Turning the Tide in TNBC: Trop2-Targeted Therapies Improve Patient Outcomes

Triple-negative breast cancer (TNBC) represents approximately 15% of all breast cancer cases in the United States. This aggressive subtype lacks expression of estrogen, progesterone, and HER2 receptors, which limits treatment options. The absence of these receptors makes standard therapies—including chemotherapy, hormone therapy, endocrine therapy, and immunotherapy—less effective.¹

“Treatment options are limited, and prognosis is poor for the approximately 70% of patients with locally recurrent inoperable or [metastatic] TNBC for whom immunotherapy is not an option,” the researchers wrote in the abstract for the TROPION-Breast02 trial (NCT05374512).^2,3

Emerging research identified trophoblast cell surface antigen 2 (Trop2), a calcium-transducing transmembrane protein that is expressed at low levels in normal tissues and high levels in many malignant tumors, particularly TNBC. Trop2 is involved in several signaling pathways that lead to tumor development, invasion, and metastasis.⁴

Experts at the European Society for Medical Oncology 2025 Congress shared clinically meaningful data from the phase 3 TROPION-Breast02 and ASCENT-03 trials (NCT05382299), demonstrating the significant benefit of Trop2-targeting agents for patients with TNBC.⁵

TROPION-Breast02

TROPION-Breast02 is a phase 3, open-label, randomized trial evaluating first-line datopotamab deruxtecan (Dato-DXd; Datroway; AstraZeneca) compared with investigator's choice of single-agent chemotherapy—including options such as eribulin, capecitabine, vinorelbine, or gemcitabine—in patients with locally recurrent inoperable or metastatic TNBC (mTNBC) for whom immunotherapy was not an option.²

Dato-DXd is an antibody-drug conjugate that targets Trop-2 and delivers a topoisomerase I inhibitor directly to tumor cells via a humanized IgG1 monoclonal antibody linked through tumor-selective, cleavable connectors. In January 2025, the therapy received FDA approval for adults with unresectable or metastatic hormone receptor–positive, HER2-negative breast cancer who had previously undergone endocrine-based therapy and chemotherapy. In the TROPION-2 trial, dato-DXd shows its efficacy in the mTNBC setting.⁶

Patients (n = 644) were randomized 1:1 to receive either dato-DXd at a dosage of 6 mg/kg intravenously (IV) once every 3 weeks (n = 323) or chemotherapy (n = 321). The study’s dual primary end points were progression-free survival (PFS) and overall survival (OS) by Blind Independent Central Review (BICR) per RECIST 1.1.²

Dato-DXd met both primary end points in the trial. At a median follow-up of 27.5 months, patients receiving dato-DXd saw statistically significant improvements in OS and PFS.²

"Median PFS was 5.6 months in those patients receiving chemotherapy,” explained Rebecca A. Dent, MD, deputy chief executive officer (Clinical) & senior consultant at the National Cancer Centre Singapore in China, “10.8 months in those patients receiving [dato-DXd], a Delta of 5.3 months."⁷

The median [OS] was also favorable at 18.7 months in those patients receiving chemotherapy. This increased by 5 months in patients receiving [dato-DXd], with a median [OS] of almost 24 months.²

"These results support [dato-DXd] as the first new first-line standard of care for patients with locally recurrent, inoperable, or [mTNBC], for whom immunotherapy is not an option."⁷

ASCENT-03

ASCENT-03 is a randomized, open-label, phase 3 trial comparing sacituzumab govitecan (SG, Trodelvy; Gilead Sciences) treatment with physician's choice in patients with previously untreated, locally advanced, inoperable, or metastatic TNBC. The study focused on patients whose tumors do not express PD-L1 or who were previously treated with anti-PD-(L)1 agents in the early setting.

SG is a Trop2-targeting ADC that was first approved by the FDA in 2021 as a monotherapy for patients with unresectable, locally advanced, or mTNBC who received 2 or more prior lines of therapy. The decision was supported by data from the phase 3 ASCENT trial (NCT02574455), which showed SG therapy yielded greater PFS benefits when compared with single-agent chemotherapy.

