Treatment patterns and outcomes with second line (2L) therapies in patients (pts) with advanced urothelial carcinoma (aUC) previously treated with first line (1L) enfortumab vedotin (EV) with pembrolizumab (pembro).

676 Background: EV+pembro has significantly transformed 1L treatment of aUC and has become the standard of care. Treatment selection following progression on EV/pembro has emerged as an important clinical question. Currently, no prospective data are available evaluating outcomes of different therapies in this setting. Methods: This study used the US-based, electronic health record-derived deidentified Flatiron Health Research Database. Inclusion criteria: Pts who received 1L EV+pembro and had 2L therapy data available. The analytical cohort included pts diagnosed with aUC between 01/27/2017 and 01/22/2025, and initiated 2L therapy between 10/20/2021 and 06/26/2025. The data cut-off date was 06/30/2025. 2L treatment types were categorized as cisplatin-based therapy, carboplatin-based therapy, EV rechallenge, or other. Real-world overall survival (rwOS) was defined as the time from 2L initiation to death and was censored at the lost to follow-up according to structured activities. Real-world time to next therapy (rwTTNT) was defined as the time from 2L initiation to 3L initiation or death and was similarly censored at the lost to follow-up according to structured activities. Results: Among 15236 pts in the dataset, 757 received 1L EV+pembro and 118 pts who subsequently received 2L therapy were eligible and included in the analysis. Treatment distribution in 2L was: carboplatin-based regimens in 42 pts (35.0%), cisplatin-based therapy in 16 pts (13.3%), other regimens in 46 pts (38.3%), and EV rechallenge in 16 pts (13.3%). Most common regimens in other category included erdafitinib (11 pts, 24%), fam-trastuzumab deruxtecan (11 pts, 24%), sacituzumab govitecan (10 pts, 22%) and gemcitabine (7 pts, 15%). Median rwTTNT was 3 months (95% CI, 2.4 - NR) for cisplatin-based therapy, 4.7 months (95% CI, 2.8 - 7.5) for carboplatin-based therapy, 8.5 months (95% CI, 5.1 - NR) for EV rechallenge, and 3.9 months (95% CI, 3.3 - NR) for other regimens. Median rwOS was 8.3 months (95% CI, 2.4 - NR) for cisplatin-based therapy, 7.1 months (95% CI, 6.2 - NR) for carboplatin-based therapy, 8.5 months (95% CI, 5.3 - NR) for EV rechallenge, and 14.0 months (95% CI, 7.1 - NR) for other regimens. Baseline characteristics will be presented at the meeting. Conclusions: This is the largest real-world study to date evaluating treatment patterns and outcomes with various 2L therapies after progression on 1L EV+pembro in aUC. Platinum based therapies and antibody drug conjugates are the most common 2L therapies. Median rwOS and rwTTNT were modest across all treatment groups. These findings underscore the limited efficacy of current 2L options in the post EV+pembro setting, highlight the urgent need for novel therapies in this setting and provide survival estimates for future trial design and patient counseling.