Homologous recombination repair gene alterations and outcomes with enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma.

829 Background: Enfortumab vedotin plus pembrolizumab (EV-P) represents the standard of care first-line therapy for patients with metastatic urothelial carcinoma (mUC). Homologous recombination repair (HRR) gene alterations are known to confer sensitivity to platinum-based regimens; however, their impact on outcomes in patients treated with EV-P remains elusive. Methods: We retrospectively identified patients with mUC treated with EV–P at the Oncology Institute of Southern Switzerland between December 2023 and August 2025. Targeted sequencing was performed on diagnostic FFPE tissue samples using the Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific). Clinical data, including objective response rate (ORR) and progression-free survival (PFS) on EV-P (PFS1) and on subsequent platinum-based chemotherapy (PFS2), were extracted from electronic medical records. Results: Nineteen patients received EV–P during the study period. Median age was 74.6 years; 42.1% had primary upper tract tumors; 68.4% had visceral metastases; median follow-up was 7.6 months. Six patients (31.6%) carried HRR-associated alterations: 4 carried BRCA mutations, 1 FANCA and 1 FANCD2 pathogenic variants. All patients received EV–P as first-line therapy, followed by second line carboplatin–gemcitabine in eligible patients. No patients with HRR-altered tumors achieved an ORR to EV-P versus 63.6% in patients with HRR–wild-type tumors (p = 0.034), including three complete responses. Median PFS1 was numerically shorter for the first group (4.3 vs 10.7 months, HR: 3.54, 95% CI: 0.83-15.09 p = 0.0874). Two patients without HRR alterations received second-line carboplatin–gemcitabine and had a PFS2 of 2 and 4 months, shorter than those observed in the three HRR-altered patients who received the same regimen (5, 9, and 14 months, respectively). Among them, the two BRCA2-mutated patients achieved longer PFS on platinum-based chemotherapy (9 and 14 months) than during EV–P treatment (≤6 months). Conclusions: In this small, single-institution retrospective cohort, HRR gene alterations were associated with lower ORR and shorter PFS under first-line EV–P. Patients with BRCA2-mutated tumors had a longer response with second-line platinum-based chemotherapy than with first-line EV-P. These findings require validation in larger cohorts and prospective trials. Characteristic HRR-altered, N=6 Others, N = 13 Median age, y (range) 71.5 (61-80) 76 (60-83) Male sex, n (%) 5 (83.3) 11 (84.6) Primary bladder cancer, n (%) 3 (50.0) 8 (61.5) Prior local treatment, n (%) 3 (50) surgery; 1 (16.7) trimodal 6 (46.2) radical surgery ECOG PS (0 / 1 / ≥2), n (%) 3 (50.0)/ 3 (50.0)/ 0 (0.0) 7 (53.8%)/ 4 (30.8)/ 2 (15.4) Visceral metastasis, n (%) 4 (66.7) 9 (69.2) Other somatic gene alterations, n FGFR3: 0ERBB2: 1CDKN2A/B: 0TERT: 3TP53: 4ARID1A: 0RB1: 1 FGFR3: 1ERBB2: 2CDKN2A/B: 0TERT: 4TP53: 2ARID1A: 3RB1: 0