Hurvitz Discusses Use of SERDs in Patients With Breast Cancer

Sara A. Hurvitz, MD

Associate Professor, David Geffen School of Medicine

Medical Director, Jonsson Comprehensive Cancer Center Clinical Research Unit

Codirector of the Santa Monica-UCLA Outpatient Oncology Practices

Director of the Breast Cancer Clinical Trials Program

University of California, Los Angeles

Targeted Oncology^TM: Where do ESR1 mutations typically occur in patients with breast cancer, and how often?

HURVITZ: Different mutations can occur in coding regions of the estrogen receptor [ER]. Most of the mutations are in the ligand-binding [AF2] domain. If you get your circulating tumor DNA [ctDNA] or tumor biopsy and you’re looking for a PI3 kinase mutation, and you see an ESR1 mutation, you may see 1 of many of these [AF2 mutations].

The thing about ESR1 mutations is they’re rare in patients who are endocrine therapy [ET]-naive. [Fewer] than 3% of these patients will have one. [However], if you’re checking ctDNA or tumor tissue in the second- or third-line setting after a patient has been on an aromatase inhibitor [AI] for some time, chances are you’re going to pick up patients who have one of these mutations. Anywhere from 30% to 50% of patients with ER-positive breast cancer who are treated long term with an AI will develop an ESR1 mutation.¹

How have fulvestrant [Faslodex] and exemestane [Aromasin] performed in patients with ESR1–wild type vs ESR1-mutant advanced breast cancer?

Those data come from an analysis of the SoFEA [NCT00253422] and EFECT [NCT00065325] studies that looked at exemestane vs fulvestrant in metastatic breast cancer. With respect to progression-free survival [PFS] and overall survival [OS], the patients with wild-type ESR1 did equally well with exemestane or fulvestrant.

There was no benefit in terms of PFS or OS. But among those patients who had mutant ESR1, the patients who were treated with exemestane had much worse PFS [median PFS, 2.4 months; 95% CI, 2.0-2.6] and OS [rate at 12 months, 62%; 95% CI, 45%-75%], and the patients treated with fulvestrant did well [median PFS, 3.9 months; 95% CI, 3.0-6.0; 12-month OS rate, 80%; 95% CI, 68%-87%].²

This is a very early indication that if you see a patient who has an ESR1 mutation, an AI is probably not going to be the best ET for them—at least when given as monotherapy—and you might want to choose fulvestrant.

What are the highlights of the development of fulvestrant?

Fulvestrant was approved 20 years ago, and then the higher dosing schedule was approved 5 years later.³ It was then evaluated [and approved] in combination with the CDK4/6 inhibitor palbociclib [Ibrance] and in combination with alpelisib [Piqray].^4,5 In the past several years, we’ve had a lot of studies looking at oral formulations of selective ER downregulators [SERDs], with data this year from 2 studies.

Which SERDs have been evaluated in clinical trials?

One such drug was elacestrant. It was studied in the EMERALD trial [NCT03778931]. That was the first phase 3 randomized trial of an oral SERD to be reported, and it was a positive study.

There are other studies ongoing. Giredestrant has been studied in [several] trials, and acelERA [NCT04576455] was a phase 3 study of this drug. It did not meet its end point, and there was an announcement regarding that. Amcenestrant is another drug that’s been evaluated. The AMEERA-3 [NCT04059484] study of this drug was negative, and the AMEERA-5 [NCT04478266] study didn’t pass the futility analysis, so you won’t see anything about amcenestrant going forward. [However], we still have camizestrant, imlunestrant, rintodestrant, and [several] other “-estrants.” You’re going to see a lot about these types of drugs in the coming months and years.

How was the EMERALD study designed for the breast cancer population?

In this study, patients had to have ER-positive breast cancer, 1 to 2 prior lines of previous ET, up to 1 line of chemotherapy for metastatic disease, and prior treatment with a CDK4/6 inhibitor [or an AI]. They allowed patients [to enroll] regardless of whether they had an ESR1 mutation in the tumor, and patients received elacestrant at 400 mg daily or investigator’s choice of an AI or fulvestrant. The primary end point was PFS in all the patients, and PFS in patients with ESR1 mutations.⁶

At baseline, two-thirds of the patients had visceral metastases. Approximately a quarter of patients had prior fulvestrant therapy. [Approximately 80% to 85%] had prior AI therapy. Very few patients had received a prior mTOR or PI3 kinase inhibitor [0.4%-5.2%], and approximately 20% of patients had received prior chemotherapy for metastatic disease. There was an approximate 50/50 split between 1 or 2 prior lines of ET.⁶

What was the efficacy and safety seen in these patients?

