Highlights
• In OASIS‑3, daily oral elinzanetant 120 mg produced a statistically significant reduction in moderate–severe vasomotor symptom (VMS) frequency at 12 weeks vs placebo (least‑squares mean difference −1.6; 95% CI −2.0 to −1.1; P < .001).
• Numerical improvements in VMS frequency and severity, sleep disturbance measures, and menopause‑related quality of life persisted through 50–52 weeks in descriptive analyses.
• No treatment‑related hepatotoxicity, endometrial hyperplasia, or clinically meaningful bone effects were observed; treatment‑related adverse events were more frequent with elinzanetant (30.4% vs 14.6%), most commonly somnolence, fatigue, and headache.
Background and unmet need
Vasomotor symptoms (VMS), commonly experienced as hot flashes and night sweats, affect a majority of women during the menopausal transition and after menopause, and are a leading cause of sleep disturbance, reduced quality of life, and functional impairment. Hormone therapy (HT) remains the most effective treatment for VMS but is contraindicated or undesired in many women because of risks, comorbidities, or personal preference. Nonhormonal pharmacotherapies that are safe, effective, and suitable for long‑term use remain an important unmet need.
Basic science has implicated hypothalamic “KNDy” neurons (kisspeptin/neurokinin B/dynorphin) and neurokinin receptor signaling in the pathophysiology of VMS. Targeting neurokinin receptors, particularly neurokinin‑3 (NK3) and potentially NK1, has therefore emerged as a rational, nonhormonal approach to reduce hot flashes.
Study design and methods (OASIS‑3)
OASIS‑3 is a randomized, double‑blind, placebo‑controlled phase 3 clinical trial conducted at 83 sites in North America and Europe between August 27, 2021, and February 12, 2024. The trial enrolled postmenopausal women aged 40–65 years who were seeking treatment for moderate to severe VMS; a minimum weekly VMS count was not required for eligibility. Participants were randomized to once‑daily oral elinzanetant 120 mg or matching placebo and treated for 52 weeks. The primary efficacy end point was the mean change from baseline to week 12 in frequency of daily moderate to severe VMS, analyzed by a mixed model with repeated measures (MMRM). Secondary end points included changes over 52 weeks in sleep disturbance and menopause‑related quality of life measures; exploratory end points included VMS frequency and severity over 50 weeks. Secondary and exploratory analyses were descriptive and the study was not powered for between‑group comparisons of these end points. Safety assessments included adverse events (AEs), laboratory monitoring (including liver tests), transvaginal ultrasound/endometrial assessments, and bone density/turnover markers. Data analysis was performed on March 11, 2024. The trial is registered at ClinicalTrials.gov (NCT05030584).
Key findings
Participants
Among randomized participants, 313 women received elinzanetant (mean age 54.6 years) and 315 received placebo (mean age 54.9 years). The trial enrolled a reasonably diverse population with 14–16% Black or African American participants and approximately 11% Hispanic or Latina participants; the majority were White.
Primary efficacy outcome
At week 12 the mean change from baseline in daily moderate to severe VMS frequency was −5.4 (95% CI −6.3 to −4.5) for elinzanetant and −3.5 (95% CI −4.1 to −2.9) for placebo. The least‑squares mean difference (elinzanetant vs placebo) was −1.6 (95% CI −2.0 to −1.1), P < .001, demonstrating a statistically significant reduction in VMS frequency at 12 weeks with elinzanetant.
Secondary and exploratory efficacy outcomes
Although the trial was not powered to test statistical hypotheses for secondary and exploratory end points, descriptive analyses reported numerically greater improvements with elinzanetant vs placebo in VMS frequency and severity over 50 weeks and in measures of sleep disturbance and menopause‑related quality of life over 52 weeks. These findings indicate that the early separation from placebo at 12 weeks persisted numerically through the one‑year observation period.
Safety and tolerability
Overall, elinzanetant was generally well tolerated but treatment‑related adverse events were more common than with placebo (30.4% vs 14.6%). The most frequently reported treatment‑related events were somnolence, fatigue, and headache. Importantly, no signal emerged for clinically meaningful hepatotoxicity or endometrial hyperplasia, and there were no meaningful changes in bone mineral density or bone turnover markers reported in the trial. These safety observations are notable for a nonhormonal, centrally acting compound evaluated for long‑term use, but longer and broader postmarketing data would eventually be required to confirm the safety profile in routine clinical practice.
