Presentations at both the European Society for Medical Oncology Congress 2025 and the 2025 San Antonio Breast Cancer Symposium® have initiated a wave of optimism about the therapeutic landscape in first-line metastatic triple-negative breast cancer (mTNBC). In the conversation below, Dr. Laura Huppert and nurse practitioner Magdelena Ford provide context for the excitement providers are feeling through insights about the nuances of the data and of potential real-world implications for patient care.

Please note that this article was previously published and has been corrected to address errors regarding the PFS in ASCENT-03 (9.7 months for sacituzumab govitecan vs. 6.9 months for chemotherapy; previously reported as 6.0 months for chemotherapy) and the incidence rate of dry eye with datopotamab deruxtecan (24%; previously reported as 22%). Clarification regarding crossover from first-line chemotherapy to subsequent antibody–drug conjugate (ADC) in ASCENT-03 has also been added.

Editor’s Note: On February 3, 2026, the supplemental Biologics License Application for datopotamab deruxtecan was accepted by the U.S. Food and Drug Administration and Priority Review was granted for treatment of patients who are not candidates for PD-1/PD-L1 inhibitors and who have unresectable or metastatic TNBC.

As breast cancer specialists who treat patients with mTNBC, why is there so much excitement about novel data in the first-line setting? 

Dr. Huppert: Triple-negative breast cancer is the most aggressive breast cancer subtype, and many of these patients are younger than 50. Unfortunately, the 5-year survival for patients with mTNBC is estimated to be 15%,¹ so it’s an extremely devastating diagnosis and definitely an area of unmet clinical need.

The current standard of care for mTNBC is to first check a patient’s PD-L1 and BRCA statuses. If a patient is PD-L1 positive, the standard of care is to give chemotherapy and pembrolizumab, per the KEYNOTE-355 trial.² However, if a patient has PD-L1–negative disease and no BRCA mutation, the standard of care is chemotherapy alone. If a patient has PD-L1–negative disease and a BRCA1 or BRCA2 mutation, then a PARP inhibitor — either olaparib or talazoparib — is added.

We recently saw data from the TROPION-Breast02³ for datopotamab deruxtecan (Dato-DXd) and ASCENT-03 trials⁴ for sacituzumab govitecan in first-line mTNBC, both of which looked at patients who were not candidates for a PD-L1 inhibitor. Both of these trials were positive, with improvements in progression-free survival (PFS); however, a key difference was that TROPION-Breast02 showed a statistically significant improvement in overall survival (OS). ASCENT-04 reported on sacituzumab govitecan plus pembrolizumab for patients with PD-L1–positive mTNBC.⁵ In addition, the ongoing TROPION-Breast05 (NCT06103864) is evaluating Dato-DXd plus durvalumab for patients with high PD-L1 expression and mTNBC.

The three first-line mTNBC trials with antibody–drug conjugates (ADCs) that we have seen data from so far (ASCENT-03, ASCENT-04, TROPION-Breast-02) are all positive studies, which is very exciting. They are not yet approved by the FDA, but we anticipate ADCs will be approved in the first-line setting for patients with mTNBC, which will lead to better outcomes for these patients.

Ms. Ford: I fully agree that this is a really exciting time for treatment options for patients with mTNBC, which historically is such a difficult-to-treat diagnosis. Although the adverse event (AE) profiles do differ, I think that both of these ADC options can offer better quality of life, as they both are associated with mostly mild AEs that are easily managed through preventative measures and patient education. In the absence of head-to-head trials, there are a few things that will differentiate them, with one being their very different treatment schedules. Dato-DXd is given once every 21 days, with the first infusion lasting around 90 minutes and subsequent infusions lasting 30 minutes. Sacituzumab govitecan is given on Days 1 and 8 in a 21-day cycle. These infusions are a little longer, with the first lasting about 3 hours and subsequent infusions lasting 1 to 2 hours.

