SAN ANTONIO — Updated results with the investigational oral selective estrogen receptor degrader (SERD) elacestrant give a hint of where it could find a place in the treatment paradigm for estrogen receptor positive (ER+) and HER2- advanced or metastatic breast cancer.
Elacestrant is currently awaiting approval from the US Food and Drug Administration, with a decision expected in February.
Data from the pivotal EMERALD trial reported last year show that elascestrant significantly improved progression-free survival (PFS) in patients with ER+/HER2-negative metastatic breast cancer when compared with standard of care in the second- and third-line settings,
New data from the same trial have now shown that the benefit was greatest in a subgroup of patients whose tumor harbored an ESR1 mutation and who had received at least 12 months of treatment with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor.
In this subgroup, the median PFS was more than quadrupled to over 8.5 months with elacestrant, reported Virginia Kaklamani, MD, leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, San Antonio, Texas.
With “no new safety signals,” no cases of sinus bradycardia and low antiemetic use, “these updated results demonstrate that monotherapy use of elacestrant is safe,” she added.
The drug can therefore “become an important oral endocrine therapy agent in the second and third line as an alternative to combination therapies that are associated with challenging safety profiles,” Kaklamani said.
Kaklamani, the co-director of the San Antonio Breast Cancer Symposium, presented the data here at the annual conference.
Reacting to the presentation on Twitter, Shipra Gandhi, MD, assistant professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, commented that an “important point” from the study is that patient selection is “key” to achieving better efficacy with elacestrant.
Fabrice André, MD, PhD, director of research at the Gustave Roussy Cancer Center in Villejuif, France, commented that the current challenge in the second-line setting ER+/HER2- metastatic breast cancer is to achieve a PFS of more than 12 months.
André acted as a discussant for this presentation, and also another one that followed about the SERENA-2 trial with another investigational SERD, camizestrant.
He said that patients who have a short PFS following combined first-line CDK4/6 inhibitor and endocrine therapy do not appear to gain a further benefit from single-agent SERDs and should perhaps be excluded from second-line trials.
However, patients with ER-driven resistance do benefit from combination first-line therapy, and so the question becomes how to define resistance. The simplest definition is ESR1 mutated tumors, although that does not capture all ER-driven resistant patients.
Among those with ESR1 mutated tumors, it has been shown that patients with secondary resistance to first-line therapy endocrine therapy derive a “clinically meaningful benefit” from SERDs, André said, although that definition for a group of patients is “too vague.”
And what about patients who are ESR1 wild-type tumors? André believes SERDs can still be “transformative” in this subgroup, as long as they are “at least as effective as fulvestrant.”
Greatest Benefit in Subgroups of Patients
Kaklamani opened her presentation by reminding the audience that, for ER+/HER2- metastatic breast cancer, the “mainstay” of first-line therapy is endocrine therapy plus CDK4/6 inhibition.
However, tumors “eventually develop hormonal resistance,” she said, primarily through the development of mutations in the ESR1 gene.
Yet current practice is to use sequential endocrine or combinations in the second and/or third lines, which can be associated with a low PFS, as well as significant toxicities, resulting in discontinuation rates of about 25%.
The EMERALD trial involved postmenopausal women and men with advanced or metastatic ER+/HER2- breast cancer who had progressed following up to two lines of endocrine therapy, one of which was given in combination with CDK4/6 inhibition.
Patients were randomly assigned to elacestrant or investigator’s choice of therapy (choosing from fulvestrant, anastrozole, letrozole, or exemestane), and followed up until progressive disease or withdrawal from the trial.
A total of 478 patients were enrolled, of whom 228 (47.7%) had ESR1 mutated tumors.
The median age of the patients was 63 years. Around 70% had visceral metastasis. All had received prior CD4/6 inhibition alongside endocrine therapy, and about 56% had received one prior line of therapy. Chemotherapy had been given in approximately 22% of cases.
The results show that elacestrant significantly improved PFS when compared with investigators’ choice of therapy, and that the PFS benefit was affected by the duration of prior CDK4/6 inhibitor therapy.
After 6 or more months of CDK4/6 inhibition, the median PFS was 2.79 months with elacestrant and 1.91 months with standard of care (hazard ratio [HR] = 0.69).
After 12 or more months of CDK4/6 inhibition, this increased to 3.78 vs 1.91 months (HR = 0.61). After 18 or more months of treatment, it increased further to 5.45 vs 3.29 months (HR = 0.70).
“These results show that, the longer the duration of CDK4/6 inhibitor therapy, the greater the benefit from later lines of endocrine theory,” said Kaklamani, potentially “reflecting a more endocrine sensitive tumor.”
The effect was more pronounced in patients with ESR1 mutated tumors, at a median PFS with elacestrant of 4.14 months and 1.87 months with standard of care (HR = 0.52) after ≥6 months of prior CDK4/6 inhibition, rising to 8.61 months vs 1.19 months (HR = 0.41) after ≥12 months, and 8.61 months vs 2.10 months (HR = 0.47) after ≥18 months.
The updated safety data were “consistent with previously reported results,” Kaklamani said, with the majority of adverse events grade 1 or 2, no grade 4 treatment-related adverse events (TRAEs), and no deaths reported.
Moreover, only 3.4% of patients treated with elacestrant and 0.9% of those receiving standard of care discontinued treatment as a result of a TRAE.
Looking specifically at grade 3 nausea, Kaklamani showed that 2.5% of patients given elacestrant and 0.9% of those given standard of care experienced the adverse event.
Grade 3 nausea led to dose reduction in 1.3% of elacestrant patients, with the same proportion discontinuing as a result. No patients in the standard of care group were similarly affected.
The study was sponsored by Radius Health, Inc. and co-funded by Menarini Group; the two companies are developing elacestrant. Kaklamani reported relationships with Puma, AstraZeneca, Daiichi-Sankyo, Menarini, Gilead, Pfizer, Gilead, Genentech, Exact Sciences, Novartis, Seagen, and Eisai. André reported relationships with AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, Roche.
San Antonio Breast Cancer Symposium (SABCS) 2022: Abstract GS3-01. Presented December 8, 2017.
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