Sacituzumab or Dato-DXd? Experts Weigh First-Line ADCs in Metastatic TNBC

Sacituzumab govitecan-hziy (SG; Trodelvy) became a first-line option for metastatic triple-negative breast cancer (TNBC) in June 2026, when the FDA approved it as monotherapy for patients who are not candidates for PD-(L)1 inhibitors and in combination with pembrolizumab (Keytruda) for tumors with a PD-L1 combined positive score (CPS) of 10 or higher.¹ The approvals, based on the phase 3 ASCENT-03 (NCT05382299) and ASCENT-04 trials (NCT05382286),^3,4 followed the May 2026 approval of datopotamab deruxtecan-dlnk (Datroway) based on the strength of the phase 3 TROPION-Breast02 trial (NCT05374512).^2,5 In a virtual peer exchange, Hope S. Rugo, MD, FASCO, and Irene M. Kang, MD, of City of Hope led oncologists from across Southern California through the efficacy and safety data behind SG. They discussed how to choose between TROP2-directed antibody-drug conjugates (ADCs), whether to continue immunotherapy after early relapse, how crossover complicates survival analyses, and practical management of neutropenia and diarrhea.

Rugo is division chief of Breast Medical Oncology and director of the Women’s Cancers Program at City of Hope, and Kang is medical director of Women’s Health Medical Oncology at City of Hope Orange County. Panelists included Linnea Chap, MD, of Beverly Hills Cancer Center; Preeti Chaudhary, MD, of Pomona Valley Hospital Medical Center; Alexis LeVee, MD, of University of California Los Angeles Health; and Pamela Miel, MD, community oncologist at Starling Oncology, Orange County. They were joined by City of Hope oncologists Gregory Gilmore, DO (Corona); Nikhila Kethireddy, MD (Duarte); Adnan Khan, MD (South Bay); Benjamin Leach, MD (Mission Hills); Leah Naghi, MD (Duarte); Neel Talwar, MD (Upland); Shanmuga Subbiah, MD, MRCP, (Upland); and Marissa Tadi, MSN, A-GNP-C (Orange County).

ASCENT-04 and ASCENT-03: Durable Disease Control With Sacituzumab Govitecan

Kang: A key portion of this trial design was that eligible patients who were enrolled to the control arm were provided crossover to second-line SG following BICR-verified progression of disease… Overall survival (OS) was a secondary end point, but keep in mind that there was crossover written into the protocol, and so that may impair our ability to assess a survival benefit here… There are statistical limitations to assessing PFS2, but it is encouraging to see that perhaps that benefit in the first line is preserved across the second line, especially considering the crossover rate… Look at this duration [of response]; this is where I think the ADCs shine… We are seeing a higher response rate, but that duration of response is what shines with SG plus pembrolizumab.

ASCENT-03 is the sister study to ASCENT-04, with a similar trial design except that patients cannot be candidates for PD-L1 inhibitors… Response rates, interestingly, are very similar… We’re seeing that same story as ASCENT-04, with similar response rates, maybe because the chemotherapy arm had gemcitabine/carboplatin, but this prolonged duration with the ADC… It speaks to the high rate of crossover and the limitations in assessing OS with this study. The fact that PFS2 is still prolonged, again, with all the limitations with PFS2, as well as the very short follow-up, seems to suggest that there’s a benefit in the first line.

Combining an ADC With Immunotherapy, and the Rechallenge Question

Leach: Some of the concerns for me with combining the ADCs with immunotherapy are increased toxicity [like] gastrointestinal [toxicity and] fatigue, although you could see that with chemotherapy as well. I’m not sure if one is necessarily better than the other, but those are some of the things that are in my mind when I’m thinking about prescribing these.

Rugo: I looked in ASCENT-04, which I thought was a nice analysis, at the incidence of immune toxicity, which is much less, of course, in the metastatic setting than in the neoadjuvant and adjuvant setting because your immune system isn’t quite as happy. There was no added immune toxicity with adding SG. SG caused a little bit more diarrhea than chemotherapy, but there’s a group of patients who are at risk for more diarrhea, and the rate of high-grade diarrhea is relatively low. Other than that, there’s probably less nausea with SG than there is with gemcitabine/carboplatin. Taxanes are a little bit different.

Talwar: ASCENT-04 had a 6-month requirement. They didn’t have any of these patients, so it’s hard to say. Could there be a synergistic effect by adding the ADC and continuing the pembrolizumab? That’s the big question. We have tons of these patients. I was going to ask this question to you because I have one right now who progressed on adjuvant pembrolizumab, and I’m waiting for PD-L1 expression to come back. Should I continue the pembrolizumab or not? It’s a data-free zone, so it’s a judgment call.