The study was positive. The PFS in all patients was one of the primary end points, and it was statistically significantly improved, with an HR of 0.7 [95% CI, 0.55-0.88; P = .002]. The 6-month PFS rate was 34.3% vs 20.4% in the experimental and control arms, respectively. In patients whose tumors had an ESR1 mutation, the benefit seemed to be a little more pronounced. Again, it was statistically significant [6-month PFS rate, 40.8% vs 20.8%, respectively; HR, 0.55; 95% CI, 0.39-0.77]. This was a positive clinical trial for PFS.

There are no OS [data] yet, but PFS was [improved] in both of those populations. Pretty much all subgroups benefitted, even patients who had prior treatment with fulvestrant. Patients with an ESR1 mutation did appear to benefit quite a lot.⁶ An analysis looked at elacestrant outcome [relative to the specific] standard of care that patients received in the control arm. They evaluated all patients, regardless of ESR1 mutation status, and [they did a separate evaluation of] just those patients who had ESR1 mutations.

[The results were similar] when elacestrant was compared with fulvestrant and when elacestrant was compared with an AI. Elacestrant seemed to benefit patients [more than] either fulvestrant or an AI, and the benefit seemed to be greater in those patients with an ESR1 mutation.⁷ The adverse events [AEs] were similar between the 2 treatment arms. There were more grade 5 AEs in the standard-of-care arm [2.6% vs 1.7% in the control and experimental arms, respectively] and slightly more grade 3 or grade 4 AEs in the elacestrant arm [27.0% vs 20.5% in the experimental and control arms, respectively].⁶ Gastrointestinal [GI] toxicity was the main thing that distinguished elacestrant from the standard of care; 2.5% of patients in the experimental arm had grade 3 or 4 nausea [vs 0.9% in the control arm].

There was more diarrhea in patients [in the experimental arm than in the control arm, 13.9% vs 10.0%, respectively], but it tended to be grade 1 or 2. The rest of the AE profile looked similar when you compare the arms, with perhaps more constipation in the experimental arm.⁶ So, GI toxicity is the standout [concern] for me when I’m considering elacestrant.

What were the design details and results of the EMBER trial (NCT04188548) investigating imlunestrant?

Imlunestrant is another SERD. The EMBER study was a dose-escalation study, and they did dose expansion in multiple cohorts—[parts A, B, C, D, and E]. In some of these cohorts, [imlunestrant was given] in combination with abemaciclib [Verzenio] or with a PI3 kinase inhibitor. Part C was done in HER2-positive breast cancer.

They were looking at dose-limiting toxicity and tolerability. In phase 1b of this trial, they allowed up to 2 prior regimens for advanced disease. All patients had to have received a CDK4/6 inhibitor, and they had to have demonstrated sensitivity to ET to have untreated de novo advanced disease.⁸

The objective response rate [ORR] of the 400-mg dosing level was 12% in advanced breast cancer; at the higher doses, ORR was 7%. The overall ORR [for patients of all dose cohorts] was approximately 8%. The clinical benefit rate was 42%. The median PFS among all patients with advanced breast cancer was 4.3 months, and for those in the second-line setting, median PFS was 6.5 months. Then [when the data were evaluated] based on the presence of ESR1 mutation, those patients with an ESR1 mutation, who typically tend to do worse, seemed to do as well or better [than patients without an ESR1 mutation].

Are there data to support the use of camizestrant in advanced breast cancer?

There was a press release that reported an improved PFS for camizestrant vs fulvestrant in the SERENA-2 study [NCT04214288]. It was a phase 2 trial in advanced ER-positive breast cancer.⁹ We’re expecting to see a report of this at an upcoming meeting.

_REFERENCES

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_{4. 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}

_{5. FDA approves alpelisib for metastatic breast cancer. FDA. Updated May 28, 2019. Accessed November 14, 2022. https://bit.ly/30Lzsak}

_{6. 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}

_{7. Aftimos PF, Cortés J, Bidard FC, et al. Elacestrant vs fulvestrant or aromatase inhibitor (AI) in phase III trial evaluating elacestrant, an oral selective estrogen receptor degrader (SERD), vs standard of care (SOC) endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC): subgroup analysis from EMERALD. Ann Oncol. 2022;33(suppl 7):S88-S121. doi:10.1016/annonc/annonc1040}

_{8. Jhaveri KL, Jeselsohn R, Lim E, et al. A phase 1a/b trial of imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) in ER-positive (ER+) advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): monotherapy results from EMBER. J Clin Oncol. 2022;40(suppl 16):1021. doi:10.1200/JCO.2022.40.16_suppl.1021}

_{9. Camizestrant significantly improved progression-free survival vs Faslodex in SERENA-2 phase II trial in advanced ER-positive breast cancer. News release. AstraZeneca. October 26, 2022. Accessed November 15, 2022. https://bit.ly/3Vg5TJq}