How Will the Continued Success of ADCs in Breast Cancer Be Propelled in the Future?

Aditya Bardia, MD, highlights the successes and challenges associated with ADC treatments in breast cancer.

Antibody drug conjugates (ADCs) in breast cancer represent 3 strong treatment options, including sacituzumab govitecan-hziy (Trodelvy), fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), and datopotamab deruxtecan-dlnk (Dato-DXd; Datroway).

At the 16th World ADC Conference, Aditya Bardia, MD, MPH, FASCO, spoke about the future of ADC research, what challenges are currently being overcome, and how they can expand ADC research.1

Throughout the presentation, Bardia touched on pivotal trials involving ADCs, including the phase 3 ASCENT-03 trial (NCT05382299), phase 3 TROPION-Breast01 trial (NCT05104866), and phase 3 TROPION-Breast02 trial (NCT05374512). He also looked at characteristics of how to select the best therapy by weighing efficacy and toxicity.

Bardia is a professor in the Department of Medicine, Division of Hematology/Oncology, and the director of Translational Research Integration at the University of California Los Angeles Health Jonsson Comprehensive Cancer Center.

Behind Sacituzumab Govitecan Treatment

The selective delivery of the toxic payload comes in 5 key areas:2

• Binding of an ADC to an antigen
• Internalization to the early endosome
• Degradation of ADCs in the lysosome
• Release and action of the payload
• Apoptosis of the cancer cell

Bardia highlighted that sacituzumab govitecan was different from other ADCs, as it was highly specific for Trop-2 and had a high drug-to-antibody ratio of 7.6:1, among others.

Results from a phase 1/2 trial (NCT01631552) were referenced, which assessed sacituzumab govitecan in patients with refractory metastatic triple-negative breast cancer.3 Results showed an overall response rate of 33%, with a clinical benefit rate of 45.4%. These results then led to the approval of sacituzumab govitecan by the FDA in April 2020. Bardia noted that this was the first time a treatment was approved in breast cancer based on a single-arm study.4

Following this approval, the randomized phase 3 ASCENT trial (NCT02574455) tested sacituzumab govitecan vs chemotherapy further in this setting.5 The median progression-free survival (PFS) was 5.6 months (95% CI, 4.3-6.3) in the sacituzumab arm and 1.7 months (95% CI, 1.5-2.6) in the chemotherapy arm (HR, 0.41; 95% CI, 0.32-0.52; P <.0001). The median overall survival (OS) was 12.1 months (95% CI, 10.7-14.0) in the sacituzumab arm and 6.7 months (95% CI, 5.8-7.7) in the chemotherapy arm (HR, 0.48; 95% CI, 0.38-0.59; P <.0001).

Recently, at the European Society for Medical Oncology Congress 2025, results from the phase 3 ASCENT-03 trial were presented, highlighting a PFS improvement by Blinded Independent Central Review (BICR).6 In the sacituzumab arm, the median PFS was 9.7 months (95% CI, 8.1-11.1) vs 6.9 months (95% CI, 5.6-8.2) in the chemotherapy arm (HR, 0.62; 95% CI, 0.50-0.77; P <.0001).

“The decision to develop this drug was more driven by the clinical unmet need, rather than biology per se. You can see that that paid dividends because [of the FDA] approval based on a single-arm study. That could not have happened in estrogen receptor [ER]–positive metastatic breast cancer,” Bardia said.

Next, the aim of the phase 3 TROPiCS-02 trial (NCT03901339) was to assess OS in sacituzumab govitecan vs chemotherapy.7 Results showed the median OS was 14.4 months (95% CI, 13.0-15.7) in the sacituzumab arm vs 11.2 months (95% CI, 10.1-12.7) in the chemotherapy arm (HR, 0.79; 95% CI, 0.65-0.96; P = .020).

Dato-DXd in HER2 Breast Cancer

The TROPION-Breast01 trial looked at Dato-DXd vs investigator’s choice of chemotherapy in patients with hormone receptor–positive/HER2-negative breast cancer.8 The median PFS by BICR was 6.9 months (95% CI, 5.7-74.4) in the Dato-DXd arm vs 4.9 months (95% CI, 4.2-5.5) in the chemotherapy arm (HR, 0.63; 95% CI, 0.52-0.76; P <.0001). The PFS by investigator assessment was 6.9 months vs 4.5 months (HR, 0.64; 95% CI, 0.53-0.76).

The median OS was 18.6 months (95% CI, 17.3-20.1) in the Dato-DXd arm and 18.3 months (95% CI, 17.3-20.5) in the chemotherapy arm (HR, 1.01; 95% CI, 0.83-1.22). When adjusted for subsequent ADC therapy, the median OS was 19.1 months vs 17.5 months (HR, 0.86; 95% CI, 0.70-1.06).

Results from TROPION-Breast02 showed a median PFS by BICR of 10.8 months (95% CI, 8.6-13.0) in the Dato-DXd arm and 5.6 months (95% CI, 5.0-7.0) in the chemotherapy arm (HR, 0.57; 95% CI, 0.47-0.69; P <.0001).9 A reduction in the risk of death of 43% was noted.

The median OS was 23.7 months in the Dato-DXd arm and 15.7 months in the chemotherapy arm (HR, 0.79; 95% CI, 0.64-0.98; P = .0291). There was a reduction in the risk of death by 21%.

Bardia noted that there were multiple ADCs in development to target antigens that were overexpressed in metastatic breast cancer, which in the future would most likely replace chemotherapy. Additionally, there are 100 ADCs in clinical development across various tumor types.