Rugo: It is a data-free zone. It’s so unfortunate. I don’t know what everybody else would do with that, but personally, if I could continue the pembrolizumab, I would through the SG. There’s the potential for synergy, and the outcome is so hideous in these patients that [it’s worth] anything you can do. I did have one patient like that long before we had the results from ASCENT-04. She was on her pembrolizumab and capecitabine [Xeloda], had a lung metastasis that was removed, and then had brain metastases 6 weeks later. That patient stayed on her first-line therapy for a long time and had terrible disease, so I was sold on the approach… The Dato-DXd trial [TROPION-Breast05; NCT06103864] that will look at one arm with just Dato-DXd, and allows patients within the first 6 months, may give us a little window into that, but the numbers are going to be small because all these trials have capped [enrollment] at 20% of patients relapsing in the first year.

Weighing Crossover, PFS2, and OS

Naghi: In terms of PFS2 as a meaningful surrogate for OS, it’s interesting and important because of the poor OS in these patients. There are other factors that can come into play, and that is meaningful.

Gilmore: [Crossover] is clearly going to impact OS. We’re not going to rely on that as the deciding factor. For me, having the PFS2 at least helps indicate that there’s probably a benefit to using it in the first line vs, say, second line.

Chap: For me, [the subgroup analyses] wouldn’t influence my choice of treatment. The OS was most definitely impacted by the crossover.

Subbiah: On the first slide, we presented the attrition rate of 51% for second-line treatment. With a patient population with an attrition rate of 51%, ADCs play a bigger role here [and keep patients] on treatment for a longer time. PFS2 makes sense in that setting as well because you’re not going to have that many patients to count upon.

Rugo: It’s important to keep in mind a lot of people are still on therapy, and some people aren’t going to go on. You’re going to need more maturity to know how many people go on in the second line. But that’s a good point; if you know a fair number of people aren’t going to make it to second-line treatment, you want to put your best foot forward.

Choosing Between Sacituzumab Govitecan and Dato-DXd

Irene Kang: In North America, we saw OS favoring chemotherapy, with a wide confidence interval. [That’s] maybe speaking to the access of ADCs in the second- and later-line setting here… It’s interesting to see this fantastic response rate with ADCs compared with chemotherapy, which we did not see with the ASCENT trials.

Chap: Well, there are the OS [outcomes] with Dato-DXd, [and] there’s the crossover with [SG] that complicates things. To a large degree, I look at the [adverse] effect profile. With Dato-DXd, there’s having to have an eye exam every 3 cycles, [and] the stomatitis. I tend to lean more toward SG than Dato-DXd… [It requires] a lot more patient involvement: the eye drops 4 times a day and the mouthwash 4 times a day.

LeVee: I agree. PFS is similar. Response rates were a little bit higher with Dato-DXd, but ultimately, I feel like it’s the toxicity profile, and patients have a clear preference [regarding] [adverse] effects. I would say Dato-DXd once every 3 weeks is a bit more patient friendly.

Chaudhary: I lean more toward SG just because of more experience with the drug… I find SG easier to give.

Rugo: Which toxicities do you see?

Chaudhary: Mostly the mucositis [and] the skin rash. I have been leaning more toward SG. It’s also that I have more experience with the drug.

Kethireddy: The data with Dato-DXd is more convincing. I personally have been leaning toward it, especially because for the disease-free interval they included 0 to 6 months, whereas ASCENT-03 didn’t; they had a longer disease-free interval. Ultimately, [patients] are going to end up getting both. I’d just discuss the dosing schedule and toxicity with the patients.

Managing Sacituzumab Govitecan Toxicities

LeVee: It’s funny. I just inherited a patient for whom they did check, and the patient was positive for UGT1A1, so we ordered prophylactic G-CSF. Then, for this patient, we tried to enroll her on the phase 3 TroFuse-011 trial (NCT06841354), and unfortunately, the control arm of that is chemotherapy. Is there a role in which you wouldn’t give an ADC in the first-line setting? The only role is maybe on a study in which the control arm is chemotherapy and not an ADC. When [a patient is] randomly assigned to that arm, I feel very conflicted for the patient.

Subbiah: You do get these pharmacogenomics in Guardant360, [including] DPYD. Sometimes, it’s much faster; you get it within a week, and on the second page, you get UGT1A1 and DPYD. It’s automatically baked into Guardant360. When I do it for other tumors, I’ve been able to see that.

Rugo: Atropine is for patients who get diarrhea in the infusion center. I personally have never seen that. Do not give atropine to patients who develop diarrhea 3 days later. It’s only for that immediate cholinergic response… [SG is] classified as a highly emetogenic drug, but I have to say it is just not the same as giving T-DXd or even Dato-DXd… With the triplet and with some rescue as needed, nausea is, in my experience, very easy to control with SG.

Chap: I have a low threshold for using long-acting [G-CSF] at day 9. I always advise them to have loperamide [Imodium] and send them home with a prescription for loperamide, but [I] do not automatically [give] prophylaxis. I have had patients who had constipation.

Case Discussion: Diarrhea on SG Plus Pembrolizumab

Rugo: That is one of the big challenges: if somebody shows up with diarrhea and they’re on pembrolizumab and SG, which are you deciding it is?

Gilmore: Typically, with SG, I can see the diarrhea right away. If that’s the case, I would probably lean more toward that. If it’s happening several cycles in, I might be more concerned about the pembrolizumab.

