DNA damage repair alterations as predictive biomarker for platinum-based chemotherapy in metastatic urothelial cancer.

853 Background: DNA damage repair gene alterations (DDRa), especially ERCC2 mutations, have been associated with improved clinical outcomes in patients with urothelial cancer (UC) treated with cisplatin-based neoadjuvant chemotherapy. The predictive value of DDR alterations for platinum-based chemotherapy in metastatic disease is not well-defined. Methods: We analyzed the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative consortium (BPC), including patients with UC treated at 4 academic centers in North America between 2013 and 2018, with Next Generation Sequencing (NGS) data available. We assessed overall survival among patients treated with first line platinum-based chemotherapy for metastatic UC, and compared the outcomes based on DDRa status using Cox models adjusted with risk-set adjustment for delayed entry. DDRa were defined as any mutation defined as “likely oncogenic” or “oncogenic” in OncoKB for the genes ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, ATM, ATR, RAD51C and FANCC . Results: Of 716 patients with UC, 103 (14%) had any DDRa, and 32 (4.5%) had an ERCC2 mutation. Among 566 patients (79%) who developed metastatic disease at any time during follow up, median age was 66 years, 22% were female and 25% had upper tract UC. The median overall survival (mOS) from diagnosis of metastatic disease was 15.1 months (95% CI 12.6-18.6). For patients treated with first line platinum-based chemotherapy (n=258), the presence of DDRa was associated with significantly improved mOS compared with absence of DDRa: 22.7 versus 11.2 months, hazard ratio (HR) 0.54 (95% CI 0.34-0.86, p=0.009). Similar trends were seen when analyzing patients treated with cisplatin or carboplatin, separately. Conclusions: DDRa were associated with improved survival in metastatic UC patients treated with platinum-based chemotherapy. Further studies are needed to explore the prognostic and predictive value of DDRa as the role of platinum-based chemotherapy evolves in the enfortumab vedotin and pembrolizumab era. DDRa No DDRa First Line treatment for metastatic UC N Median OS months (95% CI) N Median OS months (95% CI) HR (95% CI) P value Any platinum-based chemotherapy 32 22.7 (14.5, 66.9) 226 11.2 (9.4, 15.1) 0.54 (0.34, 0.86) 0.009 Cisplatin-based chemotherapy 22 25.9 (14.5, NR) 142 13.6 (10.4, 18.8) 0.57 (0.32, 1.01) 0.06 Carboplatin- based chemotherapy 10 17.4 (7.26, NR) 84 9.9 (6.6, 12.7) 0.53 (0.25, 1.17) 0.12 CI= Confidence interval; DDRa= DNA damage repair alteration; HR=Hazard ratio; NR=Not reached; OS= Overall survival; UC= Urothelial Carcinoma.