TROP2-Directed ADCs Are Poised to Shake Up Frontline TNBC Management

On the heels of 3 positive phase 3 studies reported in 2025, TROP2-directed antibody-drug conjugates (ADCs) are positioned to bring meaningful change to the frontline metastatic triple-negative breast cancer (TNBC) treatment paradigm, with patients across the population experiencing meaningful survival improvements with these agents in randomized clinical trial settings, according to Mabel Mardones, MD.

“Treatment of metastatic TNBC is very complex, and patients, unfortunately, don't [experience]...the median PFS and OS outcomes that they truly deserve,” Mardones said. “Therefore, any meaningful improvement or statistical significance [represents] headway.”

In 2025, data presented from the phase 3 TROPION-Breast02 trial (NCT05374512) showed that datopotamab deruxtecan-dlnk (Dato-DXd; Datroway; n = 323) significantly improved overall survival (OS; HR, 0.79; 95% CI, 0.64-0.98; P = .0291) and progression-free survival (PFS; HR, 0.57; 95% CI, 0.47-0.69; P < .0001) vs investigator’s choice of chemotherapy (n = 321) in the first-line treatment of patients with locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option.¹

Additionally, in the phase 3 ASCENT-03 trial (NCT05382299), sacituzumab govitecan-hziy (Trodelvy; n = 279) improved PFS vs chemotherapy (n = 279) in patients with previously untreated, locally advanced unresectable, or metastatic TNBC who were ineligible for PD-1/PD-L1 inhibitors (HR, 0.62; 95% CI, 0.50-0.77; P < .0001).2 In the phase 3 ASCENT-04 trial (NCT05382286), sacituzumab govitecan plus pembrolizumab (Keytruda; n = 221) yielded a PFS improvement vs chemotherapy plus pembrolizumab (n = 222) in patients with PD-L1–positive, advanced or metastatic TNBC (HR, 0.65; 95% CI, 0.51-0.84; P < .001).

In an interview with OncLive®, Mardones provided context on how data from these 3 studies will affect the frontline TNBC treatment paradigm; explained key safety considerations for the use of TROP2-directed ADCs; and outlined other key areas for future research to address.

Mardones is a breast medical oncologist at Rocky Mountain Cancer Centers in Denver, Colorado.

OncLive: Starting with TROPION-Breast02, what are the potential clinical implications of these data for first-line Dato-DXd in patients with advanced TNBC who were ineligible for immunotherapy?

Mardones: The first thing to say about TROPION-Breast02 is that it fundamentally [had] a very different patient population than the counterpart, ASCENT-03. [In TROPION-Breast02], there was no minimum disease-free interval [DFI] requirement, suggesting that the patient population possibly [had] more aggressive [disease] compared with [the ASCENT-03 population]. In addition, there was a slight difference in the group of patients with brain metastases, which was slightly higher in TROPION-Breast02 at 9.9% vs 5% in ASCENT-03. 

Overall, it's nice to see that there are 2 options now for this group of [immunotherapy-ineligible] patients [with Dato-DXd and sacituzumab govitecan]. How we decide to use these 2 options will very much be dependent on things like patient population, DFI, patient preference, difference in toxicities, and the dosing schedule. If a patient is coming to see me to treat their breast cancer and they live 4 hours away, they may not want to come in for day 1 and day 8 treatment [with sacituzumab govitecan], as opposed to treatment once every 3 weeks [with Dato-DXd]. There are fundamental differences [between the ADCs] that will be important to take into consideration.

Looking at the ASCENT-03 data, how could sacituzumab govitecan fit into the frontline, immunotherapy-ineligible TNBC treatment paradigm?

[Sacituzumab govitecan] is another option for patients [and is] an agent that we're very familiar with. Another point to make is that many of us don't always [immediately] know the PD-L1 status of a patient. Therefore, with sacituzumab govitecan is [potentially] available and approved for both [immunotherapy-eligible and -ineligible] indications, it's a nice, friendly option for us to use. Maybe we can start a patient with sacituzumab govitecan up-front and then wait for the PD-L1 results, then add in pembrolizumab [for eligible patients]. I do find that rather nice, because we have to remember that the patient population we're treating with metastatic TNBC often includes patients for whom time sensitivity is of the essence. They may have visceral disease, liver/lung metastases, or metastases that are symptomatic. They may be on oxygen. Even waiting a couple of weeks to get a [PD-L1] result is not ideal, and what [we may] see in the community is the start of sacituzumab govitecan up-front before having the PD-L1 results.

Turning to the PD-L1–positive population, what were the key takeaways for the PFS improvement observed with sacituzumab govitecan plus pembrolizumab in the ASCENT-04 trial?