I think it’s nice to be able to have a conversation with patients about what each treatment schedule looks like. For patients who live near the infusion center and have no problem coming in for treatment 2 weeks in a row, sacituzumab govitecan might be a reasonable choice compared with those patients who live far away, are working while on treatment, or have a hard time securing transportation for multiple weeks in a row — Dato-DXd may be more ideal for these patients.

How do the ASCENT-03 and TROPION-Breast02 trial designs and populations differ, and what do these differences mean when looking at endpoint data?

Dr. Huppert: ASCENT-03 was a phase 3 first-line trial for patients with mTNBC who were not candidates for PD-L1 inhibitor therapy. These patients were randomly assigned one-to-one to receive sacituzumab govitecan versus physician’s-choice chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin). Patients must have had a disease-free interval of at least 6 months from prior therapy for early-stage TNBC. Importantly, if a patient was randomly assigned to the chemotherapy arm, they were able to crossover to receive sacituzumab govitecan in the second line provided by the study, which was a really nice feature of the trial. The study showed an improvement in progression-free survival (PFS) favoring sacituzumab govitecan versus chemotherapy (9.7 months vs. 6.9 months; HR, 0.62). The objective response rate was fairly similar between the arms: 48% versus 46%, respectively. Importantly, of the 64% (n=179) of patients in the chemotherapy arm who received any subsequent therapy after discontinuation, 82% (n=147) crossed over to sacituzumab govitecan in the second line. This crossover may have impacted overall survival (OS) data, which is still immature. PFS2 did favor sacituzumab govitecan versus chemotherapy (18.2 months vs. 14.0 months; HR, 0.70).⁶

TROPION-Breast02 was also a phase 3 trial evaluating patients with mTNBC who had not received any prior therapy for their metastatic disease and who were not candidates for PD-L1 therapy. This study randomly assigned patients one-to-one to receive Dato-DXd versus physician’s choice chemotherapy (paclitaxel, nab-paclitaxel, or capecitabine, carboplatin, or eribulin). This trial allowed enrollment of patients with any disease-free interval from their early-stage therapy, but there was a cap at 20% for those with a disease-free interval of less than or equal to 12 months, which was met. As Dato-DXd is not approved in the mTNBC setting, there was no crossover to Dato-DXd specifically, but about 30% of patients in the chemotherapy arm received a subsequent ADC if available. There were dual primary endpoints of PFS and OS, with a statistically significant OS benefit for Dato-DXd of 23.7 versus 18.7 months for chemotherapy.³ In addition, there was an improvement in median PFS with Dato-DXd of 10.8 versus 5.6 months (HR, 0.57). There also was a doubling of the objective response rate (ORR) for Dato-DXd (63% vs. 29% for chemotherapy).

It’s important to keep in mind that it’s hard to compare the survival endpoints because of the crossover to sacituzumab govitecan provided by the study in ASCENT-03, which was not included in the design of TROPION-Breast02, again given that Dato-DXd is not approved in mTNBC. TROPION-Breast02 included those patients who had faster relapse from their early-stage disease, with no limit on time from prior therapy for their early-stage breast cancer, which was nice to see. Also, the objective response rates were different in each study, with 63% for Dato-DXd versus 48% for sacituzumab govitecan,^3,6 so if the ORR is slightly higher for Dato-DXd this may be important for patients with symptomatic disease.

Ms. Ford: I agree — choice is a great problem to have! I think the fact that we’re able to have these conversations with patients where we are considering multiple treatment options, especially alternatives to chemotherapy as first-line therapy is really wonderful. Overall, I think it is important to provide education to patients about the different potential AEs and find out which they are more willing to navigate, while also taking into consideration comorbidities and pre-existing conditions.

What are the most common AEs associated with Dato-DXd and sacituzumab govitecan, and how can they most effectively be avoided or minimized prophylactically?

