Chapters Transcript Video 2026 ASCO Breast Cancer Highlights: Triple Negative Breast Cancer Harold Burstein, MD, PhD, and Ana C. Garrido-Castro, MD discuss new antibody drug conjugate treatment options in first line triple negative breast cancer. I'm Doctor Harold Burstein at Dana-Farber Cancer Institute. Welcome to our continuing programs on breast cancer breakthroughs where we are featuring some of the most exciting data presented at the 2026 ASCO meeting as they relate to breast cancer. Today, a focus on important updates for ADC-based therapy, uh, with Ana Grita Castro, who's been a lead investigator for many of the trials with ADCs. Uh, Ana, this is a class of drugs. Which is taking the world by storm in advanced breast cancer. Tell us what's new for us since 3 and 4 in the Tropiant-RESO2 study. Thanks so much, Hal. Yes, so we've seen over the past year the results from three phase 3 studies that have changed how we think about the first line metastatic TNBC setting. So with two trials for patients with PDL1 negative tumors, ascent of 3 and tropion breast type 2. And then uh another trial for those patients with PDL1 positive metastatic TBC ascent 04, looking at combination of trope to ABC with immunotherapy, and there now are indications for all of these agents in the first line setting. And so we know that. Um, there are some important differences if we focus on the PDL-1 negative trials, Essento 3 and trompion-breast 2, in terms of the clinical trial design, the endpoints of the study, use of subsequent therapies. And so the question that was posed is after the improvements that we've seen in PFFs with the trope to ADCs, are there other efficacy endpoints that can be relevant to understand the long-term impact of these ADCs in the first line study? So starting with the cent 3, just as a reminder, this was a randomized phase 3 trial for those patients with metastatic triple negative breast cancer who are not candidates for immune checkpoint inhibition, primarily due to PDL1 negative tumors, and patients were randomized 1 to 1 to receive either sausages and up goatecan or SG or chemotherapy of physician's choice in the control arm. Now an important distinction of this trial was the fact that in the control arm of chemotherapy, at the time of confirmed disease progression, patients were offered the option to cross over and receive SG as subsequent therapy, which was offered by the trial. And of those patients who went on to receive subsequent therapy in the control are about 80% received an antibody drug conjugate in that second line study. So this trial was designed with progression-free survival as the primary endpoint, which was met. And here the authors conducted an exploratory analysis to look at progression through survival 2 at PFS 2. And PFS 2 was defined as time from randomization to the first documented progression after the next line of therapy. We know that the overall survival data remained immature at the time of the initial data cut up, so the question was, could SG prolong PFS2 when given in the first line setting, uh, compared to chemotherapy. And here what you can see is that PFS2 was numerically prolonged in the SG arm, 18.2 months versus 14 months in the control arm of chemotherapy. Now, in contrast, if we look at the other clinical trial, tropium breast 02, some important differences here. So this phase 3 trial also enrolled patients with metastatic triple negative breast cancer, not candidates uh for immune checkpoint inhibition, again, primarily due to PDL1 negative disease, and here patients were randomized to receive either Data DXD or chemotherapy of its choice. Now, in contrast to sasatituzumab Govetecan, where we have data in the second line setting from a scent that there is demonstrated overall survival advantage to SG in later lines, there are no randomized data for Dato DXD in that pre-treated setting. And so this trial did not offer the option to crossover to Dato DXD in the control arm. But patients after participating in a clinical trial and uh after receiving protocol therapy, if they were on that control on the investigators' choices chemotherapy, they could go on to receive a subsequent ADC that may have been available in that area of the world. And so the actual crossover rate to ADC therapy in the control arm uh for those patients who went on to receive subsequent treatment was about half of that seen in Esendo 3, about 40% of those who went on to receive subsequent therapy. Now this study was prior for both with power for both progression free and overall survival, and both of those endpoints were met. And in fact, the median OS with Dado DXD reached almost 2 years in tropy and reststo too. Here, the authors had as a key secondary endpoint is this clinical trial PFS 2, which was defined slightly different than a center 3. So here, progression free survival 2 was defined as the time from randomization. To second progression on subsequent therapy. Uh, and so here you can see that, uh, also Dado DXD had numerically prolonged PFS2 compared to chemotherapy, that's choice. So 15.6 versus 11.8 months. Now, what I think is challenging, um, is to reconcile the PFS data, uh, the PFS2 data and contextualize that across both in the clinical trials when there are differences in the definition of PFS2, um, does, um, in terms of what happened after the first line of therapy, what was the reason for treatment discontinuation? Was it toxicity? Was it progression? Um, and also the heterogeneity and subsequent use of therapies, which is different in both of the clinical trials. And also an important factor to think about is, are there differences in the patient populations between patients who crossover and receive subsequent therapy versus those who do not. So overall I think the take home message from both of these clinical trials is that all the caveats of PFS2 um and the differences in definitions is that PFS2 is prolonged with the trope 2 ADC in the first line setting, and this reinforces the importance of utilization of a trope 2 ADC. As a and and consideration of a trip to DC as a preferred first line regimen for metastatic TNBC. That makes a lot of sense and thank