ASCO 2026 Updates in Metastatic Breast Cancer

This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

Intro:

Hello and welcome to the Decera Clinical Education Oncology Podcast. I’m your host, Sharif Morsalin. Today’s podcast features Dr. Hope Rugo from City of Hope Comprehensive Cancer Center and Dr. Nerea Lopetegui-Lia from The Ohio State University Comprehensive Cancer Center. They will discuss key metastatic breast cancer findings presented at the 2026 ASCO Annual Meeting.

For more information on our presenters, along with a link to the full educational program, please visit the show notes for this episode.

Now, let’s get started and hear what the experts have to say.

Dr. Rugo: It is a pleasure having you with me today and to talk together. There were a lot of data at ASCO this year that were updates on studies, which already either are impacting clinical practice or will in the near future. We will start and talk about SERENA‑6 and some of the other endocrine therapies, and then the TROP2 ADCs.

SERENA‑6 is a unique trial that evaluated patients who had been on endocrine therapy and a CDK4/6 inhibitor for at least six months, with every two to three‑month blood draws for ctDNA. Evaluating the development of ESR1 mutations and then randomized those who did not have progressive disease on scans but did have an ESR1 mutation to switch to camizestrant or stay on their AI, with both groups continuing their CDK4/6 inhibitor.

This was actually a double‑blind randomized phase III trial. Interestingly, because most patients joined it about a year and a half, about half of them had an ESR1 mutation already, but the median time to be randomized was just under two years.

It is really interesting looking at the data that was presented. It was an updated PFS, PFS2, and then some data on ctDNA.

What did you think of that data?

Dr. Lopetegui‑Lia: Very interesting to see that switching roughly doubled PFS. As you mentioned, in the extended analysis, it significantly improved second PFS. Just as importantly, I would highlight that it also delayed quality of life deterioration, which in the metastatic setting, is something important to highlight. This trial validates a monitoring plus pre‑emptive or proactive switching paradigm by serial plasma ESR1 testing.

There are a few things that we should not overinterpret yet. I think the overall survival remains immature. While the data seems very encouraging, the clinical utility of pre‑progression switching is not fully established until there is a little bit more mature PFS‑2, confirm durable benefit rather than simply lead time.

Things that I think about with this study, very interesting findings, but widespread serial ctDNA surveillance may carry logistical and cost implication that has yet to be resolved. Those are my initial thoughts.

The ctDNA clearance certainly was something that I found interesting by switching to Camizestrant and continuing the CDK4/6 inhibitor cleared the ctDNA by week eight in comparison to continuing on the AI and CDK4/6 inhibitor, which tell us that the proactive switching and ctDNA clearance we know usually does correlate with better outcomes. Certainly, a lot of very promising data.

Dr. Rugo: Yes, it was really interesting. The PFS‑2 data we heard a lot about at ASCO that there are some issues with the looking at PFS2 where people are not being followed on study, but it is a real‑world setting. That is helpful.

I thought the ctDNA data showing the big clearance at week four and then eight was quite interesting because the AI arm had a big increase in ctDNA by week eight.

It is important to note that the availability of oral SERDs, and certainly not in combination, just was not there for them as the control arm. Not as many people received oral SERDs, so you do not know if you were able to sequence and use a combination, what would happen.

The quality‑of‑life issue is really important that you brought up. That we are going to prioritize this approach in people who have more symptomatic disease in general, because being able to try and improve symptoms, as you pointed out, is a critical goal in the way we treat patients with metastatic breast cancer. Very, very interesting, well tolerated, though, which is great.

We also saw some other data on combinations for patients with or without ESR1 mutations: elacestrant combined with capivasertib. Those patients had to have AKT alterations. Then we saw data from PIKALO‑1 using a novel alpha‑specific pan‑mutant selective PI3 kinase inhibitor called trasolisib.

What do you think about the combination of endocrine agents and these targeted therapies as we move forward?

Dr. Lopetegui‑Lia: I certainly think that it makes a lot of sense to target concurrent, especially if they are there at the ESR1 and PI3K/AKT‑resistant, especially with an all‑oral doublet. The scientific rationale is very sound. It makes a lot of sense, and I am very encouraged by the data that we are seeing thus far.

In the ELEVATE study, the combination of Elacestrant with Capivasertib is not practice‑changing yet. The preliminary efficacy was only seen in about nine patients. Small sample size, 10‑month follow‑up, single‑arm. The phase II enrollment is ongoing, and I will be very interested in seeing that data. The conceptual takeaway was that ESR1 PI3K/AKT pathway alterations frequently do co‑occur, especially at progression, and so important to do comprehensive genomic profiling at progression to identify patients to offer different combination agents once they are approved.

