What is the Role of Oral SERD Therapy in HR+ Metastatic Breast Cancer?

Transcript:

Eva M. Ciruelos Gil, MD, PhD: I was going to give an overview of SERDs [selective estrogen receptor degraders], Sara, because they have been promising drugs and so pharmacologists, patients, and clinicians have high expectations for them. However, we’ve had some disappointing data from European Society for Medical Oncology Congress 2022; ESMO on SERDs. Could we have your general view on these drugs and particular view on some of them?

Sara M. Tolaney, MD, MPH: There has been so much hope placed in these agents. We’ve been looking for better endocrine therapies for patients, and the opportunity to have an oral agent instead of the intermuscular fulvestrant [Faslodex] has been attractive to both patients and physicians. We’ve been eagerly awaiting these data. We initially saw data came out from the EMERALD trial [NCT03778931], which had compared the oral agent elacestrant with endocrine therapy, a physician’s choice. That study was a positive study, but we all felt the benefit was fairly modest. For the intent-to-treat population, there was only a delta of approximately 1 month. What we saw was that the ESR-mutant patients were seeing larger benefits. ESR-mutant patient population intent delta increased from just under 2 months to almost 4 months. This seemed like a promising group of patients. This agent is currently under FDA [United States Food and Drug Administration] review, so we’ll see if it leads to an approval soon. It would be nice to have an oral agent.

As you point out, post CDK4/6 inhibition, there is a 2-month PFS [progression-free survival] that we’re seeing with standard endocrine therapy, which is a bit disappointing. I think combination therapy is probably where we need to go. There are multiple oral SERDs in development, not just elacestrant. We saw data at ESMO. One study was AMEERA-3 [NCT04059484], which compared an oral SERD, amcenestrant, with treatment, the physician’s choice. This was in a patient population where 80% of patients had had a prior CDK4/6 inhibitor. This is different than the EMERALD study where 100% of patients were post CDK. SERDs were also compared with endocrine therapy, but here about 90% of patients got fulvestrant, which was more than in EMERALD where it was more like 70%. So there were some differences in patient populations. It was a smaller, randomized, phase 2 trial with 290 patients. It showed that there isn’t a difference with amcenestrant compared with endocrine therapy of choice. Both therapies had almost identical progression-free survivals at 3.6 and 3.7 months. The trend was seen in the ESR-mutant patients. Similar to what we saw in EMERALD, there seems to be this benefit in that group of ESR-mutant patients. It went from approximately 2 months to 3.7 months. That trend, in that group, although present, is not statistically significant. I think the data were a bit disappointing. We kept hoping for more. Sanofi decided to discontinue development of amcenestrant based on the data from AMEERA-3, but they also had a readout from their interim analysis of their phase 3 study, which was in the first-line metastatic setting, combining amcenestrant with palbociclib (Ibrance), and comparing it with letrozole with palbociclib. That interim did not meet prespecified criteria to continue. That was also disappointing. Given the combined data, they’ve decided to not develop that agent further. We also saw data on giredestrant, an oral SERD. Those data were somewhat similar to what we saw in AMEERA-3. It was a different patient population. All of these trials have slightly different populations. In this one, only 40% of patients had a prior-CDK4/6 inhibitor. They didn’t show a real difference between giredestrant and treatment of choice endocrine therapy, but in the ESR population, that seems to be the theme.

Eva M. Ciruelos Gil, MD, PhD: There’s a trend there.

Sara M. Tolaney, MD, MPH: I think there were modest benefits, but really only in the ESR-mutant patient population. It’s interesting because despite the limited data that we have here, these agents have already moved to the adjuvant setting in development. We have an adjuvant giredestrant study that’s currently enrolling. There are other agents moving into the adjuvant setting very quickly as well, so we’ll have to see what happens with the SERDs. There was some thought that maybe they could be used in the first-line setting with CDK4, but then we saw the press release for the readout of AMEERA-5. I truthfully wasn’t expecting those studies to be positive given what we’ve seen from PARSIFAL [NCT02491983]. When you compared fulvestrant with palbociclib vs letrozole with palbociclib, there wasn’t really a difference. It makes you think that maybe the endocrine backbone doesn’t matter here so much. I think we need to figure out the correct patient population. My hope is that these agents will have benefit post CDK on the ESR-mutant population, but I do think more combination therapy studies are needed.

Eva M. Ciruelos Gil, MD, PhD: Combination therapies and better selection of patients are needed, including patients with ESR1 mutations and maybe others. This is a reflection to not go to adjuvant trials with more than 3000 to 4000 participants until we have robust data biomarkers. For advanced disease, the adjuvant scenario is the best one to explore about biomarkers selection of patients. That is what’s happening with different new drugs and SERDs. You think that these drugs have nearly the same mechanism of action as PROTACs [proteolysis-targeting chimeric molecules] or Seran’s agent? Could we improve in the efficacy results? Do you have expectations of them?

Sara M. Tolaney, MD, MPH: That’s an excellent question because you’re right, there are so many other agents in development that also work to degrade the estrogen receptor. Maybe a different mechanism of action could be different or better. We’ve seen some data come out with Arvinas’ PROTAC agent ARV-471. I think that agent looks very promising. They’ve had some data from phase 1 that showed responses in patients who have progressed on fulvestrant and in oral investigational SERDs, and then went on to ARV-471, which is really interesting.

Eva M. Ciruelos Gil, MD, PhD: Difficult scenario.

Sara M. Tolaney, MD, MPH: It is generally well tolerated, but we only have data in heterogenous patients. There’s the Olema agent, and the Seran agent, which we also think looks really interesting. There are lots of drugs in development, but we just need more data.

Eva M. Ciruelos Gil, MD, PhD: My final question is: Would you still recruit your patients into the ongoing adjuvant trials with different SERDs? Or do you prefer to wait until you see what happens?

Sara M. Tolaney, MD, MPH: It’s interesting. I think our group has struggled with this decision quite a bit. Obviously, these are curable patients, and we have drugs that do work. Aromatase inhibitors and tamoxifen are standard and definitely prevent recurrence, but at least we’re seeing that they’re probably equivalent to endocrine of choice. It’s different to compare in a treatment-naïve population where they’re not the same resistance mechanisms. I think it’s reasonable to consider, and I don’t think it’s going to do harm. I think there’s a chance it could be better. I think the challenge is, as you’re pointing out, the patient selection. I wonder, in an adjuvant setting, if therapy should be up front or more sequential when resistance mechanisms have built up? Should it be in particular adjuvant patients? Is there just clinical pathologic risk or does it need to be biomarker driven, even in the early-stage setting? We just don’t have enough information. I would enroll patients to an adjuvant trial. I feel comfortable with it, and generally, they’re pretty well tolerated.

Eva M. Ciruelos Gil, MD, PhD: They’re not worse. They’re not harmful. That should be the main thing to focus on.

Transcript edited for clarity.