Two randomized phase III trials presented at the European Society for Medical Oncology (ESMO) Congress 2025 bolster support for the use of antibody–drug conjugates—in particular, trophoblast cell surface antigen 2 (TROP2)-targeted agents—as first-line treatments for patients with triple-negative breast cancer who are not candidates for immunotherapy. In the ASCENT-03 trial1, sacituzumab govitecan-hziy reduced the risk of disease progression by 38%, while in TROPION-Breast022, datopotamab deruxtecan-dlnk (Dato-DXd) decreased the risk by 43% and notably demonstrated an overall survival benefit, investigators reported.
The findings from ASCENT-03presented by said Javier Cortés, MD, PhD, Head of the International Breast Cancer Centre in Barcelona and IOB Madrid, in Madrid, were concurrently published in The New England Journal of Medicine.3
Javier Cortés, MD, PhD
“TROPION-Breast02 is the first study to demonstrate a significant improvement in overall survival in first-line PD-(L)1–negative metastatic triple-negative breast cancer, reaching almost 24 months, with a hazard ratio (HR) of 0.79. These are remarkable results compared with the historical 1-year
median overall survival with chemotherapy observed a decade ago,” said the invited discussant, Ana Garrido-Castro, MD, Director of Triple-Negative Breast Cancer Research in the Division of Breast Oncology at the Dana-Farber Cancer Institute, Boston.
“We have seen significant improvement in outcomes with TROP2 antibody-drug conjugates in the first-line metastatic triple-negative breast cancer setting for patients who are not candidates for immune checkpoint inhibitors…. Today marks a shift in the treatment paradigm.In my opinion, ASCENT-03 and TROPION-Breast02 support TROP2 antibody-drug conjugate therapy as the new preferred first-line regimen for this patient population,” she said as the late-breaking abstracts’ invited discussant.
Both studies enrolled patients with previously untreated, locally advanced inoperable or metastatic triple-negative breast cancer who were not candidates for PD-(L)1 inhibitors. Patients were randomly assigned to the antibody-drug conjugate or the physician/investigator’s choice of chemotherapy.
ASCENT-03: Key Findings
ASCENT-03 randomly assigned 558 patients to sacituzumab govitecan or chemotherapy, with crossover to sacituzumab govitecan allowed upon disease progression. The primary endpoint was progression-free survival by blinded independent review.
The median progression-free survival was found to be significantly longer with sacituzumab govitecan compared with chemotherapy (9.7 vs 6.9 months; HR = 0.62; P < .0001). The results appeared to be similar by investigator assessment (HR = 0.64; 95% confidence interval [CI] = 0.52–0.79). “A progression-free survival benefit of sacituzumab govitecan over chemotherapy was observed across key prespecified subgroups,” said Dr. Cortés.
The objective response rates were found to be similar (48% vs 46%), but the median duration of response was longer with sacituzumab govitecan (12.2 vs 7.2 months).
Descriptive analyses of overall survival and progression-free survival 2 were conducted. Progression-free survival 2 was numerically prolonged with sacituzumab govitecan, with a median duration of 18.2 vs 14.0 months with chemotherapy (HR = 0.70; 95% CI = 0.55–0.90). At a median follow-up of 13.2 months, overall survival data remained immature (HR = 0.98; 95% CI = 0.75–1.30).
The rate of treatment-emergent adverse events of grade 3 or higher was 66% with sacituzumab govitecan and 62% with chemotherapy. Fewer patients treated with the antibody-drug conjugate discontinued treatment because of adverse events.
TROPION-Breast02: Key Findings
TROPION-Breast02 randomly assigned 644 patients to Dato-DXd or chemotherapy. Following progression or discontinuation of study treatment, patients in TROPION-Breast02 could receive any appropriate subsequent therapy, including approved antibody-drug conjugates, at the discretion of the investigator. The dual primary endpoints were progression-free survival by blinded independent central review and overall survival.
