Bone metastases in advanced urothelial carcinoma patients receiving enfortumab vedotin: A Real-World study from the ARON-2^EV project

Enfortumab vedotin (EV) has been approved for the treatment of metastatic urothelial carcinoma (mUC), either as monotherapy or in combination with immune checkpoint inhibitors, following results of recent practice-changing clinical trials. However, limited data exist regarding patients with bone metastases, leaving a critical gap in knowledge regarding the efficacy of EV in this subgroup. The study aimed to evaluate the impact of bone metastases on survival outcomes in patients with mUC treated with EV using data the ARON global real-world retrospective database, thereby addressing an important unmet clinical need. A total of 201 mUC patients with bone metastases and 377 without bone metastases who were treated with EV were analyzed from the ARON-2EV dataset. The coprimary endpoints were overall survival (OS) and progression-free survival (PFS) in mUC patients with and without bone metastases. Secondary endpoints included OS and PFS among patients with bone metastases who received versus did not receive radiotherapy or bone-targeted agents. The median OS was 11.2 months (95% CI 8.34–15.04) and 12.4 months (95% CI 10.71–15.21) in mUC patients with and without bone metastases, respectively. The median PFS was 6.0 months (95% CI 5.72–6.9) and 7.6 months (95% CI 6.6–8.24), respectively. No statistically significant difference in OS was observed between two groups (HR 1.16; 95% CI 0.9–1.5; p = 0.251), while patients without bone metastases had significantly longer PFS (HR 1.26; 95% CI 1.01–1.57; p = 0.0442). No significant survival differences were observed among patients with bone metastases based on receipt of radiotherapy or bone-targeted agents. In multivariate analyses, concomitant mixed histology and lung metastases were associated with shorter OS, while lung metastases and current smoking were associated with shorter PFS. This real-world analysis identified clinical factors associated with poorer outcomes in mUC patients with bone metastases treated with EV, including histology subtype, lung metastases, and smoking status. Further multicentric translational studies are warranted to validate these findings and to better understand the biologic mechanisms underlying limited EV efficacy in bone-metastatic disease.