you for, for sharing a pretty detailed analysis of some important data. So, let me just sort of step back and say in triple negative breast cancer at the moment, it seems like every is going to get a trope 2 or perhaps a HER2 directed, I suppose, ADC at some point in the course of therapy. Um, these data make an argument for using it sooner rather than later, though you acknowledge, as you said, that not everybody got uniform, uh, crossover and things like that. Um, is there any role for like first line capecitabine or are there any patients who you don't go directly to an ADC for and first line triple negative at this point? So it's an excellent question, and I think uh what is very important to keep in mind in metastatic TMBC is that unfortunately, there is attrition within the first months of diagnosis of metastatic TMBC where we see across multiple databases around the world that up to 20-25% of patients may no longer be alive at 6 months from the time of metastatic TMBC diagnosis. And that is the median progression free survival standard chemotherapy in first, in the first response setting. And so an agent that is a drug that is able to significantly improve progression-free survival with an acceptable toxicity profile and not compromise long-term outcomes should be sufficient to change that first line standard of care. And so I do think that in for most patients, unless there is a contraindication to the antibody drug conjugate. Um, considering atrope 2 ADC as the preferred first line regimen in the metastatic TNBC setting, um, that these agents should be considered. One, important, um, uh, patient population also to think about is are those who carry germ like BRCA or BRCA2 or PAL-B2A mutations, one might argue as well, where we know that HARP inhibitors improve progression-free survival but also quality of life compared to the chemotherapy physician's choice. And there is no head to head comparison between TRP 280C and ARPA inhibitor. So what do I know about uh TRP 280Cs and ARPA inhibitors? So it's an excellent question. Um, and in fact, uh, there were some biomarker data presented. The first biomarker data, uh, from Asendo 3 and Asendo 4, looking at the activity in subgroups of patients. Um. Uh, the activity of these trope 2 ABCs. So we, uh, just reviewed Asendo 3, that comparison of SG versus chemotherapy in patients primarily with PDL1 negative tumors, and Asendo 4 was, uh, the phase 3 study that looked at the combination of SG plus pendolizumab versus chemotherapy. It was pendolizumab in patients with PDL1 positive tumors. And here there were two primary, uh, uh, there were two biomarker analysis that were performed. The first looking at trope 2 neohistochemistry, and you can see here that in both Eento 3 and Eento 4, the numerical values for median progression-free survival do appear to increase at increasing levels of trope 2 expression, but overall, uh, there's no consistent trend in terms of the magnitude of benefit from the trope 2 ADC versus chemotherapy by quartile. So not clinically relevant to measure trope 2. And um I do think, and you can see here the separation of the Kaplan-Meier curves across different quartiles. I do think this underscores the importance of uh better methods of quantification of the target, perhaps beyond immuno chemistry, but also a better Understanding, um, that is needed of the actual mechanism of action of the ADCs and how much does perhaps the metabolism of the ADC before reaching the tumor cell impact the activity of the agent. All right, but I was asking you about RACA. What do you got for me? And so here, uh, there were, uh, data presented on tumor BRCA status. So germline BRCA status was, uh, not available for most patients enrolled in the clinical trial, but they did sequencing of the tumors and looked at BRCA1 and BRCA18 mutations. And here you can see that irrespective of BRCA status, the hazard ratios to favor the trope to ADC, arms versus chemotherapy physician's choice. What I do think is particularly interesting in the ascend 03 clinical trial. which is that PDL1 negative, uh, setting where we were discussing use of a trope 2 ADC versus a CARP inhibitor in that Asian population. Here you do see, uh, a median PFS in the mutant, in the BRCA mutant group with SG of just over 1 year, just over 12 months. So suggesting that there is high anti-tumor activity with trope 2 ADC in that BRCA mutant population. And we've actually seen previously data in early stage setting. For SG in patients who carry germline BRCA mutations with um high PCR rates seen with the TRP 2ADC. So suggesting that these agents uh seem to be, uh, have high anti-tumor activity in that patient population. So I do think that that choice of TRP 2ADC versus PARP inhibitor, um, is a conversation with patients about the differences in the administration of the agents and toxicity profiles. Makes sense. So I'm intrigued that in the Ecento 4 study, actually the mutation. Mutated associated tumors, uh, there's no substantial benefit and perhaps that's because the pembrolizumab here is so important in these cancers, uh, high mutational burden in tumor, all those kinds of things, so more to come. So, um, just again, big picture here, most of your patients were offering a trope 2 directed ADC as first line therapy for triple negative disease. At the moment, you don't know which agent is better, obviously, and it doesn't look like biomarker testing is gonna solve the conundrum for us here in any big way. Is that a fair summary? I think so. Great. We've been talking about new directions with antibody drug conjugates in first line therapy of triple negative breast cancer. It's exciting to see that after decades of using chemotherapy as our only tool in the toolbox for TNBC, we're now clearly looking at an era of immunotherapy for selected tumors, PDL1 positive ones, and of course the new ADCs. I'm Dr. Hal Burstein, but talking with Dr. Ana Grita Castro, Go Spain in the World Cup, and we're glad you joined us today. Published August 22, 2026 Created by Related Presenters Harold Burstein, MD, PhD Medical Oncology View Full Profile Ana C. Garrido-Castro, MD Medical Oncology View full profile