The patients have spoken: how does enfortumab vedotin impact quality of life?

Introduction

Antibody-drug conjugates have improved outcomes in many cancers. In advanced urothelial carcinoma (aUC), enfortumab vedotin (EV), a nectin-4 targeting antibody-drug conjugate has received regulatory approval in the United States and Europe both as a single agent in refractory aUC and as a front-line treatment for aUC in combination with pembrolizumab. These approvals were based on superior efficacy compared to prior standard of care regimens in the EV-301 and EV-302 studies, respectively (1,2). The EV-301 study randomized patients with aUC who previously received platinum-containing chemotherapy and an anti-programmed death-1 (PD-1) or anti-programmed death ligand 1 (PD-L1) immune checkpoint inhibitor to either EV or investigator selected chemotherapy, either docetaxel, paclitaxel, or vinflunine. The EV-301 trial met its primary endpoint of improved overall survival (OS), with the most recently reported hazard ratio (HR) =0.74 [95% confidence interval (CI): 0.581–0.852; P=0.00015] (3).

Safety and efficacy were not the only outcomes measured in the EV-301 study. The recently published manuscript in European Urology by Rosenberg et al., reports results of a prespecified secondary endpoint of patient-reported outcomes (PROs) in the EV-301 clinical trial (4). This editorial aims to provide context by summarizing the available literature regarding quality of life analyses in urothelial carcinoma and explore the value and shortcomings of this tool in patients with urothelial carcinoma.

PROs from EV-301

In Rosenberg et al., PRO data were prospectively collected at regular intervals via two patient-reported surveys. The first questionnaire was the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), a 30-question survey that addresses both role, physical, emotional, social and cognitive functioning and symptoms, including fatigue, pain, dyspnea, nausea, vomiting, diarrhea, constipation, appetite loss, and insomnia. The other questionnaire was the EuroQol 5-dimension 5-level (EQ-5D-5L) survey that asks patients to rate mobility, self-care, usual activities, pain/discomfort, and anxiety/depression on a 5-point scale from no problems to extreme problems (4).

Rosenberg et al. reported high patient baseline compliance rates with these surveys, 91% in the EV arm and 89% in the chemotherapy arm, although these decreased to average rates of 70% and 67% over the course of the study, respectively. There were no reported significant differences in the EORTC QLQ-C30 functioning scales between the two arms, although physical and role functioning were numerically superior in the EV arm. In regard to the symptom scale, pain was statistically improved in the EV arm (HR =−5.7; 95% CI: −10.8 to −0.7; P=0.027). Conversely, appetite loss was worse in the EV arm (HR =7.3; 95% CI: 0.9–13.7; P=0.026).

Two additional analyses were performed using the EORTC QLQ-C30 data in this study. In responder analysis, clinically meaningful improvement in the majority of categories, including all QLQ-C30 functioning scales, was observed in the EV arm compared to chemotherapy arm. The greatest difference was observed in improvement in pain [odds ratio (OR) =2.76; 95% CI: 1.81–4.22], favoring the EV arm. In time to event analysis, clinically meaningful improvement in overall global health status/quality of life (GHS/QoL) was achieved sooner in the EV arm compared to the chemotherapy arm (HR =1.43; 95% CI: 1.00–2.05). Improvement in pain (HR =2.03; 95% CI: 1.45–2.84; P<0.001) and fatigue (HR =1.98; 95% CI: 1.35–2.91; P<0.001) were observed as well. EV also delayed the first clinically meaningful deterioration compared to chemotherapy, with reported median time to deterioration 5.4 months in the EV arm and 2.3 months in the chemotherapy arm (HR =0.75; 95% CI: 0.58–0.97).

