Imlunestrant vs Elacestrant: MOA and Clinical Trial Differences

While the newly approved imlunestrant (Inluriyo) and elacestrant (Orserdu) are both oral selective estrogen receptor degraders (SERDs) targeting ESR1 mutations indicated for adult patients with estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer, key distinctions separate the 2 drugs, explained Komal Jhaveri, MD, FACP, a breast medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

In an interview with Oncology Nursing News, Jhaveri explained that having another ESR1-targeting agent in the post-endocrine breast cancer setting is a natural addition to the existing therapies available for breast cancer, which include multiple aromatase inhibitors, CDK4/6 inhibitors, TROP2-targeting antibody-drug conjugates, and more.

She emphasized that while elacestrant has properties similar to other agents, imlunestrant is closer to a “pure” ER antagonist and degrader. Along with this difference in the drugs’ respective mechanisms of actions, Jhaveri pointed out differences between the clinical trials leading to each therapy’s approvals.

The phase 3 EMERALD trial (NCT03778931), which led to elacestrant’s approval, enrolled patients with up to 2 prior lines of endocrine therapy, largely those who had received fulvestrant and chemotherapy. In the phase 3 EMBER-3 trial (NCT04975308), which led to imlunestrant’s approval, patients had received an aromatase inhibitor either alone or alongside a CDK4/6 inhibitor.

Transcript

We already had approval for an oral SERD in late 2023, which was so exciting. This was elacestrant, and we have that available in clinic. Now we have a second drug, imlunestrant, which was approved September 25.

Why is it exciting? It’s always good to have a good set of options. We’re used to that when we think about 3 aromatase inhibitors: we have letrozole [Femara], anastrozole [Arimidex], and exemestane [Aromasin]. We have 3 CDK4/6 inhibitors: palbociclib [Ibrance], ribociclib [Kisqali], and abemaciclib [Verzenio]. We have 2 TROP2 antibody-drug conjugates: sacituzumab deruxtecan-hziy [Trodelvy] and datopotamab deruxtecan [dato-DXd; Datroway]. Now we have 2 oral SERDs.

There are some differences if we think about this same class of drugs. When we think about imlunestrant, it’s more of a pure ER antagonist and a degrader. When we think about elacestrant, it has both SERM- and SERD-like properties. From a mechanism of action perspective, there are slight differences between the 2 drugs.

Elacestrant was approved based on the phase 3 EMERALD trial, which incorporated a distinct group of patients, including up to 2 prior lines of endocrine therapy, some of which had received prior fulvestrant-based therapy, and some also had chemotherapy.

Imlunestrant is approved based on the phase 3 EMBER-3 trial, which was predominantly first- and second-line patient population. These were patients who recurred on or within 12 months of their adjuvant aromatase inhibitor, with or without CDK4/6 inhibitor, or first-line metastatic therapy with an adjuvant with aromatase inhibitor, with or without a CDK4/6 inhibitor. Slight differences in patient populations there.

When it comes to results, we’ve seen that with imlunestrant, the median progression-free survival was 5.5 months compared with the standard-of-care arm, which was 3.8 months.

This transcript has been edited for clarity and conciseness.