The ASCENT-04/KEYNOTE-D19 study¹ examined sacituzumab govitecan (SG) plus pembrolizumab for patients with PD-L1–positive metastatic triple-negative breast cancer (mTNBC) in the first-line setting. ASCENT-03^2,3 looked at PD-L1–negative patients in the same setting. Both of these trials were positive.

In ASCENT-03, patients who were PD-L1 negative or not eligible for immunotherapy in the first-line setting were randomly assigned one-to-one to receive SG 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. Crossover from chemotherapy to SG was allowed, with a cross-over rate of 82%. This crossover may impact overall survival data, which is still immature. However, data presented at the European Society for Medical Oncology Congress 2025 showed that the primary endpoint was met, with progression-free survival 2 (PFS2) more favorable for SG versus chemotherapy (18.2 months for vs. 14.0; HR, 0.70). The objective response rate was 48% compared with 46%, respectively.³ 

TROPION-Breast02 was another phase 3 trial looking at patients who were not candidates for PD-L1 therapy in first-line mTNBC. In this trial, patients were randomly assigned one-to-one to receive datopotamab deruxtecan-dlnk (Dato-DXd) versus physician’s choice chemotherapy (paclitaxel, nab-paclitaxel, or capecitabine, carboplatin, or eribulin). Patients who had early or immediate relapse from early-stage therapy were eligible, although those who relapsed within 12 months of curative therapy were capped at 20%. There were dual primary endpoints of PFS and overall survival (OS), and there was an improvement in median PFS with Dato-DXd of 10.8 versus 5.6 months (HR, 0.57). Dato-DXd significantly improved OS, with a median OS of 23.7 months versus 18.7 months with chemotherapy — a 21% reduced risk of death. There also was a doubling of the objective response rate for Dato-DXd (63% vs. 29% for chemotherapy).⁴ 

In the associated Q&A, Drs. Rebecca A. Shatsky and Manali Bhave, along with oncology nurse Lynne Dillender, discuss the “apples to oranges” trial data for ASCENT-03 and TROPION-Breast02. Although both trials used antibody–drug conjugates (ADCs) with topoisomerase I payloads, there are key differences between these TROP2 ADCs for mTNBC that may be used for treatment-decision making in the future. In addition, understanding the nuances involved with prophylactic regimens is essential to optimal outcomes. 

Both ADCs that have recent first-line data in mTNBC have shown positive results across the board for the drug of study, but what are the important nuances about each trial? 

Dr. Shatsky: It has been too long since we had really great data in mTNBC like we saw in 2025 for the first-line setting. We have based the current standard of care on KEYNOTE-355, so pembrolizumab plus either gemcitabine and carboplatin or a taxane,² but the truth is that this regimen is no longer as beneficial as it once was because we have seen a change in standard of care in the curative setting. In the United States, we use the KEYNOTE-522 regimen.⁵ When disease relapse is seen after that regimen, patients do tend to have a pretty refractory phenotype and aggressive disease.

We’re not supposed to do cross-trials comparison, but we all do, so it’s important to note that we are comparing apples to oranges in some ways when looking at data from ASCENT-03 and TROPION-Breast02.

What we have seen across the data for SG in ASCENT-03 and ASCENT-04/KEYNOTE-D19 and Dato-DXd in TROPION-Breast02 is that novel ADCs actually can not only treat patients with de novo metastatic disease, which was about one-third of the TROPION-Breast02 population, but also patients with refractory, very difficult-to-treat relapsed disease. TROPION-Breast02 allowed patients who had relapsed within 12 months of curative-intent therapy, capping those who had immediate progression to 20%. ASCENT-03 also allowed patients with recurrent disease 6 to 12 months after curative treatment. Both trials did allow patients with stable, treated brain metastases at enrollment, which is also, I think, very important and a very patient-friendly feature that should be included in any trial for metastatic disease at this point.  

TROPION-Breast02 also did something a little different in that it allowed eribulin as a chemotherapy of investigator’s choice, which hasn’t been given in the first-line setting in a lot of trials. We call it a “super taxane” because it can work when patients are taxane-refractory. The ASCENT-03 trial allowed carboplatin and gemcitabine, a doublet that is considered to be closer to the real-world standard of care. TROPION-Breast02, however, only allowed carboplatin without gemcitabine, which is not commonly used in the real-world practice for mTNBC.

