BACKGROUND: Recently, a plethora of novel systemic agents have been incorporated into the therapeutic armamentarium of advanced urothelial carcinoma (aUC). The antibody-drug conjugate (ADC), enfortumab vedotin (EV), has demonstrated relevant clinical benefit in patients with aUC refractory to platinum and immune-checkpoint inhibitor (ICI) therapy. Our study provides a retrospective, international, real-world analysis comparing the effectiveness of EV to chemotherapy in this setting. METHODS: The data were extracted from the medical records of patients treated with EV or chemotherapy following pembrolizumab for recurrent or progressive aUC after platinum-based chemotherapy. Patients were assessed for overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and duration of response (DoR). RESULTS: Our analysis included 247 patients treated with EV (88, 36%) or chemotherapy (159, 64%). Median OS was 9.1 months (95%CI 7.2-10.7) in the overall study population, 13.6 months (95%CI 10.0-31.0) in patients receiving EV and 6.8 months (95%CI 6.0-8.9) in patients receiving chemotherapy (p < 0.001). The OS benefit of EV was not affected by primary tumour site and histology, metastatic sites, type of first platinum-based chemotherapy or response to pembrolizumab. In the EV cohort, the median PFS was significantly longer (8.8 months [95%CI 6.5-17.0] vs. 3.0 months [95%CI 2.6-3.7]) and the ORR was significantly higher (56% vs. 23%) than in the chemotherapy cohort. CONCLUSIONS: The results of our international analysis of real-world data confirm the effectiveness of EV in the sequential strategy of aUC patients who have received prior platinum-based chemotherapy and anti-PD-1 pembrolizumab, regardless of commonly considered prognostic factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05290038.

• Keywords
• ARON‐2 study, NCT05290038, chemotherapy, enfortumab vedotin, pembrolizumab, real‐world data, sequencing, urothelial carcinoma,
• MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   administration & dosage   MeSH
• Immunoconjugates * therapeutic use   administration & dosage   adverse effects   MeSH
• Carcinoma, Transitional Cell * drug therapy   mortality   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Antibodies, Monoclonal * therapeutic use   administration & dosage   MeSH
• Urinary Bladder Neoplasms * drug therapy   mortality   pathology   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Urologic Neoplasms * drug therapy   mortality   pathology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Names of Substances
• enfortumab vedotin MeSH Browser
• Antibodies, Monoclonal, Humanized MeSH
• Immunoconjugates * MeSH
• Antibodies, Monoclonal * MeSH
• pembrolizumab MeSH Browser

The addition of metastasis-directed radiotherapy (MDRT) to immunotherapy in patients with advanced urothelial carcinoma (aUC) has shown promising results. We report the real-world data from the ARON-2 study (NCT05290038) on the impact of conventional (CRT) or stereotactic body radiotherapy (SBRT) on the outcome of aUC patients receiving pembrolizumab after platinum-based-chemotherapy. Medical records of 837 patients were reviewed from 60 institutions in 20 countries. Two hundred and sixty-two patients (31%) received radiotherapy (cohort A), of whom 193 (23%) received CRT and 69 (8%) received SBRT. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. With a median follow-up of 22.7 months, the median OS was 10.2 months, 6.8 months and 16.0 months in no RT, CRT and SBRT subgroups (p = 0.005), with an 1y-OS rates of 47%, 34% and 61%, respectively (p < 0.001). The 1y-OS rate in the SBRT subgroup were significantly higher for both lower (63%) and upper tract UC (68%), for pure urothelial histology (63%) and variant histologies (58%), and for patients with bone (40%) and lymph-node metastases (61%). Median PFS was 4.8 months, 9.6 months and 5.8 months in the CRT, SBRT and no RT subgroups, respectively (p = 0.060). The 1y-PFS rate was significantly higher (48%) in the SBRT population and was confirmed in all patient subsets. The difference in terms of ORR was in favour of SBRT. Our real-world analysis showed that the use of SBRT/pembrolizumab combination may play a role in a subset of aUC patients to increase disease control and possibly overall survival.

• Keywords
• ARON-2 study, Pembrolizumab, Radiation therapy, Real-world data, Stereotactic radiation therapy, Urothelial carcinoma,
• MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   administration & dosage   MeSH
• Carcinoma, Transitional Cell therapy   pathology   mortality   drug therapy   MeSH
• Combined Modality Therapy MeSH
• Middle Aged MeSH
• Humans MeSH
• Urinary Bladder Neoplasms therapy   pathology   mortality   drug therapy   MeSH
• Antineoplastic Agents, Immunological therapeutic use   MeSH
• Radiosurgery methods   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Urologic Neoplasms pathology   mortality   therapy   drug therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Names of Substances
• Antibodies, Monoclonal, Humanized * MeSH
• pembrolizumab MeSH Browser
• Antineoplastic Agents, Immunological MeSH