News|Articles|June 2, 2026

Sacituzumab Govitecan–Based Regimens Show PFS Benefit Across Biomarker Subgroups in First-Line Advanced TNBC

Fact checked by: Chris Ryan

Listen

0:00 / 0:00

Key Takeaways

Phase 3 ASCENT-03 showed PFS 9.7 vs 6.9 months (HR 0.62) for sacituzumab govitecan vs chemotherapy in the ITT population.
Across TROP2 quartiles in ASCENT-03, hazard ratios favored sacituzumab govitecan without a monotonic exposure–response relationship to higher TROP2 expression.
Tumor BRCA-mutant and BRCA–wild-type subsets derived PFS benefit with sacituzumab govitecan in both trials, though confidence intervals widened in smaller mutant cohorts.
ASCENT-04 demonstrated PFS 11.2 vs 7.8 months (HR 0.65) for sacituzumab govitecan plus pembrolizumab vs chemotherapy plus pembrolizumab in PD-L1–positive disease.
Key limitations included descriptive, underpowered subgroup comparisons and immature overall survival, necessitating cautious interpretation despite consistent directionality across biomarkers.

Prespecified biomarker analyses of ASCENT-03 and ASCENT-04 showed longer PFS with sacituzumab govitecan–based regimens vs comparators in TNBC.

Sacituzumab govitecan-hziy (Trodelvy) demonstrated longer median progression-free survival (PFS) vs chemotherapy across all assessed biomarker subgroups in the phase 3 ASCENT-03 trial (NCT05382299), and sacituzumab govitecan plus pembrolizumab (Keytruda) similarly outperformed chemotherapy plus pembrolizumab across biomarker subgroups in the phase 3 ASCENT-04 trial (NCT05382286), according to data from 2 prespecified exploratory analyses presented at the 2026 ASCO Annual Meeting.¹^,²

Data from the ASCENT-03, which included patients who were not candidates for PD-(L)1 inhibitors, analysis showed that the median PFS with sacituzumab govitecan was longer vs chemotherapy across all biomarker subgroups, including TROP2 expression quartiles, BRCA-mutant and wild-type subgroups, and HER2 subgroups per immunohistochemistry (IHC).¹ Similarly, in ASCENT-04, which included patients with PD-L1–positive disease, sacituzumab govitecan in combination with pembrolizumab outperformed chemotherapy plus pembrolizumab across all key subgroups. These findings were consistent with the results from the primary analyses of both studies.²

“The results of this analysis reinforce the significant and clinically meaningful benefit of sacituzumab govitecan plus pembrolizumab as a first-line treatment option for patients with previously untreated metastatic PD-L1–positive TNBC,” Sara M. Tolaney, MD, MPH, the chief of the Division of Breast Oncology and the associate director at the Susan F. Smith Center for Women's Cancers, as well as a senior physician at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston Massachusetts, said in her presentation on the ASCENT-04 analysis.

“Sacituzumab govitecan demonstrated efficacy vs chemotherapy across TROP2expression, tumor BRCA genotypes, and HER2 expression subgroups, reinforcing the significant and clinically meaningful benefit of this drug in the first-line treatment of patients with previously untreated TNBC [who are] not candidates for immunotherapy,” Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group in Porto Alegre, Brazil, added in his presentation on the ASCENT-04 analysis.¹

How were the biomarker analyses designed?

In ASCENT-03, patients with previously untreated advanced TNBC who were either PD-L1 negative (combined positive score [CPS] <10) or PD-L1 positive but not candidates for PD-(L)1 inhibitors were randomly assigned 1:1 to receive sacituzumab govitecan or investigator's choice of chemotherapy, with PFS by blinded independent central review (BICR) as the primary end point.¹ The prespecified biomarker analysis used central testing of fresh or archival formalin-fixed paraffin-embedded tumor samples; 41% of TROP2 samples came from metastatic sites. At the primary data cutoff in April 2025, the median follow-up was 13.2 months (range, < 0.1-29.2), and OS data were not mature (37% maturity).¹

Key Findings From the ASCENT-03 and ASCENT-04 Biomarker Analyses

Sacituzumab govitecan demonstrated longer median PFS vs chemotherapy across all assessed biomarker subgroups in the phase 3 ASCENT-03 trial.

Sacituzumab govitecan plus pembrolizumab similarly outperformed chemotherapy plus pembrolizumab in terms of PFS across biomarker subgroups in the phase 3 ASCENT-04 trial.