Interpretation and clinical implications
OASIS‑3 extends earlier 26‑week phase 3 findings (OASIS‑1 and OASIS‑2) by evaluating elinzanetant’s effects over 52 weeks and in a broader clinical population. The trial demonstrates that elinzanetant produces a modest but statistically significant reduction in daily moderate to severe VMS frequency at 12 weeks compared with placebo, with descriptive evidence of sustained benefit through 50–52 weeks. The safety data—particularly the lack of hepatotoxicity or endometrial proliferation signals in this trial—are reassuring but should be interpreted in the context of the trial size and duration.
For clinicians, elinzanetant may represent a nonhormonal oral option for patients who cannot, should not, or choose not to take hormone therapy. The magnitude of benefit (approximately 1.6 fewer moderate–severe VMS per day vs placebo at 12 weeks) should be weighed against patient expectations, baseline symptom burden, presence of comorbidities, and treatment tolerability. Shared decision‑making is essential: some patients may prefer the modest efficacy and favorable organ safety profile of a neurokinin‑targeted therapy, while others with more severe or highly disruptive VMS may elect hormone therapy when not contraindicated.
Mechanistic and comparative context
Elinzanetant is described as a dual neurokinin‑targeted therapy, consistent with the mechanistic approach of modulating central neurokinin signaling implicated in thermoregulatory dysfunction at menopause. This mode of action places elinzanetant in the same mechanistic class as other neurokinin antagonists that have shown efficacy for VMS. OASIS‑3 adds clinically relevant long‑term data to the evolving evidence base for neurokinin‑targeted agents and supports biological plausibility for symptomatic benefit through central modulation of thermoregulatory pathways.
Limitations and unanswered questions
Key limitations of OASIS‑3 include the absence of a minimum VMS frequency for enrollment, which may have introduced greater symptom heterogeneity and could attenuate observed treatment effects compared with trials requiring a defined baseline symptom rate. Secondary and exploratory analyses were descriptive and not powered for formal hypothesis testing. Although the 52‑week duration is appreciable, longer‑term safety and real‑world effectiveness data will be important to confirm the durability of benefit and to further evaluate rare or delayed adverse effects. Finally, head‑to‑head comparisons with other available therapies (hormonal or nonhormonal) are lacking, leaving clinicians to make comparisons across trials with differing populations and designs.
Expert commentary
Specialists in menopause care are likely to view elinzanetant as an incremental but meaningful addition to nonhormonal options for VMS, particularly for women seeking an oral therapy with a central mechanism and encouraging one‑year safety data. The clinically significant threshold for benefit varies among women; the observed mean effect size suggests that while many patients will experience meaningful symptom relief, others may achieve only modest benefit and may seek alternative or adjunctive therapies. Ongoing postmarketing surveillance and additional comparative effectiveness research will help place elinzanetant within treatment algorithms.
Conclusion
OASIS‑3 establishes that once‑daily oral elinzanetant 120 mg provides a statistically significant reduction in moderate–severe VMS frequency at 12 weeks versus placebo, with descriptive evidence of sustained benefit through 50–52 weeks and an acceptable safety profile in this trial. Elinzanetant appears to be a promising nonhormonal option for the management of menopausal VMS, expanding clinicians’ therapeutic choices. Clinicians should balance the modest average effect size against individual patient severity, treatment goals, and tolerance of adverse effects when considering elinzanetant for long‑term symptom management.
Funding and trial registration
For funding disclosures and detailed conflict‑of‑interest statements, refer to the primary publication. ClinicalTrials.gov Identifier: NCT05030584.
References
1. Panay N, Joffe H, Maki PM, et al. Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause: A Phase 3 Randomized Clinical Trial. JAMA Intern Med. 2025 Nov 1;185(11):1319‑1327. doi:10.1001/jamainternmed.2025.4421. PMID: 40920404; PMCID: PMC12418220.
Note: This article synthesizes data reported in the referenced JAMA Internal Medicine publication. Readers should consult the original paper for full methodological detail, complete safety tables, and sponsor/funding disclosures.