Another difference is that, because ASCENT-03 involved a drug that is FDA approved in the second line and beyond, patients were allowed to cross over at progression if they had been randomly assigned to chemotherapy in the first line. The majority of patients — 82% — did crossover to SG, which will affect overall survival results. TROPION-Breast02 was predominately run outside of the United States, and Dato-DXd is not yet FDA approved in mTNBC, which means that trial participants didn’t necessarily have access to an ADC as a subsequent line of therapy. In addition, ASCENT-03 reported on a 30-month interim analysis, whereas TROPION-02 reported on a 40-month interim analysis. So overall survival data for ASCENT-03 is still quite immature. It doesn’t necessarily mean that SG performed worse than Dato-DXd in respect to overall survival; it means the two trials reflect different geographic patient populations, where access to an ADC after progression was variable.

One thing about the ASCENT-03 trial that I’ve discussed with colleagues is that the response rate in the ASCENT-O3 (48%) was lower than in TROPION-Breast02 (62%). The duration of the response however, in ASCENT-O3 with SG was longer than standard of care, which is very important. We want a durable response, and we want a longer time to next therapy, both of which were seen in ASCENT-03.

So overall, I think these are both practice-changing trials, and I’m really excited about the data. 

What are some important considerations about adverse events for shared decision-making conversations with patients, if these drugs are approved for first-line use? 

Dr. Shatsky: The toxicities between the two drugs are fairly different, with Dato-DXd’s being more unique. Stomatitis can happen with the first dose so we do recommend that patients use a dexamethasone-based mouthwash to prevent this, but it’s not 100% effective even in patients using it religiously. This can be more difficult for patients to manage.

There is also potential for eye toxicities with Dato-DXd, making an initial ophthalmologic exam by either an optometrist or an ophthalmologist required to rule out underlying keratitis. It is recommended that patients don’t wear contacts when receiving this drug and lubricating eyedrops should be used frequently. As a general rule, I would say, anything that patients have administered more than twice a day is going to have a low compliance rate because who can remember to take something four times a day?

Similar to trastuzumab deruxtecan, Dato-DXd also can cause significant nausea, however it does at least seem to be less severe than trastuzumab deruxtecan and some of the patients I have treated can do well with only occasional additional antiemetic agents at home. I do always give the maximum IV antiemetics prior to infusions with either ADC — high-dose dexamethasone, long-acting 5-HT3 antagonist, and a neurokinin 1 inhibitor — but, in general, I find patients do better with nausea and vomiting with SG compared with Dato-DXd.

Dato-DXd also is associated with moderate alopecia, but SG, on the other hand, is known for more extreme alopecia, which may occur on the head very quickly after first administration and may also occur in the eyebrows and eyelashes. Any extent of alopecia is always very concerning for patients, as it really affects the way they are perceived by society.

Ms. Dillender: In discussing alopecia I have found in my experience that the alopecia is important to our breast cancer patient population, especially our younger patients. I make sure to provide anticipatory guidance to our patients about alopecia and its potential severity so that they can prepare and know what to expect.  We provide them with multiple resources from information on scalp cooling and hair preservation, local companies who supply cranial prosthesis (wigs), and age and developmental stage-appropriate books for our patients with young children so that they can prepare them as well.  

Dr. Shatsky: Satituzumab govitecan is known to cause diarrhea on Days 2 and 3. It is usually not too prolonged or severe in patients who metabolize the drug normally, although there are always exceptions. 

Ms. Dillender: I agree. I know that diarrhea is one of the more common toxicities for SG, but it is generally manageable and only rarely leads to treatment discontinuations. I think it’s also important to note that, when you account for longer time on treatment, serious side effects happened at about the same rate for SG as with many chemotherapies, and adding pembrolizumab did not seem to have unexpected side effects beyond what we would expect from an immune checkpoint inhibitor. I educate my patients early on regarding what is considered diarrhea and the importance of managing diarrhea with anti-diarrheals, as well as early reporting of out-of-control diarrhea. As we all know, if diarrhea is out of control and poorly managed, a patient can deteriorate quickly. Close follow up and coaching within a couple of days after initially starting SG can help with compliance to the anti-diarrheals. Interestingly, we have been seeing a handful of patients who have been on SG for a while, with no diarrhea-related issues, who suddenly got uncontrollable diarrhea. In situations such as these we have found it’s important to rule out infection first before assuming it’s a new side effect of SG. Because our patients are immunocompromised, infections are more likely than a sudden new side effect in someone who has been stable on the drug for a long time.

