Advanced or metastatic triple-negative breast cancer (TNBC) has seen a dramatic improvement in overall outcomes with the standard use of immunotherapy, antibody-drug conjugates (ADCs), and PARP inhibitors. With new agents at every stage of development, emerging data could usher in even more changes to daily clinical practice in the near future.

In this Q&A, Sonya Reid, MD, MPH, discusses the evolving treatment landscape for metastatic TNBC, including what agents and combinations have potential for first-line use and the therapies on the horizon that are most exciting to her. Manali Bhave, MD, provides insights on HER2-low/HER2-ultralow breast cancer and addresses some unanswered questions. Kayla Freeman, DNP, discusses best practices for adverse event management for several agents currently used for patients with TNBC. Dr. Freeman also provides insights about how she and her advanced practitioner (APP) team stay current despite the continuous release of practice-changing data. 

Please explain the current approach to therapeutic decision making in the first line for patients with advanced or metastatic TNBC.

Dr. Reid: When a patient has metastatic TNBC, we really want our approach to be biomarker driven, especially in the first-line setting. We want to make sure that we obtain PD-L1 testing, as well as germline testing, because we know that treatment will be based on whether a patient has PD-L1–positive disease, defined as a combined positive score (CPS) of 10 or more, or if they have a germline BRCA1/BRCA2 mutation.

Patients with PD-L1–positive disease would receive upfront immunotherapy — pembrolizumab — plus chemotherapy. Patients with PD-L1–negative status usually receive single-agent chemotherapy, or a PARP inhibitor, such as olaparib or talazoparib, if they have a germline BRCA mutation.

The KEYNOTE-355 study established the rationale for upfront chemotherapy plus immunotherapy for patients with TNBC whose tumors expressed PD-L1 with a CPS of 10 or more.^1,2 Final results showed a distinct advantage in overall survival rate for pembrolizumab with chemotherapy versus chemotherapy alone for these patients.² Regarding patients with germline BRCA1/BRCA2 mutation, the OLYMPIA trial showed a 3-year invasive disease-free survival benefit with olaparib compared with placebo,³ leading to the first PARP inhibitor approval in this space. Talazoparib followed, with the EMBRACA trial having shown an improved median progression-free survival for patients with advanced breast cancer and a germline BRCA1/BRCA2 mutation.⁴

Knowing the data, I always like to think about the patient in front of me as well. Is this a patient who received immunotherapy before in the adjuvant setting, or is this a patient that has de novo TNBC? For example, if a patient with PD-L1–positive metastatic TNBC had received neoadjuvant/adjuvant immunotherapy within the past 6 to 12 months, I would have a discussion about the pros and cons of adding immunotherapy in the metastatic setting, also taking into account a patient’s performance status and comorbidities. I think it is important to review treatment history, especially now that we have more therapeutic options and are adding on new therapies in the adjuvant setting.

What research in locally advanced/metastatic TNBC do you feel will be most clinically impactful once reported?

Dr. Reid: We have already seen the efficacy of those ADCs approved for use in later lines, so I was excited to see the data from the ASCENT-04/KEYNOTE-D19 trial presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. This trial showed that use of sacituzumab govitecan plus pembrolizumab in the first-line setting for patients with PD-L1–positive advanced TNBC resulted in clinically meaningful improvement in progression-free survival and durable responses, with no huge safety concerns, when compared with chemotherapy plus pembrolizumab.⁵ This is especially important for patients who have experienced disease progression 6 to 12 months after chemotherapy in the adjuvant setting because we know that moving to chemotherapy alone will not have the same benefit as a therapy with a different mechanism of action, such as an ADC. Overall survival data are still immature, so we’re waiting to see what that will yield, but I think that will definitely be practice changing for us, and hopefully we get an FDA approval there soon. 

Regarding safety, we have dealt with the side effects of chemotherapy and immunotherapy for a while, and now we have experience with the side effects of ADCs, just not in the first-line setting. There were no new safety concerns in the ASCENT-04/KEYNOTE-D19 study. The most frequent grade 3 or 4 reactions for the patients who received sacituzumab govitecan plus pembrolizumab were nausea, diarrhea, and neutropenia.⁵ Dr. Freeman gives a nice overview further in this article of best practices for both prophylactic and reactive management of the most common adverse events by agent.