Tersolisib: The eligibility criteria is important to highlight that it did include patients with baseline metabolic fasting blood glucose of less than 140. Patients with diabetes with a hemoglobin A1c of less than 8%. The central limitation of approved PI3K and alpha inhibitors is toxicity, especially hyperglycemia. The data that we saw with Tersolisib was very encouraging because it was very well tolerated.

What is genuinely new with the PIKALO‑1 is the tolerability signal. Being able to enroll patients with pre‑diabetes and diabetes, and how well it was tolerated even when there was hyperglycemia. It was effectively managed with supportive care, including adjusting antihyperglycemic medications. Really good options for our patients who have baseline diabetes or pre‑diabetes, where I have personally had some issues managing other PIK3CA inhibitors in this patient population specifically.

Dr. Rugo: I agree with you entirely. We really needed drugs that effectively target PI3 kinase pathway without the same toxicity of our first alpha‑specific drug, alpelisib. We have capivasertib. It is great to be able to combine an AKT inhibitor with a drug and oral SERD, where we have approval in the ESR1 mutant population, because the co‑mutations probably occur in the pre‑treated population in as many as 20% of patients. If you figure 40% for each of them, in the earlier lines of therapy, it is going to be quite a bit lower. This is a really important move going forward. Seeing the phase II data where enrollment has been completed for ELEVATE will be very helpful.

Similarly, being able to target patients who have PIK3CA mutations with an alpha‑specific pan‑mutant selective drug with less toxicity, like tersolisib is important in PIKALO‑1 showed us a lot of efficacy and minimal hyperglycemia, as you pointed out. We do see some elevation in liver enzymes, but overall, the drug is very well tolerated.

PIKALO‑2 is a first‑line study looking at patients both with endocrine‑sensitive and resistant disease in triplet versus doublet. Of course, we do not have an oral SERD there, but we hope to be able to look at that combination in the future.

There is another drug that targets patients who have PIK3CA mutations, again, alpha‑specific pan‑mutant selective, called zovegalisib. That is being studied in the second and greater line setting in the ReDiscover‑2 trial in a doublet, compared directly to capivasertib, both drugs given with fulvestrant. Those patients can have similar to the PIKALO ‑1 trial, a mutation in PIK3CA, but not alterations in AKT and PTEN loss that are acceptable for capivasertib.

Really an interesting area with a lot of advances expected over the next few years as we enroll to these studies and start seeing results.

Another big area that we saw at ASCO this year, and I think we saw last year, the very first data at ESMO 2025 was moving the TROP-2 antibody‑drug conjugates that carry topoisomerase payloads to the first‑line metastatic setting. We saw data from ASCENT‑04 and then ASCENT‑03 with sacituzumab govitecan, and then TROPION‑Breast02 with datopotamab deruxtecan. Both drugs already approved in pre‑treated hormone receptor‑positive metastatic breast cancer, where those patients in those trials had not received trastuzumab deruxtecan, which they probably would now because T‑DXd has been so effective in the HR‑positive HER2‑low and ultra‑low population.

For metastatic triple‑negative breast cancer, we really need ongoing improvements in treatment and so moving these drugs to the first‑line setting was important. Sacituzumab govitecan already approved in pre‑treated metastatic triple‑negative breast cancer, where it improved progression‑free and overall survival.

The first trial we saw was ASCENT‑04, where chemotherapy approved in KEYNOTE‑355, in combination with pembrolizumab in PD‑L1‑positive disease, was replaced with sacituzumab govitecan in a head‑to‑head randomized phase III trial. Patients had to be at least six months after their last treatment with curative intent.

We had already seen the benefits in PFS and understood that more than 80% of patients crossed over with progression to receive sacituzumab govitecan alone, but we saw data with PFS2 as well as some biomarker subsets.

What did you take out of that data that was presented at ASCO this year?

Dr. Lopetegui‑Lia: The ASCENT‑04 subgroup data showed that PFS benefit across TROP2 quartiles, tumor BRCA status, and HER2 subgroups. There was a benefit in all the subgroups. I really do think that those analyses strengthen support for the significant clinically meaningful benefit of SG with Pembro as first‑line treatment in metastatic TNBC across subgroups.

Dr. Rugo: One of the issues that was brought up in the discussion at ASCO was what to do with PFS2. It is not a real trial endpoint because people use it as secondary endpoints, but you are not mandating the frequency of scans or having any RECIST read. You do have to realize it is not a hard statistical endpoint. My thought on PFS2 is it represents real‑world treatment after progression on the first‑line study treatment after disease progression. We know that most of these patients in the control arm received SG.  

Now there was almost 80% in the second line, and then the rest were in the third line. But, we still saw a difference in PFS2, suggesting that the benefit is maintained. That helps me a little bit because of sequencing questions. Could you just wait and start at second line and get the same benefit? It is not definitive, but it is a little helpful. It really has led to us now thinking the TROP2 ADCs are our first‑line approach for triple‑negative breast cancer.

