Editor’s Note: At the 2025 ASCO Annual Meeting, two important studies—TRADE and OASIS-4—brought forward new treatment concepts and methods for early breast cancer, particularly in improving treatment adherence and patient quality of life. The TRADE study (Abstract No. 517) introduced a dose-escalation strategy for the CDK4/6 inhibitor abemaciclib in HR+/HER2− breast cancer patients, significantly improving adherence and tolerability. Meanwhile, the OASIS-4 study (Abstract No. 508) demonstrated, for the first time, the rapid onset and long-term safety of elinzanetant in alleviating vasomotor symptoms (VMS) caused by adjuvant endocrine therapy in HR+ breast cancer, offering a new option for enhancing quality of life and adherence. Oncology Frontier invited Prof. Songqing Ye of Fujian Provincial Hospital, affiliated with Fuzhou University, to provide in-depth insights into these two key studies.Study One
TRADE Study – A Phase II Trial Evaluating Dose-Escalation Tolerability of Abemaciclib in Early HR+/HER2− Breast Cancer
TRADE is a prospective, single-arm phase II clinical trial evaluating whether a dose-escalation strategy for adjuvant abemaciclib could improve tolerability and treatment adherence in patients with early HR+/HER2− breast cancer. A total of 90 eligible patients (median age 58, range 24–78) were enrolled to receive abemaciclib combined with endocrine therapy. The starting dose was 50 mg twice daily for 2 weeks, escalated to 100 mg twice daily for another 2 weeks, and finally to 150 mg twice daily, with antidiarrheal medications allowed if necessary.
The primary endpoint was a composite adverse event rate at week 12, defined as treatment discontinuation or failure to achieve or maintain the target 150 mg dose for any reason. The study hypothesized that the 12-week composite adverse event rate would be below 40%. Dose escalation was permitted only if no persistent grade 3/4 or sustained grade 2 adverse events occurred.
The results showed that 26 patients (29.2%; 90% CI [21.3–38.2]; P=0.046) met the composite endpoint at week 12: 6 patients (6.7%) discontinued treatment early, 3 patients (3.4%) discontinued due to adverse events, 8 patients (9.0%) failed to reach the 150 mg dose, and 12 patients (13.5%) required dose reduction after reaching 150 mg. The most common grade ≥2 treatment-related adverse events were neutropenia (24.4%), diarrhea (26.7%), and fatigue (21.1%). The incidence of grade ≥2 diarrhea during weeks 0–4, 4–8, and 8–12 was 8.9%, 19.1%, and 16.5%, respectively, compared to 20.5%, 12.1%, and 7.3% in the monarchE study.
At week 12, 70.8% of patients in the TRADE study maintained the target dose (150 mg) of abemaciclib, and the early discontinuation rate was only 6.7%. In contrast, the monarchE study reported a 18.5% discontinuation rate due to adverse events and a 43.6% dose reduction rate, with fewer than 60% of patients able to maintain the full 150 mg dose. The TRADE strategy was associated with reduced incidence and severity of diarrhea.
CDK4/6 inhibitors (CDK4/6i) like abemaciclib have become cornerstone treatments for HR+/HER2− breast cancer. However, tolerability—particularly gastrointestinal and hematologic toxicities—often leads to dose reductions or discontinuation, which may compromise efficacy. The dose-escalation approach in the TRADE study, as reported at ASCO 2025, offers an innovative strategy by starting at a lower dose and gradually increasing to the target based on individual tolerability. Previous research suggests that dose reduction may not compromise efficacy. In exploratory analyses of the monarchE trial, patients receiving reduced doses of abemaciclib (100 mg or 50 mg vs. 150 mg twice daily) showed comparable invasive disease-free survival (IDFS) hazard ratios (HR=0.905). Diarrhea is one of the most frequent side effects during abemaciclib treatment, especially in the early phase, occurring in over 75% of patients, with grade ≥3 diarrhea observed in approximately 7.8%. Older patients (≥75 years) have a significantly higher incidence of grade 2/3 diarrhea.
Given the wide inter-individual variability in plasma drug concentrations, dose escalation allows gradual exposure of intestinal epithelial cells to CDK4/6 inhibition, helping to prevent abrupt rises in blood levels among patients with low tolerability, and reducing the risk of acute toxicity–induced discontinuation. The TRADE study demonstrates how gradual dose escalation can optimize the balance between efficacy and safety, improving adherence and treatment completion—critical for patients requiring long-term therapy (2–3 years in the adjuvant setting). This approach may also offer a safer alternative for elderly patients or those with comorbidities.
In recent years, CDK4/6i have often been combined with endocrine or targeted therapies, increasing the risk of cumulative toxicity. Dose escalation could serve as a “safety foundation” for such combinations—for example, when used with PI3K inhibitors, adjusting the abemaciclib dose first may reduce toxicity. Reducing adverse events may also lower hospitalization and supportive care costs, improving pharmacoeconomic outcomes.
The TRADE study provides valuable clinical insights and practical reference for implementing abemaciclib in the adjuvant setting. Long-term follow-up will be needed to determine whether dose escalation affects resistance patterns (e.g., TP53 deletion or MDM2 amplification), or whether lower doses may accelerate resistance. Further investigation is warranted to explore whether biomarkers (e.g., ctDNA, ESR1 mutations) can guide dose adjustment and promote precision de-escalation.
