Background: SG, a Trop-2–directed antibody-drug conjugate, was granted FDA accelerated approval for pts with mUC previously treated with PT-based chemotherapy and a CPI. Approval was based on the pivotal TROPHY-U-01 Cohort 1 study of 113 pts, where SG demonstrated an objective response rate (ORR) of 27%, a median overall survival (OS) of 10.9 mo, and a manageable safety profile (median follow up 9.1 mo [range, 0-19.9], Tagawa et al. JCO 2021). A phase 3 confirmatory study TROPiCS-04 (NCT04527991) is ongoing. Here, we report updated safety outcomes by UGT1A1 status. Methods: Cohort 1 pts were ≥18 y, had progression of UC following PT and a CPI, and ECOG PS 0-1. Pts received SG 10 mg/kg on D1 and D8 of 21-D cycles (growth factor was allowed per investigator discretion). The primary endpoint was ORR per central review by RECIST 1.1. Post hoc safety analyses were exploratory with descriptive statistics reported. Results: As of July 26, 2022, the median follow-up was 10.5 mo (range, 0.3-40.9) for treated pts (N=113). As previously reported, pts were heavily pretreated with a median of 3 prior therapies (78% male; median age 66 y; 66% with visceral metastases). Known baseline comorbidities included chronic kidney disease (12%), coronary artery disease (10%), myocardial infarction (8%), and diabetes mellitus II (8%). Grade (Gr) ≥3 treatment-related adverse events (TRAEs) occurrence and treatment-related discontinuation were consistent with prior reports. In total, 94% of treated pts (n=106) had evaluable UGT1A1 status (wild-type [*1|*1], n=45 [42%]; heterozygous [*1|*28], n=47 [44%]; and homozygous [*28|*28], n=14 [13%]). Gr ≥3 TRAEs occurred in 62% of wild-type, 60% of heterozygous, and 79% of homozygous pts. The incidence of treatment-related any Gr diarrhea was 53%, 72%, and 71%, respectively; any Gr neutropenia was 38%, 55%, and 50%, respectively; and any Gr anemia was 38%, 32%, and 29%, respectively. The incidence of treatment-emergent Gr ≥3 diarrhea was 4%, 15%, and 7%, respectively; Gr ≥3 neutropenia was 31%, 36%, and 50%, respectively; and Gr ≥3 anemia was 13%, 19%, and 29%, respectively. TRAEs led to SG discontinuation in 7%, 6%, and 14% of pts with wild-type, heterozygous, and homozygous status, respectively; incidence of SG interruption was 42%, 43%, and 71%, respectively and incidence of SG dose reduction was 38%, 34%, and 43%, respectively. Conclusions: With longer follow-up, SG safety profile was consistent with prior reports. The incidence of adverse events varied across UGT1A1 subgroups, with dose interruptions being more frequently observed in homozygous pts. This was an exploratory analysis with relativity low numbers in each subgroup. Additional studies are needed to confirm the impact of UGT1A1 status on safety outcomes with SG in UC. Clinical trial information: NCT03547973.