Cancer Care · global
Padcev Enters the Real World: One in Four Patients With Advanced Urothelial Cancer Experiences Severe Toxicity
A retrospective study of 770 people across 17 countries found that skin reactions, neuropathy, and diarrhea were the most common severe adverse events associated with enfortumab vedotin; beyond efficacy, early recognition of toxicity is becoming key to maintaining treatment.
The antibody-drug conjugate enfortumab vedotin (brand name Padcev) has changed treatment options for advanced urothelial cancer. But when the drug moves beyond rigorously selected clinical trials and into routine care involving patients with more complex ages and health conditions, large-scale data on how much toxicity patients experience have remained lacking. The ARON-2EV study, published in *Scientific Reports*, provides a multinational real-world picture of this issue.
The research team retrospectively analyzed 770 patients with locally advanced or metastatic urothelial cancer treated at 50 oncology centers across 17 countries. After receiving platinum-based chemotherapy and immune checkpoint inhibitors, these patients received enfortumab vedotin monotherapy between January 2022 and April 2025. The median age was 70 years, and 76% were men.
A total of 195 people, approximately 25%, experienced grade 3–4 adverse events. Severe skin toxicity was the most common, occurring in 10%, followed by neuropathy in 9% and diarrhea in 7%. The study also recorded one case each of Stevens–Johnson syndrome and toxic epidermal necrolysis, underscoring that medical teams cannot uniformly regard early rashes as minor side effects.
Toxicity also materially altered the course of treatment: 74 people, approximately 10%, discontinued treatment because of severe adverse events, with skin reactions and neurotoxicity being the main reasons. The study found no significant association between severe toxicity and sex, age, body mass index, primary tumor location, or the platinum-containing drug previously used. It therefore remains difficult to identify high-risk patients in advance based solely on basic clinical characteristics.
Median overall survival and progression-free survival appeared longer among patients who started at the standard dose than among those who began treatment at a reduced dose. However, this was a nonrandomized, retrospective comparison; frailer patients or those with more comorbidities may have been more likely to start at a lower dose, so the findings cannot establish that dose reduction itself caused worse outcomes. Patients who underwent subsequent dose reduction initially showed better survival, but this advantage weakened or disappeared in a landmark analysis that adjusted for differences in treatment duration, also suggesting that the ability to remain on treatment longer may itself introduce bias.
Background Context
Enfortumab vedotin targets Nectin-4, delivering a microtubule-disrupting cytotoxic drug into tumor cells. In recent years, its combination with pembrolizumab has moved from advanced disease into the care of earlier-stage, still-operable bladder cancer. Although this study focused on patients receiving monotherapy after platinum-based chemotherapy and immunotherapy, the accumulated experience in managing skin and neurological toxicities may still influence clinical arrangements as the use of such therapies expands.
Overall, the study identified no new safety signals, and its toxicity profile was broadly consistent with that described in existing trials. However, its retrospective design, differences in management practices among centers, and the availability of complete dose-adjustment data for only 580 people limit causal inference. The paper is also currently a prepublication version awaiting editing. The clearest message from these data is not that the drug carries unexpected risks, but that skin reactions, sensory abnormalities, and diarrhea, if not managed early, can cause an effective treatment to be discontinued prematurely.