Exploring Updated Subgroup Data From the EMERALD Trial of Elacestrant

Sara 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

Santa Monica, CA

Targeted Oncology^TM: What did the updated data from the phase 3 EMERALD trial (NCT03778931) investigating elacestrant (Orserdu) show for patients with metastatic estrogen receptor–positive, HER2-negative breast cancer?

HURVITZ: In the update at the 2022 San Antonio Breast Cancer Symposium [SABCS], they did analysis looking at outcomes in terms of PFS [progression-free survival] based on prior duration of CDK4/6 inhibitor.¹ Patients who had longer use of a CDK4/6 inhibitor had more endocrine-sensitive disease and had better PFS. But the elacestrant arm looked better in all of these analyses than standard of care.

[Looking] at the same analysis but now restricting it to patients who had ESR1 mutations, patients who did well for a longer period of time on a CDK4/6 inhibitor did better on this line of therapy than patients who had a shorter duration. I don’t like this analysis because [the analysis of patients who were treated for] at least 6 months is inclusive of all those patients who did at least 12 months and at least 18 months.

I prefer [an analysis that] breaks up patients based on whether they had less than 6 months of prior CDK4/6 inhibitor, 6 to 12 months, 12 to 18 months, or more than 18 months. The numbers are very small, but those patients who were on a CDK4/6 inhibitor for at least 18 months have the longest PFS, 5.45 months with elacestrant, better than standard-of-care therapy [HR, 0.703; 95% CI, 0.482-1.019].

Overall, the summary is elacestrant does better than standard of care regardless of which box they fall into. But the outcome for patients is worse when [they received] less than 12 months of prior CDK4/6 inhibitor [compared with a longer duration]. [Looking at those with an] ESR1 mutation, these are very small numbers, but it’s interesting that patients who were on a CDK4/6 inhibitor for at least 18 months previously, have an ESR1 mutation, and now get elacestrant have a median PFS of 8.61 months compared with 2.1 months with standard of care. I might use this data in the back of my mind to select patients for single-agent endocrine therapy with elacestrant using the ESR1 mutation status but also thinking about how likely they are to do well on single-agent endocrine therapy based on their prior response to CDK4/6 inhibitor.

What conclusions can you draw about patients with an ESR1 mutation who received CDK4/6 inhibitor for less than 12 months?

I wouldn’t draw any strong conclusions from these data. These are subgroups, not preplanned analyses. I think they’re interesting analyses that underscore what we know intuitively, and that is that patients whose disease appears to be endocrine sensitive are probably the ones who will do best with the single-agent endocrine therapy after CDK4/6 inhibitor. That’s how I would use it.

The take-home point is that the patients who did better earlier are going to do better on the next line of therapy. This may be where elacestrant benefits them because you are beginning to see this widening in the gap comparing the elacestrant with the standard of care. This was a post hoc analysis so I wouldn’t draw too much from it, but it does help us as we think about the patient sitting before us.

What else stood out in subgroup analyses of the EMERALD trial?

I thought it was interesting that those who’d had prior treatment with fulvestrant [Faslodex] didn’t cross [above 1.0 on a confidence interval for PFS].² Everyone seems to benefit, but I was interested in understanding the benefit of elacestrant in fulvestrant-pretreated patients. A fair number of my own patients who I might want to give elacestrant to will have already seen fulvestrant.

There was a subgroup analysis based on which endocrine agent was used in the standard-of-care arm: elacestrant compared with fulvestrant in all patients, in those with ESR1 mutations, and elacestrant versus AI; all patients versus those with ESR1 mutation. Elacestrant benefits patients regardless of whether you’re comparing it with fulvestrant or AI, perhaps more so with comparing with AI.³ But in the ESR1 mutation carriers, I don’t think we could say that necessarily.

What was the safety and tolerability reported in this trial?

There were dose reductions required in 3% of those who received elacestrant but otherwise there were fairly similar [tolerability outcomes between elacestrant and other endocrine therapies].²

There were more GI [gastrointestinal] adverse events [AEs] with elacestrant, and more nausea—35%, which is double that for endocrine therapy, but only 2.5% had grade 3/4. There was more vomiting, more constipation, and more dyspepsia with elacestrant, so I think GI [toxicities] are what you have to watch for with this agent in terms of comparing to other endocrine therapy.

They updated the safety data [at SABCS 2022]; it looks fairly similar to previous reporting.¹ Approximately 3% of patients receiving elacestrant versus less than 1% who received standard of care discontinued due to a treatment-related AE. There were no deaths that were treatment related in either arm. There were no events of bradycardia, which is something that is watched for with oral selective estrogen-receptor degraders.

_References:

_{1. Bardia A, Bidard FC, Neven P, et al. 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. Presented at San Antonio Breast Cancer Symposium 2022. December 6-10, 2022. Abstract GS3-01.}

_{2. 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}

_{3. Aftimos PG, et al. Elacestrant vs fulvestrant or aromatase inhibitor (AI) in phase 3 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):S638. doi:10.1016/j.annonc.2022.07.259}