The study authors noted that these findings should be cautiously interpreted due to the small sample sizes of some of the subgroups.

In ASCENT-04, patients with previously untreated, locally advanced unresectable or metastatic PD-L1–positive TNBC were randomly assigned 1:1 to receive sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab.² The primary end point was also PFS by BICR. Central biomarker testing used the same tissue approach, with 48% of TROP2 samples from metastatic sites. At the primary data cutoff in March 2025, the median follow-up was 14.0 months (range, 0.1-28.6).

Both analyses assessed the same 3 biomarker categories.^1,2 TROP2 expression was characterized by H-score via IHC and patients were grouped into quartiles. Tumor BRCA status was assessed by whole-exome sequencing (WES), with mutant status defined as a mutation in BRCA1, BRCA2, or both. HER2 expression was measured by in situ hybridization (ISH) and IHC, with participants grouped as HER2 IHC 0 or HER2 low (IHC 1+ or IHC 2+/ISH–).

What did the additional ASCENT-03 biomarker data show?

In the ASCENT-03 intention-to-treat (ITT) population, the median PFS was 9.7 months (95% CI, 8.1-11.1) with sacituzumab govitecan (n = 279) vs 6.9 months with chemotherapy (n = 279; HR, 0.62; 95% CI, 0.50-0.77).¹ In the TROP2 biomarker analysis set, the median PFS was 9.7 months (95% CI, 7.8-11.1) in the investigational arm (n = 252) vs 6.8 months (95% CI, 5.4-8.1) in the control arm (n = 247; HR, 0.64; 95% CI, 0.51-0.80). PFS curves separated in favor of the investigational arm across all 4 TROP2 quartiles, with HRs of 0.54 (95% CI, 0.35-0.84), 0.62 (95% CI, 0.40-0.97), 0.84 (95% CI, 0.54-1.31), and 0.60 (95% CI, 0.38-0.95) in quartiles 1, 2, 3, and 4, respectively. There was no clear trend of increasing efficacy at higher TROP2 expression levels.

In the tumor BRCA biomarker analysis set, 18% of patients in each arm had mutant status. Median PFS was longer with sacituzumab govitecan vs chemotherapy in the BRCA wild-type subgroup (HR, 0.70; 95% CI, 0.54-0.92) and in the mutant subgroup (HR, 0.59; 95% CI, 0.32-1.09), with numerically longer PFS in the mutant subgroup (12.7 months [95% CI, 7.2-18.7]) vs wild-type subgroup (8.8 months [95% CI, 7.2-9.9]) in the sacituzumab govitecan arm. For HER2 subgroups, the HER2 IHC 0 subgroup showed a median PFS of 8.3 months (95% CI, 6.9-10.3) with sacituzumab govitecan (n = 115) vs 5.6 months (95% CI, 4.3-7.0) with chemotherapy (n = 277; HR, 0.63; 95% CI, 0.46-0.85); a significant PFS advantage with sacituzumab govitecanwas also reported in the HER2-low subgroup (HR, 0.74; 95% CI, 0.55-1.01).

What did the further ASCENT-04 biomarker data show?

In the ASCENT-04 ITT population, the median PFS was 11.2 months (95% CI, 9.3-16.7) with sacituzumab govitecan plus pembrolizumab (n = 221) vs 7.8 months (95% CI, 7.3-9.3) with chemotherapy plus pembrolizumab (n = 222; HR, 0.65; 95% CI, 0.51-0.84).² In the TROP2 biomarker analysis set (sacituzumab govitecan plus pembrolizumab n = 204; chemotherapy plus pembrolizumab; n = 196), the median PFS was 11.7 months vs 7.8 months, respectively (HR, 0.63; 95% CI, 0.48-0.82). Unlike in ASCENT-03, ASCENT-04 showed a trend toward greater Kaplan-Meier curve separation at higher TROP2 expression, with PFS HRs of 0.81 (95% CI, 0.48-1.36) in quartile 1, 0.73 (95% CI, 0.44-1.22) in quartile 2, 0.46 (95% CI, 0.27-0.80) in quartile 3, and 0.57 (95% CI, 0.33-0.99) in quartile 4.