“TROPION-Breast02 met both dual primary endpoints,” Rebecca A. Dent, MD,MSc, FRCP, FASCO, of the National Cancer Center Singapore, announced. The median progression-free survival was 10.8 months with Dato-DXd vs 5.6 months with chemotherapy (HR = 0.57; P < .0001). At a median follow-up of 27.5 months, the median overall survival was 23.7 vs 18.7 months, respectively (HR = 0.79; P = .0291).
Rebecca A. Dent, MD, MSc, FRCP, FASCO
“Dato-DXd demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with chemotherapy, reducing the risk of death by 21%,” she said. The overall survival benefit was consistent across subgroups, except for patients enrolled from the United States, Canada, and Europe (HR = 1.22) and those with a prior disease-free interval of less than 12 months (HR = 1.02).
Improvements in the objective response rate (63% vs 29%) and duration of response (12.3 vs 7.1 months) were also observed. “With Dato-DXd, the confirmed response rate was more than double that with chemotherapy, and the confirmed complete response rate was more than three times that (9% vs 2.5%),” she said.
The rates of treatment-related adverse events of grade 3 or higher were similar between the groups (Dato-DXd: 33%; chemotherapy: 29%). Fewer patients discontinued treatment with Dato-DXd because of a treatment-related adverse event (4% vs 7%).
DISCLOSURE: Dr. Cortés has held a consulting or advisory role with Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, HiberCell, BioInvent, GEMoaB, Gilead, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, ExpreS2ion Biotechnologies, Jazz Pharmaceuticals, AbbVie, BridgeBio, BioNTech, Biocon, Circle Pharma, Delcath Systems, Hexagon Bio, and Bliss Biopharmaceutical; has received honoraria from Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca, Gilead, Stemline Therapeutics, and Zuellig Pharma; has received institutional research funding from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai, F. Hoffmann-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, PIQUR Therapeutics, IQVIA, and Queen Mary University of London; owns stock with MAJ3 Capital and Leuko (relative); has received reimbursement for travel expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead, Merck Sharp & Dohme, and Stemline Therapeutics; and has patents related to cancer therapies. Dr. Dent reported relationships with AstraZeneca, MSD, Pfizer, Eisai, Novartis, Daiichi Sankyo/AstraZeneca, Roche, Gilead Sciences, and DKSH.
REFERENCES
1. Cortés JC, Bardia A, Punie K, et al: Primary results from ASCENT-03: A randomized phase 3 study of sacituzumab govitecan vs chemotherapy in patients with previously untreated metastatic triple-negative breast cancer who are not candidates for PD-(L)1 inhibitors. ESMO Congress 2025. Abstract LBA20. Presented October 19, 2025.
2. Dent R, Shao Z, Schmid P, et al: First-line datopotamab deruxtecan vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer for whom immunotherapy was not an option: Primary results from the randomised, phase 3 TROPION-Breast02 trial. ESMO Congress 2025. Abstract LBA21. Presented October 19, 2025.
3. Cortés J, Punie K, Barrios C, et al: Sacituzumab govitecan in untreated, advanced triple-negative breast cancer. N Engl J Med 393:1912-1925, 2025.
EXPERT POINT OF VIEW
Ana Garrido-Castro, MD, Director of Triple-Negative Breast Cancer Research in the Division of Breast Oncology at the Dana-Farber Cancer Institute, Boston, invited discussant, said the results of ASCENT-03 and TROPION-Breast02 warrant a shift in the first-line treatment of patients with locally advanced inoperable or metastatic triple-negative breast cancer ineligible for immunotherapy.
Ana Garrido-Castro, MD
“The sobering truth is that across retrospective studies from the U.S. and Europe, approximately 25% to 30% of patients diagnosed with metastatic triple-negative breast cancer are no longer alive 6 months from their metastatic diagnosis, and 6 months is just about the median progression-free survival of first-line chemotherapy. So, if there is a new drug that is able to significantly improve progression-free survival with an acceptable toxicity profile, that should be sufficient to change the current standard of care in the first line setting,” she said.
