Evidence Elevates TROP2-Directed ADCs Over Chemotherapy in First-Line Metastatic TNBC

Consistent efficacy signals from multiple first-line studies support a paradigm shift toward TROP2-directed antibody-drug conjugates (ADCs) in the frontline setting for most patients with metastatic triple-negative breast cancer (TNBC), with PARP inhibitors remaining a consideration for select mutation-defined subgroups, according to Ana C. Garrido-Castro, MD.

“I’m excited to see some of the data from ongoing trials,” Garrido-Castro said in an interview with OncLive®. “There are multiple clinical studies that are evaluating new ADCs in the first-line metastatic setting, [and] also as neoadjuvant and adjuvant therapy for early-stage TNBC. New combinations are being explored, and bispecific ADCs are being developed. There is much more to come in the world of ADCs for the management of [TNBC].”

In the interview, Garrido-Castro discussed the designs and clinical implications of 3 of the largest phase 3 TNBC trials that reported out in 2025: TROPION-Breast02 (NCT05374512),¹ ASCENT-03 (NCT05382299),² and ASCENT-04 (NCT05382286).³ She noted that data from TROPION-Breast02 showed significant improvements in progression-free survival (PFS) and overall survival (OS) with first-line datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) vs chemotherapy for patients with metastatic TNBC who were ineligible for immunotherapy. She also highlighted the benefits of sacituzumab govitecan-hziy (Trodelvy)—based therapy in the ASCENT trials. This included PFS improvements with the ADC as monotherapy in patients ineligible for checkpoint inhibitors in ASCENT-03, and with sacituzumab govitecan plus pembrolizumab (Keytruda) in those with PD-L1–positive TNBC in ASCENT-04. Contextualizing these findings within updates to the NCCN Clinical Practice Guidelines in Oncology for breast cancer, she emphasized the importance of considering these ADCs as upfront treatments for patients with TNBC.

Garrido-Castro is director of Triple-Negative Breast Cancer Research and a physician at Dana-Farber Cancer Institute, as well as assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What is important to know about the design of the TROPION-Breast02 trial?

Garrido-Castro: This was a first-line study in metastatic TNBC for patients who were not candidates for immune checkpoint inhibitors, primarily due to PD-L1–negative disease. Patients were randomly assigned to receive either Dato-DXd or chemotherapy of physician’s choice in that first-line setting. The study was designed with dual primary end points: PFS and OS. Both those end points were met, demonstrating significant improvements for both, favoring Dato-DXd vs chemotherapy.

What was the design of the ASCENT-03 trial?

The other study that was presented at the same time [as TROPION-Breast02] at the 2025 ESMO Congress was the ASCENT-03 study, which investigated another TROP2-directed ADC, sacituzumab govitecan, vs chemotherapy of physician’s choice, also in the first-line setting, for patients who were not candidates for PD-L1 inhibition primarily due to PD-L1–negative disease. This study was powered for PFS and met that primary end point. OS was a key secondary end point, and those data were immature at the time of the presentation at ESMO 2025.

Do TROP2-directed ADCs work in combination with immune checkpoint inhibition for PD-L1–positive metastatic TNBC?

[In the context of the data from TROPION-Breast02 and ASCENT-03, we should also consider] the data that we saw from ASCENT-04, [which were presented] at the 2025 ASCO Annual Meeting. That was a study for patients with first-line, PD-L1–positive (defined as a combined positive score greater than or equal to 10 using the 22C3 assay) metastatic TNBC, comparing sacituzumab govitecan plus pembrolizumab with chemotherapy plus pembrolizumab. [ASCENT-04 data] also demonstrated a significant improvement in median PFS, favoring the combination with the TROP2-directed ADC.

[Sacituzumab govitecan plus pembrolizumab] has also been listed in the NCCN guidelines for the first-line treatment of patients with PD-L1–positive metastatic TNBC.

How should all these recent data readouts be integrated into clinical practice?

There are some important differences in the designs between TROPION-Breast02 and ASCENT-03, such as the eligibility criteria (including the disease-free interval from treatment in the curative setting, chemotherapy options in the control arm, incorporation of cross-over and subsequent ADC therapy, and the statistical design. However, we saw a consistent PFS benefit for both TROP2-directed ADCs in the first-line setting vs chemotherapy. This is shifting how we think about first-line treatment for metastatic TNBC in patients who are not candidates for immune checkpoint inhibition, primarily due to PD-L1–negative disease. These TROP2-directed ADCs are now endorsed by the NCCN guidelines as a first-line treatment approach for these patients.⁴ We still await regulatory approval of these agents in that setting.

What do current data for TROP2-directed ADCs show about the potential evolution of this class of agents in TNBC, especially given disease heterogeneity and the role of other classes of agents, such as PARP inhibitors?

We are seeing how the TROP2-directed ADCs are positioning themselves as preferred first-line regimens for patients with metastatic TNBC. In the PD-L1–negative setting (no demonstrated survival benefit with the addition of pembrolizumab to chemotherapy), for the approximately 10% of patients who carry germline BRCA1/2 mutations or PALB2 mutations, it remains unclear if we should consider using a TROP2-directed ADC vs a PARP inhibitor as first-line therapy.

PARP inhibitors were not included in the control arms of ASCENT-03 or TROPION-Breast02. There is no direct head-to-head comparison between TROP2-directed ADCs and PARP inhibitors in these patients, and PARP inhibitors have [been] demonstrated to improve not only PFS, but also quality of life [QOL], compared with standard chemotherapy of physician’s choice in metastatic TNBC. Although the phase 3 EMBRACA [NCT01945775] and OlympiAD [NCT02000622] studies did not show significant improvements in OS with a PARP inhibitor vs chemotherapy, in an exploratory analysis from OlympiAD, the subgroup of patients who received the PARP inhibitor olaparib [Lynparza] as first-line therapy appeared to derive OS benefit compared with chemotherapy; this signal was not observed in the second-/third-line setting. Although this was an exploratory analysis, given considerations about the toxicity profiles between these agents and their effects on QOL, it is reasonable to consider the use of a PARP inhibitor in the first-line setting for patients with TNBC [harboring] germline BRCA1/2 or PALB2 mutations who are not candidates for immune checkpoint inhibition. For most patients who do not carry germline BRCA1/2 or PALB2 mutations, TROP2-directed ADC therapy will be a preferred approach in the metastatic TNBC setting.

References

1. Dent RA, Shao Z, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: primary results from the randomised, phase 3 TROPION-Breast02 trial. Ann Oncol. 2025;36(suppl 2):S1566-S1567. doi:10.1016/j.annonc.2025.09.031
2. Cortés JC, Bardia A, Punie K, et al. Primary results from ASCENT-03: a randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). Ann Oncol. 2025;36(suppl 2):S1565-S1566. doi:10.1016/j.annonc.2025.09.030
3. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109
4. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2026. Accessed March 2, 2026. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf