ASCENT-03, ASCENT-04, and Dato-DXd: How ADCs Are Replacing Chemotherapy in Metastatic TNBC

Triple-Negative Breast Cancer in 2026: ADCs Displace Chemotherapy Across PD-L1 Status Lines

Antibody-drug conjugates have arrived in the first line for metastatic triple-negative breast cancer — and they're outperforming chemotherapy regardless of PD-L1 status. Dr. VK Gadi reviews the practice-changing data from ASCENT-03, ASCENT-04, and the Dato-DXd trial, addresses the emerging question of sequential ADC use, and previews the next wave of agents in late-stage development.

Introduction: ADCs Are Displacing Chemotherapy, One Line at a Time

The metastatic triple-negative breast cancer treatment algorithm has undergone a rapid and substantial transformation. For years, the first-line standard depended on PD-L1 status: immunotherapy plus chemotherapy for the roughly 40% of patients with PD-L1 positivity (CPS ≥10), and chemotherapy alone for the rest. Two major trials presented at ESMO 2025 and published soon thereafter have now established sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) as first-line options regardless of PD-L1 status, fundamentally shifting the treatment landscape.

The short summary: ADCs are outperforming chemotherapy across PD-L1 lines. More are coming.

First-Line PD-L1 Positive: ASCENT-04

ASCENT-04 addressed a well-defined population: patients with PD-L1 positive (CPS ≥10) metastatic TNBC in the first-line setting. The comparator was chemotherapy (either a taxane or gemcitabine plus carboplatin), each combined with pembrolizumab. The experimental arm was sacituzumab govitecan plus pembrolizumab.

This is a clean trial design, comparing the best available immunotherapy-chemotherapy backbone against the ADC plus immunotherapy combination for patients most likely to benefit from checkpoint inhibition.

Results: PFS was 11 months versus 8 months, approximately; hazard ratio approximately 0.65, representing a roughly 35% improvement. Overall response rate 60% versus 53%. Overall survival has not been reached in either arm. The gemcitabine/carboplatin combination outperformed the taxane comparator arm, likely partly because some taxane patients were being rechallenged after prior taxane exposure.

Toxicities reflect the mechanism of SG, which metabolizes to SN-38 (an irinotecan metabolite): nausea, diarrhea, and neutropenia are the dominant concerns on the SG arm. The chemotherapy comparator arm produces more thrombocytopenia and peripheral neuropathy. The distribution differs; the burden is similar.

One important representation issue: Black patients were substantially underrepresented in ASCENT-04 despite well-documented differences in taxane toxicity profiles and pharmacogenomics (particularly UGT1A1 polymorphisms that affect SN-38 metabolism). This matters for applying trial findings to the clinical populations most affected by triple-negative breast cancer in the United States.

This regimen is now a category 1 NCCN recommendation for first-line PD-L1 positive metastatic TNBC.

First-Line PD-L1 Negative: Two New Options

ASCENT-03: Sacituzumab Govitecan Alone

ASCENT-03 enrolled patients with PD-L1-negative or PD-L1-ineligible metastatic TNBC, the roughly 60% of patients who don’t qualify for checkpoint inhibitor-based approaches. These patients received SG or investigator-choice chemotherapy (a taxane or gemcitabine/carboplatin).

Results: PFS approximately 10 months versus 7 months; hazard ratio approximately 0.62, representing a 38% improvement. Overall response rates favor SG. Overall survival data may be partially eroded by a crossover design that allowed chemotherapy arm patients who progressed to receive SG on the company’s funding. The gemcitabine/carboplatin arm again outperformed the taxane arm.

ASCENT-03 was published in the April 3 issue of Annals of Oncology and is now a category 1 NCCN recommendation for PD-L1-negative or ineligible first-line metastatic TNBC. The same racial representation concerns from ASCENT-04 apply here.

Dato-DXd (Datopotamab Deruxtecan): Adding an OS Benefit

Dato-DXd is an antibody-drug conjugate targeting TROP2 with a different payload and linker chemistry than SG. The trial comparing Dato-DXd versus investigator-choice single-agent chemotherapy (paclitaxel, docetaxel, capecitabine, eribulin, or carboplatin; no doublets) enrolled patients with PD-L1-negative or ineligible metastatic TNBC.

Results: PFS improvement of 43%, deeply significant. Overall survival 21% improvement with a clean signal, unaffected by crossover (there was none in this trial, unlike ASCENT-03). Objective response rate substantially favors Dato-DXd. Duration of response 12 months versus 7 months.

Important context: 75% of the comparator arm received a taxane, meaning many patients who may have already seen taxane in the neoadjuvant or adjuvant setting were being rechallenged. This likely depresses the comparator arm’s performance, which makes the magnitude of Dato-DXd’s benefit appear even larger relative to a head-to-head comparison against a fresh agent.

The trial has heavy Asian enrollment (50% of the Dato-DXd arm was Asian; the drug was co-developed by Daiichi Sankyo and Astellas), and Black/African American representation was again approximately 4%, a meaningful gap.

New toxicities with Dato-DXd: Stomatitis and dry eyes are the distinguishing adverse events of this agent. Stomatitis is common (any grade) but grade 3 occurs in only approximately 8% of patients. Dry eyes, while frequent at any grade, are generally low-grade and manageable. Ophthalmology evaluation before starting Dato-DXd is recommended; management includes lubricating eye drops and topical steroid-based solutions.

