Editor’s Note: At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, ESMO President-Elect Professor Giuseppe Curigliano of the European Institute of Oncology (IEO), Milan, Italy, presented findings from the patient-reported outcomes (PRO) analysis of the Phase III EMBER-3 trial. The data revealed changes in overall health status, quality of life, and physical function scores in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer treated with either imlunestrant alone or in combination with abemaciclib. Oncology Frontier conducted an exclusive interview with Professor Curigliano at the conference to discuss the clinical applicability of imlunestrant monotherapy and its combination with abemaciclib, as well as their impact on patient quality of life—offering new perspectives for clinical practice.Study Overview
Title: Patient-reported outcomes (PROs) in patients with ER+, HER2- advanced breast cancer (ABC) treated with imlunestrant, investigator’s choice standard endocrine therapy, or imlunestrant + abemaciclib: Results from the phase III EMBER-3 trial.
Study Background
Imlunestrant (imlu) is a next-generation, brain-penetrant, oral selective estrogen receptor degrader. The EMBER-3 trial, in patients (pts) with ER+, HER2- ABC who haddisease progression on or after aromatase inhibitor-based therapy, showed significantprogression free survival (PFS) improvement with imlu vs standard therapy (SOC, fulvestrantor exemestane) in pts with ESR1 mutations (ESR1m), and with imlunestrant+abemaciclib(imlu+abema) vs imlu in all pts, regardless of ESR1m. Exploratory PRO analyses arepresented here.
Study Methods
EORTC QLQ-C30 was administered at baseline (BL) and every 8 weeks until treatment discontinuation. Prespecified QLQ-C30 analysis used a longitudinal mixed model for repeated measures to calculate mean change from BL in pts with BL and≥1 post-BL score. PRO-CTCAE (diarrhea frequency) was administered weekly, reporting (never) to 4 (almost constantly). PRO-CTCAE (injection site reaction [ISR]) was administered to fulvestrant recipients weekly for 2 weeks post-injection, reporting yes/no (pain, swelling, redness). Descriptive analysis was used for PRO-CTCAE.
Study Results
Among patients with ESR1 mutations, imlunestrant monotherapy was associated with either improvement or maintenance across several EORTC QLQ-C30 scores, in contrast to the standard therapy group, which showed either score declines or stability. Specifically, ESR1-mutated patients receiving imlunestrant reported improvements in global health status (GHS)/quality of life (QoL) and physical functioning (PF) scores, whereas patients on standard therapy showed declines. The between-group mean differences in score changes were 9.9 [0.1, 19.7] for GHS/QoL and 6.2 [-0.8, 13.1] for PF. These patient-reported outcome (PRO) findings were consistent with the improved progression-free survival (PFS) observed in this subgroup.
In the overall patient population, both the imlunestrant and standard therapy groups experienced similar declines in GHS/QoL scores (mean difference: 0.5 [-4.7, 5.7]). Physical functioning scores remained stable in the imlunestrant group but declined slightly in the standard therapy group (mean difference: 2.5 [-1.1, 6.1]).
Most fulvestrant recipients(72%) reported ISR at any time while on treatment, with a mean of 31% during the first week of the first 6 cycles. Imlu+abema vs imlu showed broadly similar declines in all pts, with minimal mean change differences in GHS/QOL and PF scores (0.8 [-7.4, 5.9]; -2.2 [-6.6, 2.2],respectively).
Pts reported similarly low rates of “frequent” or “almost constant” diarrhea with imlu (3%) and SOC (2%) and higher rates with imlu+abema (22%).
Study Conclusion
PROs from EMBER-3 demonstrated that patients with ESR1m had better GHS/QOL and PF with imlu vs SOC, mirroring efficacy results. While the frequency of CTCAE defined ISRs was low, the high rate of PRO-CTCAE ISR demonstrates that this clinically relevant adverse event is underappreciated by physicians. Additionally, all pts had generally comparable GHS/QOL and PF with imlu+abema vs imlu. Overall, these results support the efficacy and safety of imlu compared to existing SOC.
Researcher Interview
Oncology Frontier: Could you please share with us which Patient-Reported Outcomes (PROs) assessment tools were utilized in the EMBER-3 study you presented? How was the accuracy and reliability of the PROs data ensured?
Prof. Giuseppe Curigliano: EMBER-3 was a prospective randomized trial comparing Imlunestrant alone to standard of care in endocrine therapy and Imlunestrant alone versus Imlunestrant plus abemaciclib. In EMBER-3, as a secondary endpoint, we evaluated patient-reported outcomes, global health status and quality of life. What we discovered is that when comparing A versus B, Imlunestrant versus standard of care, quality of life was numerically improved in all the variables of functional status. Similar results have been obtained when comparing Imlunestrant alone to Imlunestrant plus abemaciclib. So, when evaluating global health status and quality of life in our patients, we have a better outcome, a better patient-reported outcome.
Only in one variable there was a difference, that was the incidence of diarrhea. Importantly, injection site reaction of fulvestrant was the main complaint for the majority of the patients that had been enrolled in EMBER-3. So, according to this data, we confirm Imlunestrant plus abemaciclib in all population and Imlunestrant alone in ESR1-mutant patients, is a new option for patients with HR-positive/HER2-negative disease.
Oncology Frontier: The combination therapy of imlunestrant and abemaciclib demonstrated certain efficacy in the EMBER-3 study, yet patient-reported quality of life did not significantly surpass that of monotherapy. What do you believe are the applicable scenarios and potential challenges for this combination strategy in future clinical practice? Are there specific patient populations that might be more suitable for this combination treatment regimen?
Prof. Giuseppe Curigliano: I believe the most important information from this study is the opportunity to offer an all oral combination in patients with HR-positive/HER2-negative disease, both those who received the CDK4/6 inhibitors or those who progressed to CDK4/6 inhibitors. I don’t see major challenges. I see only an opportunity to offer the patients an all oral combination.
Oncology Frontier:Despite the relatively low incidence of injection site reactions (ISR) as defined by the Common Terminology Criteria for Adverse Events (CTCAE), PRO-CTCAE findings suggest that ISR are an underrecognized clinically relevant adverse event. How do you believe clinicians should more accurately identify and manage such underrecognized adverse events in clinical practice to improve patients’ treatment experience and adherence?
Professor Giuseppe Curigliano: More dramatically, it’s easier to take an oral pill rather than doing an intramuscular injection. Of course, if you have a patient that should receive every 28 days an intramuscular injection, this is a logistical problem and at the same time can also be an adverse event. So, personally, I believe in clinical practice that having an oral option for my patients, it’s a huge opportunity for our patients, both in terms of logistics and in terms of quality.
Professor Giuseppe Curigliano, MD, PhD
President-Elect, European Society for Medical Oncology (ESMO) Director, Division of Early Drug Development and Co-Chair, Experimental Therapeutics Program, European Institute of Oncology (IEO), Milan, Italy Member of the Steering Committee, Department of Oncology and Hemato-Oncology, University of Milan Member, Italian National Health Council Editor-in-Chief, ESMO Open Editorial Board Member of leading international journals including European Journal of Oncology, Journal of Clinical Oncology, and Annals of Oncology
