Patient-reported outcomes among patients who received elacestrant were consistent with other endocrine therapies.
An analysis of patient-reported outcomes (PROs) from the phase 3 EMERALD trial (NCT03778931) showed that patients with ER-positive/HER2-advanced or metastatic breast cancer receiving oral elacestrant (Oserdu) had quality of life outcomes that were comparable with the standard of care (SOC) arm and consistent with other endocrine therapies. Findings were reported at the 2023 ESMO Breast Congress.1
The PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) demonstrated that, by cycle 6, fewer patients had reported nausea with elacestrant than those receiving SOC (4.0% vs 14.3%, respectively). Similarly, by cycle 6, fewer patients in the elacestrant arm had reported vomiting (9.1% vs 50%, respectively). There was no difference between the all-patient population and the population with ESR1 mutations in terms of these adverse events (AEs). The PRO-CTCAE also demonstrated that were no clinically meaningful differences across all time points in other AEs commonly associated with endocrine therapy, including fatigue, joint pain, muscle pain, and hot flashes.
The EuroQol 5 Dimensions 5 Level (EQ-5D-5L) scores demonstrated that, at cycle 6, patient function was comparable for mobility, self-care, and usual activities, across both treatment arms. Again, no differences were reported in the ESR1 mutation subgroup. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) revealed similar scores between elacestrant and SOC. No significant differences were observed for function, symptom, and global health status, by cycle 6.
According to Javier Cortés, MD, PhD, the head of breast cancer and gynecological cancers at Hospital Universitario Ramón y Cajal in Madrid, Spain, as well as clinical investigator in the breast cancer research program at Vall d’Hebron Institute of Oncology, the oral SERD demonstrated a manageable safety profile that was consistent with other endocrine therapies.
“Quality of life was clearly maintained between treatment groups in the EMERALD study,” he said in his presentation, adding that “In my opinion, taking into account all this data, elacestrant is the endocrine [therapy] sequencing of choice for patients with mutations in the estrogen receptor gene after CDK4/6 [therapy].”
In patients receiving elacestrant (n = 237), the rate of grade 3 nausea was 2.5% (n = 6), the percentage of patients who require a dose reduction because of nausea was 1.3% (n = 3), the nausea-related discontinuation rate was 1.3% (n = 3), and the rate of antiemetic use was 8%. In the SOC arm (n = 230), the rate of grade 3 nausea was 0.9% (n = 2), the percentage of patients who required a dose reduction because of nausea was not applicable, the nausea-related discontinuation rate was 0%, and the rate of antiemetic use was 10.3% with an aromatase inhibitor and 1.3% with fulvestrant.
Moreover, most AEs were grade 1 or 2, and no grade 4 treatment-related AEs (TRAEs) were reported with elacestrant. The rate of TRAE-related treatment discontinuation was 3.4% in the experimental arm and 0.9% in the SOC arm. The rate of dyslipidemia was comparable between the elacestrant and SOC populations and was mostly grade 1. No treatment-related deaths were reported in the study, no hematologic safety signals were observed, and no patient in either arm showed signs of sinus bradycardia.
The EMERALD trial enrolled men and postmenopausal women with advanced or metastatic ER-positive, HER2-negative, breast cancer whose disease had progressed on 1 or 2 prior lines of endocrine therapy, including a CDK4/6 inhibitor. Patients also needed to have an ECOG performance status of 0 or 1 and have received 1 or less of lines of chemotherapy for their advanced or metastatic disease.
Patients were randomly assigned to receive either 400 mg of daily elacestrant (n = 239) or investigators choice of therapy, which was either fulvestrant (n = 166) or an aromatase inhibitor (n = 73). PFS, both in the all-patient population, and in the stratified ESR1-mutant subgroup, represented the coprimary end points. PROs and HRQOL were secondary end points.
The data presented showed that elacestrant increased the median PFS compared with SOC, as well as the 6-month and 12-month landmark PFS rates, although the PFS benefit was most pronounced in patients with detectable ESR1 mutations and in patients with longer previous exposure to CDK4/6 inhibition.
Patients with ESR1 mutations who received elacestrant and at least 6 months of CDK4/6 inhibition (n = 103) had a median PFS of 4.14 months (95% CI, 2.20-7.79) vs 1.87 months (95% CI, 1.87-3.29) for those who received SOC hormonal therapy (n = 102; HR, 0.517; 95% CI, 0.361-0.738). The 6-, 12-, and 18-month PFS rates were 42.43% (95% CI, 31.15%-53.71%), 26.02% (95% CI, 15.12%-36.92%), and 20.70% (95% CI, 9.77%-31.63%), respectively, with elacestrant vs 19.15% (95% CI, 9.95%-28.35%), 6.45% (95% CI, 0.0%-13.65%), and 0.00%, respectively, with SOC.