Dr. Huppert: When discussing AEs with patients, there are different ways to go about this, but one thing that I often do is pull up the trial data and walk through both the efficacy and the safety data. For sacituzumab govitecan, common AEs include neutropenia, diarrhea, alopecia, and fatigue, with fatigue being a common cause for dose reductions. ASCENT-03 showed that neutropenia of any grade was seen in 67% of patients, with 43% experiencing  grade 3 or higher.⁶ Diarrhea of any grade was seen in 54% of patients in ASCENT-03, with grade 3 or higher found in 9% of patients.⁶

For Dato-DXd, the main AE, which occurred in 57% of patients on this trial, was stomatitis.³ Most of these cases were grade 1 or 2, and grade 1 cases included asymptomatic patients. The use of prophylactic steroid mouthwash can help to reduce the incidence and severity of stomatitis, so it is important to counsel patients about adherence to this regimen. Magdelena, I know you’ll discuss this in more detail later.

Ocular surface events were experienced by 47% of patients, although most of these were grade 1 (24%) or grade 2 (16%). Dry eye was the most common of these, with 24% of patients experiencing any grade of dry eye and only 1% experiencing grade 3 or higher.³ Dry eye was the most common of the ocular events, so prophylactic preservative-free eyedrops are recommended four times a day and as needed to reduce the incidence of this, and an initial eye exam is required. We have learned from the hormone receptor-positive (HR+) space, where Dato-DXd is already approved, that a patient can see an optometrist or an ophthalmologist around the time of treatment initiation. This is how the label is worded, and I find that helpful because I feel comfortable, given how mild the ocular effects usually are, to start the drug and then have the patient see an optometrist or an ophthalmologist within one or two cycles after that for the initial exam. After that initial visit, the recommendation is to have the patient see an eye provider annually or as needed should any symptoms occur, such as eye dryness or blurry vision. It’s also important to counsel patients that it’s better not to use contact lenses.

Grade 1 dry eye is defined as when the patient is asymptomatic but evidence of dryness is observed by an optometrist or an ophthalmologist. Once a patient starts to experience symptoms of dry eye, that indicates grade 2 toxicity. I have found that most optometrists do feel comfortable doing the baseline exam and managing lower-grade toxicities. Ophthalmologists should typically be consulted for ocular events that are grade 3 or higher.

Ms. Ford: Regarding the details of AE management, I think that advanced practitioners (APPs) are in a really unique role where we can really emphasize patient education and the importance of prophylactic measures.

There’s a lot that can be done for the stomatitis. In general, with prophylactic measures, most cases are grade 1 or 2. It does tend to happen early in treatment — median time to onset in TROPION-Breast01 was 22 days^7,8 — which makes it vital to emphasize the importance of starting the prophylactic regimen prior to starting treatment with Dato-DXd. I spend time educating patients about monitoring for redness, pain, and edema both with and without the presence of ulcerations, as these can be early manifestations. I think it’s also important for APPs to not rely exclusively on exam features for this AE, but also on what patients are reporting, making patient education important.

As mentioned, oral stomatitis is quite common with Dato-DXd, but it can be highly manageable with diligent prophylaxis and frequent monitoring. We recommend a prophylactic non-alcoholic corticosteroid containing mouthwash — dexamethasone (0.1 mg/mL) for example — four times daily after meals and at bedtime from Day 1 and throughout treatment. I do think it’s really important to counsel patients on the importance of swishing 5 to 10 mL around for a full 1 to 2 minutes. They should try to cover the full throat and even gargle to cover the back of the throat. It can be helpful to have patients bring their mouthwash to the clinic so you can walk them through the preferred technique. It can be hard for patients to adhere to this prophylactic regimen so I emphasize that it’s much easier to address this AE prophylactically rather than wait to treat it once symptoms are onset.

Other things to educate patients on are good oral hygiene and how to monitor for thrush, as this is a common AE of dexamethasone mouthwash, although I don’t typically initiate nystatin prophylaxis right away. Lastly, patients should be counseled about dietary changes such as avoiding crunchy, spicy, hot, or acidic foods — all the foods that you think about that could be irritating to the mouth — and avoiding tobacco and alcohol consumption.

