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Roles of TROP-2–Directed ADCs in the Management of HER2-Negative Metastatic Breast Cancer

Released: January 12, 2026

Javier Cortes
Javier Cortes, MD, PhD
Sara M. Tolaney
Sara M. Tolaney, MD, MPH
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Key Takeaways
  • Phase III ASCENT-03 and TROPION-Breast02 trials for patients with previously untreated, advanced TNBC demonstrated significantly improved PFS with frontline sacituzumab govitecan and datopotamab deruxtecan, respectively, vs chemotherapy.
  • TROP-2–directed ADCs may be preferred over PARP inhibitor therapy for some patients with newly diagnosed HER2-negative, PD-L1–negative advanced breast cancer harboring a germline BRCA mutation with high volume and/or symptomatic disease.
  • In the PRIMED trial, primary prophylaxis with G-CSF yielded clinically significant reduction in the occurrence and severity of neutropenia associated with sacituzumab govitecan.

In this commentary, Javier Cortes, MD, PhD, and Sara M. Tolaney, MD, MPH, address key questions posed by the audience during the recent webinar titled, “Optimizing Management of HER2-Negative MBC: Experts Discuss the Now and Future Roles of TROP-2–Directed ADCs” held following ESMO Congress 2025.

In which line of treatment would you consider the use of sacituzumab govitecan or datopotamab deruxtecan (Dato-DXd) for your patients with metastatic triple-negative breast cancer (TNBC)? 

Sara M. Tolaney, MD, MPH:
We have data from the phase III ASCENT trial of sacituzumab govitecan vs chemotherapy for patients with metastatic TNBC who have received ≥2 prior lines of chemotherapy. ASCENT demonstrated significant progression-free survival (PFS) and overall survival (OS) improvement with use of sacituzumab govitecan in the pretreated setting. Of importance, the data recently presented by Dr Cortes at ESMO Congress 2025 from the phase III ASCENT-03 trial of sacituzumab govitecan vs chemotherapy for patients with previously untreated, advanced TNBC who are not eligible to receive immunotherapy demonstrated that when sacituzumab govitecan is used in the first-line setting, PFS is significantly improved.

Results from another important trial, TROPION-Breast02, for patients who are ineligible to receive immunotherapy were presented at ESMO Congress 2025 by Dr Dent. The phase III TROPION-Breast02 trial investigated Dato-DXd vs chemotherapy for patients with locally recurrent inoperable or metastatic TNBC who had not previously received chemotherapy or targeted systemic therapy in this setting. TROPION-Breast02 demonstrated that the use of first-line Dato-DXd significantly improved PFS and OS vs chemotherapy.

If the use of these TROP-2–directed antibody–drug conjugates (ADCs), sacituzumab govitecan and Dato-DXd, is delayed until the second line or later, some patients will be excluded from deriving this benefit as some patients may not survive to be able to receive an ADC in subsequent-line settings. In metastatic TNBC, we know that 30% to 50% of patients are not able to receive a second line of treatment because of either the deterioration of health or death. So, for this reason, I would recommend the use of sacituzumab govitecan or Dato-DXd upfront rather than delaying use until later lines of therapy. In my opinion, for the vast majority of patients, ADCs should become the standard of care in the first-line setting.

Javier Cortes, MD, PhD:
I had the privilege of presenting data from ASCENT-03 at ESMO Congress 2025. As Dr Tolaney alluded to, the trial enrolled patients with untreated advanced TNBC with PD-L1–negative disease or those with PD-L1–positive disease who were not candidates for immune checkpoint inhibitor therapy because they previously received immunotherapy in the curative setting for early breast cancer. PFS with sacituzumab govitecan was significantly improved compared with chemotherapy, but OS data are still immature.

The design of ASCENT-03 is similar to that for TROPION-Breast02, but there are some differences. For instance, the ADC studied in each trial is different. Also, although crossover was allowed from the chemotherapy arm upon disease progression to the sacituzumab govitecan arm in the ASCENT-03 trial, TROPION-Breast02 did not allow crossover to receive Data-DXd from the chemotherapy arm. In the TROPION-Breast02 trial, Dato-DXd demonstrated statistically significant improvements in both PFS and OS compared with chemotherapy.

Based on the results of the ASCENT-03 and TROPION-Breast02 trials, I would certainly recommend the earlier use of sacituzumab govitecan and Dato-DXd, respectively, if approved as first-line therapy for patients with advanced disease in this setting.