“Both studies demonstrate that a trophoblast cell surface antigen 2 (TROP2) antibody-drug conjugate improves progression-free survival compared with chemotherapy in the first-line setting, with consistent hazard ratios of about 0.6,” she said. Although the absolute difference in median progression-free survival is larger in TROPION-Breast02—5.3 vs 2.8 months—the 6-month progression-free survival rates were relatively similar, around 65%, she noted. She also called attention to the “tail” of the Kaplan-Meier curve, showing at least 40% of patients remaining progression-free after 12 months of treatment with either antibody-drug conjugate.
Datopotamab deruxtecan-dlnk (Dato-DXd) yielded an absolute 15% higher response rate, she added, “which may be a determining factor for selection of a TROP2 antibody-drug conjugate, particularly for those patients who have high symptom and disease burden.”
Although noting that the improvement in overall survival with Dato-DXd is particularly encouraging, Dr. Garrido-Castro emphasized that the data for overall survival with sacituzumab govitecan-hziy are still immature, and the results will likely be complicated by crossover from the chemotherapy arm. Moreover, there are other differences in the design and eligibility criteria of the trials, particularly in the choice of chemotherapy backbones and the inclusion of potentially higher-risk patients in TROPION-Breast02. Of note, the median follow-up in TROPION-Breast02 was double that of ASCENT-03. Comparisons between the studies, therefore, are not straightforward, she cautioned.
She noted that the current descriptive ASCENT-03 overall survival analysis, at this early time point, appears numerically comparable between the two treatment arms—approximately 20–21 months—but added, “What is interesting to note, is that the 12-month overall survival rate for the antibody-drug conjugates in both studies is identical at 75%.” It remains to be seen whether the prolongation in progression-free survival 2 achieved by sacituzumab govitecan will prove to be a surrogate endpoint for overall survival, she continued, “but what is clear is that any amount of crossover is sufficient to bias overall survival results.”
In ASCENT-03, 53% of the control arm ultimately crossed over to receive sacituzumab govitecan. Elaborating, Dr. Garrido-Castro took the opportunity to question the ethics of not allowing crossover when the experimental agent has demonstrated overall survival benefit in a later-line setting. Sacituzumab govitecan significantly improved overall survival compared with chemotherapy of physician’s choice in the ASCENT trial in patients with previously treated metastatic triple-negative breast cancer. To date, there are no randomized phase III data comparing Dato-DXd and chemotherapy in a pretreated metastatic triple-negative breast cancer setting. To audience applause, she praised the ASCENT-03 study team for incorporating crossover into their design, “knowing that sacituzumab govitecan could potentially impact their final overall survival results and their path towards regulatory approval.”
“With two drugs with consistent progression-free survival benefit and limitations in the comparison of overall survival, it becomes key to look carefully at the toxicity profiles, and here we see that the safety profile of Dato-DXd appears more favorable, with fewer grade 3 or higher adverse events,” she continued. She noted that, while fewer patients treated with this antibody-drug conjugate developed neutropenia or gastrointestinal toxicity, more experienced oral mucositis and stomatitis (60% any grade, with 8% grade ≥ 3) and ocular surface toxicity (47% any grade, with 7% grade ≥ 3); most of these events resolved without dose interruptions or reductions. There were no treatment-related deaths related to Dato-DXd, whereas there were six with sacituzumab govitecan (all related to infection; five in the setting of neutropenia without primary prophylaxis). Of note, the rates of discontinuation of the antibody-drug conjugate because of toxicity were the same for both drugs (4%).
Finally, she said that selection of a first-line antibody-drug conjugate will likely depend on multiple factors, including disease burden, side-effect profile, and patient preference for aspects such as the infusion schedule (which differs between these drugs). Assessment of patient-reported outcomes will be key to understanding if these antibody-drug conjugates improve outcomes without compromising quality of life. ν
DISCLOSURE: Dr. Garrido-Castro reported personal financial relationships with AstraZeneca, Daiichi Sankyo, Gilead, Novartis, Pfizer, TD Cowen, Merck, Bicycle Therapeutics, and Roche/Genentech.
