Questions are now being asked about the comparator arm of a phase 3 trial in advanced breast cancer in which the investigational drug elacestrant (developed by Menarini/Radius Health) showed enough benefit for the companies to consider applying for approval from the US Food and Drug Administration.
Elacestrant is a novel oral selective estrogen receptor degrader (SERD), and was shown to improve progression-free survival (PFS) over standard of care (SOC) options in patients with pretreated ER-positive/HER2-negative advanced/metastatic breast cancer in the phase 3 EMERALD trial.
The results were presented at the San Antonio Breast Cancer Symposium in December, as reported by Medscape Medical News, and have now been published in full in the Journal of Clinical Oncology.
“Elacestrant is the first oral SERD that demonstrated a significant improvement in PFS vs SOC therapy in a randomized phase 3 study in patients with ER-positive/HER2-negative advanced or metastatic breast cancer in the second- or third-line setting,” the authors conclude.
“These data represent a long-awaited opportunity to potentially offer second- or third-line, including heavily pretreated, patients with breast cancer a new effective option and further advance toward precision medicine in the ER-positive/HER2-negative subtype,” they add.
However, two medical oncologists have now taken issue with the treatment that was used on the standard of care (SOC) arm of the trial.
“The expression ‘standard of care’ is applied generously, as the control arm is restricted to only four options” and no combinations, which “may have led to a substandard” comparison group, say the two authors, Timothée Olivier, MD, of the Geneva University Hospital, Switzerland, and Vinay Prasad, MD, MPH, of the University of California San Francisco.
“Trial designs should allow us to answer clinical questions that are directly relevant to real-life practice,” they comment in their analysis of the trial, published in Translational Oncology.
Questions Over Standard of Care Arm
The EMERALD trial involved 477 patients who had progressed after one or two rounds of endocrine therapy, one of which must have included the standard first-line option: a CDK4/6 inhibitor plus either the intramuscular SERD fulvestrant or an aromatase inhibitor.
A total of 239 patients were randomly assigned to receive elacestrant 400 mg once daily and 238 to a single-agent standard of care arm that included investigator choice of either fulvestrant or one of three aromatase inhibitors (AIs): anastrozole, letrozole, or exemestane.
This is the main objection from Olivier and Prasad — that the SOC arm used only single drug treatment, and no combinations, which are often used in real-world settings.
The EMERALD investigators, led by Francois-Clement Bidard, MD, a medical oncologist at the Institut Curie, Paris, acknowledged that there are issues with the SOC control group. They comment that in the “United States and Europe, combination therapy with fulvestrant” — instead of single agents — “is increasingly being used as the second-line SOC treatment.”
However, the goal of the study “was to compare a novel endocrine therapy vs currently available endocrine therapies,” not combination regimens, Bidard and his team said.
Also, “the benefit of elacestrant over fulvestrant and AIs in our monotherapy trial…suggests that incorporating elacestrant as the preferred endocrine therapy backbone in future earlier-line combination studies is a promising strategy.”
In the future, trials could investigate elacestrant/everolimus in lieu of exemestane/everolimus or elacestrant/alpelisib vs fulvestrant/alpelisib, they suggested.
Radius Health is considering investigating such combinations, according to the company’s first quarter 2022 report.
Results Show Benefit in Advanced Breast Cancer
The results from EMERALD show a median PFS of 2.8 months in the elacestrant group vs. 1.9 months in the control arm, corresponding to 30% reduction in the risk of progression or death with elacestrant in the overall cohort.
The effect was even larger in the subgroup of patients (nearly half) with estrogen receptor 1 (ESR1) mutations — which confer resistance to AIs. In this subgroup, there was a median PFS of 3.8 months in the elacestrant arm vs. 1.9 months among controls, corresponding to a 45% risk reduction with elacestrant.
Twelve-month PFS was 22.3% with elacestrant vs. 9.5% in the control arm, which widened to 26.8% with elacestrant vs. 8.3% when limited to ESR1 mutation patients.
The results held in separate analyses of elacestrant against AIs and fulvestrant separately. Almost all of patients who were randomly assigned to receive fulvestrant were new to it.
The researchers also conducted a further analysis limited to the 371 patients who had no prior chemotherapy, and found a median PFS of 3.68 with elacestrant vs. 1.97 months with SOC among all comers. (This new subgroup analysis was reported in a poster presentation at the recent annual meeting of the American Society of Clinical Oncology).
Overall survival data are immature in EMERALD but also favor elacestrant on interim analysis.
Grade 3-4 treatment-related adverse events were reported by 7% of patients taking elacestrant, and 3.4% discontinued treatment, compared with rates of 3.1% and 0.9% in the SOC control group.
Nausea was the most common side effect with elacestrant, reported by 35% of patients, and grade 3/4 nausea was reported in 3.4%. The nausea incidence was 19% in the control arm with less than 1% of cases grade 3/4.
The EMERALD investigators concluded that “when single-agent endocrine therapy is appropriate at a later line, our findings are applicable and demonstrate that elacestrant is a more effective option than fulvestrant or an AI.”
Radius Health recently announced plans to apply for approval in both the United States and Europe. The goal is to “establish elacestrant as a preferred endocrine monotherapy regimen in 2/3L including highly pretreated patients,” according to the first quarter report.
The two oncologists who criticized the trial design, Olivier and Prasad, have their doubts.
“Although we are excited about the option of a first-in-class, oral selective estrogen receptor degrader, questions remain regarding the design and interpretation of this study,” they said.
The EMERALD trial was funded by Radius Health. Numerous investigators disclosed research funding from the company and/or, like Bidard, being consultants. One investigator is an employee. Three authors work for the Menarini Group, which has licensed commercialization rights to elacestrant. Prasad and Olivier report no relevant financial relationships; their analysis was funded by Arnold Ventures.
J Clin Oncol. Published online May 18, 2022. Full text
Transl Oncol. Published in the January 2022 edition. Full text
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape and is also an MIT Knight Science Journalism fellow. Email: [email protected]
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