EMERALD updates highlight therapeutic potential of elacestrant for ER+/HER2– mBC

In the updated analysis of the phase III EMERALD trial, the next-generation oral SERD* elacestrant continued to show favourable signals for the treatment of ER+/HER2– metastatic breast cancer (mBC).

Although endocrine therapy (ET) + CDK4/6 inhibitor (CDK4/6i) is standard first-line therapy for ER+/HER2– mBC, tumours eventually develop endocrine resistance, primarily through the development of ESR1 mutation (ESR1m). [J Clin Oncol 2021:JCO2101374] Also, ET has shown limited efficacy in the second- and third-line setting after prior CDK4/6i use, and intramuscular injections have poor bioavailability and are burdensome to patients.

Recent studies evaluating CDK after CDK has shown mixed results. “In this context, there is a significant need for potent oral SERD for monotherapy use to enable oral-oral combinations,” said Dr  Virginia Kaklamani from the University of Texas Health Sciences Center, San Antonio, Texas, US, at SABCS 2022.

“[In our previous analysis,] progression-free survival (PFS) in all patients and among those with ESR1m were statistically significant in favour of elacestrant,” said Kaklamani. “[Our] updated results demonstrate that elacestrant monotherapy is safe and significantly prolongs median PFS vs standard of care (SoC) and meaningfully extends landmark PFS rates.”

PFS by CDK4/6i duration

In the overall cohort, a longer duration of prior CDK4/6i therapy is associated with longer median PFS on elacestrant vs SoC (2.8 vs 1.9 months; hazard ratio [HR], 0.69 [6 months], 3.8 vs 1.9 months; HR, 0.61 [12 months], and 5.4 vs 3.3 months; HR, 0.70 [18 months]). [SABCS 2022, abstract GS3-01]

“[These imply] that the longer the duration of CDK4/6i therapy, the greater the benefit from later lines of ET, reflecting a more endocrine-sensitive tumour,” said Kaklamani.

In the ESR1m subgroup, the benefit of elacestrant was more pronounced across all prior CDK4/6i exposures (4.1 vs 1.9 months; HR, 0.52 [6 months], 8.6 vs 1.9 months; HR, 0.41 [12 months], and 8.6 vs 2.1 months; HR, 0.47 [18 months]). Almost a third of elacestrant recipients with 18 months of prior CDK4/6i usage were progression-free as opposed to none in the Soc arm, noted Kaklamani.

Evaluation by 6-month intervals highlighted that the elacestrant benefit became evident after 12 months of prior CDK4/6i exposure. “The 6–12-month interval seems to be a transition period where ESR1 resistance starts to build,” noted Kaklamani. Median PFS at this timepoint for elacestrant was 1.91 months in the overall cohort and the ESR1m subgroup. The corresponding rates in the SoC arm were 1.87 and 1.84 months.

“It is important to note that [elacestrant had benefit] in the <6-month CDK4/6i duration subset (median PFS 3.55 vs 1.87 months). [Despite the small] patient numbers … this gives us a further feeling of the patient population and the dynamics of endocrine sensitivity,” Kaklamani stressed.

Safety profile

Updated safety data aligned with previously reported results. Most adverse events (AEs) including nausea were grade 1/2, with no grade 4 treatment-related AEs (TRAEs) reported. Three percent of elacestrant recipients discontinued treatment owing to TRAEs. There were no treatment-related deaths reported in either arm nor were there any reports of haematologic safety issues or sinus bradycardia. Antiemetic use was low.

Alternative to combination therapies

The investigators randomized 478 participants (median age 63 years; n=228 with ESR1m) 1:1 to either elacestrant 400 mg daily or SoC ET (investigator’s choice of fulvestrant or an AI**). Over two-thirds of participants had visceral metastases. All patients had prior CDK4/6i (median duration of exposure ~17 months).

Multiple oral SERDs are currently being investigated as second-line therapy in HR+/HER2– advanced BC, with different inclusion criteria. “EMERALD is the only trial that mandated 100-percent prior CDK4/6i usage and allowed for prior use of CT and fulvestrant,” underscored Kaklamani.

“[Our findings show that] elacestrant can become an important oral endocrine monotherapy in the second and third-line treatment as an alternative to combination therapies that are associated with challenging safety profiles,” she concluded.