Study Two
Phase III OASIS-4 Trial – Efficacy and Safety of Elinzanetant for Vasomotor Symptoms Related to Adjuvant Endocrine Therapy
The OASIS-4 study is a randomized, double-blind, placebo-controlled phase III clinical trial. Between October 2022 and November 2024, a total of 474 patients were enrolled across 90 centers worldwide. Eligible participants were patients with hormone receptor (HR)-positive early breast cancer who were experiencing moderate to severe vasomotor symptoms (VMS) while undergoing endocrine therapy, or high-risk individuals undergoing endocrine therapy for cancer prevention (only one such participant was ultimately enrolled).
VMS were defined as follows: Mild – sensation of hot flashes without sweating; Moderate – sensation of hot flashes with sweating; Severe – sensation of hot flashes with sweating that interferes with daily activities.
Patients with advanced or metastatic disease, those scheduled for surgery within 3 months prior to enrollment, or those planning to receive surgery, radiation, chemotherapy, or immunotherapy during the study period were excluded.
Participants were randomized in a 2:1 ratio: Intervention group (316 patients) received Elinzanetant 120 mg/day continuously for 52 weeks. Control group (158 patients) received placebo for 12 weeks followed by Elinzanetant for 40 weeks.
Approximately 55% of patients were receiving tamoxifen, and about 45% were receiving aromatase inhibitors (AIs).
Primary endpoints: change in the average daily frequency of moderate-to-severe VMS from baseline to Week 4 and Week 12. Secondary endpoints: severity of VMS, sleep quality, quality of life, and safety.
Study Results
Primary Endpoint At baseline, the mean daily frequency of moderate-to-severe vasomotor symptoms (VMS) was 11.4 in the Elinzanetant group and 11.5 in the Placebo–Elinzanetant group. By Week 4, the mean reduction in VMS was −6.51 vs. −3.04 episodes, respectively (P < 0.001). By Week 12, the reduction further increased to −7.76 vs. −4.20 episodes (P < 0.001).
Key Secondary Endpoints At Week 12, the Elinzanetant group showed a reduction in severe VMS that was 1.0 episode per day greater than the placebo group (P < 0.0001). Sleep quality and quality of life also significantly improved in the Elinzanetant group at Week 12, as measured by the Insomnia Severity Index (ISI) and the Menopause-Specific Quality of Life Questionnaire (MENQOL).
Safety Data From Weeks 1 to 12, the overall incidence of any-grade adverse events was 69.8% in the Elinzanetant group versus 62.0% in the placebo group. The most common events were headache (9.5%), fatigue (9.5%), and somnolence (10.8%), and were mostly mild to moderate. Serious adverse events occurred in 2.5% of patients in the Elinzanetant group and 0.6% in the placebo group, with no treatment-related deaths reported. Long-term safety over the 52-week treatment period was consistent with prior postmenopausal VMS studies, and no new safety signals were identified.
Hormone receptor–positive (HR+) breast cancer accounts for approximately 70% of all breast cancers. Many patients require at least 5 years of adjuvant endocrine therapy—such as tamoxifen, aromatase inhibitors (AIs), or ovarian function suppression (OFS)—to reduce the risk of recurrence and mortality. However, up to 80% of patients experience moderate-to-severe vasomotor symptoms (VMS) due to the abrupt decline in estrogen levels. These symptoms—hot flashes, night sweats, and sleep disturbances—can severely impact sleep, mood, and overall quality of life. In fact, nearly 30% of patients prematurely discontinue treatment, with VMS being one of the leading causes of endocrine therapy interruption.
Until now, no safe and effective nonhormonal therapies have been widely available. Hormone replacement therapy (HRT) may increase the risk of breast cancer recurrence. Alternatives like antidepressants or non-pharmacologic approaches such as cognitive behavioral therapy and acupuncture have shown only limited benefit. The clinical need remains unmet, making the development of nonhormonal targeted therapies for VMS a pressing priority.
Elinzanetant is a first-in-class oral dual neurokinin-1 and neurokinin-3 (NK-1,3) receptor antagonist. It targets KNDy neurons in the hypothalamus, which become hyperactive due to estrogen deficiency and trigger thermoregulatory instability leading to hot flashes. By blocking neurokinin signaling, Elinzanetant directly inhibits KNDy neuron activity and relieves VMS.
The OASIS-4 study is the first to confirm that Elinzanetant provides rapid relief within one week and maintains long-term safety for up to 52 weeks. It offers a novel, nonhormonal option for sustained relief of breast cancer–associated VMS. By targeting neural pathways instead of hormones, Elinzanetant preserves anti-tumor efficacy while improving quality of life, treatment adherence, and long-term outcomes in HR+ breast cancer patients.
The results of the OASIS-4 study were presented at the 2025 ASCO Annual Meeting and simultaneously published in The New England Journal of Medicine. This landmark study emphasizes a dual focus on survival and quality of life in early breast cancer management and may reshape clinical practice by establishing Elinzanetant as a new standard for VMS management.
Prof. Songqing Ye Chief Physician, Department of Breast Surgery Fujian Provincial Hospital, Affiliated Hospital of Fuzhou University