How to Select Therapy

“How do we select therapy? We already have Dato-DXd approved in ER–positive cancer. You have sacituzumab govitecan that is approved. You have trastuzumab deruxtecan that’s approved. How would we select between these drugs? It’s a balance of efficacy and toxicity in general; at least at this time, the efficacy results are not that different, particularly between the Trop-2 ADCs. In large part, the decision-making at this time is based on toxicity,” Bardia questioned.

Firstly, he highlighted the need to optimize biomarker response. He provided an example slide of an immunohistochemistry (IHC) stain and asked the audience to determine if the patient had an IHC of 0 or 1+. Notably, patients with IHC 0 cannot be given T-DXd.

The challenge, Bardia noted, is that IHC-based assays are not sensitive enough to identify low expressors.

Efficacy results from the phase 3 DESTINY-Breast06 trial (NCT04494425) demonstrated a confirmed ORR of 56.5% in the T-DXd arm vs 32.2% in the chemotherapy arm for patients who are HER2-low, 57.3% vs 31.2% for patients in the intention-to-treat population, and 61.8% vs 26.3% for patients who are HER2-ultralow.10

When looking at results from the ASCENT trial with the efficacy of sacituzumab govitecan stratified by Trop2 expression, tThe PFS probability in Q1 (H-score, 0-130) was 2.7 months (95% CI, 1.4-5.7) in the sacituzumab arm vs 1.5 months (95% CI, 1.4-2.2) in the chemotherapy arm (HR, 0.583; 95% CI, 0.339-1.003).11 In Q2 (H-score, 130-220), the median PFS was 4.8 months (95% CI, 2.9-7.1) vs 2.8 months (95% CI, 1.7-4.3; HR, 0.517; 95% CI, 0.291-0.920); Q3 (H-score, 220-275) had rates of 6.8 months (95% CI, 4.3-8.3) vs 1.6 months (95% CI, 1.4-2.7; HR, 0.196; 95% CI, 0.105-0.364); and Q4 (H-score, 275-300) had rates of 6.9 months (95% CI, 5.6-8.1) vs 2.8 months (95% CI, 1.4-3.1), respectively (HR, 0.314; 95% CI, 0.166-0.592).

Regarding the biomarker and ADC response, Bardia highlighted that the expression of the antigen was not strongly correlated with ADC efficacy. Additionally, he asked whether there was an issue of target measurement vs ADC mechanism of action or study design, and whether there should be more quantitative methods for target assessment.

To answer some of these, Bardia discussed ADCs in combination with immunotherapy.

“We know chemotherapy plus immunotherapy works, and with ADCs, it’s somewhat of a similar principle in the sense that you have apoptosis, which can activate the cells in the tumor microenvironment, but if there’s PD-L1 present, that would reduce the efficacy of the T cells, so you could combine immune checkpoint inhibitors with ADCs. In phase 1 studies, we’ve seen success combining ADCs with immunotherapy, but the final proof of principle came from a phase 3 trial presented at ASCO this year, where sacituzumab govitecan was combined with immunotherapy, with pembrolizumab, and compared with chemotherapy plus immunotherapy. You could see improvement in PFS, and a trend towards improvement in OS as well,” Bardia said.12

In his final point, Bardia asked how toxicity can be reduced and what ways the ADC safety profile can be optimized. He took a look at the 3 different ADCs. Dato-DXd had a common adverse effect of stomatitis, which was different from sacituzumab govitecan and T-DXd. Patients being treated with vic-trastuzumab duocarmazine often experienced keratitis, and the phase 3 trial resulted in a complete response letter by the FDA because of this.13

Looking towards the future, Bardia believes that trials will assess various ADCs targeting different antigens. However, there will still be challenges regarding biomarker development, ADC mechanism of action, and toxicity management.

Overall, to deliver the best possible care, a multidisciplinary team streamlining cross-disease and translation research will help to determine the most applicable antibody-based therapies and improve outcomes of patients with cancer.

References

1. Bardia A. Moving forward with ADCs in clinic: challenges and opportunities. Presented at the 2025 World Antibody Drug Conjugate Conference; San Diego, CA; November 3-6, 2025.
2. Nagayama A, Ellisen LW, Chabner B, Bardia A. Antibody-drug conjugates for the treatment of solid tumors: clinical experience and latest developments. Target Oncol. 2017;12(6):719-739. doi:10.1007/s11523-017-0535-0
3. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213
4. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. News release. FDA. April 22, 2020. Accessed November 4, 2025. https://tinyurl.com/bdt7dw75
5. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384:1529-1541. doi:10.1056/NEJMoa2028485
6. 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). Abstract presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA20.
7. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423-1433. doi:10.1016/S0140-6736(23)01245-X
8. Pistilli B, Jhaveri K, Im SA, et al. VP1-2025: Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Final overall survival (OS) from the phase III TROPION-Breast01 trial. Annal Oncol. 2025;36(3):P348-350.
9. 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. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.
10. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000
11. Bardia A, Rugo HS, Tolaney SM, et al. Final results from the randomized phase III ASCENT clinical trial in metastatic triple-negative breast cancer and association of outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 expression. J Clin Oncol. 2024;42(15):1738-1744. doi:10.1200/JCO.23.01409
12. 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
13. U.S. Food and Drug Administration issues complete response letter for Byondis’ [vic-]trastuzumab duocarmazine. News release. Byondis B.V. May 15, 2023. Accessed November 4, 2025. https://tinyurl.com/yvcfxp5d