First-line therapies analysis in advanced/metastatic urothelial carcinoma: prognostic insights in ADCs combined therapy with propensity score analysis and RNA-Seq.

[BACKGROUND] Antibody-drug conjugates (ADCs) combined with immunotherapy show promise in treating advanced/metastatic urothelial carcinoma (a/mUC). This study assessed the efficacy, safety, and prognostic biomarkers of disitamab vedotin (DV) plus a PD-1 inhibitor compared to other first-line treatments without DV.

[METHOD] Patients with advanced UC received first-line treatment and were enrolled retrospectively from July 2021 to December 2023 in two cancer centers. Propensity score (PS) matching analysis was used to compare the DV group and the non-DV group. In the DV group, RNA-seq was performed to identify differentially expressed genes. Further molecular docking and cellular experiments were conducted to validate the findings.

[RESULT] A total of 97 patients were included. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 74.4 % and 49.7 %, respectively. PS score and first-line treatment regimen were independent prognostic factors for both OS and PFS. DV combined with a PD-1 inhibitor significantly improved PFS compared to chemotherapy alone, PD-1 inhibitor plus chemotherapy, and PD-1 inhibitor alone. DV combined with a PD-1 inhibitor also led to better OS compared to chemotherapy or PD-1 inhibitor alone, with a trend toward improved OS versus PD-1 inhibitor plus chemotherapy (P = 0.129). After PS matching, Significant differences were also observed between the DV and Non-DV groups in terms of objective response rate (77.5 % vs. 37.5 %), 1-year PFS rate (72 % vs. 22.2 %), and 1-year OS rate (84 % vs. 62 %). Differentially expressed genes were identified between patients in DV group with PFS ≥1 year and PFS <1 year. RNA-Seq analysis highlighted enriched pathways such as cytosolic and metabolic pathways, offering potential insights into DV resistance mechanisms. Then, we conducted PFS and OS analysis on the top 5 DEGs according to Log2FC. Finally, molecular docking, in vivo and in vitro experiments demonstrated that CPA2 might be a crucial key gene in DV-based regimen resistance.

[CONCLUSION] The first-line regimen of DV plus immunotherapy for patients with advanced UC was more effective and safer than the regimen without DV. Additionally, CPA2 might be a crucial key gene correlated with resistance to DV-based regimens.