalized likelihood sensitivity analysis was therefore performed. In that analysis, age 70 years or older remained significantly associated with severe toxicity, and reduced starting dose was associated with lower odds of grade 3 or higher toxicity.
What the Findings Mean
The EVOLUTE results suggest that enfortumab vedotin can retain activity in older patients with advanced or metastatic urothelial carcinoma, but tolerability remains a major issue. Older patients had no statistically significant decrement in progression-free or overall survival compared with younger patients, yet they experienced substantially more severe toxicity and more frequent treatment discontinuation due to toxicity.
The reduced-dose findings are notable but should be interpreted cautiously. The 12 patients who started at a reduced dose had no grade 3 or higher toxicity and had survival outcomes comparable to patients who started at the standard dose. However, the reduced-dose group was small, and the authors emphasized that this observation is hypothesis-generating rather than definitive.
The authors also noted that the rationale for upfront dose reduction was not systematically recorded. Patients who started at a reduced dose did not differ meaningfully in age, performance status, or Charlson comorbidity index from those treated at the standard dose, but renal impairment and diabetes were more common in the reduced-dose group. This suggests that specific organ dysfunction, rather than global vulnerability, may have informed dose selection.
Study Limitations
Several limitations should be considered. The study was retrospective, and reliance on medical records may have led to underreporting of adverse events compared with prospective trials. There was no central radiology review, meaning progression-free survival was based on investigator assessment. Detailed geriatric data were limited, and validated frailty assessments such as the G8 score were rarely available.
The reduced-dose subgroup was small, with only 12 patients, limiting the ability to make practical dosing recommendations. The rationale for upfront dose reduction was not recorded, and confounding by indication cannot be excluded. Baseline characteristics were also not fully balanced between age groups, with de novo metastatic disease and nonurothelial histology more frequent among younger patients.
Takeaway
EVOLUTE provides real-world evidence on enfortumab vedotin monotherapy in older patients with locally advanced or metastatic urothelial carcinoma. In this cohort, patients aged 70 years or older had preserved efficacy outcomes but experienced significantly more severe toxicity, more treatment interruptions, and more treatment discontinuations due to toxicity than younger patients.
Age 70 years or older was the only independent predictor of grade 3 or higher toxicity in the multivariable model. Upfront dose reduction was associated with fewer severe toxicities in a small subgroup, with no statistically significant difference in PFS or OS compared with standard dosing; however, this strategy requires prospective evaluation before it can be considered a definitive approach.
The findings support close monitoring of older patients receiving enfortumab vedotin and highlight the need for future studies that integrate geriatric assessment and evaluate dosing strategies in older adults with high comorbidity burden or reduced performance status.
The full article is available in Clinical Genitourinary Cancer.
Find more videos on OncoDaily YouTube TV.
