ESR1 Mutations May Signal Better Results With Oral SERDs in Advanced Breast Cancer

Jane Lowe Meisel, MD

Associate Professor

Department of Hematology and Medical Oncology

Department of Gynecology and Obstetrics

Emory University School of Medicine

Winship Cancer Institute of Emory University

Atlanta, GA

At a live virtual event, Jane Lowe Meisel, MD, provided insights into the latest practice updates for patients with hormone receptor–positive, HER2-negative metastatic breast cancer. She focused on the practice-changing use of the oral selective estrogen receptor degrader (SERD) elacestrant (Orserdu) for this patient population and how it has come into use in her own practice. Meisel also discussed how patient characteristics such as ESR1 mutation status and length of treatment with a CDK4/6 inhibitor allow physicians to evaluate the potential impact of elacestrant.

SYSTEMIC THERAPY WITH CDK4/6 INHIBITORS

There was an interesting real-world study looking at systemic therapy after initial progression on first-line CDK4/6 inhibitors.¹ It was a medical records–based study looking at patients who’ve been on first-line CDK4/6 inhibitors plus endocrine therapy from 2015 to 2020 and then looking at what these patients received after that. [In summary], the article showed that patients who went on to second-line chemotherapy didn’t do as well in terms of progression-free survival [PFS; HR, 0.48; 95% CI, 0.43-0.53; P < .0001] and overall survival [OS; HR, 0.30; 95% CI, 0.26-0.35; P < .0001] as patients who went on to a second-line CDK4/6 inhibitor. So the conclusion of the article was that second-line CDK4/6 inhibitors plus endocrine therapy may very well be a good [treatment] option and patients may do better than if they’re on chemotherapy. The caveat was that, of course, these were retrospective [data], and prospective data on second-line CDK4/6 inhibitors are needed.

HISTORY OF SERDS

The development of SERDs goes from 2002 to the present. In 2002 fulvestrant [Faslodex] was approved by the FDA,² and then in 2016 fulvestrant plus palbociclib [Ibrance] was approved by the FDA.³ The long window [2002- 2016] with fulvestrant monotherapy was [essentially] the only thing we had going to treat these patients. In 2019 we received approval of fulvestrant plus alpelisib [Piqray] for patients with PIK3CA mutations [in their disease], based on the SOLAR-1 [NCT02437318] study.⁴ Then in 2022 there had been mixed results from studies of various novel oral SERDs, and it has become sort of that holy grail to get away from the injection [of therapy] into the buttocks.

During this time, there were positive results from a phase 3 trial of elacestrant called the EMERALD study [NCT03778931].⁵ As a result, in 2023 elacestrant became the first oral SERD approved by the FDA for [patients with] estrogen receptor– positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer.⁶ The Guardant360 CDx assay, as many have said they are using, is also approved as a companion diagnostic device to identify patients with breast cancer who might be appropriate for treatment with elacestrant. We still have a lot of drugs, a lot of oral SERDs in development, and other novel endocrine agents as well. Some of these oral SERDs are being studied as monotherapy and others in combination, but I think we’re going to see a lot [more] in the decades to come.

CONSIDERATIONS FOR ESR1 MUTATIONS

In this setting, it’s one of those situations where you want to be strategic about your choices, because whatever you choose now will also affect what options open up for you later. I like elacestrant [ for patients with an] ESR1 mutation in their disease because not only are you choosing [a treatment] that’s targeted for this patient, but you’re also potentially leaving fulvestrant open as a partner drug for other treatments down the line. ESR1 mutations are usually not present in the beginning of someone’s metastatic breast cancer journey. If you look at a patient who’s never seen an aromatase inhibitor [AI], you might rarely see an ESR1 mutation [in their disease], but if you see a patient who’s had treatment with an AI [and] then progressed on it, you’ll see ESR1 mutations [quite a bit].⁷ These mutations are acquired during AI treatment kind of in response to the AI...so ESR1 mutations predict resistance to aromatase monotherapy. [For] someone who is on an AI and has an ESR1 mutation [in their disease], the chances that patient may progress quickly are high. So if you see an ESR1 mutation, that might tell you…to start something else instead of an AI to treat this patient.⁷