Those with ESR1 mutations who received elacestrant and at least 12 months of CDK4/6 inhibition (n = 78) had a median PFS of 8.61 months (95% CI, 4.14-10.84) vs 1.91 months (95% CI, 1.87-3.68) for those who received SOC hormonal therapy (n = 81; HR, 0.410; 95% CI, 0.262-0.634). The 6-, 12-, and 18-month PFS rates were 55.81% (95% CI, 42.69%-68.94%), 35.81% (95% CI, 21.84%-49.78%), and 28.49% (95% CI, 14.08%-42.89%), respectively, with elacestrant vs 22.66% (95% CI, 11.63%-33.69%), 8.39% (95% CI, 0.0%-17.66%), and 0.00%, respectively, with SOC.
Lastly, those with ESR1-mutations who received elacestrant and at least 18 months of CDK4/6 inhibition (n = 55) had a median PFS of 8.61 months (95% CI, 5.45-16.89) vs 2.10 months (95% CI, 1.87-3.75) for those who received SOC hormonal therapy (n = 56; HR, 0.466; 95% CI, 0.270-0.791). The 6-, 12-, and 18-month PFS rates were 58.57% (95% CI, 43.02%-74.12%), 35.79% (95% CI, 19.54%-52.05%), and 30.68% (95% CI, 13.94%-47.42%), respectively, with elacestrant vs 27.06% (95% CI, 13.05%-41.07%), 7.73% (95% CI, 0.0%-20.20%), and 0.00%, respectively, with SOC.
“The medium time to progression was clearly longer when the patient had sensitive, or very active [disease], in terms of CDK 4/6 inhibitor,” Cortés said. “This is important because some guidelines for some NCCN guidelines have changed the definition for secondary resistant metastatic disease. Now, when the patients are on CDK4/6 inhibitor, plus endocrine therapy, secondary resistance will be more than 12 months.”
As part of the trial methodology, the EORTC QLQ-C30, the PRO-CTCAE, and the EQ-5D-5L were selected as the 3 PRO measurement tools to describe mean score change and changes from baseline between the 2 groups. The assessments were to be conducted at the time of screening, at cycle 1, and at all subsequent cycles.
The rate of PRO completions remained between 80% and 90% until cycle 4, at which point it dropped, landing at approximately 70% by cycle 6. Chief reasons for incomplete PRO assessments included patient language, patient refusal, technical problems, and COVID-19–related issues, as the study period overlapped with the pandemic. ALL PRO data presented at ESMO 2023 included the full intent-to-treat population up to cycle 6.
Carey Heeds Caution on PRO-Data Excitement
During his presentation, Cortés implored audience members not to compare PFS across clinical trials with other oral SERDS, because each have different inclusion criteria and assessed patients with varying levels of pretreatment, and, also, because EMERALD is a phase 3 trial, whereas AMEERA-3 (NCT04059484), aceIERA (NCT04576455), and SERENA-2 were phase 2 (NCT04214288), and only the ongoing EMBER-3 (NCT04975308) is also a phase 3 trial. Among all these studies, EMRALD was the only one to require precious CDK4/6 inhibition, he pointed out.
However, in a postpresentation discussion of the EMERALD trial, Lisa A. Carey, MD, ScM, FASCO, placed these trials side by side for the audience to compare.2
“I want to first note what [Dr. Cortés] said earlier about the caveats, [which] are very real; these are different populations, in levels of pretreatment, [whether they] required CDK4/6 inhibition, etc,” Carey, the L. Richardson and Marilyn Jacobs Preyer Distinguished Professor for Breast Cancer Research at UNC Lineberger Comprehensive Cancer Center in Chapel Hill, said. “But there is something to be said that SOC intervention of endocrine therapy [alone] in the pretreated setting is not doing very well, and all of these trials, including those that are negative, did show there is a numeric difference [in PFS]—so there is a value for these kinds of interventions.”
Carey reiterated that elacestrant showed PFS improvements in those patients with ESR1 mutations who had previously received CDK4/6 inhibition, however, she cautioned the audience not to value PROs over clinician reported outcomes.
“PROs are great,” Carey said, “however, they do not replace clinician assessment.” She went on to note that clinicians and patients capture different risks: clinicians report are more centered around hospitalization and death, whereas PROs provide insight into daily health status. Moreover, patients are less likely to complete these assessments than clinicians.
Previously reported clinician-reported outcomes form the EMERALD trial showed that, among patients receiving elacestrant, 92% experienced any grade AEs, 27% experienced grade 3 or higher AEs, 3% needed a dose reduction, and 6% needed to discontinue treatment. In comparison, in the SOC arm, 86% percent of patients experienced any grade AEs, 20% experienced grade 3 or higher AEs, 0% needed a dose reduction, and 4% needed to discontinue treatment.3
Nevertheless, Carey went on to note that the PROs are encouraging, and the 3 tools used to assess the PROs are well validated measures. She concluded by emphasizing the importance of QOL measures when treating patients with metastatic disease.2
“[With] metastatic disease, disease control is one goal, quality of life is the other, and they are both equally important because these patients are on therapy generally for the rest of their lives,” she said.