“SG is the only antistructure antiviral conduit with survival improvements in different phase 3 trials,” explained Javier C. Cortés, MD, PhD, head of the International Breast Cancer Centre (IBCC) in Barcelona, “not only in HER2 and [TNBC], but also in [estrogen receptor]-positive or -negative disease.”⁷

In ASCENT-03, SG in the first line demonstrates superiority to physician’s choice chemotherapy in 558 patients with centrally confirmed PD-L1 mTNBC (defined as combined positive score [CPS] < 10) or PD-L1+ mTNBC (CPS ≥ 10). They were randomized 1:1 to receive either SG (10 mg/kg IV, days 1 & 8 in 21-day cycles) or chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin) based on disease status and geography. The primary end point was PFS by BICR, with secondary end points of OS, overall response rate (ORR) and duration of response (DOR) by BICR, and safety.⁴

SG showed a significant improvement in median PFS vs chemo (9.7 vs 6.9 mo; HR, 0.62; 95% CI, 0.50-0.78; P < .0001) with a median DOR of 12.2 months vs 7.2 months (Table). OS data were immature.

“The curves separated early—at about 2 months—and continue to separate across the study,” said Cortés, “and are maintained with a 6-month DFS rate of 65% with SG and 53% with chemotherapy. The 12-month PFS rates were 41% and 24%, respectively.”

The most frequent grade 3 or higher treatment-related adverse events were neutropenia (43%) and diarrhea (9%) with SG and neutropenia (41%) and anemia (16%) with chemotherapy.

“The safety of sacituzumab govitecan was consistent with its known profile,” explained Cortés, “with the least rate of treatment discontinuation at 4% compared with 12% with chemotherapy."

Overall, this data might support sacituzumab govitecan as a new standard of care for patients with triple-negative breast cancer who cannot receive immunotherapy.

Continuing Research

The recent findings from the TROPION-Breast02 and ASCENT-03 phase 3 trials mark a significant advancement in the treatment landscape for triple-negative breast cancer (TNBC), particularly for patients who are not candidates for immunotherapy. Both datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) demonstrated substantial clinical benefit over traditional chemotherapy, with meaningful improvements in progression-free and overall survival. These Trop2-targeting antibody-drug conjugates represent a promising new standard of care for patients with locally recurrent or metastatic TNBC, offering hope in a historically challenging and underserved subset of breast cancer. Continued research and long-term follow-up will be crucial to further define their role and optimize treatment strategies in this aggressive disease.

REFERENCES

1. Gerlach A. Statins and metformin improved survival in patients with triple-negative breast cancer. Pharmacy Times. October 15, 2025. Accessed October 20, 2025. https://www.pharmacytimes.com/view/statins-and-metformin-improved-survival-in-patients-with-triple-negative-breast-cancer

2. Dent R, Shao Z, Schmid P, et al. LBA21 - First-line (1L) datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (mTNBC) for whom immunotherapy was not an option: Primary results from the randomised, phase 3TROPION-Breast02 trial. Presented at: European Society for Medical Oncology 2025 Congress. October 17, 2025, to October 21, 2025. Berlin, Germany. Abstract LBA21

3. A study of dato-DXd versus investigator's choice chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer, who are not candidates for PD-1/​PD-L1 inhibitor therapy (TROPION-Breast02). Clinicaltrials.gov. July 10, 2025. Accessed October 20, 2025. https://clinicaltrials.gov/study/NCT05374512

4. Liao Q, Zhang R, Ou Z, et al. TROP2 is highly expressed in triple-negative breast cancer CTCs and is a potential marker for epithelial mesenchymal CTCs. Molecular Therapy Oncology. January 9, 2024. doi: 10.1016/j.omton.2024.200762

5. Study of sacituzumab govitecan-hziy versus treatment of physician's choice in patients with previously untreated locally advanced inoperable or metastatic triple-negative breast cancer (ASCENT-03). Clinicaltrials.gov. Setpember 5, 2025. Accessed October 20, 2025. https://clinicaltrials.gov/study/NCT05382299

6. Novel agents, promising data: The evolving landscape of oncology care, Pharmacy Times. May 30, 2025. Accessed October 20, 2025. https://www.pharmacytimes.com/view/novel-agents-promising-data-the-evolving-landscape-of-oncology-care

7. Bartsch R, Im S, Loibl S, et al. Proffered paper session 2: Breast cancer, metastatic. Presented at: European Society for Medical Oncology 2025 Congress. October 17, 2025, to October 21, 2025. Berlin, Germany.