1772P Characterisation of a DNA Repair Deficiency (DRD) Biomarker Phenotype in Metastatic Urothelial Carcinoma (muc) Within the ATLANTIS Clinical Trial Platform

A subset of mUC exhibits a DRD phenotype predicting benefit from platinum based chemotherapy (PBC). We previously reported switch maintenance therapy with the PARP inhibitor rucaparib, following PBC, in patients with mUC harbouring a DRD biomarker. Rucaparib extended progression free survival (Crabb et al, J Clin Oncol 40, 2022 (suppl 6; abstr 436)). We undertook an exploratory analysis of the phenotypic and genomic characteristics of the DRD biomarker allocated cohort, involving all patients from the ATLANTIS clinical trial where next generation sequencing (NGS) was possible. DRD biomarker allocation was performed using the FoundationOne NGS assay of over 300 cancer related genes. Biomarker positive status was based on high (≥10%) percentage genome wide loss of heterozygosity (%LOH) and/or somatic alteration within defined DRD associated genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L) and/or germline mutations in BRCA1 or BRCA2. Somatic alterations were analysed using Maftools and survival outcomes by logrank testing. 248 patients were screened for DRD biomarker status and biomarker allocation was possible in 194 (78%). 78/194 (40%) were biomarker positive with 20/78 (26%) due to a gene alteration, 47/78 (60%) by high %LOH and 11/78 (14%) both. Median overall survival from commencing PBC in biomarker defined patients was 95.6 weeks (95% CI 71.0-127) in biomarker positive versus 70.1 weeks (95% CI 52.4-102) in biomarker negative patients (p=0.07). Mean tumour mutational burden was greater in DRD biomarker positive patients (p=0.003). KAT6A (odds ratio (OR) 7.3, p=0.008), TERC (OR Inf, p=0.010, AKT2 (OR 9.4, p=0.02) and FGFR3 (OR 0.43, p=0.04) were differentially altered with respect to biomarker positive versus negative groups, although none retained significance after false discovery rate correction (n=43 genes mutated in at least 5 samples). DRD biomarker positive mUC was associated with higher tumour mutational burden. Trends were also found for extended overall survival following PBC and differential somatic gene alteration status.