Although the majority of patients [with TNBC] are actually PD-L1–negative, [the ASCENT-04 data] have tremendous implications. Any meaningful improvement in outcomes—in this case, a delta of [3.4] months with a HR of 0.65 [95% CI, 0.51-0.84; P < .001]—is a gain for patients. What we hope to see eventually is that as we sequence other options and other ADCs, we're going to move the needle forward on OS, ideally,

Looking at the frontline TNBC space following these 3 positive phase 3 trials, how do you ultimately see TROP2-directed ADCs affecting this treatment paradigm?

I hope to see the natural history of metastatic TNBC change, where we can really reach OS greater than 24 months. In the ideal world, that's the impact that I see. It's also nice to have options that are lessening the burden of toxicity for patients in the frontline setting. Not to say that these ADCs don't come with their own set of [toxicities], but I do think [these agents] lower the incidence of...neuropathy, which can be life-changing for patients.

Fatigue and the monitoring of neutropenia [are key]. There's been an update in the FDA label for sacituzumab govitecan [to include] primary prophylaxis with granulocyte colony-stimulating factor [GCSF], which is going to be utilized much more frequently. That's going to change the evolution of febrile neutropenia that was seen from the trials [with sacituzumab govitecan], and hopefully we will see much less of that [in clinic]. [In ASCENT-03], the rate of grade 3 neutropenia [in the] sacituzumab govitecan arm was 43%. We're hoping to lessen that to a very impactful incidence. As you might recall, with ASCENT-03, there were 2% deaths [in the sacituzumab govitecan arm] due to [infections secondary to] neutropenia. We are hoping that [with GCSF prophylaxis], those toxicities are something of the past that we can change in clinical practice.

Considering Dato-DXd and sacituzumab govitecan, what should be known regarding the general safety profiles of TROP2-directed ADCs?

With sacituzumab govitecan, the topline concerns on the phase 3 trials that got these drugs near approval or approved are going to be neutropenia, nausea, and alopecia. Neutropenia with sacituzumab govitecan wasn't infrequent, but again, with primary prophylaxis, that will likely change.

Fatigue is a universal toxicity of both of [Dato-DXd and sacituzumab govitecan], and I do think that the dosing schedule matters. As we get utilization of sacituzumab govitecan more and more in the community and we see readouts of other schedules that are potentially equally effective, we might be able to come up with more patient-friendly schedules. However, right now, the day 1 and day 8 treatment can be a bit taxing, particularly for those who come out from cancer centers or to our cancer center from longer distances.

Some of the differences with Dato-DXd include the incidence, for example, of stomatitis, which is much higher than we see with sacituzumab govitecan. [The rate of] all-grade [stomatitis] was 57% [in the Dato-DXd arm in TROPION-Breast02]. The incidence of any-grade nausea was a little lower, but still at 45%. [The rate of] alopecia was a little lower, but still at 41%. Importantly, when it comes to the stomatitis, the grade 3 or higher incidence was not very high at 8%. We hope that with more vigilant monitoring, dose reductions, and the use of a steroid mouthwash, [we can address] these issues up-front to lower that these rates.

The other differing toxicity with Dato-DXd is ocular toxicity. Any-grade dry eyes occurred in 24% of the population [in the experimental arm of TROPION-Breast02]. This was not a common reason for discontinuation. In fact, treatment-related discontinuation is due to AEs were low for both Dato-DXd and chemotherapy, at 4% with Dato-DXd and 7% with chemotherapy, suggesting that we're doing a good job monitoring patients on both sides of the scale. These are the things that stand out [with Dato-DXd]: mucositis, stomatitis, and dry eyes.

With these TROP2-directed ADCs poised to reshape that frontline TNBC treatment paradigm, how do you first-line treatments continuing to evolve?

All of us are excited about the evolution of ADCs. Bispecific [antibodies] targeting 2 different proteins in someone's cancer [could have a role in this setting]. I also think that regarding sequencing, if we really want to change survival [outcomes] for patients, we need to understand what the next line of therapy will be. Many of us have been focusing on time to second progression [PFS2], and some of us are critiquing the fact that with there was crossover allowed in the ASCENT trials, whereas there wasn't a crossover allowed in TROPION-Breast02, so these are also fundamental differences [between the studies]. What's going to make a difference [in OS outcomes] is sequencing.

At the end of the day, both [Dato-DXd and sacituzumab govitecan] are going to be options for us as I'm thinking about the PD-L1–negative population, at least, and a lot of oncologists feel comfortable and hopeful about the fact that more options are all good things for our patients.

For patients with brain metastases, that always seems to be an unmet need in this population. I would be hopeful to see progress made with respect to preventing the onset of brain metastases. In the HER2-positive space, we have TKIs in the maintenance setting and maybe even the frontline setting. I'd like to see an evolution and a change in the prevention of brain metastases in [the TNBC] population.

References

1. 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. Ann Oncol. 2025;36(suppl 2):S1566-S1567. doi:10.1016/j.annonc.2025.09.031
2. 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. doi:10.1016/j.annonc.2025.09.030
3. 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. doi:10.1200/JCO.2025.43.17_suppl.LBA109