Neurokinin pathway antagonists for vasomotor symptoms in women with breast cancer: focus on elinzanetant and fezolinetant

Abstract

Vasomotor symptoms (VMS) have a major impact on quality-of-life in women with hormone receptor–positive breast cancer receiving adjuvant endocrine therapy. As menopause hormone therapy is contraindicated in this setting, effective non-hormonal treatment options are urgently needed. We performed a focused narrative review of neurokinin (NK) receptor antagonists for VMS, including the OASIS-1-4 program for elinzanetant and the SKYLIGHT, MOONLIGHT, and DAYLIGHT programs for fezolinetant, with emphasis on breast cancer–specific data, safety, drug-drug interactions, and selected special populations relevant to oncology practice. Elinzanetant, a dual NK1/NK3 receptor antagonist approved by the European Medicines Agency and the U.S. Food and Drug Administration, provides the first phase III evidence in the specific cohort of patients with breast cancer receiving endocrine therapy. In the OASIS-4 trial, elinzanetant demonstrated rapid and clinically meaningful reductions in moderate-to-severe VMS, with sustained improvements in sleep and menopause-specific quality of life and a favorable tolerability profile without a signal for clinically significant hepatotoxicity. Fezolinetant, a selective NK3 receptor antagonist approved for menopausal VMS in the general population, has shown robust efficacy across multiple phase III trials; however, its use requires liver function monitoring due to hepatotoxicity, and its role in breast cancer survivors remains under investigation. Safety considerations of NK receptor antagonists include their use alongside CDK4/6 inhibitors. With breast cancer–specific data for elinzanetant and ongoing trials of fezolinetant, these agents will change clinical practice by improving symptom control and adherence to adjuvant endocrine therapy overall.

Highlights

• •Vasomotor symptoms substantially impair quality of life in breast cancer survivors.
• •OASIS-4 is the first phase III trial of an NK antagonist in breast cancer patients.
• •Elinzanetant provides effective, non-hormonal VMS control during endocrine therapy.
• •Safety, drug-drug interactions and liver monitoring are key clinical considerations.
• •NK antagonists may improve adherence to adjuvant endocrine therapy.

1. Introduction

Vasomotor symptoms (VMS), including hot flashes and night sweats, affect up to 90% of women with hormone receptor-positive breast cancer receiving adjuvant endocrine therapy, markedly exceeding the prevalence observed in naturally postmenopausal women [1,2]. Endocrine treatments such as selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and ovarian function suppression (OFS) induce profound estrogen deprivation, thereby triggering or exacerbating VMS [3]. In this setting, symptoms are typically more severe, persistent, and disruptive, contributing to sleep disturbance, mood and cognitive impairment, sexual dysfunction, reduced work productivity, and impaired quality of life (QoL) [4,5].

Beyond symptom burden, VMS have direct implications for oncologic care. Their severity is a major driver of non-adherence to adjuvant endocrine therapy, with observational studies reporting premature discontinuation or dose omission in approximately 20–40% of patients, largely due to uncontrolled symptoms and QoL concerns [[6], [7], [8], [9]]. This challenge is particularly relevant in premenopausal women, in whom OFS is frequently indicated [10]. Given that 5-10 years of endocrine therapy remains the standard of care for hormone receptor–positive breast cancer, effective and well-tolerated management of VMS is essential to sustain treatment adherence and preserve long-term survival benefits [11].

1.1. Limitations of hormone-based therapy for VMS in breast cancer

Systemic menopausal hormone therapy (MHT), the most effective treatment for VMS in the general population, is contraindicated or strongly discouraged in women with previous history of hormone receptor-positive breast cancer because of concerns regarding disease stimulation and recurrence risk [[12], [13], [14]]. Accordingly, major oncology and menopause guidelines including those from the National Comprehensive Cancer Network (NCCN), the North American Menopause Society (NAMS), and the European School of Oncology–European Society for Medical Oncology (ESO–ESMO), advise against systemic MHT in breast cancer survivors [[15], [16], [17]].

As a result, non-pharmacological measures such as lifestyle modification, yoga, and acupuncture are recommended as first-line interventions [3]. For patients with persistent or clinically significant symptoms, non-hormonal pharmacologic therapies constitute the mainstay of management. These include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), gabapentin, and clonidine, which achieve modest reductions in VMS frequency, typically in the range of 20-50% compared with placebo [18]. However, their clinical utility is limited by tolerability issues and clinically relevant drug-drug interactions, like the CYP2D6 inhibition by paroxetine and fluoxetine which may impair tamoxifen activation [19]. Overall, effect sizes remain suboptimal and patient satisfaction low, underscoring a persistent unmet need for effective, well-tolerated, non-hormonal therapeutic options.