In the tumor BRCA biomarker analysis set, 23% of patients in the sacituzumab govitecan plus pembrolizumab arm and 20% of the chemotherapy plus pembrolizumab arm had mutant tumors. PFS improvement was observed with sacituzumab govitecan in the wild-type subgroup (9.6 months vs 7.4 months; HR, 0.67; 95% CI, 0.49-0.91) and the mutant subgroup (16.6 months vs 12.9 months; HR, 0.88; 95% CI, 0.45-1.74). For HER2 subgroups, the HER2 IHC 0 subgroup showed a median PFS of 16.6 months (95% CI, 9.1-21.2) in the sacituzumab govitecan arm (n = 42) vs 9.0 months (95% CI, 7.2-10.8) in the control arm (n = 82; HR, 0.69; 95% CI, 0.46-1.04). In the HER2-low subgroup, the median PFS values were 11.2 months (95% CI, 9.1-16.6) vs 7.7 months (95% CI, 7.0-9.4), respectively (HR, 0.67; 95% CI, 0.48-0.92).

What are the limitations and implications of these findings?

Barrios and Tolaney both cautioned that small sample sizes in several subgroups, and they noted the descriptive, exploratory nature of the analyses require careful interpretation. Neither analysis was powered for subgroup comparisons, and neither had mature overall survival data at the time of reporting.

Disclosures: Barrios has stock and other ownership interests with CPO, MedSIR, and Thummi. He received honoraria from Adium Pharma, AstraZeneca, Daiichi Sankyo/Astra Zeneca, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, and Roche/Genentech. He holds consulting or advisory roles with AstraZeneca, Daiichi Sankyo/Astra Zeneca, Gilead Sciences, Lilly, MSD Oncology, Novartis, Pfizer, and Roche/Genentech. He received research funding from Amgen (Inst), AstraZeneca (Inst), Aveo (Inst), BioNTech SE (Inst), BMS Brazil (Inst), Bristol-Myers Squibb (Inst), Daiichi Sankyo (Inst), Dizal Pharma (Inst), Exelixis (Inst), Exelixis (Inst), FORTREA (Inst), FORTREA (Inst), Gilead Sciences (Inst), GlaxoSmithKline (Inst), ICON Clinical Research (Inst), IQvia (Inst), Janssen (Inst), LabCorp (Inst), Lilly (Inst), Merck (Inst), Novartis (Inst), Novocure (Inst), Nuvisan (Inst), OBI Pharma (Inst), Parexel (Inst), Pfizer (Inst), PharmaMar (Inst), PPD Global (Inst), PSI (Inst), Regeneron (Inst), Roche/Genentech (Inst), Samsung (Inst), Sandoz (Inst), Sanofi (Inst), Servier (Inst), Sremline (Inst), Syneos Health (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), TRIO US (Inst), Worldwide Clinical Trials (Inst). He received travel, accommodations, and expenses from AstraZeneca, BMS Brazil, Lilly, MSD Oncology, Novartis, Pfizer, Roche/Genentech.

Tolaney holds consulting or advisory roles with AADi, Aktis Oncology, Ambrx, Arvinas, AstraZeneca, Avenzo Therapeutics, Bayer, BeiGene, Bicycle Therapeutics, BioNTech, Boehringer Ingelheim, Boundless Bio, Bristol-Myers Squibb, Celcuity, Circle Pharma, Corcept Therapeutics, Cullinan Oncology, Daiichi Sankyo, Denali Therapeutics, eFFECTOR Therapeutics, Eisai, Ellipses Pharma, Genentech, Immunomedics/Gilead, Jazz Pharmaceuticals, Johnson & Johnson, Launch Therapeutics, Lilly, Menarini Group, Merck, Mersana, Novartis, Olema Pharmaceuticals, Pfizer, Reveal Genomics, Samsung Bioepis, Seagen, Summit Therapeutics, Systimmune, Tempus, and Zuellig Pharma. She received research funding from AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Daiichi Sankyo, Exelixis (Inst), Genentech/Roche (Inst), Gilead Sciences (Inst), Jazz Pharmaceuticals (Inst), Lilly (Inst), Menarini/Stemlin (Inst), Merck (Inst), NanoString Technologies (Inst), Novartis (Inst), Olema Pharmaceuticals (Inst), OncoPep (Inst), Pfizer (Inst), Seagen (Inst). She received travel, accommodations, and expenses from Arvinas, AstraZeneca, Gilead Sciences, Jazz Pharmaceuticals, Lilly, Pfizer, and Roche.

References

Barrios C, Hurvitz SA, Tolaney SM, et al. 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). J Clin Oncol. 2026;44(suppl 16):1014. doi:10.1200/JCO.2026.44.16_suppl.1014
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 16):1013. doi:10.1200/JCO.2026.44.16_suppl.1013