Elacestrant With Targeted Agents May Overcome ET Resistance in Breast Cancer

CancerNetwork® spoke with Hope S. Rugo, MD, professor and director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, about how elacestrant (Orserdu) in combination with targeted therapies work to overcome prior endocrine therapy resistance in patients with estrogen receptor–positive (ER–positive)/HER2-negative metastatic breast cancer in patients who have received prior endocrine therapy and CDK4/6 inhibition. Rugo presented pooled findings from the phase 3 EMERALD Trial (NCT03778931) and phase 1b ELEVATE trial (NCT05563220), evaluating elacestrant (Orserdu) plus abemaciclib (Verzenio), at the 2024 San Antonio Breast Cancer Symposium (SABCS).

Rugo expressed that combining elacestrant with targeted agents is aimed to concurrently target both endocrine resistance pathways and overcome ESR1 mutational resistances, which she believes may benefit patients with ER–positive/HER2-negative metastatic breast cancer who have experienced endocrine therapy resistance.

Furthermore, Rugo suggested that a synergistic interaction has been observed with these combinations, where endocrine therapy is enhanced through the use of targeted therapies, which block resistance pathways. Additionally, she explained that targeted therapies do not work as singular therapies, suggesting that endocrine therapies are essential in this indication to elicit activity from targeted therapies.

In the pooled analysis, elacestrant was evaluated in combination with abemaciclib. The overall response rate (ORR) was 18% at a dose level of 345 mg daily elacestrant plus 150 mg abemaciclib every other day. Furthermore, 5% of patients achieved a complete response, 13% achieved a partial response, and 66% had stable disease. Furthermore, the clinical benefit rate was 84% at the time of data cutoff.

Of note, the median progression-free survival for patients who have received 12 or more months of prior endocrine therapy and CDK4/6 therapy was 16.6 months (95% CI, 7.5-not calculable [NC]). Furthermore, a phase 2 portion of the ELEVATE trial is ongoing, assessing the recommended phase 2 dose (RP2D) of 345 mg daily elacestrant plus 150 mg abemaciclib every other day.

Transcript:

[For] elacestrant combined with these other agents, the idea is that the targeted agents are targeting pathways that lead to resistance and that the combination with an oral SERD [selective estrogen receptor degrader] that could overcome some of the resistance from ESR1 mutations, for example, and also not need 2 injections every month, like fulvestrant [Faslodex], has a lot of potential benefit for our patients.

The mechanism of this working together has already been well elucidated with standard endocrine therapies [and] these targeted agents, where you see the ability to block the acquired resistance to endocrine therapy so that the endocrine therapy can function more. Also [we see] synergistic interactions as well, where it seems as though the combination is much better than the endocrine therapy alone and that targeted agents do not work by themselves.

Reference

Rugo HS, Tolaney SM, Chan N, et al. Elacestrant plus abemaciclib (abema) combination in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced or metastatic breast cancer (mBC). Presented at: San Antonio Breast Cancer Symposium 2024; December 10-13, 2024; San Antonio, TX. Session PS7-07.