Dr. Shatsky: Great point, Lynne. As we know, the most important toxicity in general with SG is neutropenia. Many providers have learned to manage this adverse event really well now, because we have been using this drug since its presentation several years ago when the original ASCENT trials came out and we started using it in the third line. But, if it is not precisely managed, neutropenia can lead to life-threatening infection. Even in ASCENT-03, we saw death due to neutropenic fever, which is unfortunate because this can be prevented. This is especially concerning for those patients with insurance plans that might not cover use of granulocyte colony-stimulating factor (G-CSF) or for oncology practices that still do not include growth factor as part of their care pathways for patients with metastatic cancer. Five of the six deaths from treatment-emergent adverse events were due to infections secondary to neutropenia and none of those patients, who had risk factors for febrile neutropenia, received prophylactic growth factor. In my discussions with community oncology colleagues at the 2025 San Antonio Breast Cancer Symposium^®, I found the inconsistent use of growth factor to be really surprising. While I admit this reflects my lack of experience with care pathways and practice patterns outside of academia, I can see how this would be a somewhat dangerous drug in that setting when you don’t have access to growth factor, which we do really recommend heavily here to prevent neutropenic infection.

Ms. Dillender: That is very discouraging to hear, Dr. Shatsky. We are very fortunate because we don’t have any issues with adding pegfilgrastim on Day 8. This is a relief, as pegfilgrastim has been found to be strongly associated with significantly less neutropenia and will last the duration of treatment. This means fewer treatment interruptions, better patient outcomes, and less hospitalizations for febrile neutropenia. If a nurse or advanced practitioner is faced with a situation where approval is for pegfilgrastim is denied, it’s possible to advocate for approval upon appeal just using the available data regarding association of neutropenia with SG and the prevention of febrile neutropenia and further hospitalizations with inclusion of pegfilgrastim. 

Dr. Bhave: The PRIMED, phase II clinical trial, evaluated primary prophylaxis for neutropenia and diarrhea for patients on SG. G-CSF (5 MU/kg/day) and loperamide (2 mg/twice a day or 4 mg/day) were given during the first two cycles and at physician’s discretion thereafter. Primary endpoints included the incidence of grade ≥ 3 neutropenia and grade ≥ 2 diarrhea. The study showed that primary prophylactic administration of G-CSF and loperamide resulted in a clinically relevant reduction of the incidence and severity of SG-related neutropenia and diarrhea.⁶ This is particularly important with earlier use of SG in the disease course for patients with TNBC. 

Dr. Shatsky: We need to be really thoughtful and proactive in our supportive care measures to manage each agent’s associated adverse events.

Dr. Bhave: In addition to differences in the adverse event profiles, there are also differences in the schedule of administration of the drugs. Dato-DXd is administered intravenously every 21 days, while SG is administered intravenously on Days 1 and 8 of a 21-day cycle. While the data for both Dato-DXd and SG in the front-line setting are exciting, differences in the adverse event profiles and schedule of administration may impact patient and provider choice on which ADC to use for these patients in the future. 

With these important advances realized in 2025, what do you see in the short-term future for mTNBC research? 

Dr. Shatsky: It was good to see that these drugs, although they do have toxicity, are controlling disease more effectively and for longer periods of time. Better disease control in mTNBC helps patients ultimately feel better because this disease can progress quickly and cause a lot of pain and suffering. That is always a bit of a confusing part of patient-reported outcome data in mTNBC — it’s hard to say what was the disease versus what was the drug. I’m waiting for some long-term CNS outcome data from these trials, which I think are going to be really important too, but I’d like to see updates to the patient-reported outcomes regarding rates of brain metastasis in the ADC groups, because that is something that affects patient’s quality of life really dramatically as well.

Dr. Bhave: As the treatment landscape expands for patients with mTNBC, a key question will be how best to select and sequence these novel and more targeted therapies to not only improve quality of life, but prolong patients’ lives. Currently, clinical factors such as symptomatic disease, early progression after curative intent therapy, CNS disease, toxicity profile, and schedule of administration may impact decision-making on first-line ADC therapy of choice. We are waiting on further data on patient-reported outcomes and CNS disease control as Dr. Shatsky mentioned, although there is also a significant need to identify additional biomarkers to help guide therapy selection. This is particularly important as we consider how best to sequence our ADCs. Ongoing clinical trials and real-world evidence will be critical to help guide sequencing strategies to maximize the efficacy of these agents and quality of life. 

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References:

1. 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.
2. Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022;387:217-226.
3. 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.
4. 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.
5. Schmid P, Cortes J, Dent R, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med. 2024;391:1981-1991. 
6. García JMP, Gión M, Ruiz-Borrego M, et al. Prevention of sacituzumab govitecan (SG)-related neutropenia and diarrhea in patients (pts) with triple-negative or HR+/HER2- advanced breast cancer (ABC; PRIMED): A phase 2 trial. J Clin Oncol. 2024;42(16 suppl):1101.