Beyond the Primary End Point: Diving Deeper into the EMERALD trial | Written Recap

In this Managed Healthcare Executive “Between the Lines" video series, Daphne Stewart, M.D., and Kirollos Hanna, Pharm.D., discuss the EMERALD trial, a pivotal phase 3 trial that compared elacestrant, an oral selective estrogen receptor degrader, with standard endocrine therapies in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Stewart is a clinical professor of medicine at the Keck School of Medicine at the University of Southern California in Los Angeles and a breast cancer oncologist at the Norris Comprehensive Cancer Center. Hanna is director of pharmacy at Minnesota Oncology, a community oncology practice in Minneapolis-St. Paul, and an assistant professor of pharmacy at the Mayo Clinic College of Medicine in Rochester, Minnesota.

Current standard of care

Hanna said that endocrine-based therapies, such as fulvestrant or even aromatase inhibitors, are used in the second- or third-line setting for patients with ER+, HER2- disease. He said that cyclin-dependent kinase (CDK) 4/6 inhibition plays a critical role in this patient population. When CDK4/6 inhibition fails for patients, clinicians start to look at various driver mutations. There are niche populations for whom phosphoinositide 3-kinase (PI3K) inhibitors or mammalian target of rapamycin (mTOR) inhibitors are appropriate. Stewart added that standard guidelines indicate that aromatase inhibitors by themselves are not very effective as a second-line treatment but that the addition of everolimus has been shown to lead to longer progression-free survival. Stewart noted, though, that first-line treatment with a CDK4/6 inhibitor plus an aromatase inhibitor or fulvestrant, while improving progression-free survival, may affect endocrine resistance and therefore the choice of second-line therapy.

In their discussion of unmet needs of the patient populatiion with ER+, HER2- advanced breast cancer, Hanna and Stewart discussed testing the cancers for mutations that might affect prognosis and treatment choices. Hanna said one of the biggest challenges from the standpoint of health systems or even community oncology practices is when to test for estrogen receptor 1 (ESR1) gene mutations. Those mutations confer resistance to some of the endocrine therapies and may also be indicators of future rapid progression, particularly after treatment with CDK4/6 inhibition. Stewart said that “we haven’t been able to define a very accurate assessment of how to do the best testing and the perfect timeline in order to optimize the therapy."

Overall spending for and healthcare utilization by the ER+, HER2- patient population have increased as novel therapies have been introduced, but outcomes are also better, observed Hanna. He also noted that the CDK4/6 inhibitors are “certainly not benign” and may lead to hospitalizations due to infections and neutropenias. Stewart noted that there are also costs associated with monitoring patients on CDK4/6 inhibitors and that the second-line treatments that include targeted therapies have significant toxicities that affect the quality of life of patients and may affect outcomes because patients discontinue treatment.

EMERALD trial design

The EMERALD trial investigators randomly assigned 478 patients with ER+, HER2- advanced breast cancer on a 1:1 basis to receive elacestrant or physician’s choice of standard therapy, which was defined as fulvestrant or one of three aromatase inhibitors: anastrozole, letrozole or exemestane. The researchers recommended that patients who had been previously treated with an aromatase inhibitor take fulvestrant, according to Stewart. The researchers assigned and stratified patients according to ESR1 mutational status, visceral metastases and prior fulvestrant use. The primary end point was progression-free survival in all those patients and those with ESR1 mutations. The patient population primarily consisted of those who had previously been treated with CDK4/6 inhibitors and up to one prior chemotherapy line.

Hanna said the patients enrolled in EMERALD were a real-world reflection of those who might be eligible for elacestrant treatment. Stewart noted that all the trial participants had been treated with a CDK4/6 inhibitor, more than half had received adjuvant therapy, and approximately half had cancers with ESR1 mutations. Hanna commented that the study participants, whose median age was approximately 60 years, were older than typical patients with ER+, HER2- advanced breast cancer.

