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4574 Background: MTAP loss of function alt in aUC has been associated with poor prognosis. MTAP is an enzyme involved in the adenine salvage pathway and deficiency of the protein leads to susceptibility to antifolate agents, e.g., pemetrexed. MTAP loss has also been correlated with immunosuppressive tumor microenvironment, inducing a “cold tumor” that may be less responsive to ICI. Response and outcomes to ICI in pts with MTAP altered aUC need further assessment. We hypothesized that pts with MTAP altered aUC would have lower response and shorter survival on ICI. Methods: We used our database from 26 centers (US/Europe) of pts with aUC treated with ICI. We included pts with available NGS data who received ICI for aUC. We excluded pts with pure non-UC, treated with adjuvant ICI, ICI combinations, or on clinical trials. Outcomes (observed response rate [ORR], progression free survival [PFS] and overall survival [OS]) were compared in pts who received either 1st line [1L] or 2nd line and beyond [2+L] ICI with and without MTAP alt. We compared ORR using logistic regression; PFS and OS were compared using Kaplan-Meier and Cox proportional hazards. We separately describe outcomes in pts with MTAP alt who received avelumab switch maintenance. Results: 211 pts from 8 centers met inclusion criteria with available MTAP alt status; 174 received ICI as distinct aUC treatment line (16% had MTAP alt; n=28) either in 1L or 2+L setting; 37 pts received avelumab switch maintenance (19% had MTAP alt; n=7). Pts with known MTAP status were 72% men, 91% White, 72% pure UC, 25% upper tract UC, 64% ECOG PS 0-1, 56% visceral mets, 18% bone mets, 15% liver mets. Median follow up from starting ICI was 44 months [mo] (IQR 29-51). ORR to ICI (1L + 2+L) in pts with MTAP alt was 25% (95%CI 10-47) vs 47% (95%CI 39-55%) in pts without MTAP alt [OR 3.11 (95%CI 1.15-7.82)]. PFS for pts with MTAP alt was not significantly different vs pts without MTAP alt (median 3 vs 6 mo, respectively: HR 1.46 [95%CI 0.91-2.35]). OS was similar between groups (median 14 vs 15 mo, respectively: HR 0.93 [95%CI 0.53-1.63]). Table describes outcomes by ICI treatment line (1L, 2+L, maintenance) in pts with and without MTAP alt. Conclusions: In pts with aUC receiving ICI, the presence of MTAP alt was significantly associated with lower ORR and a trend towards shorter PFS compared to absence of MTAP alt. Limitations include retrospective nature, small sample size, selection/confounding biases, lack of randomization and central scan review. Findings need external validation and might inform discussion on the optimal therapy sequence in aUC. [Table: see text]