Jamie DePolo: Hello. Thanks for listening. Dr. Aditya Bardia is associate professor of medicine at Harvard Medical School and director of the breast cancer research program at Massachusetts General Hospital Cancer Center. At the 2021 San Antonio Breast Cancer Symposium he presented results from the EMERALD trial comparing the experimental medicine elacestrant to the standard of care for postmenopausal women and men diagnosed with metastatic hormone receptor-positive, HER2-negative breast cancer that has grown during treatment with hormonal therapy and a CDK4/6 inhibitor. That standard of care is either Faslodex or an aromatase inhibitor.
He joins us to talk about the results and what they mean for people diagnosed with this type of breast cancer. Dr. Bardia, welcome to the podcast.
Dr. Aditya Bardia: Thank you for having me.
Jamie DePolo: So, to start, before we get into the EMERALD study results, I know that like Faslodex, elacestrant is an estrogen receptor downregulator, but elacestrant is a pill and Faslodex is an injection. So, before we get into the EMERALD study, could you explain how elacestrant works and how it’s different from tamoxifen and the aromatase inhibitors?
Dr. Aditya Bardia: Absolutely. So, elacestrant is a selective estrogen receptor degrader, or blocker, and that’s how it’s different from tamoxifen — because tamoxifen is a selective estrogen receptor modulator. The point being that elacestrant can not only bind to the estrogen receptor but also degrade it, which tamoxifen cannot do. In terms of the difference with aromatase inhibitor; aromatase inhibitors do not block the estrogen receptor, they lower estrogen. So they have no impact on the receptor per se. The way aromatase inhibitors work is they lower estrogen.
So, the mechanism of action of elacestrant is novel in the sense that it’s a oral selective estrogen receptor blocker, which we’ve not had before in clinical practice.
Jamie DePolo: Okay, thank you. And I have to believe that most people would prefer to take a pill than to have to go to their doctor’s office and get an injection — I think it’s once a month — like Faslodex.
Dr. Aditya Bardia: That’s exactly correct, and that’s the advantage of elacestrant — it’s two-fold. The first is that it’s oral, as opposed to a shot that’s given with fulvestrant. And the second is that in pre-clinical models — and we saw it in [the] EMERALD trial as well — elacestrant is better as compared to fulvestrant in terms of clinical outcomes.
Jamie DePolo: Okay, great. Now, could you summarize the EMERALD study for us and also the results?
Dr. Aditya Bardia: Absolutely. So, EMERALD was a phase 3 clinical trial that directly compared elacestrant with a standard of care endocrine therapy, which could include either fulvestrant or an aromatase inhibitor. It was a global trial and enrolled more than 400 patients who were randomized one-to-one to either elacestrant or standard of care endocrine therapy.
In terms of the study results, the bottom line is that the trial was positive. It met its primary endpoints. Patients who received elacestrant had a 30 percent lower risk of disease progression or death as compared to standard endocrine therapy. We also looked at a subgroup of patients who had a specific mutation in the estrogen receptor, the so-called ESR1 mutations — those are mutations in the estrogen receptor per se — and in that subgroup there was a 45 percent reduction in the risk of disease progression or death in favor of elacestrant, as compared to standard of care endocrine therapy.
And finally, in terms of overall survival, again there was a trend in favor of elacestrant as compared to standard of care endocrine therapy. So, the trial met its primary endpoint: It showed that elacestrant is a better endocrine agent, as compared to standard endocrine therapy in terms of outcomes.
In terms of side effects, patients who received elacestrant had more nausea, as compared to standard endocrine therapy — but besides nausea, the other adverse events were pretty much similar between the study ops.
Jamie DePolo: Okay. Thank you. Now, I do want to ask about the previous treatments that the people in the study received. Because, my understanding is everyone in the study the cancer had grown while they were being treated with hormonal therapy and a CDK4/6 inhibitor. Is that correct?
Dr. Aditya Bardia: That’s exactly correct. So, if you look at our treatment landscape, first-line therapy comprises of endocrine therapy plus a CDK4/6 inhibitor. Patients eventually have disease progression on first-line therapy, and then they get second-line endocrine therapy, and that’s where the EMERALD trial comes in. So, it was designed as a second-line, third-line clinical trial. Once patients have disease progression on first-line therapy, then after that, comparing elacestrant to standard of care endocrine therapies, which is what we use in clinical practice.
Jamie DePolo: Okay. I guess the thing I don’t understand — and excuse my ignorance. So, if the cancer had grown while it was being treated with a CDK4/6 inhibitor and an aromatase inhibitor or Faslodex, then the standard of care in your study was either Faslodex or an aromatase inhibitor. I guess that’s what I’m not understanding, because it’s — to me anyway,
and I’m probably misunderstanding something — it sounds like the cancer already grew on those treatments so, how does that become the standard of care? That’s what I was confused about.