The other thing that they presented, which is important, and this was presented for all three trials, was time to first and second subsequent treatment, which was prolonged. That is important for patients too. I think survival is a pretty hard endpoint, unlike TB-02, which had dual primary endpoints, ASCENT‑04 and ASCENT‑03 had PFS as the primary endpoint, and then OS was a secondary endpoint because of the crossover of more than 80% receiving SG from the control arm in both trials.

In contrast to a little over 40% in TB-02. I do think this gives us some nice real‑world data. That is really what I took out of this, was that it sort of cements the use of these drugs in the first‑line setting.

Dr. Rugo: I did think that PFS2, where we had some interesting discussions about the lack of statistical validity, is still important as a real‑world endpoint, because even with the crossover, it does represent what people do in clinical practice. In the second‑line setting, a little under 80% of patients in the control arm went on to receive SG without Pembro because it was only approved in the first‑line setting.

Although the median PFS for PFS‑2 was not reached in the SG + Pembro arm, the hazard ratio is 0.67 with confidence intervals that do not cross one. That does suggest to me some impact on sequencing, as does the time to first subsequent treatment and second subsequent treatment. These are all, I think, important endpoints for us as we are thinking about how to treat our patients and whether or not we should just give the ADC, which is more expensive in many countries and has differential toxicity, for example, hair loss versus gem and carbo.

What should we do? This data for me gives more credence to the idea that we should be really having TROP2 ADCs as our first‑line approach to treating triple‑negative breast cancer. This is the PD‑L1‑positive population, but we saw in ASCENT‑03 and TROPION‑Breast02 very similar data and efficacy across different biologic subsets.

How do you put the ASCENT‑03 and TBO2 data into clinical practice? We now have two positive trials. Survival benefit for TBO2, where crossover, of course, was not employed because Dato‑DXd was not approved for triple‑negative breast cancer. The majority of patients in the control arm crossed over to receive SG in the ASCENT‑03 trial. Again, half the follow‑up duration with ASCENT‑03 compared to TBO2 because you had a single endpoint of PFS versus the combined endpoint of PFS and OS for TBO2, which takes longer to reach.

The data is very good for both drugs. How do you put these into practice?

Dr. Lopetegui‑Lia: It is a great question. Typically, if I have a newly diagnosed metastatic triple‑negative breast cancer case, oftentimes if I want to start treatment very quickly, I will go ahead and start them on sacituzumab govitecan while the PD‑L1 testing is pending. Then, if it is PD‑L1‑positive, I will add the pembrolizumab. If it is negative, then I will just continue sacituzumab govitecan monotherapy.

If I have all the data upfront, if I know that there are PD‑L1‑negative, I will discuss with my patients both options. I talk to them about toxicities, also the schedule of the drugs. Sacituzumab govitecan, we give day one, day eight, every 21 days, versus Dato‑DXd, which is once every three weeks. Again, very different toxicity profile. I will talk to them about neutropenia and diarrhea in the setting of SG. More so the mucositis, stomatitis, keratitis, or the ocular toxicities with Dato‑DXd. Then again, it is mostly shared decision‑making. I do find data from both of the studies, and we should not be doing cross‑trial comparisons, but both of the data is very compelling. That is usually how I approach it.

Dr. Rugo: I think that is a balanced and great way to look at this. We have to talk about the differences between the agents with our patients. There are patients who have specific comorbidities that will really push us to one drug versus another. I just saw a patient who had next‑generation sequencing done, but she is on her first‑line therapy and doing fine, but she just had these cysts show up on her spleen. She had less than 0.05% variant allele fraction, so you cannot see anything.

Where we send this test, they are able to do pharmacogenomics, and she is a star 28 homozygote. In that situation, I said, "Well, thankfully you do not need this information now, but someday in the distant future, when you do need the information, it might suggest that you go on one drug versus another, because with SG, of course, you have more neutropenia and diarrhea at higher grade when you are a homozygote for the metabolic pathway, for SN‑38, the payload for SG."

I think we really can think about those patients who get a lot of aphthous ulcers. Maybe not the best candidates again for Dato‑DXd, or patients who have underlying corneal issues. We are learning a lot about managing all of these side effects as we go along.

These were really interesting data at ASCO about metastatic breast cancer. We are excited about what the future will show. We are going to see a lot more data on oral SERDs both in the metastatic and early‑stage setting over the next year or so, and probably further updates on some of these trials, as well as updates from the early‑stage setting where we have continued to see advances in treatment.

It’s been great talking with you. Thank you so much for your thoughts and opinions, and thanks for listening.

Dr. Lopetegui‑Lia: Likewise. Thank you.