1.2. Thermoregulatory neurocircuitry and neurokinin signaling

The biological basis of menopausal VMS lies in dysregulation of hypothalamic thermoregulatory pathways. The preoptic area (POA) of the anterior hypothalamus integrates thermal inputs to maintain core body temperature within a narrow thermoneutral zone [20]. Estrogen deprivation markedly narrows this zone, rendering individuals hypersensitive to minor temperature fluctuations and triggering inappropriate heat-dissipation responses, including cutaneous vasodilation and sweating [21].

A central role in this process is played by kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the arcuate nucleus of the hypothalamus. Estrogen deprivation leads to KNDy neuronal hypertrophy and increased neurokinin B (NKB) signaling through neurokinin-3 receptors (NK3R) in the POA, precipitating episodic vasodilation, sweating, and transient tachycardia - the clinical manifestation of VMS [[20], [21], [22]]. Human proof-of-concept studies have demonstrated that exogenous NKB administration induces objective hot-flash responses, whereas pharmacologic NK3R antagonism rapidly reduces VMS frequency and severity, establishing NK3R as a validated therapeutic target in menopausal and cancer therapy-induced VMS [22,23]. The neurokinin-1 receptor (NK1R), which binds substance P, is also implicated in thermoregulation, sleep, and mood, providing the rationale for dual NK1/NK3 receptor antagonism (Fig. 1) [24,25].

Fig. 1.

Mechanisms of action of neurokinin-1 and neurokinin-3 receptor inhibitors in patients with breast cancer. Created in BioRender. Arecco, L. (2026) Abbreviations: KNDy, kisspeptin/neurokinin B/dynorphin; NK1, neurokinin-1 receptor; NK3, neurokinin-3 receptor; ERα, estrogen receptor alpha.

This review synthesizes emerging clinical evidence on neurokinin receptor antagonists for the management of VMS in breast cancer and related populations, with particular emphasis on translational mechanisms, pivotal phase III trials, and pragmatic considerations for clinical practice.

2. Methods

A focused narrative review was conducted to identify clinical trials evaluating NK receptor antagonists for the management of VMS. All phase III trials of elinzanetant and fezolinetant were included, irrespective of study population, to provide a comprehensive overview of pivotal efficacy and safety data. In addition, all available clinical studies involving women with breast cancer were included, regardless of trial phase, in order to capture oncology-specific evidence and ongoing research. Searches of PubMed, major oncology and menopause conference proceedings, and clinical trial registries were performed up to December 2025. Data were synthesized qualitatively with attention to efficacy, safety, QoL outcomes, and clinically relevant subgroups.

2.1. Elinzanetant: dual NK1/NK3 receptor antagonist

Elinzanetant (formerly NT-814) is an orally bioavailable, potent, and selective dual antagonist of NK1 and NK3 receptors. Preclinical studies demonstrated high binding affinity for both receptor subtypes and confirmed adequate brain penetration consistent with central nervous system target engagement [24]. By acting simultaneously on these two receptors, elinzanetant addresses distinct yet interconnected neurochemical pathways implicated in the generation of VMS.

Pharmacokinetic analyses indicate that elinzanetant exhibits dose-proportional exposure and a terminal half-life of approximately 30-40 h, supporting once-daily oral dosing. The compound is metabolized primarily via cytochrome P450 3A4 (CYP3A4), which may necessitate caution when co-administered with strong CYP3A4 inhibitors or inducers (Table 1) [24,26].

Table 1.

Mechanisms and pharmacology of elinzanetant and fezolinetant.

Parameter	Elinzanetant	Fezolinetant
Mechanism of action	Dual neurokinin-1 (NK1) and neurokinin-3 (NK3) receptor antagonist	Neurokinin-3 (NK3) receptor antagonist
Primary target(s)	NK1R (substance P) and NK3R (neurokinin B)	NK3R (neurokinin B)
Receptor selectivity	Dual blockade; no NK2 activity	Highly selective for NK3R; minimal NK1/NK2 activity
Oral bioavailability	High	High
Time to peak (Tmax)	2–4 h	1–4 h
Elimination half-life (t1/2)	30–40 h	10 h
Dosing frequency	Once daily	Once daily
Metabolism	Primarily via CYP3A4	Primarily via CYP1A2
Major drug interactions	Avoid strong CYP3A4 inhibitors/inducers	Contraindicated with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin)
Hepatotoxicity	None reported in clinical trials	Elevated ALT/AST in ∼1–2%; FDA boxed warning; LFT monitoring required
Approved dose	120 mg once daily	45 mg once daily
Breast cancer data	Yes – phase III OASIS-4	Pending – NCT06440967, NCT06917313, NCT06617455
Regulatory status in breast cancer	Approved	Off-label use only; approved for menopausal VMS

2.2. Clinical evidence – elinzanetant (OASIS program)

Based on the results from the OASIS clinical program, elinzanetant has been registered by both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) for the treatment of moderate-to-severe VMS associated with menopause, including those induced by adjuvant endocrine therapy for breast cancer.