Datopotamab deruxtecan (Dato-DXd), a TROP2-directed ADC, is also being evaluated alone or in combination for first-line TNBC. TROPION-Breast05 is a phase 3, randomized, open-label trial for patients with locally recurrent inoperable or metastatic PD-L1–high TNBC who have not received prior chemotherapy or other targeted systemic therapy. The trial will compare Dato-DXd plus durvalumab with investigator’s choice plus pembrolizumab, and, in some countries, Dato-DXd alone. The primary endpoint is progression-free survival, and secondary endpoints include overall survival, overall response rate, duration of response, and patient-reported outcomes.⁶ The combination of Dato-DXd plus durvalumab has shown good durable response rates in this same population in the phase 2 BEGONIA trial, with no new adverse events.⁷

Dr. Bhave: Thanks for the nice review, Dr. Reid. I do think one of the huge positives coming out of all of these studies on ADCs and other novel agents is that we have options for our patients, which means that we can be more selective based on the patient’s disease, comorbidities, and preferences. We are also rethinking our paradigm regarding the most important clinical trial outcomes to guide decision-making on use of these novel therapies. Is overall survival our gold standard still, or are patient-reported outcomes as important as survival endpoints, especially as we see multiple ADCs in development that target the same antigen? Will toxicity profiles, comorbidities, and/or biomarkers help us better select treatment? I think all of these could contribute to improved therapeutic selection as we move forward with research.

How is research in the metastatic setting translating to early TNBC or vice versa?

Dr. Bhave: What we’re seeing now are that a lot of the ADCs that showed promising results in the metastatic setting are being transitioned into the early-stage setting for TNBC. In the TNBC space, there are ongoing studies looking at the TROP2-directed ADCs sacituzumab govitecan and Dato-DXd with or without immunotherapy in the early-stage setting. We are waiting on the results of those studies, but I do think that we are going to see more ADCs transition over from the metastatic setting to the early-stage setting.

As this happens, the questions are going to be: What are some of the newer agents that we can use for patients who develop recurrence after treatment with ADCs in the early-stage setting? How are we going to define resistance to those ADCs when we consider using them in the metastatic space for patients with recurrent disease? And then, for patients who develop de novo or recurrent metastatic disease, how are we going to sequence ADCs?

Please explain how therapeutic developments for HER2-low and HER2-ultralow overlap with TNBC.

Dr. Bhave: HER2-low/HER2-ultralow is a new biomarker that allows for eligibility and access to T-DXd for patients who have traditional TNBC but is now re-defined as having HER2-low or ultralow disease. In the TNBC space, sacituzumab govitecan is currently approved in the second line or beyond for metastatic TNBC based on ASCENT. Because of those data, many of us select sacituzumab govitecan first over potential use of T-DXd in the triple-negative, HER2-low, or HER2-ultralow space.

I do think, however, that we’re seeing more data on the efficacy of T-DXd across different populations of patients now with the ultra-low indication, which will encompass close to about 80% of patients that have metastatic breast cancer. A key question is understanding resistance as we potentially sequence multiple ADCs. Is it resistance to the antibody or the payload? I think understanding resistance mechanisms will help answer the question of how to sequence these drugs, as well as evaluate if there are other biomarkers that we can use to discern which patients may benefit from multiple ADCs.

In the hormone receptor-positive space, we have a second TROP2-directed ADC, Dato-DXd, that is approved. I do think that, in the near future, we’ll probably see the approval of this ADC in the TNBC space as well. A question is whether there is a role for use of two TROP2-directed ADCs, which as of now, I don’t believe there is. So it might be more of a question of therapeutic selection based on toxicity profiles or schedule of administration for patients with metastatic TNBC should Dato-DXd get approved in this patient population. But we also have several newer ADCs in the pipeline that have novel targets and payloads. I think that’s a really important category of new drugs that we’re all interested in, especially because, again, we know that there is resistance to sequential use of the ADCs that are currently available.

Going into the European Society for Medical Oncology (ESMO) Congress 2025 and then the San Antonio Breast Cancer Symposium (SABCS)®, what topics are you most excited about?

Dr. Bhave: I think there are a lot of exciting presentations that we’re looking forward to at ESMO 2025 in the TNBC space. We are looking out for the sister study to the positive ASCENT-04 trial that was presented at ASCO 2025, which evaluated the benefit of sacituzumab govitecan plus pembrolizumab versus chemotherapy and pembrolizumab in the first-line setting for patients with TNBC who were PD-L1–positive. Now the sister study, ASCENT-03, is evaluating sacituzumab govitecan in the first line- setting but for patients who are PD1/PD-L1–negative with metastatic TNBC.⁸ This study will be comparing sacituzumab govitecan versus chemotherapy of physician’s choice, which is our current standard of care for patients with PD-L1–negative metastatic TNBC.

Dr. Reid: I agree, Dr. Bhave. Now that we have seen such encouraging data in the PD-L1–positive patients from ASCENT-04/KEYNOTE-D19, I think it will be intriguing to discuss the impact of the primary results of ASCENT-03 that will have been presented at ESMO with colleagues in San Antonio. I’m interested to hear the data at ESMO and then discuss the implications at SABCS®.