How would you sequence treatment with a PARP inhibitor and a TROP-2–directed ADC for patients with germline BRCA mutation–positive advanced TNBC? 

Sara M. Tolaney, MD, MPH:
For patients who are newly diagnosed with HER2-negative, PD-L1–negative advanced breast cancer harboring a germline BRCA mutation, my choice between a PARP inhibitor and an ADC will be based on the volume of the disease. For example, for an asymptomatic patient with low-volume disease, specifically one with very low visceral involvement, I would recommend a PARP inhibitor (olaparib or talazoparib) particularly because it is oral and it does not require administration in a clinic setting. PARP inhibitors have been associated with an improved quality of life compared with standard chemotherapy, and most patients will prefer an orally available drug to intravenously administered drugs that do not cause hair loss. Although PARP inhibitors do not have OS benefit when compared with chemotherapy, an exploratory subgroup analysis of the randomized phase III OlympiAD trial for patients with germline BRCA1/2 mutation–positive HER2-negative metastatic breast cancer who had received ≤2 lines of chemotherapy in the metastatic setting demonstrated a trend toward OS benefit with olaparib compared to chemotherapy.

Regarding ADCs, however, we do not yet have data for the subset analysis of survival outcomes according to germline BRCA mutation status for either Dato-DXd or sacituzumab govitecan. In the ASCENT-03 trial, there are future plans to conduct a subset analysis of outcomes by BRCA mutation status determined by central testing so we should see these data in the near future.

In my practice, if a patient has high-volume disease, I would recommend treatment with a TROP-2–directed ADC. However, for patients with low-volume disease, I would consider a PARP inhibitor.

Javier Cortes, MD, PhD:
I completely agree. The treatment choice between an ADC and a PARP inhibitor for patients with newly diagnosed HER2-negative, PD-L1–negative advanced breast cancer harboring a germline BRCA mutation should depend on the volume of the patient’s disease and whether the patient is symptomatic or not.

Would you feel comfortable using sacituzumab govitecan or Dato-DXd in the second-line setting after first-line trastuzumab deruxtecan (T-DXd)? 

Sara M. Tolaney, MD, MPH:
Currently, we have very little data to guide us on the efficacy of the sequential use of ADC treatments. There are no datasets from randomized registrational trials of the efficacy and/or safety of administering an ADC after disease progression on the prior ADC in patients with advanced breast cancer. However, some real-world data have suggested that the PFS for the second ADC could be less than that obtained with the first, but that is not always the case. Sometimes, patients fare better on their second ADC than on the previously used ADC that they received and on which they experienced progression of disease.

Looking at this issue from a different perspective, it is beneficial that we have multiple effective options to choose from. For example, one can choose to administer Dato-DXd or sacituzumab govitecan if the patient previously received T-DXd. However, the challenge remains how to select between Dato-DXd and sacituzumab govitecan in the next line of therapy after progression on T-DXd. As the patient moves through the lines of treatment, there is also the choice of administering single-agent chemotherapy.

One of the unanswered questions about sequencing ADCs one after the other is the concern of whether one of the mechanisms of resistance to an ADC is resistance to the cytotoxic payload, and at this time, we only have ADCs approved that have payloads that inhibit topoisomerase 1.

In all, the decision to sequence one ADC after another is complicated. It is not a one-size-fits-all approach because the lack of continued response to the initially used ADC may be attributable to more than one mechanism of resistance.

Javier Cortes, MD, PhD:
I completely agree with Dr Tolaney. Both sacituzumab govitecan and Dato-DXd are humanized anti–TROP-2 monoclonal antibodies attached to a topoisomerase I inhibitor payload. In essence, they are similar drugs in more than one respect. The payload for sacituzumab govitecan is a camptothecin derivative (SN-38) with a cleavable hydrolyzable linker (CL2A), and the payload for Dato-DXd is an exatecan derivative with a tetrapeptide-based cleavable linker. Of note, both agents are capable of eliciting the bystander antitumor effect that results in the elimination of target tumor cells, as well as neighboring TROP-2–negative tumor cells. So, the decision to select between sacituzumab govitecan and Dato-DXd after progression on T-DXd is not an easy one to make with very little available data to guide treatment selection.

