Biomarker Findings Extend the Primary ASCENT-04 Results

A prespecified exploratory analysis from the phase 3 ASCENT-04 study indicates that first-line sacituzumab govitecan plus pembrolizumab improved progression-free survival (PFS) across biomarker-defined subgroups of patients with previously untreated, unresectable locally advanced or metastatic PD-L1–positive triple-negative breast cancer (TNBC). The analysis evaluated Trop-2 expression, tumor BRCA1/BRCA2 mutation status, and HER2 expression.

Study Design and Biomarker Methods

ASCENT-04 randomized 443 patients 1:1 to sacituzumab govitecan plus pembrolizumab or investigator-selected chemotherapy plus pembrolizumab. Chemotherapy consisted of gemcitabine plus carboplatin or a taxane. Tumor samples were centrally tested, and PFS was assessed by blinded independent central review.

Trop-2 expression was measured by immunohistochemistry (IHC) and analyzed by H-score quartiles. Tumor BRCA status was determined by whole exome sequencing and categorized as wild-type or mutant in BRCA1, BRCA2, or both. HER2 expression was assessed using in situ hybridization and immunohistochemistry, with subgroups defined as HER2 IHC 0 or HER2 low. Biomarker analyses were descriptive and were not powered for formal comparisons between subgroups.

PFS Benefit Observed Across Trop-2 Expression Levels

Sacituzumab govitecan plus pembrolizumab was associated with longer PFS than chemotherapy plus pembrolizumab across all Trop-2 quartiles. Median PFS was 9.3 versus 9.0 months in quartile 1, 9.6 versus 7.4 months in quartile 2, 13.5 versus 8.4 months in quartile 3, and 16.6 versus 9.2 months in quartile 4. The hazard ratios were 0.81, 0.73, 0.46, and 0.57, respectively.

The presentation showed a trend toward greater separation of the PFS curves in the higher Trop-2 expression quartiles. However, benefit was observed in every quartile, suggesting that Trop-2 expression level did not identify a subgroup without activity from the sacituzumab govitecan combination.

Benefit Extended Across Tumor BRCA Subgroups

Tumor BRCA mutations were present in 23% of patients receiving sacituzumab govitecan plus pembrolizumab and 20% receiving chemotherapy plus pembrolizumab. Among patients with BRCA wild-type tumors, median PFS was 9.6 versus 7.4 months, with a hazard ratio of 0.67. In the smaller BRCA-mutated subgroup, median PFS was 16.6 versus 12.9 months, with a hazard ratio of 0.88. The analysis therefore showed longer median PFS with the investigational regimen in both groups, although the wide confidence interval in the mutated subgroup warrants caution.

Results Were Consistent Across HER2 Expression Categories

PFS also favored sacituzumab govitecan plus pembrolizumab across HER2-defined subgroups. In patients with HER2 IHC 0 tumors, median PFS was 16.6 months with sacituzumab govitecan plus pembrolizumab and 9.0 months with chemotherapy plus pembrolizumab. In patients with HER2 low tumors, median PFS was 11.2 and 7.7 months, respectively. Corresponding hazard ratios were 0.69 and 0.67.

Practice Takeaway

In previously untreated PD-L1–positive advanced TNBC, the ASCENT-04 biomarker analysis showed longer PFS with sacituzumab govitecan plus pembrolizumab across all evaluated Trop-2 quartiles, tumor BRCA categories, and HER2 expression subgroups. The consistency of benefit supports the combination as a broadly active first-line strategy while confirmatory and additional biomarker analyses continue.

References

1. Tolaney SM, Schmid P, de Azambuja E, et al. ASCENT-04: analysis of efficacy by biomarker subgroups with sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab in participants with previously untreated PD-L1+ metastatic triple-negative breast cancer. Presented at: 2026 American Society of Clinical Oncology Annual Meeting. Abstract 1013. Slide presentation.
2. Tolaney SM, Schmid P, de Azambuja E, et al. ASCENT-04: analysis of efficacy by biomarker subgroups with sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2026;44(suppl). Abstract 1013.doi:10.1200/JCO.2026.44.16_suppl.1013