Dr. Aditya Bardia: Yes, absolutely, and that’s an excellent question and this point comes up often, and it came up yesterday as well. The key is that there’s a switch in endocrine therapy. So, if there’s a patient who receives an aromatase inhibitor plus CDK4/6 inhibitor as first-line, in the second-line we use fulvestrant. So, we switch the type of endocrine therapy before going to chemotherapy because chemotherapy is much more toxic, has more side effects, is less effective than endocrine therapy.
So, coming back to the example that you were saying, if a patient gets an aromatase inhibitor plus CDK4/6 in first-line, has disease progression, then in the second-line we would use fulvestrant. We will not use the same endocrine agent, we would use a different endocrine
agent as second-line therapy, and that’s where this trial was designed.
We can also look at the opposite scenario. If a patient gets fulvestrant plus a CDK 4/6 inhibitor as first line as disease progression, then in the second line we would use an aromatase inhibitor. So, the idea is to switch the type of endocrine therapy and get the maximum mileage out of endocrine therapy options before we go to chemotherapy.
Jamie DePolo: Oh, I see. I see. Thank you for explaining that. And the idea is that this would give another option — a third-line option — before going to chemotherapy, because that’s really what... if possible, you want to keep people from going to chemotherapy because, as you said, it’s more toxic.
Dr. Aditya Bardia: That’s exactly correct. That’s exactly correct. And so, that was the intent: Can we come up with a newer endocrine therapy option that can improve the outcomes of patients so we can delay the use of intravenous or toxic chemotherapy.
Jamie DePolo: Okay. And I do want to ask a little bit about the ESR1 mutation. Now, my understanding is that cancers that develop that, that is going to make them more likely to be resistant to hormonal therapy, whether it’s Faslodex or an aromatase inhibitor. Is that correct?
Dr. Aditya Bardia: That is correct. The resistance is more to aromatase inhibitors than fulvestrant, because what happens with ESR1 mutations is that the tumor becomes estrogen-independent and aromatase inhibitors work by lowering estrogen. But if the tumor is estrogen-independent, aromatase inhibitors will not work. Technically, estrogen receptor
degraders like fulvestrant should work in that setting, but the problem is fulvestrant is not the best estrogen receptor degrader, and that’s why there’s been a need and interest in developing better estrogen receptor degraders like elacestrant.
Jamie DePolo: I see. I see. Okay. And I do want to ask, too: You’ve mentioned that your future research is going to look at combining elacestrant with a CDK4/6 inhibitor. Do you think that, then, that would sort of move up in the chain? Would that kind of become a second-line treatment as opposed to a third-line treatment if it’s successful, or is that a premature question?
Dr. Aditya Bardia: No, absolutely. That’s exactly the intent, and I'll clarify. EMERALD was a second-, third-line study, so included both second-line and third-line. And if a drug gets approved, that will be the usage in the second- or the third-line setting. But we can also potentially look at combination therapy as first-line. Currently aromatase inhibitor plus
CDK4/6 or sometimes fulvestrant plus CDK4/6 inhibitors used as first-line. If elacestrant is a better endocrine agent, eventually elacestrant should be combined with a CDK4/6 inhibitor in the first-line setting. And that’s an ongoing plan — a planned study I should say — to look at this oral SERD with a CDK4/6 inhibitor in the first-line setting.
Jamie DePolo: Okay. Okay. Well, that sounds very promising. And I guess, finally, if you were talking to your patients that were diagnosed with this particular type of breast cancer, what does EMERALD — what do these results mean for them? I know that the company that makes elacestrant is working with the FDA on approval. Do you see this coming soon? Do you see this becoming a standard of care?
Dr. Aditya Bardia: I think so. I think this would potentially be a standard of care in the future, it depends on the timelines in terms of potential regulatory approval. Overall, I would say that this is great news for the field, and I say that because of three reasons. The first is it’s great to see a newer endocrine therapy option for patients with ER-positive breast cancer.
Second, there are a number of other oral-selective estrogen receptor degraders in development by other companies. So, this is great news for the field in general that these oral SERDs, as we like to call them, could potentially be better than currently available endocrine therapy agents.
And the third is these drugs would potentially work even in early breast cancer and if these drugs are utilized in early breast cancer, we can potentially prevent disease recurrence or metastases.
So, it’s great news for the field of endocrine therapies in general because we have a potentially new option and other similar options that’ll be coming from other companies.
Jamie DePolo: Thank you so much, Dr. Bardia. This has been really helpful in understanding these results.
Dr. Aditya Bardia: Absolutely. Thank you again for having me.
