Response to platinum-based therapy (PBT) and immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC) patients (pts) with genomic alterations (GA) in homologous recombination repair (HRR) genes.
447 Background: Deleterious GA in genes of the HRR pathway and tumor mutational load (TML; mutations/Mb) were shown to predict response to PBT and ICI; further validation can be informative. We assessed the predictive role of such GA in mUC. Methods: Tissue from mUC pts treated with PBT or ICI in the 1st line setting underwent genomic profiling (GP) via FoundationOne. Pts were analyzed in 2 groups based on the presence of potentially function-impairing GA (using classification criteria) in any of 15 pre-selected HRR genes. Exploratory assessment of overall response rate (ORR; RECIST v1.1), progression-free and overall survival (PFS, OS) based on presence of relevant GA was performed using Cox proportional hazards model, Kaplan Meier estimates, and Fisher’s exact test. Results: GA were noted in 22% of 88 identified mUC pts with available GP from 2012 to 2017. The most common deleterious GA were BRCA1/2 (n=6), ATM (n=6), CDK12 (n=2), BRIP1 (n=2), BARD1 (n=1), RAD51 (n=1), and CHEK2 (n=1). Of 88 pts, 62 were treated in the 1st line setting (median age 69; 27% women; 42% never smokers). Of these 62 pts, 42 received PBT and 20 ICI. Deleterious GAs were noted in ≥1 HR gene in 24% and 10% of pts in each group, respectively. The ORR was 40% and 43% in PBT pts with and without GA in any HRR gene, respectively. Analysis showed a median OS (10.6 vs 14.3 months, p=0.11), median PFS (6.1 vs 7.9 months, p=0.05), and no difference in the rate of responders vs non-responders (p=0.53) to PBT in pts with vs without GA in HRR genes. Analysis of ICI treated pts was not feasible (only 2 had GA in HRR genes). Median TML was 8 and 10 in pts with available data treated with PBT and ICI, respectively. There was no correlation between TML and response to either 1st line therapy (analysis underpowered). Of pts with GA in HR genes, the one with the longest OS had 2 GA (CDK12; FANCA). Conclusions: Deleterious GAs in genes of HRR pathway are frequent in mUC supporting TCGA and other datasets but did not confer sensitivity to 1st line PBT in our relatively small cohort. Further biomarker validation combined with LOH assessment can inform decision making and clinical trial designs.