Miel: There was an ANC of 700 so I might just send the patient to the [emergency department] and get a stat CT because I would be concerned about typhlitis. I would think this might be more related to SG than immunotherapy, as it’s more acute in onset, because I think [immunotherapy toxicity] takes a while longer. I’d work on that one first.

Rugo: I’ve seen colitis on the early side. If it all cleared up when you stopped the SG and gave her antibiotics, which I would absolutely give for an ANC of 700 and a lot of diarrhea because the mucosal barrier is breached, they’re at risk for much more serious infections. If it didn’t clear up right away, then I would be concerned about whether there was a contribution from the pembrolizumab. You’re right, [immune-related] diarrhea is generally a little bit later.

Naghi: [On rechallenge,] if it gets better quickly on steroids and just quiets down, I would rechallenge, but if it was refractory or severe, then no, [I’m] not as interested in restarting [immunotherapy].

Don’t Forget Chemotherapy: Closing Perspectives

Khan: Over the last year and a half, I feel like my mind has slowly been shifting to ADCs. In my mind, it’s just ADC, ADC, ADC, and then chemotherapy is your last step. Unless they’re urgently admitted to the hospital and need something inpatient, then I’ll think of chemotherapy. Maybe that’s not the appropriate approach, but that’s just why [I’ve] shifted.

Rugo: [I had] one patient who had ER-positive disease, had a pathologic complete response, and then presented on endocrine therapy with a huge liver mass obstructing her bile duct and a rapidly rising bilirubin; [it] became a horrible case. [The recurrence was] ER/PR negative. [We] never found another ER-positive cell. She went on to SG and T-DXd, neither of which had any response. Progression was her best response. She went on to gemcitabine/carboplatin along with a biliary stent and is still on it a year later. It’s interesting to me that we just don’t know. In some situations, we may see odd responses, so you don’t want to give up on the chemotherapy, is the only point.

Tadi: My comfort is [greater]. I feel like there’s just a shift in comfort in using the ADCs in practice. I work with Dr Kang, so I feel like we just do it all the time, which is why I brought up the access issue. With the unmet needs, there’s still no clear guidance on going back to the chemotherapy; when do you place it? Are you going to sandwich it? Are you going to put it at the end? Some of that is still a little unclear for me, at least.

References

1. FDA approves sacituzumab govitecan-hziy as monotherapy and in combination with pembrolizumab for first-line triple-negative breast cancer. US Food and Drug Administration. June 24, 2026. Accessed October 15, 2026. https://tinyurl.com/4fpzzhux

2. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic triple-negative breast cancer. US Food and Drug Administration. May 22, 2026. Accessed October 15, 2026. https://tinyurl.com/5frerd3a

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4. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026;394(4):354-366. doi:10.1056/NEJMoa2508959

5. Dent R, Shao Z, Schmid P, et al. Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial. Ann Oncol. 2026;37(8):1066-1080. doi:10.1016/j.annonc.2026.03.008

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). Ann Oncol. 2025;36(suppl 2):S1565-S1566.

7. Kalinsky K, Schmid P, de Azambuja E, et al. Progression-free survival after next line of treatment (PFS2) and subsequent therapies (subs tx) in the ASCENT-04 study of participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC) treated with sacituzumab govitecan (SG) plus pembrolizumab (pembro) vs chemotherapy (chemo) plus pembro. J Clin Oncol. 2026;44(suppl 17):LBA1000. doi:10.1200/JCO.2026.44.17_suppl.LBA1000

8. Hurvitz S, Cortes J, Tolaney SM, et al. Progression-free survival after next line of treatment (PFS2) and subsequent therapies (subs tx) in the ASCENT-03 study of participants (pts) with previously untreated metastatic triple-negative breast cancer (mTNBC) treated with sacituzumab govitecan (SG) vs chemotherapy (chemo). J Clin Oncol. 2026;44(suppl 16):1001. doi:10.1200/JCO.2026.44.16_suppl.1001

9. Cescon D, Traina TA, 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: Additional efficacy endpoints from the TROPION-Breast02 study. J Clin Oncol. 2026;44(suppl 16):1002. doi: 10.1200/JCO.2026.44.16_suppl.1002

10. Tolaney SM, Schmid P, de Azambuja E, et al. ASCENT-04: Analysis of efficacy by biomarker subgroups with sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2026;44(suppl 16):1013. doi: 10.1200/JCO.2026.44.16_suppl.1013

11. Barrios C, Hurvitz SA, Tolaney SM, et al. ASCENT-03: Efficacy by biomarker subgroup with sacituzumab govitecan (SG) vs chemotherapy (chemo) in participants (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are not candidates for PD-(L)1 inhibitors (PD-[L]1i). J Clin Oncol. 2026;44(suppl 16):1014. doi:10.1200/JCO.2026.44.16_suppl.1014

12. Trodelvy (sacituzumab govitecan-hziy). Prescribing information. Gilead Sciences, Inc; revised June 2026. Accessed October 15, 2026. https://tinyurl.com/3rj3n4jk