Harold Burstein, MD, PhD, and Erica Mayer, MD, MPH discuss results from the SERENA-6 trial, which were presented at the 2026 ESMO Breast Cancer Congress.
I'm Doctor Hal Burstein, and we're talking about highlights and breast cancer breakthroughs from the ESMO breast cancer meeting in May 2026 in Berlin. Here joining me now is Doctor Erica Mayer, one of the lead investigators for the Serena Six trial. Certainly a trial that's gotten a lot of attention in recent weeks. Uh, Erica, tell us briefly sort of about this study. What was the rationale for the trial and what did we learned that was new in the past few weeks? So, um, we increasingly understand mechanisms of endocrine resistance that make it more challenging when we're giving therapies to our patients with metastatic hormone receptor positive disease, um, leading to resistance and progression. And so, one of the major mechanisms of resistance is development of mutations in the estrogen receptor that can make a cancer less sensitive to medications such as aromatase inhibitor. Perhaps more sensitive to better medicines like oral certs. And so the purpose of Serena 6 was to look at kind of two questions. One is, can we identify the emergence of resistance over time through looking for emergence of this ESR1 mutation. And then the second part of the trial is thinking about once you have identified the emergence of resistance, if you apply a better medication, does that help patients do better? So, um, we have seen the results from Serena 6 presented now several times, including initially at ACO plenary last year, demonstrating that we could identify the emergence of resistance and that when patients who had an ESR1 mutation were randomized to switch to the oral ser camazestrin, they had a prolongation in progression free survival compared to those who remained on their, uh, aromatase inhibitor, both with CDK46 inhibitor. At east this year, we saw results that were presented by the trial primary investigator Francois Clement Berard looking a little bit more into the mechanics of the screening for ESR1 mutation using serial CT DNA. First, what what was noted was that in the trial, just as a reminder, there were 3700 or 3300 patients who entered the trial who had all been on. First line aromatase inhibitor with CDK46 inhibitor for at least 6 months. And then they had CT DNA testing done every 2 to 3 months to correspond to the time of, uh, restaging. So, essentially about 4 to 5 times a year. What was being looked for was finding the ESR1 mutation in the absence of radiologic clinical progression. So, of the 3300 patients who were screened a, A total of about 550 patients were found to have the mutation of that group. 315 were able to go on into the step two of the trial to be randomized. What we saw at EM Breast this year was a lot more granularity about the testing step. First of all, it was noted that the incidence of detecting an ESR-1 mutation rose steadily over the period of time during which patients were receiving first line. Aromatase inhibitor and CDK 46 inhibitor. So this is not something that necessarily is all front loaded into the very early years of treatment, but it actually could be detected even in patients who had been on their first line therapy for quite some time. I ask you one of the things that surprised me about this curve, since we think that ESR-1 resistance mechanisms are so important, actually 5 years into first line therapy, only 30% had developed such a mutation. Well, I would have guessed it would have been much higher. That number's pretty much in line with what we see in other trials. If you look at rates of ESR-1 mutation at the time of initiation of second line trials, so taking patients who had progressed on first line therapy, the number is about 30 to 40% will have an ESR-1 mutation. You know, admittedly, there are other mechanisms of resistance, including PF3 kinase pathway mutations and, and others. So this, this is one of the mechanisms that can be identified. Um, additional information that was shown was that, um, for patients who were being tested, um, about 10% of them were found to be positive at the time of their first test. And, um, looking over the period of time when patients were tested between years 1 to 5 was when there was the greatest likelihood of the first test being positive. Perhaps suggesting that might be, uh, a bit of the sweet spot of time, When testing should happen. Additionally, it was shown that, um, within a year of testing, so having 4 to 5 tests, about, um, 20%, uh, there's a detection rate of 20%. So, again, suggesting a little bit of a sweet spot. So, if this became operationalized and something we used in clinic, it might suggest the timing when we might approach patients for testing, when to start, and importantly, when to stop. So there are a couple of different layers to this study. Obviously one of them is would Camazestrin get an approval here? We don't know the answer to that. There was a recent FDA ODAC, and the vote was 3 to 6, the majority against an approval based on the study. But in theory one could do this now, right? I mean, you can order the test. There are commercially available oral serDs on the market. We have safety data for at least nimunnerine in combination with the CDK 46. Are you doing this now? I'm not doing this routinely in my practice, but I do find this data very compelling. Um, aside from what was shown at ESO breast, I think one of the other very interesting signals out of Serena 6 is the quality of life data suggesting that the patients who make the, the early switch to the oralcED have a very prolonged time to deterioration in quality of life when they're not experiencing symptoms of subclinical cancer progression, pain, shortness of breath, fatigue, things like that. So, I, I do think the data is very clinically compelling. I think we're all waiting to see what the FDA decides to do and if this becomes an approved option for us in clinic. And the second question I had is we've now had multiple trials, including Serena 6, Ember 3, the POTA 1 study, where CDK 46 in combination with a CERD, be it oral or intramuscular, um, uh, beyond progression, continuing the CDK 46 looks to be an active regimen. Is there anybody who shouldn't get that at this point? Continuation of oral SER with CDK 46. Or even just regular, uh, SERD. But yes, I mean, it looks like if you continue the SERD with the CDK46 multiple trials, that looks to be clinically advantageous. Is that your practice? Well, I think the strongest signal for use of oral SERDS is in patients whose cancers have an ESR1 mutation. So, my use of oral SERD, either as monotherapy or in combination would be targeted towards patients whose cancers have developed ESR1. If a patient has, let's say PICC3CA mutation, there's a whole category of drugs that have been developed for those patients, and then it becomes a kind of patient level decision as to which pathway do you prioritize in terms of your targeting strategy. Perhaps one day we'll have a combination that has both oral cert and, uh, PAM pathway inhibitor, and that might be the magical selection for that patient. The peanut butter and jelly goobers of the world of P PIC3CA and ESR1 targeting. Thank you. So, um, uh, looking forward for more data on that trial and, um, certainly very exciting to see that again, I think we're now seeing a real pattern here of acquisition of ESR1 mutation, ongoing therapy with, um, uh, SERDS with the oral or intramuscular plus, uh, CDK46 looks to be, to be very promising.
