Physicians Discuss Elacestrant Vs Alternatives in ER+, HER2- MBC

Reshma L. Mahtani, DO

Chief of Breast Medical Oncology

Miami Cancer Institute

Miami, FL

DISCUSSION QUESTIONS:

• Have you used the oral selective estrogen receptor degrader (SERD) elacestrant (Orserdu) for your patients with breast cancer?​
• What efficacy and/or safety data most impacts your decision to prescribe oral SERDs, approved or investigational?​

RESHMA MAHTANI, DO: Have any of you had the opportunity to use elacestrant? Do you have experience with any of the other oral SERDs? What are your impressions in terms of efficacy and safety data that are most impactful as you consider using these agents?

SUMITHRA VATTIGUNTA, MD: I had a patient whom I started on elacestrant who progressed on a CDK4/6 inhibitor with extensive disease, and she had a good duration of progression-free interval. I switched her to abemaciclib [Verzenio], which worked for 4 to 6 months. She had the ESR1 mutation. We couldn't get elacestrant at that time, and she had progression of disease. I had to start her on chemotherapy because the mass was causing compression; it was in the pectoralis area causing compression of the vein with deep vein thrombosis, lymphedema, [etc]. I gave her chemotherapy for a short time with a major response, and then I switched to elacestrant, which she is on currently and is tolerating well.

PHU TRAN, MD: I have a patient whose been on elacestrant for the past few months, and I think overall it's tolerable. The patient has partial response. But 1 adverse event [AE] that I tried to look up and I didn't see [documented] is severe peripheral edema…I read the label and it's not documented. Her cardiac function and everything was checked out and they were OK, just the edema.

MAHTANI: I have not had that experience either. Do any of you have experienced with other SERDs?

SIMON VINARSKY, MD: I agree with you that this mutation is considered to be a negative prognostic feature. I have 1 patient on [elacestrant] who is now doing reasonably well. I don't consider its AE profile to be that challenging compared with other things we have to do for patients with breast cancer. I have 1 patient right now on this medication doing well using it in the second-line setting prior to moving to systemic chemotherapy.

JONATHAN TICKU, MD: What is the percentage of patients that we should expect to pick up the ESR1 mutation? How frequently should we be expecting it?

MAHTANI: Great question. I think it depends on the series that you review, but on average it’s quoted to be around 30% to 40%. It’s important…because a considerable portion of patients will have the opportunity to use this therapy.

DISCUSSION QUESTIONS

• Do the EMERALD trial (NCT03778931) data on duration of CDK4/6 inhibitor treatment influence your practice for the ESR1-mutated population or the dual mutation ESR1/PI3K subgroups?​¹
• How does the safety data from EMERALD compare with standard therapies used in the second-line/third-line setting, e.g., everolimus (Afinitor) plus exemestane (Aromasin) or alpelisib plus fulvestrant (Faslodex)?​

MAHTANI: [Considering] the data on duration of prior CDK4/6 inhibitor treatment, how does this influence your practice for your ESR1-mutated patients? What do you do in the situation where you see someone who has both mutations and there are opportunities to use alpelisib and fulvestrant or elacestrant?

KARIM ARNAOUT, MD: The longer they have been responding to the CDK4/6 inhibitors, the higher the response rate to elacestrant.1 With alpelisib, I worry about some AEs for it, so I would probably rather try elacestrant. What do you think about choosing everolimus after trying elacestrant? I think [in the data] these patients don't do very well with them.¹

MAHTANI: That brings up an important question because the randomization in the EMERALD trial was [compared with] single-agent endocrine therapy, which brings up the question, "Is that the best randomization?" In the situation where we're not using elacestrant and where they don't have the opportunity to use alpelisib, we would consider everolimus plus exemestane or everolimus and fulvestrant or even everolimus and tamoxifen [Soltamox]. We don't have the answer to that question in terms of how that combination with everolimus would do against single-agent elacestrant, but to answer your question of whether I try it: yes, I would definitely try it. But I think it is an area where we don't have information.

LAZARUS LEKAKIS, MD: What is the difference [in outcomes] between fulvestrant [alone] vs fulvestrant plus everolimus?

MAHTANI: That was shown in the PrE0102 trial [NCT01797120]. I don't remember the efficacy data off the top of my head, but it was a positive trial where the addition of everolimus to fulvestrant did improve outcomes.² I don't believe there was an [overall] survival benefit, but there was a progression-free survival benefit.

ANAMIKA KATOCH, MD: I have had an extremely difficult time getting my patients to alpelisib so if I found the ESR1 mutation, I would most likely drift towards [elacestrant].

MAHTANI: What if you found both?

KATOCH: I think I would still go for [targeting] ESR1, but like you said, patients who've been on the CDK4/6 inhibitor longer tend to have a better response [to elacestrant].¹ But I have had a difficult time getting patients through the PIK3 inhibitors.

MAHTANI: Yes, it's been tough. Do any of you consider prophylactic treatment for nausea and vomiting when you give elacestrant or do you wait and see how patients do?

VATTIGUNTA: I do give the prophylactic because I don't want them to go through it if they're home, like we do for many other agents.

The EMERALD trial had patients who were [previously] on fulvestrant and they had a response with elacestrant later.³ I know there's a trial that is adding elacestrant to everolimus, which I'm [leaning] towards if the patient has already progressed on fulvestrant. We have a trial available, which I have not had put any patients on yet, but I was thinking [of doing]…. What do you think?

MAHTANI: You're bringing up a point that a lot of us are very anxious to get some data on, which is elacestrant combinations. I believe the trial you're referring to is the ELEVATE trial [NCT05563220] where there are 4 arms and elacestrant in combination with everolimus is one of the arms. It's also in combination with alpelisib, and in combination with the CDK4/6 inhibitors [palbociclib (Ibrance) or ribociclib (Kisqali)]. It will be an important point going forward because we are utilizing combination treatments much more commonly than endocrine monotherapy. But outside of the context of that trial or any other ongoing studies, I wouldn't recommend combination strategies with elacestrant when we don't know the toxicity profile and any interactions. We need to do that cautiously in the context of a trial.

_References:

_{1. Bardia A, Bidard FC, Neven P, et al. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting. Cancer Res. 2022;83(5_suppl):GS3-01. doi:10.1158/1538-7445.SABCS22-GS3-01}

_{2. Kornblum N, Zhao F, Manola J, et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol. 2018;36(16):1556-1563. doi:10.1200/JCO.2017.76.9331}

_{3.Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338}