Stewart said the fact that the study participants took a single agent made for a “very tolerable treatment option” and was very good for quality of life. However, she said that single-agent treatment was “suboptimal in terms of what we would expect as a general practitioner” and that an appropriate comparator might have been treatment with exemestane plus everolimus, fulvestrant plus everolimus, or fulvestrant with a second CDK4/6 inhibitor.

EMERALD trial results

Elacestrant achieved a statistically significant improvement in progression-free survival compared with standard endocrine therapy, especially among patients with ESR1 mutations. The 12-month progression-free survival was 22.3% in the group treated with elacestrant compared with 9.4% in the standard-of-care group. Among those with the ESR1 mutation, the difference in the progression-free survival rate was larger: 26.8% among those treated with elacestrant compared with 8.2% among the standard-of-care group. There were also statistically significant differences in progression-free survival at six months. Patients in the elacestrant group experienced more side effects. Stewart noted that the proportion of patients with constipation, vomiting and nausea was twice as large in the elacestrant group as in the standard-of-care group, adding, though, that most of the side effects were not rated as severe. She also noted a post hoc analysis of patient-reported outcomes that showed that study participants were happier with an oral agent (elacestrant is taken as a daily pill) than monthly injections of fulvestrant into the gluteal muscles.

Subgroup analyses

Stewart stressed the importance of identifying patients whose tumors remain sensitive to endocrine therapy as being those who might benefit most from elacestrant. The EMERALD trial investigators did not stratify patients by duration of prior treatment, an indication of endocrine sensitivity, but a separate post hoc analysis by Bardia et al. showed that in 159 patients with ESR1 mutations who had been treated for 12 months or more with endocrine therapy and CDK4/6 inhibitors, the median progression-free survival of those treated with elacestrant was 8.6 months compared with 1.9 months in the standard-of-care group. Stewart described the chart showing this result as “very inspiring.” She said the key implication is that patients who have responded to endocrine therapy for more than 12 months but who have an ESR1 mutation that might confer some resistance may do very well on single-agent elacestrant.

Stewart and Hanna also discussed a subgroup analysis of patients who had not received chemotherapy. When the analysis included patients regardless of ESR1 mutation, the median progression-free survival in the elacestrant group was 3.7 months compared with 2.0 months in the standard-of-care group. When analysis was limited to those with ESR1 mutations, the difference in median progression-free survival was greater: 5.3 months in the elacestrant group versus 1.9 months in the standard-of-care group. Stewart said the results show that there was benefit to elacestrant even in patients who had not received chemotherapy and that perhaps treatment with elacestrant before chemotherapy would “improve both quality of life and probably cost of healthcare.“ Hanna said the reasons for patients not receiving chemotherapy are worth exploring, noting that frailty might have been a factor.

Providers, payers and patients

For providers, elacestrant expands the armamentarium and adds a therapeutic option for a patient population, Hanna said. He noted that it was an oral option that could delay the need to put patients on salvage chemotherapy that has marginal benefit. Hanna said the payers will try to control and manage costs with prior authorizations or step edits. Providers will have to navigate those managed practices on behalf of patients. High cost may pose financial toxicity issues for patients, commented Hanna. Foundation funding and partnerships with pharmaceutical partners with copay assistance and other programs can help with providing timely access to care for some patients, he said.

Future sequencing

Stewart and Hanna discussed elacestrant being used earlier in the course of treatment. Hanna said it was possible that patients with ESR1-mutated tumors might be treated earlier with a combination of CDK4/6 inhibitors and elacestrant or aromatase inhibitors and elacestrant. “I do anticipate that probably in the next two or three years, we’re likely going to be sequencing some of these therapeutics differently than what we’re doing today,” Hanna said.

Last word

For right now, Stewart said that in her practice, the opportune patient for treatment with elacestrant as a single agent is someone who has been treated with a CDK4/6 inhibitor plus endocrine therapy for more than a year whom she can identify as having ESR1-mutated cancer with a circulating tumor DNA test.

“This EMERALD trial is impressive,” Stewart said. “I do believe that elacestrant is effective and — for this certain population who are endocrine therapy sensitive, ESR1-mutated — well tolerated and, I think, important to accept as our standard of care.”