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Jamie DePolo: Hello. Thanks for listening. I’m podcasting at the 2022 San Antonio Breast Cancer Symposium. I’m joined by Dr. Virginia Kaklamani, professor of medicine in the Division of Hematology/Oncology at UT Health San Antonio, who leads the Breast Cancer Program at the UT Health San Antonio MD Anderson Cancer Center.
At this conference, she presented the latest results from the EMERALD Trial, which compared the experimental medicine elacestrant with the standard-of-care of either Faslodex or an aromatase inhibitor for post-menopausal women diagnosed with metastatic, estrogen receptor-positive, HER2-negative breast cancer that had grown on earlier treatments with a hormonal therapy medicine or a CDK4/6 inhibitor. Dr. Kaklamani, welcome to the podcast.
Dr. Virginia Kaklamani: Thank you for having me.
Jamie DePolo: So, first could you explain what type of medicine elacestrant is and how it works?
Dr. Virginia Kaklamani: Absolutely. So, elacestrant is a new class of medicine, which are oral drugs, and they are SERDs, meaning, a selective estrogen receptor down regulator. So, in a sense it’s similar to fulvestrant, because that is a SERD as well, but fulvestrant is an intramuscular injection, whereas elacestrant is an oral medicine.
Jamie DePolo: Okay, so that’s a plus in my mind. That’s a plus for patients if it’s oral, correct?
Dr. Virginia Kaklamani: So, that is a plus in my mind as well and I think for our patients, too. So, how these drugs work is they basically destroy the estrogen receptor. They don’t allow it to be present and if we don’t have the estrogen receptor, then the estrogen cannot use the receptor to send signals to the cancer cells.
Jamie DePolo: Okay, great. Now, could you briefly sort of summarize the study for us? What did you want to see?
Dr. Virginia Kaklamani: Absolutely. So, the EMERALD Trial was a phase III clinical trial that compared elacestrant with a standard-of-care endocrine therapy, which was either fulvestrant or an aromatase inhibitor, depending on what endocrine therapy the patient had received previously. On the trial every patient had to have received a CDK4/6 inhibitor at some point and their cancer had to have progressed on that CDK4/6 inhibitor. And what we were trying to see was is elacestrant better than standard-of-care endocrine therapy, not only in the whole patient population, but also in patients whose tumors have mutations in the estrogen receptor.
Jamie DePolo: Okay. And the results show that elacestrant offered better progression-free survival than the standard-of-care, correct? And I also want to ask, this is kind of a two-part question, the effectiveness of elacestrant seemed to be related to how long the cancers were treated with a CDK4/6 inhibitor, am I understanding that correctly?
Dr. Virginia Kaklamani: That is correct. So, the trial that was initially presented last year showed that the two primary endpoints of the trial that were progression-free survival in the whole patient population and progression-free survival in the patients that had tumors with ESR1 mutations was superior in the elacestrant arm compared to the standard-of-care endocrine therapy arm. Now, this year what we looked at was how long had a patient been on a CDK4/6 inhibitor before they joined the EMERALD trial and is that length of treatment related to how well elacestrant is going to work later on? And the answer is, yes it is. So, the longer the patient had been on the CDK4/6 inhibitor, the longer they were on elacestrant, and the benefit was even longer.
Jamie DePolo: That’s very interesting. Now, I want to back up a little bit and talk about the ESR1 mutations. Why is that important to know that elacestrant works on those particular type of cancers?
Dr. Virginia Kaklamani: So patients that have tumors with ESR1 mutations tend to have more endocrine-resistant tumors. And so, we know that aromatase inhibitors usually don’t work very well in patients with ESR1 mutations and probably fulvestrant doesn’t either. But for the phase I clinical trial that we performed on elacestrant, we found that this drug is active even in cancers that have the ESR1 mutation. And I think that’s where you see the bigger difference favoring elacestrant compared to standard-of-care therapy.
Jamie DePolo: Okay. And before I go on to ask about side effects. I do want to ask, I mean, it’s interesting to me that elacestrant was more effective the longer there was CDK4/6 inhibitor treatment. So, I mean, it almost seems like you would go as long as you possibly could on a CDK4/6 inhibitor and then move to elacestrant. But I’m not a researcher, so what does it mean?
Dr. Virginia Kaklamani: So, tumors initially if they’re estrogen-positive, some of them have primary resistance, which means that they really, these endocrine therapies don’t work, and some of them develop resistance later on, which we call secondary resistance. If cancers are endocrine-resistant, then typically endocrine therapy doesn’t work very well. But one of the methods of endocrine resistance is the buildup of these ESR1 mutations. So, when we see ESR1 mutations, we realized that these tumors tend to be endocrine-resistant, but how do we capture that if we don’t do any genomic tests to find an ESR1 mutation?
And one way to capture it is by seeing how long treatment on the CDK4/6 inhibitor lasted for. If that treatment only lasted for six months, these cancers are endocrine-resistant and these patients really should go on to receive chemotherapy because we need to get some sort of response. But if the CDK4/6 inhibitor therapy lasted for 18 months, 24 months, then those are probably endocrine-sensitive tumors. And instead of exposing that patient to chemotherapy after progression, maybe we can give them a single-agent endocrine therapy. And in this study we found that we can.
Jamie DePolo: Okay. Now, side effects. Were there differences between elacestrant and the standard-of-care?
Dr. Virginia Kaklamani: So, side effects were actually pretty mild in both groups.
Jamie DePolo: Okay.
Dr. Virginia Kaklamani: There was a little bit more degree of nausea, but that nausea was grade 1 or grade 2 in the elacestrant arm. But interestingly, more patients on an aromatase inhibitor used an antiemetic compared to the patients on elacestrant. So, 10% of patients on an aromatase inhibitor used an antiemetic compared to 8% on elacestrant. So, overall, the side effects were mild, graded as grade 1 and grade 2, and I think this is overall, if it does get approved by the FDA — the FDA is looking at this data right now — this will be a relatively good treatment for our patients.
Jamie DePolo: Okay. And that was — you must’ve divined my next question — so what does this mean if I’m a post-menopausal woman diagnosed with metastatic, estrogen receptor-positive, HER2-negative disease and it’s grown while I received my first-line treatments? You know, how are you talking to your patients about this? Do — I mean, obviously the FDA never tells anybody when they plan to approve anything — but you know, do you see this in the near future or are we talking years? How are you talking to your patients about this?
Dr. Virginia Kaklamani: Well, the FDA fast-tracked this, so they will give us an answer by, I think, the 17th of February, if I’m not mistaken.
Jamie DePolo: Okay.
Dr. Virginia Kaklamani: And the answer could be, yes, we’re approving it, no, we’re not approving it, yes, we’re approving it in a certain patient population. So, that’s up to them to decide. But based on the data from EMERALD, and assuming this drug does get approved, I would be using it as a second-line therapy in my patients that I still believe have endocrine-sensitive disease.
Jamie DePolo: Okay. Dr. Kaklamani, thank you so much. I appreciate your time.
Dr. Virginia Kaklamani: Thank you so much.