The value of PROs

This analysis from EV-301 underscores the importance of PROs to supplement efficacy analyses of potentially practice-changing clinical trials. Certain data including symptoms not evident to observers, such as fatigue or pain, frequency and severity of symptoms, and the effects of the symptoms on patients can only be obtained from patients themselves (5). PRO instruments convert these subjective, often multidimensional reports into measurable outcomes (6). The United States Food and Drug Administration has given guidance into use of PROs to support claims in medical product labeling, stating that PRO instruments should be reliable, valid, and able to detect changes (7,8). The EORTC QLQ-C30, the main PRO used in the EV-301 clinical trial meets all three characteristics and has been found to be prognostic independent of potential confounding factors (9,10).

EV symptoms

The most notable symptom that improved with EV compared to chemotherapy was pain. Many patients with aUC experience pain, and one study showed patients with aUC refractory to cisplatin-based chemotherapy, pain scores were significantly higher compared to recurrent/metastatic cancers with other sites of origin (46.5 vs. 33.7, P<0.001) (11). Moreover, another retrospective study found that as many as 64% of patients with aUC required at least one opioid for pain management, compared with 19% of matched non-cancer controls (12). Not only is pain a significant symptom of patients with aUC, but it is also a poor prognostic factor. A post-hoc analysis of the iBlad study of PROs in bladder cancer found that high pain scores significantly correlated with worse OS than low pain scores (HR =3.06; 95% CI: 1.46–6.43) in the metastatic setting (13). Plausibly, improvement in pain with EV likely correlates with improved survival outcomes but also is a critical factor in improved quality of life for patients with aUC on the treatment.

One symptom not addressed by the QLQ-C30 is peripheral neuropathy. In the EV-301 trial, peripheral sensory neuropathy was reported in 33.8% of patients on the EV arm compared to only 21.3% of patients on the control arm, with 3.0% of patients experiencing grade ≥3 neuropathy on the EV arm compared to 2.1% in the control arm (1). This neuropathy rate was less than the 40% of patients who experienced neuropathy in the EV-201 clinical trial (14) or 50% of patients on the EV plus pembrolizumab who experienced neuropathy in the EV-302 study (2). This discrepancy could be either due to underreporting or due to the fact that neuropathy is a late toxicity, with median onset of 2.81 months (95% CI: 0.03–13.04) in EV-301 (3), which would not manifest in patients with refractory advanced cancer who progress sooner than on earlier lines of treatment. This peripheral neuropathy can be potentially debilitating, manifesting as muscle weakness and impairing ability to perform independent tasks of daily living. Nonetheless, this could have been reflected in PROs, as the QLQ-C30 instrument included assessment of physical and role functioning, which trended toward superior for EV compared to chemotherapy in this analysis of PROs from EV-301, further supporting use of EV in this patient population (4).

Stability of quality of life

A remarkable result from the EV-301 PRO analysis was the relative stability of GHS/QoL scores over time for EV, at least over the first 12 weeks of treatment. Whereas this score decreased each week following chemotherapy infusion, each EV treatment had less impact on GHS/QoL. This likely reflects the predictable timing of some chemotherapy side effects, including nausea and fatigue. Conversely, the timing and duration of EV side effects are less regular. Given this stability in GHS/QoL from week to week, there would not be much difference expected between the days 1, 8, and 15 dosing scheme in EV-301 and the days 1 and 8 dosing scheme seen in combination with pembrolizumab in the EV-302 clinical trial.

Due to the aggressive nature of aUC, the number of patients receiving therapy decreases with each line of treatment. One analysis found that among patients with aUC who received frontline therapy, only 37.4% of patients received a second-line therapy and 11.8% had more than two lines of therapy (15). Therefore, especially for patients with refractory aUC, selection of treatment is important. Given the palliative intent of treatment in this setting, optimization of quality of life is critical. This underlies the importance of PRO analyses, especially as EV is approved in earlier lines of therapy and potentially in localized disease in the future. Based on this analysis of the EV-301 study discussed here, not only does EV have superior survival outcomes but also improves quality of life compared to previously approved chemotherapy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-45/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-45/coif). J.R.B. has served on advisory boards for Pfizer, EMD Serono, and Johnson & Johnson. He is also on a speakers’ bureau for Merck. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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