In the second article of a 2-part series, Joyce O’Shaughnessy, MD, discusses the most recent findings from the phase 3 EMERALD study for patients with hormone receptor–positive metastatic breast cancer.
Targeted OncologyTM: What was the design and patient characteristics of the phase 3 EMERALD trial (NCT03778931)?
JOYCE O’SHAUGHNESSY, MD: The EMERALD trial included patients who had, on average, 1 prior endocrine therapy [ET] in the metastatic setting but they were allowed to have 2 prior [therapies and still be included].1 However, [the included patients] had to have progressed on a CDK4/6 inhibitor…. ctDNA, [along with] central ctDNA was used, [to identify for actionable mutations], finding that 50% of patients had an ESR1 mutation, which was a stratification factor.2
They were also allowed on trial. [In terms of specific prior therapies], about 29% of patients had been given prior fulvestrant, but 68.2% of patients with visceral metastasis [were on the] elacestrant [Orserdu] arm and 71% on the ET arm. They were randomized to either 400 mg daily of elacestrant vs either fulvestrant or an AI. [A majority of patients] received fulvestrant, but a small minority had AI, because they had just progressed on fulvestrant.2 [On the trial] there were co-primary end points of progression-free survival [PFS] in all patients and PFS in the ESR1-mutated population.
What were the efficacy results of the trial?
The first co-primary end point was PFS in the intent-to-treat population…. Head-to-head with fulvestrant, patients given elacestrant had a higher PFS rate [at 6 months than those on fulvestrant, at 34.3% (95% CI, 27.2%-41.5%) vs 22.9% (95% CI, 15.2%-30.6%), respectively].2 Comparing [patients given elacestrant to those on the standard-of-care arm], the median PFS delta was 0.9 months between the 2 arms…. What this says to me is that for patients whose breast cancer is still ET sensitive, that elacestrant is a better choice for them than fulvestrant.
If we look at the landmark analysis…at 6 months, 34.3% [95% CI, 27.2%-41.5%] of patients on elacestrant vs 22.9% [95% CI, 15.2%-30.6%] on fulvestrant were progression free. Then at 12 months it was 22.3% [95% CI, 15.2%-29.4%] vs 10.2% [95% CI, 3.4%-16.9%], respectively.
What is your reaction to these data?
What’s driving the clinical utility of elacestrant is the fact that at 6 and 12 months there is a substantially higher chance of being progression free with elacestrant compared with fulvestrant. This is eye opening in that [we see] there’s a subset of thesepatients with an ESR1-mutated tumor who have developed this mutation upon progression on a CDK4/6 [inhibitor], but some of those patients benefit from an oral selective ER degrader [SERD]. So we can inhibit those ESR1 mutations, but it’s not just these patients, others…have co-alterations that are also driving their cancer. So, just targeting ESR1 is not the answer for those patients.2
Elacestrant is a better agent in that subset [of patients who are] ET sensitive. How do we find them? We have no assays for that. [However, looking at patients with an ESR1 mutation on elacestrant vs an ET], there wasn’t anything that stood out as a differentiator for who you would or wouldn’t give elacestrant to, but it’s helpful…. There was a median PFS of 8.6 months [for those on elacestrant] vs only 1.9 months with ET or 2.1 months with fulvestrant [for patients on either 12 months of CDK4/6 inhibition or 18 months].1 So, this is the group of clinical interest; those are people who did well on their CDK4/6 who are now progressing and have an ESR1 mutation [in their tumor]. That’s a group where if they’re asymptomatic [then you don’t have to] push to give them chemotherapy or a doublet therapy. This is the group that it’s reasonable to consider the elacestrant.
What were some of the adverse events (AEs) of note on the EMERALD study?
[Among the different observed AEs], nausea was seen in 83 patients on elacestrant and you should probably give this agent with food.1 Food doesn’t interfere with the absorption [of the drug] and it decreases the nausea. Furthermore, if your patient’s on a proton-pump inhibitor [PPI] it’s OK. Elacestrant does not need the acidity of the stomach to be absorbed, so we don’t have to time it around the use of the PPI. So, in terms of the nausea, they can take a PPI if they need one and they can take elacestrant with food…. Three percent had to have a dose reduction and 6% of patients stopped for any reason.
Elacestrant was given at 400 mg on the trial schema, but it turns out that the pill is given in a tablet of 345 mg of elacestrant.3 There’s also an 86 mg pill, [but you should] start with the 345-mg tablet given with food, and then at the first dose reduction, they take 3 of the 86-mg tablets. The second dose reduction, they take 2 of the 86-mg tablets, and then if they need a third dose reduction they have to stop.
1. Kaklamani VG, Bidard FC, Neven P, et al. Oral elacestrant vs standard-of-care in estrogen receptor-positive, HER2-negative (ER+/HER2-) advanced or metastatic breast cancer (mBC) without detectable ESR1 mutation (EMERALD): Subgroup analysis by prior duration of CDK4/6i plus ET (ET). J Clin Oncol. 2023;41(suppl 16):1070. doi:10.1200/JCO.2023.41.16_suppl.1070
2. Kaklamani VG, Bidard FC, Neven P, et al. Oral elacestrant vs standard-of-care in estrogen receptor-positive, HER2-negative (ER+/HER2-) advanced or metastatic breast cancer (mBC) without detectable ESR1 mutation (EMERALD): Subgroup analysis by prior duration of CDK4/6i plus ET (ET). J Clin Oncol. 2023;41(suppl 16):1070. doi:10.1200/JCO.2023.41.16_suppl.1070
3. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. January 27, 2023. Accessed August 23, 2023. https://tinyurl.com/yvvafe4k