In general, though, I’m also super excited about all of the ADCs coming through the pipeline, with different antibody targets and cytotoxic payloads. As Dr. Bhave mentioned, we will, however, need to understand how to sequence these ADCs, and there are several studies trying to answer this question. We are also now seeing several studies evaluating ADCs in combination with other agents, such as checkpoint inhibitors and PARP inhibitors. There are also bispecific antibodies and even CAR T-cell therapies that are earlier in development but that may eventually help us move the mark to improve outcomes for our patients with metastatic TNBC. We have seen remarkable results with CAR T-cell therapy in hematologic malignancies. I think it would be very exciting to figure out how to incorporate the same strategy for solid tumors.

With all of the research in the TNBC space, how do APPs stay current and prepared for shifts in patient care?

Dr. Freeman: Locally advanced and metastatic TNBC is an extremely active space. It’s very exciting for our patients with TNBC because there are so many emerging and evolving therapies, whereas previously, chemotherapy was the bread and butter for these patients. You see your patients get excited about the active research and that ultimately gives all of us, as care providers, hope for our patients — it gives us something to look forward to.

With so much evolving research, it can sometimes feel overwhelming to stay informed and up to date. Attending our weekly breast clinic meetings has been incredibly helpful, as I get to hear the thoughtful collaboration among our physicians. In clinic, APPs are fully engaged participants in these discussions, which allows us to put the information into context firsthand and have meaningful conversations with our patients about how it applies to their care.

As a team, we also make a point to review abstracts from the ASCO Annual Meeting, ESMO, and SABCS® in real time each year. Our collaborating physicians do an excellent job of helping us decipher what’s headline buzz and what’s actually practice-changing data, while also partnering with us to integrate these updates into our day-to-day clinical practice.

As novel agents such as ADCs and bispecific agents gain traction in TNBC research focused on the first-line setting, what are some potential educational gaps regarding both proactive and reactive adverse event management strategies?

Dr. Freeman: ADCs are already a mainstay in breast cancer care in the second-line and later settings but for community APPs who may encounter breast cancer less often in clinic, recognizing the timing of potential side effects remains crucial. Starting with ASCENT-04/KEYNOTE-D19 and sacituzumab govitecan, diarrhea and neutropenia come to mind immediately, as these develop fairly quickly after treatment initiation.⁹ We do try to set patient expectations upfront about these symptoms, especially the diarrhea. We build loperamide into treatment plans as a take-home medication, and we prescribe lomotil if symptoms are not effectively managed with the loperamide. Regarding neutropenia with sacituzumab govitecan, I like to talk to patients early about the possibility of their counts decreasing. I explain what that means and that this might cause delays in therapy or even dose reductions, which are nerve-racking ideas for a patient. Patients worry that getting less of the drug means it won’t work as well. I think if we explain the possibility of dose modifications or delays upfront and discuss our anecdotal experiences with patients who have gone through these scenarios very successfully, it lessens the patient’s anxiety when we get to that actual moment in time. We also explain that we will monitor for neutropenia closely by obtaining labs with every infusion. We typically see patients on Day 1 of each cycle to assess for any concerning therapy-related side effects. Some individuals require closer follow-up, and we see them at each infusion. We tend to consider dose or schedule modifications on a case by case basis. 

Moving to T-DXd, the more prominent side effects with this agent are fatigue, nausea, and vomiting. We bulk up the pre-meds for nausea and vomiting, and most of these patients get dexamethasone for at least a few days after administration. Prochlorperazine and ondansetron are given as needed, and, on occasion, we prescribe olanzapine, to be taken at bedtime, if the patient has more severe symptoms. We can also add IV fluids the week following their infusion to help with hydration and overall recovery. Outside of nausea and vomiting, it is important not to turn a blind eye to a cough or shortness of breath due to the potential for interstitial lung disease (ILD) with T-DXd. Healthcare providers should make the patient and caregiver aware of the potential for ILD so that it can be caught as early as possible. ILD can occur at any point during treatment with T-DXd, but the median time to onset is around 5 to 6 months.¹⁰ Some cases develop much earlier, which is why ongoing monitoring is so important. At the first sign of symptoms, we have to do our due diligence by holding therapy and ordering imaging for further evaluation. If we have any suspicion of ILD, we loop in our pulmonology team immediately and begin a steroid taper. These patients will be seen by us and by pulmonology as they move through the ILD treatment despite being on a therapeutic hold for the breast cancer. I have had multiple patients develop ILD on T-DXd, and we chose not to rechallenge for some of them but we have rechallenged for other patients once steroids were completed. Close monitoring with a chest CT every 2 cycles is very helpful in this decision-making process.