In addition to what was already noted about prevention of ocular events, I tell patients to practice good skin hygiene around the eyes and be careful when washing off eye makeup. I certainly want to know if patients are starting to have tearing eyes, blurry vision, eye redness, or pain. If so, I will consult and collaborate with my optometry or ophthalmology colleagues.

As mentioned, the risk for neutropenia is much higher for sacituzumab govitecan than for Dato-DXd. For this reason, patients receiving sacituzumab govitecan typically require primary prophylaxis with a granulocyte colony-stimulating factor (G-CSF) for neutropenia, and counts are monitored more frequently. Typically I will start short-acting G-CSF after Day 1 treatment, and then I may give long-acting G-CSF with Day 8 treatment. This helps avoid multiple doses of short-acting G-CSF, depending on how a patient’s neutrophil counts are responding. Neutropenia can impact quality of life and can cause dose interruption, which can be cumbersome for patients, especially if they live farther from the infusion center.

Interstitial lung disease (ILD), or pneumonitis, with Dato-DXd is quite rare, with only 3.6% of a pooled population from the TROPION-Breast01 and TROPION-PanTumor01 trials experiencing any-grade ILD and 0.7% experiencing grade 3.⁹ I did want to mention this, however, because this can be an important consideration for our patients with underlying respiratory symptoms. Advanced practitioners are well positioned to educate patients about monitoring for shortness of breath, cough, chest tightness, or wheezing. Panels for COVID-19 or viral respiratory infections can help us rule these out before moving on to standard ILD management. It’s important to have a multidisciplinary approach with ILD, and I find it helpful to talk through imaging findings with radiology colleagues or consult the infectious disease team about symptoms that don’t respond to steroid initiation.

What are your hopes for the short-term future for the mTNBC landscape?

Dr. Huppert: I hope that we’ll see new approvals in 2026 that will allow us to use these agents in the first-line setting for patients with mTNBC. If that happens, I also think there will be subsequent questions that will require evaluation. For example, we’ve seen retrospective data showing decreasing efficacy when multiple ADCs with topoisomerase I inhibitor payloads are given in sequence,^10,11 so we need to understand ADC sequencing a bit better. There are multiple prospective trials that are ongoing to evaluate this in HR+/human epidermal growth factor receptor (HER2)-low/ultra-low metastatic breast cancer (NCT06263543, NCT06533826, and NCT06774027) that we can hopefully look to for guidance.

We also need ADCs with novel targets and payloads so that we can potentially use ADCs that differ from each other in sequence and hopefully see greater efficacy. In addition, there are multiple ongoing trials evaluating ADCs in early-stage (TNBC) as well (see Box 1). It will be interesting to see how metastatic treatment changes if these agents move into the earlier-stage setting.

References:

1. National Cancer Institute. Cancer Stat Facts: Female Breast Cancer Subtypes. Accessed January 9, 2026. https://seer.cancer.gov/statfacts/html/breast-subtypes.html
2. Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022;377:217-226.
3. 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.
4. Cortés J, Punie K, Barrios C, et al. Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer. N Engl J Med. 2025;393;1912-1925.
5. 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.
6. Cortés J, 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 Unable to Receive PD-(L)1 Inhibitors. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA20.
7. Bardia A, Jhaveri K, Im S-A, et al. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor–Positive Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025;43(3):285-296.
8. Lisberg A, Huppert LA, Halmos B, Ledezma B, Soto-Romano V, Traina TA. Datopotamab deruxtecan-associated select adverse events: clinical practices and institutional protocols on prophylaxis, monitoring, and management. Oncologist. 2025;30(9):oyaf225.
9. DATROWAY website. https://datrowayhcp.com. Accessed January 5, 2026.
10. Huppert LA, Mahtani R, Fisch S, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC). NPJ Breast Cancer. 2025;11(1):34.
11. Poumeaud F, Morisseau M, Reich M, et al. 312P Efficacy of sequential antibody-drug conjugates (ADCs) targeting topoisomerase-1 in HER2-low metastatic breast cancer (MBC): Updated results and additional analyses from the French multicenter retrospective ADC-low cohort. ESMO Open. 2025;10(Suppl 4):104884.