Dato-DXd is on NCCN guidelines and as of May 2026 has recently been updated to a higher recommendation category based on publication of the trial data.

ADC After ADC: Can You Re-ADC?

SG and TDXd/Dato-DXd share a topo-1 isomerase inhibitor payload, but their pharmacology is meaningfully different. SG releases its payload freely, where it circulates briefly. TDXd’s payload becomes conjugated to albumin and persists in circulation for weeks. These different dynamics mean that despite the common payload, they are not pharmacologically identical.

There are patients who respond to the first ADC and not the second, and patients whose treatment fail with the first but respond to the second agent. A publication from Laura Huppert’s group at UCSF demonstrated this unpredictability across triple-negative breast cancer patients on sequential ADCs; their analysis showed no clear pattern predicting who benefits from which ADC in which sequence.

This doesn’t mean sequential ADC use should be routine; published evidence remains limited and clinical experience is sparse. But for a patient who derived meaningful benefit from one ADC and then progressed, trying a second ADC with a different target or linker technology is a reasonable strategy rather than an automatic turn to chemotherapy. An active phase 1 ADC trials program can provide access to these options in a monitored setting.

Emerging Options: The Next Wave

Sacituzumab tirumotecan (Chinese formulation, Merck-licensed): A structurally similar compound to sacituzumab govitecan now in a phase 3 trial versus chemotherapy. The Chinese phase 2 data were strongly positive. The global trial is ongoing; results are anticipated to replicate in a broader population.

Bispecific anti-PD-L1 / anti-VEGF (BioNTech): This molecule targets both PD-L1 and VEGF simultaneously, designed to deliver immune activation directly to the tumor microenvironment. VEGF normalization improves tumor vascularization, which theoretically enhances immune cell infiltration and antigen presentation. Early-phase data in triple-negative breast cancer are promising. A phase 2 trial is open.

Izabren (TROP2 + EGFR bispecific ADC, BMS-licensed): A Chinese molecule that targets both TROP2 and EGFR simultaneously in the same ADC. The pivotal Chinese trial made the ASCO 2026 podium. The IzaBRIGHT-1 trial is beginning enrollment in the United States. This represents the next generation of ADC engineering: dual-targeting within a single molecule, and is among the most anticipated near-term data readouts in TNBC.

For Patients

If you have been diagnosed with triple-negative breast cancer that has spread, the treatment options available in 2026 are substantially more effective than they were just two years ago. Antibody-drug conjugates, targeted therapies that deliver chemotherapy directly to cancer cells, are now available in the first-line setting regardless of whether your tumor expresses PD-L1. These treatments produce higher response rates and longer disease control than standard chemotherapy, with different but manageable side effect profiles. Ask your oncologist about SG or Dato-DXd as first-line options, and ask about clinical trials — this is a rapidly evolving field with multiple new agents in late-stage development.

Key Takeaways

• ASCENT-04: SG + pembro vs chemo + pembro for PD-L1+ first-line TNBC; PFS 11 vs 8 months; category 1 NCCN.
• ASCENT-03: SG vs chemo for PD-L1-negative first-line TNBC; PFS ~10 vs 7 months (38% improvement); category 1 NCCN; OS signal may be eroded by crossover.
• Dato-DXd vs single-agent chemo for PD-L1-negative first-line TNBC: PFS 43% improvement, OS 21% improvement (no crossover, cleaner signal); new toxicities are stomatitis and dry eyes; ophthalmology evaluation recommended before starting.
• ADC after ADC is feasible but unpredictable; no reliable biomarker for sequencing; some patients respond to ADC-2 after failing ADC-1 and vice versa.
• Black patients are substantially underrepresented in all major TNBC ADC trials despite unique toxicity pharmacogenomics; real-world applicability requires careful attention.
• Upcoming: BioNTech bispecific anti-PD-L1/VEGF, Izabren (TROP2+EGFR bispecific ADC from BMS/IzaBRIGHT-1), and Merck-licensed SG formulation all in active development.

References

1. ASCENT-04. Sacituzumab govitecan plus pembrolizumab in PD-L1+ first-line TNBC. New England Journal of Medicine, 2025.
2. ASCENT-03. Sacituzumab govitecan in PD-L1-negative first-line TNBC. Annals of Oncology, April 2026.
3. Dato-DXd vs chemotherapy in PD-L1-negative first-line TNBC. Presented at ESMO 2025; published 2026.
4. Hebert LA, et al. Sequential ADC use in triple-negative breast cancer. Clinical Cancer Research, 2025.
5. Gadi VK. “Triple-Negative Breast Cancer.” Presented at the 2026 Alaska Hematology Oncology Conference, Anchorage, AK, May 2026.

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About the Author

VK Gadi, PhD, MD, is a Professor of Medicine and Director of Medical Oncology in the Division of Hematology and Oncology at the University of Illinois College of Medicine, and Deputy Director of the University of Illinois Cancer Center, both in Chicago. His research focuses on translational breast oncology, immunotherapy, antibody-drug conjugates, and the tumor microenvironment, with an active phase 1 clinical trials program evaluating novel ADC-based strategies.