Dr. Reid talked a little about TROPION-Breast05 for Dato-DXd earlier. Dato-DXd is also being compared to chemotherapy in the phase 3 TROPION-Breast02 trial for patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for PD-L1 inhibitors (NCT05374512, active not recruiting). Regarding potentially serious or life-threatening adverse events for this agent, there is a risk of ILD or pneumonitis, but this was only found in a small number of patients with breast cancer in the TROPION-Breast01 and TROPION-PanTumor01 trials, and it resolved with steroids for almost half of them.¹¹ However, I think the hardest thing about Dato-DXd for an APP to manage is that there’s so many proactive elements involved in side effect management. Patients should be using a dexamethasone rinse four times a day for stomatitis prophylaxis,¹² which is a lot to ask, especially if they aren’t actually having symptoms. This can be challenging, as some patients discontinue the prophylactic mouth rinse when asymptomatic, only to subsequently develop oral mucositis. It is the same with lubricating drops for dry eye. APPs should encourage patients to continue these prophylactic approaches at every visit or check-in discussion.  

As we don’t really use bispecific agents in breast cancer outside of trials yet, APPs who specialize in breast cancer should read relevant study data to be prepared to manage side effects associated with these, which seem to be mostly immune related. These side effects tend to develop later after administration, so vigilance regarding appropriate monitoring is really important. We already see patients who are on immunotherapies such as pembrolizumab, for example, so we have experience with delayed effects and how to piece together the puzzle of whether the events are related to the therapy. We need to keep that same mindset as we move toward incorporating bispecific agents into first-line therapy.

With so many clinical trials active in TNBC, at what point do you discuss clinical trials with patients and why?

Dr. Freeman: I believe clinical trials should be introduced early in the patient journey and revisited at every line transition or therapy change. This helps set expectations that, with the therapies we currently have, many patients may need a clinical trial at some point. I think it’s important that we keep the discussions digestible for the patient, explaining today’s standard of care and what’s on the horizon. This not only keeps patients informed but can also bring excitement and hope as they learn about the future of treatment.

From an equity standpoint, I think it’s essential to normalize these discussions for all eligible patients. This helps avoid disparities in trial access. Some patients come eager to Emory to explore trials, while others are hesitant — often because they view trials as a last resort. I highlight that clinical trials give patients early access to tomorrow’s standard of care, which can be empowering rather than intimidating.

At our institution, we support patients by providing links to trial information and, when appropriate, our clinical trial coordinators will share read-only consent forms so patients can review details at their own pace. Even if we’re not yet ready to enroll, this proactive approach helps patients prepare for future decisions if progression occurs.

The bottom line is to normalize clinical trial discussions early and throughout care. It’s an important part of empowering patients and ensuring equitable access.

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References: 

1. Cortés J, Rugo HS, Cescon DW, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022;387:217-226. 
2. Cortés J, Cescon DW, Rugo HS, et al. LBA16 KEYNOTE-355: Final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Ann Oncol. 2021;32(Suppl 5):S1289-1290. 
3. Tutt A NJ, Garber JE, Kaufman B, et al. Adjuvant Olaparib for Patients with BRCA1– or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021;384:2394-2405. 
4. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379:753-763.
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(17_suppl):LBA109.  
6. Schmid P, Oliveira M, O’Shaughnessy J, et al. TROPION-Breast05: a randomized phase III study of Dato-DXd with or without durvalumab versus chemotherapy plus pembrolizumab in patients with PD-L1-high locally recurrent inoperable or metastatic triple-negative breast cancer. Ther Adv Med Oncol. April 17, 2025. Doi: 10.1177/17588359251327992. 
7. Schmid P, Wysocki PJ, Ma CX, et al. 379MO Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Updated results from BEGONIA, a phase Ib/II study. Ann Oncol. 2023;34(suppl 2):S337. 
8. Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician’s Choice in Patients With Previously Untreated Locally Advanced Inoperable or Metastatic Triple-Negative Breast Cancer (ASCENT-03). ClinicalTrials.gov. Accessed September 15, 2025. https://clinicaltrials.gov/study/NCT05382299?term=%20NCT05382299&rank=1
9. Spring LM, Nakajima E, Hutchinson J, et al. Sacituzumab Govitecan for Metastatic Triple-Negative Breast Cancer: Clinical Overview and Management of Potential Toxicities. Oncologist. 2021;26:827-834.
10. Enhertu product information. Accessed September 30, 2025. https://www.enhertuhcp.com/en/breast/safety
11. Meric-Bernstam F, Bardia A, Bossi P, et al. Prophylaxis, clinical management, and monitoring of datopotamab deruxtecan-associated oral mucositis/stomatitis. Oncologist. 2025;30(3):doi:10.1093/oncolo/oyaf031.