However, on the brighter side of things, the field of ADCs for patients with metastatic breast cancer is increasingly exciting. I think ADCs will soon be approved for use in the first-line setting for patients with PD-L1–negative advanced TNBC. Multiple ongoing trials are investigating optimal ADC sequencing approaches for patients with advanced breast cancer. For instance, the phase II TRADE-DXd trial (TBCRC-064) is investigating Dato-DXd followed by T-DXd or T-DXd followed by Dato-DXd for patients with metastatic HER2-negative (HER2-low or HER2 IHC 0) breast cancer after progression on the initial ADC (NCT06533826). Also, the phase II SERIES trial is investigating sacituzumab govitecan after disease progression on or after experiencing intolerance of T-DXd in estrogen receptor–positive/endocrine therapy–refractory, HER2-low advanced breast cancer (NCT06263543). So, the future remains bright. I also think we will see more trials investigating ADCs in combination with other agents in the frontline setting in the near future.

Sara M. Tolaney, MD, MPH:
Of note, other ADCs are in the clinical pipeline for patients with advanced breast cancer. Sacituzumab tirumotecan (Sac-TMT) is an anti–TROP-2 ADC that was investigated in the randomized phase III OptiTROP-Breast01 trial vs chemotherapy for patients with unresectable locally advanced or metastatic TNBC who have received ≥2 lines of therapy including ≥1 for metastatic disease. The study demonstrated a statistically significant improvement in PFS with Sac-TMT vs chemotherapy. Although the median OS was not reached on the Sac-TMT arm, there was a trend in favor of Sac-TMT benefit.

Also, the ongoing phase III OptiTROP-Breast02 trial is investigating Sac-TMT vs chemotherapy for patients with unresectable locally advanced, recurrent or metastatic hormone receptor–positive/HER2-negative breast cancer who have previously received 1-4 lines of chemotherapy. Data from this trial were recently presented at ESMO Congress 2025 by Dr Li. Sac-TMT significantly improved PFS compared with chemotherapy. Although the OS data are still immature, there was a trend in favor of Sac-TMT benefit.

These results with Sac-TMT are impressive, encouraging, and exciting. It is now being investigated in the phase III TroFuse-010 trial with or without pembrolizumab vs chemotherapy for patients with previously treated advanced hormone receptor–positive/HER2-negative breast cancer who have not received any prior chemotherapy in the advanced disease setting (NCT06312176). I think Sac-TMT has a promising future for use in the management of patients with relapsed/refractory advanced breast cancer.

In your clinical practice, when do you use primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) to prevent neutropenia associated with sacituzumab govitecan? 

Sara M. Tolaney, MD, MPH:
I have started using prophylaxis more commonly for my patients. The box warning for sacituzumab govitecan recommends primary prophylaxis with G-CSF for all patients at increased risk of febrile neutropenia. In my clinical practice, examples of patients for whom I would consider primary prophylaxis upfront include patients with a history of neutropenia, those who previously experienced febrile neutropenia, and older patients with preexisting comorbidities.

Real-world data have shown that patients with metastatic TNBC who received G-CSF prophylaxis before initiating second-line therapy with sacituzumab govitecan had low rates of any-grade neutropenia. So, sacituzumab govitecan–related neutropenia can be managed effectively with G-CSF. Again, this was particularly true for patients with an increased risk of developing febrile neutropenia.

Usually, I give either 3 days of G-CSF after administering sacituzumab govitecan on Day 1 and then use long-acting pegfilgrastim after administering the Day 8 dose. I find that this approach works quite well. If I use a growth factor, I can usually maintain the same dose of sacituzumab govitecan. Typically, I use growth factor support without the need to reduce the dose of sacituzumab govitecan, and this works very well.

Javier Cortes, MD, PhD:
I agree. It is important to note that the phase II PRIMED trial investigated the prophylactic use of loperamide (for diarrhea) and G-CSF therapies (for neutropenia) for patients with metastatic TNBC or luminal breast cancer treated with sacituzumab govitecan (NCT05520723). The trial demonstrated that the use of primary prophylactic G-CSF and loperamide yielded clinically significant reduction in the occurrence and severity of neutropenia and diarrhea associated with sacituzumab govitecan.

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What are your questions and challenges with the use of TROP-2–directed ADCs in the management of your patients with HER2-negative metastatic breast cancer? Take our poll and leave a comment or question.

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If Dato-DXd and/or sacituzumab govitecan are approved or added to the updated guidelines for patients with newly diagnosed advanced TNBC who are not candidates for immunotherapy, how likely are you to recommend an anti–TROP-2 ADC for patients in this setting?

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