Background: Despite advances in therapeutic strategies, advanced BTC continue to have poor outcomes. We examined the genomic composition of these cancers and differences in clinical outcomes based on therapies (tx) received. Methods: This study included all BTC patients (pts) undergoing comprehensive genomic profiling (CGP) through an Australia-wide precision oncology program, MoST (ACTRN12616000908437). The primary outcome was overall survival (OS) measured from start of first line (1L) systemic tx. The TOPOGRAPH knowledge base was used to determine genomic actionability of alterations identified, tiered by the strength of supportive clinical evidence. Tier 1/2 are regulatory body (TGA or FDA/EMA) approved therapies in BTC; tier 3A is supported by BTC-specific clinical evidence; 3B by clinical evidence inferred from another cancer type; tier 4, pre-clinical evidence. As targeted therapies are only approved in the subsequent-line setting, a further OS analysis was performed from start of second line tx (2L). Results: Between December 2016 and August 2022, 223 pts had CGP results available: 170 cholangiocarcinoma (99 intrahepatic, 46 extrahepatic, 25 unspecified primary site) and 53 gallbladder carcinomas. Of 211 (95%) pts who received any systemic tx, median OS (mOS) was 14.6 (95% CI: 12.2—15.4) months (mo) from the start of 1L tx. Pts having received immunotherapy had a mOS of 20.7 vs 13.9 mo (HR 0.67, 0.44—1.04; p=0.07). For 198 pts with actionable findings across TOPOGRAPH tiers, receipt of matched tx (n=37) was associated with a significantly longer mOS of 21.4 (15.0—31.8) compared with receipt of unmatched tx (n=161), mOS 12.6 mo (11.5C15.2, hazard ratio for death, HR 0.46, p<0.001). Pts with tier 1-3 actionable alterations who received matched tx had a median OS of 30.5 mo (95% CI: 18.8 - not reached, NR) compared with 12.1 mo (9.8—16.1, HR 0.39, p=0.02) if only unmatched tx received. Receipt of tier 3B/4 matched tx (n=13) only showed a trend towards longer survival, 15.6 mo vs unmatched 14.0 mo (HR 0.60, p=0.16). For 149 pts who received >1 line of systemic tx: 35 matched and 103 unmatched alone, mOS (measured from 2L tx) was 11.3 (5.7-28.4) compared with 8.3 mo (6.1-10.6) respectively (HR 0.67, p=0.10). A significantly longer OS was seen for matched vs unmatched, in pts receiving tier 1-3 tx: mOS 19.0 mo vs 8.3 mo (HR 0.43, p=0.04), but not for tier 3B/4, mOS 5.6 vs 6.7 mo HR 1.31, p=0.48. The most common genomic alterations were in TP53 (86, 39%), KRAS (59, 26%), CDKN2A (43, 19%), and ARID1A (29, 13%), while actionable findings commonly involved IDH1 (26, 12%), FGFR2 (20, 9%), ERBB2 (14, 6%), and BRAF (11, 5%). Conclusions: Receipt of genomically matched tx, particularly those supported by TOPOGRAPH tiers 1-3 evidence was associated with longer OS for pts with advanced BTC. Our results support the greater use of CGP in the management of these pts.