EMERALD TRIAL

[The EMERALD study] looked at elacestrant vs fulvestrant.... So 80% [of patients in this trial] received prior AI therapy, and only about 30% had prior fulvestrant, but most patients on this trial who were receiving standard-of-care endocrine therapy did receive standard-of-care fulvestrant.... [In other studies] patients with an ESR1 mutation did better on fulvestrant than they did on an AI, but...in looking at those ESR1 mutation carriers on elacestrant vs fulvestrant, [there is] a big benefit to elacestrant instead of fulvestrant in this setting. In the 6-month and 12-month landmark analyses, 40.8% [95% CI, 30.1%-51.4%] of patients were progression-free at 6 months on assessment vs 19.1% [95% CI 10.5%-27.8%] with fulvestrant. There were similar numbers with 12-month PFS as well, which shows that elacestrant is not just better than all standard-of-care options, but it really seems to be superior to fulvestrant on its own and in the ESR1 mutation carriers too. For most subsets of patients, that we had reasonable [recruiting] numbers in, it didn’t matter whether you had visceral metastases, were older or younger, or what the number of prior lines of endocrine therapy was. All these patients seemed to do better with elacestrant than they [did] with standard of care.⁸

CDK4/6 INHIBITOR ASSOCIATION

Looking at patients [being treated in this trial], based on the duration of their CDK4/6 inhibitor use, gets into the question of endocrine therapy sensitivity.9 So if [the patient had] at least 12 or 18 months of a CDK4/6 inhibitor...they seemed to have done slightly better on elacestrant vs standard of care, but…when ESR1 mutation carriers use elacestrant, it makes a big difference. So if [the patient’s disease had] an ESR1 mutation and they received at least 12 months of the endocrine therapy [of choice] plus a CDK4/6 inhibitor, then you’re going to have at least a 6-month…PFS difference if you use elacestrant compared with standard-of-care endocrine therapy. [These results] get at who is benefiting, and it seems like it’s the ESR1 mutation carriers if [they] had a year or more of successful treatment on their endocrine therapy plus a CDK4/6 inhibitor....⁹ You want to be using the right drugs for the right patients, and to me, it seems like when I’m thinking about when to use elacestrant, I’m looking at whether they have an ESR1 mutation and then how long they were on an endocrine therapy plus a CDK4/6 inhibitor—and the longer the better.

MULTIPLE MUTATIONS AND PROGRESSION

It’s good to have options, and I think we do come across this. I’ve had this happen in my practice, where I have a patient who progresses on their AI plus a CDK4/6 inhibitor, and then I do genomic testing, and I find they have not only an ESR1 mutation but also a PIK3CA mutation.... In the 2 patients I’ve had that happen with so far, I’ve chosen to use the elacestrant first, but because it was studied mostly in that second-line setting and also because taking 1 pill as monotherapy is often so much easier than taking a shot in the buttocks every 4 weeks and doing another pill. At least in my practice, I’ve found elacestrant to be a little bit easier [ for patients] to tolerate than alpelisib, and I’ve observed a lot of hyperglycemia and diarrhea with alpelisib that’s been harder for some of my patients [to handle]. I have often been using elacestrant first and then thinking about alpelisib and fulvestrant as my third-line endocrine therapy if the patient remains endocrine sensitive.

For me, my experience with the drug is so new that if I didn’t think I had 3 months to figure out [whether a patient is]… going to respond [to treatment], I might shy away from it a little bit. I have had 1 or 2 of those situations where I have shied away from it just because the progression felt a little more rapid in tempo than I felt comfortable with, at least at this juncture, using the elacestrant. I’ve used it mostly in my slower-progressing patients, but what I find clinically is that the patients who get a year or more on their AI plus a CDK4/6 inhibitor tend to also be people who progress a little bit slowly in the beginning when they are first progressing, so I haven’t had to make that decision too many times. If it were more rapid progression, I would feel a little bit less comfortable with elacestrant at this point, but that may change over time as we get more used to the drug.

_REFERENCES

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_{2. Bross PF, Cohen MH, Williams GA, Pazdur R. FDA drug approval summaries: fulvestrant. Oncologist. 2002;7(6):477-480. doi:10.1634/theoncologist.7-6-477}

_{3. Walker AJ, Wedam S, Amiri-Kordestani L, et al. FDA approval of palbociclib in combination with fulvestrant for the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2016;22(20):4968- 4972. doi:10.1158/1078-0432.CCR-16-0493}

_{4. André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904}

_{5. Bardia A, Aftimos P, Bihani T, et al. EMERALD: phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer. Future Oncol. 2019;15(28):3209-3218. doi:10.2217/fon-2019-0370}

_{6. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed September 6, 2023. https://bit.ly/3RueKsj}

_{7. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3}

_{8. 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}

_{9. 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. 2023;83(5):GS3-01. doi:10.1158/1538-7445. SABCS22-GS3-01}