Clinical outcomes with immune checkpoint inhibitor and/or enfortumab vedotin in patients with MTAP-deleted metastatic urothelial carcinoma.

757 Background: MTAP-deletion(d) in urothelial carcinoma (UC) is associated with tumor aggressiveness, higher rates of metastasis, and treatment resistance. We investigated the impact of MTAP-d on treatment outcomes of metastatic UC (mUC) treated with checkpoint inhibitors (ICIs), enfortumab vedotin (EV), or EV/pembrolizumab (EV/P). Methods: We performed a retrospective analysis of 65 patients with mUC who underwent NGS assessment of MTAP status and were treated with first-line (1L) or 2nd+ line (2+L) ICI, EV, or EV/P between 2019 and 2025. Median treatment duration (mTD), median progression-free survival (mPFS), and objective response rate (ORR) were compared between patients with and without MTAP-d using Welch t-test, log-rank test and Cox proportional hazards, and Fisher’s test. Results: 25 patients with MTAP-d and 39 patients with MTAP-proficient(p) tumors were identified (ICI: 28 1L, 17 2+L; EV: 2 1L, 28 2+L; EV/P: 10 1L, 9 2+L). Median age was 68.5 (48 males; 16 females). FGFR3 co-alteration was seen in 24% of MTAP-d vs 10% of MTAP-p tumors (p = 0.2). Overall survival was significantly shorter in MTAP-d group (HR 2.1 95% CI 1.1-4.2, p = 0.04). In patients treated with 1L or 2+L ICI monotherapy (n = 45), mTD (2.1 vs 5.1 mo, p = 0.2), mPFS (HR 1.6 0.80-3.24, p = 0.2), and ORR (27.8% vs 35.7%, p = 0.53) were numerically lower but not significantly different in MTAP-d compared to MTAP-p. Among patients treated with 1L or 2+L EV monotherapy (n = 30), mTD (4 vs 7.2 mo, p = 0.04) and mPFS (HR 2.4 1.07-5.33, p = 0.02) were significantly shorter while ORR (6.7 vs 41.7%, p = 0.06) was numerically lower in the MTAP-d group. In patients treated with 1L or 2+L EV/P (n = 19), no significant difference in mTD (6.1 vs 5 mo, p = 0.6), mPFS (HR 1.78 95% CI 0.45-6.96, p = 0.3), or ORR (40% vs 35.5%, p > 0.99) was seen between MTAP-d and MTAP-p. Among MTAP-d patients, mPFS was numerically longer with EV/P compared to EV or ICI monotherapy (5.1 vs 3.7 vs 2.9 mo, p = 0.7). Conclusions: Our results suggest that MTAP-d is associated with inferior treatment outcomes among patients treated with ICI or EV as monotherapy. However, there was no significant difference in outcomes among patients with or without MTAP-d receiving EV/P, although findings are limited by the small cohort. Further evaluation of the impact of MTAP-d in patients treated with EV/P is ongoing. Impact of MTAP-d on the clinical outcomes of patients with mUC treated with immune checkpoint inhibitor and/or enfortumab vedotin. MTAP-d (n=25) MTAP-p (n=39) p-value ICI mTD, months IQR 2.1 0.9-7 5.1 2.9-10.3 0.1 mPFS, HR 95% CI 1.6 0.80-3.24 0.62 0.31-1.25 0.2 ORR (%) 27.8 35.7 0.53 EV mTD, months IQR 4 2.3-6.6 7.2 3.6-15.5 0.04 mPFS, HR 95% CI 2.4 1.07-5.33 0.42 0.19-0.94 0.02 ORR (%) 6.7 41.7 0.06 EV/P mTD, months IQR 6.1 3-9.6 5 3.4-6.1 0.6 mPFS, HR 95% CI 1.78 0.45-6.98 0.56 0.14-2.21 0.3 ORR, % 40 35.7 >0.99 a =0.05.