ASCENT-03: Efficacy by biomarker subgroup with sacituzumab govitecan (SG) vs chemotherapy (chemo) in participants (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are not candidates for PD-(L)1 inhibitors (PD-[L]1i).

1014 Background: SG demonstrated significant and clinically meaningful progression-free survival (PFS) improvement vs chemo in pts with previously untreated, locally advanced unresectable or metastatic TNBC who were not candidates for PD-(L)1i in ASCENT-03 (NCT05382299). We report preplanned exploratory efficacy analyses in ASCENT-03 by Trop-2 expression, BRCA status, and HER2 expression. Methods: 588 pts randomized 1:1 to SG or chemo (taxane or gemcitabine + carboplatin). Trop-2 expression was measured by immunohistochemistry (IHC), tumor BRCA (tBRCA) status by whole exome sequencing, and HER2 expression by in situ hybridization (ISH) and IHC, all in centrally tested tumor samples (fresh or archival; 43% from metastatic sites). Pts were subgrouped by Trop-2 expression quartile, tBRCA wild-type (WT) or mutant (mut; mut in BRCA1, BRCA2, or both) status, and HER2 status (IHC 0 vs Low [IHC 1+ or IHC 2+/ISH-]). Biomarker status was analyzed to determine association with PFS by blinded independent central review (BICR). Other efficacy outcomes by biomarker status will be presented. Results: Median Trop-2 H-score: 240; H-scores by quartile (Q): Q1 0-184, Q2 185-239, Q3 240-283, Q4 284-300. Trop-2 expression was available in 499 pts. PFS by BICR was longer with SG vs chemo in all Trop-2 expression quartiles (Table). Hazard ratio (HR; 95% confidence interval [CI]) was 0.54 (0.35-0.84) in Q1, 0.62 (0.40-0.97) in Q2, 0.84 (0.54-1.31) in Q3, and 0.60 (0.38-0.95) in Q4. tBRCA status was available in 423 pts; proportion of pts with tBRCA mutations was comparable between treatment groups (~18%). PFS was longer with SG vs chemo in tBRCA WT and mut subgroups, with HR (95% CI) 0.70 (0.54-0.92) in tBRCA WT and 0.59 (0.32-1.09) in tBRCA mut. HER2 status was available in 551 pts; PFS was longer with SG vs chemo in both HER2 subgroups. HR was 0.63 (0.46-0.85) in the IHC 0 subgroup and 0.74 (0.55-1.01) in the HER2 Low subgroup. Conclusions: PFS was longer with SG vs chemo across all Trop-2 categories, tBRCA genotypes, and HER2 subgroups. These results reinforce the significant, clinically meaningful benefit of SG as first-line treatment for pts in this population across multiple biomarker subgroups. Clinical trial information: NCT05382299 . Efficacy, BICR N Median PFS (95% CI), months Biomarker Subgroup SG Chemo SG Chemo HR (95% CI) Trop-2(n = 499) Q1 68 55 8.5(5.6-12.7) 5.5(4.2-8.1) 0.54(0.35-0.84) Q2 60 62 8.3(5.6-12.4) 6.8(4.2-9.0) 0.62(0.40-0.97) Q3 50 74 9.7(7.6-11.3) 7.0(5.3-8.5) 0.84(0.54-1.31) Q4 74 56 9.9(6.9-NR) 8.1(4.4-8.5) 0.60(0.38-0.95) tBRCA(n = 423) WT 177 169 8.8(7.2-9.9) 6.9(5.4-8.3) 0.70(0.54-0.92) Mut 40 37 12.7(7.2-18.7) 8.3(5.6-11.2) 0.59(0.32-1.09) HER2(n = 551) IHC 0 115 138 8.3(6.9-10.3) 5.6(4.3-7.0) 0.63(0.46-0.85) Low