2.2.1. OASIS-1 and OASIS-2: postmenopausal women from the general population

The pivotal phase III OASIS-1 and OASIS-2 trials (Table 2) were identically designed, multicenter, randomized, double-blind, placebo-controlled studies evaluating elinzanetant 120 mg once daily in postmenopausal women aged 40–65 years experiencing at least 7 moderate-to-severe vasomotor symptoms (VMS) per day [27]. Participants were randomized to elinzanetant (OASIS-1: n = 199; OASIS-2: n = 200) or placebo (OASIS-1: n = 197; OASIS-2: n = 200) for a 12-week placebo-controlled period, followed by a 14-week active-treatment extension for both groups.

Table 2.

Pivotal phase III trials of neurokinin receptor antagonists in the general postmenopausal population.

Trial	NK antagonist	Population	Design	Primary endpoints	Key Results (week 12)
OASIS-1 [27]	Elinzanetant	Postmenopausal women with moderate–severe VMS	Phase III, randomized, double-blind, placebo-controlled	Change in VMS frequency and severity	Significant placebo-adjusted reductions in VMS
OASIS-2 [27]	Elinzanetant	Postmenopausal women with moderate–severe VMS	Phase III, randomized, double-blind, placebo-controlled	Change in VMS frequency and severity	Clinically meaningful reductions in VMS vs placebo
OASIS-3 [28]	Elinzanetant	Postmenopausal women with VMS (long-term exposure)	Phase III, extension study	Long-term safety and durability	Sustained efficacy; favorable tolerability
SKYLIGHT-1 [29]	Fezolinetant	Postmenopausal women with moderate–severe VMS	Phase III, randomized, double-blind, placebo-controlled	Change in VMS frequency and severity	Placebo-adjusted reduction ∼−2.5 events/day
SKYLIGHT-2 [30]	Fezolinetant	Postmenopausal women with moderate-severe VMS	Phase III, randomized, double-blind, placebo-controlled	Change in VMS frequency and severity	Significant reductions in VMS frequency and severity
SKYLIGHT-4 [31]	Fezolinetant	Postmenopausal women with VMS (long-term safety)	Phase III, open-label extension	Long-term safety	No new safety signals; LFT monitoring required
MOONLIGHT-1 [32]	Fezolinetant	Postmenopausal Asian women with moderate–severe VMS	Phase III, randomized, double-blind, placebo-controlled (30 mg dose)	Change in VMS frequency	Did not meet primary efficacy endpoints vs placebo
MOONLIGHT-3 [33]	Fezolinetant	Postmenopausal Asian women with moderate–severe VMS (long-term exposure)	Phase III, extension study (30 mg dose)	Long-term safety and tolerability	Long-term safety study; efficacy not assessed
DAYLIGHT [34]	Fezolinetant	Postmenopausal women with VMS, unsuitable for hormone therapy	Phase III, randomized, double-blind, placebo-controlled (45 mg dose)	Change in VMS frequency	Clinically meaningful reductions in VMS vs placebo

Elinzanetant demonstrated rapid and sustained efficacy in reducing both VMS frequency and severity. At week 4, least-squares (LS) mean differences versus placebo in daily VMS frequency were −3.3 events/day (95% CI -4.5 to −2.1; P < 0.001) in OASIS-1 and -3.0 events/day (95% CI -4.4 to −1.7; P < 0.001) in OASIS-2. These effects were maintained through week 12, with LS mean differences of −3.2 events/day in both trials (P < 0.001). Significant improvements in VMS severity were also observed at week 12, with LS mean differences of −0.4 (95% CI -0.5 to −0.2; P < 0.001) in OASIS-1 and -0.3 (95% CI -0.4 to −0.1; P < 0.001) in OASIS-2 [27].

Beyond vasomotor control, elinzanetant was associated with clinically meaningful improvements in menopause-related QoL, assessed using the Menopause-Specific QoL (MENQOL) questionnaire, and in sleep quality, measured by the PROMIS Sleep Disturbance scale, compared with placebo at week 12 [27].

During the placebo-controlled period, treatment-emergent adverse events occurred in 44-51% of participants receiving elinzanetant and 38-49% receiving placebo, with most events being mild to moderate. Serious adverse events were uncommon (≤2%), and discontinuations due to adverse events were infrequent. The most commonly reported adverse events were headache (7-9% vs 2.5-2.6%) and fatigue (5.5-7% vs 1.5%), with no cases of drug-induced liver injury or other clinically relevant safety signals observed during the 26-week treatment period [27].

2.2.2. OASIS-3: long-term efficacy and safety

The OASIS-3 trial extended these findings by evaluating the long-term efficacy and safety of elinzanetant over 52 weeks in postmenopausal women with moderate-to-severe VMS, using a fully placebo-controlled design without crossover [28]. A total of 628 women were randomized to elinzanetant 120 mg daily or matching placebo. Elinzanetant significantly reduced VMS frequency and severity throughout the study duration, with numerical improvements also observed in sleep disturbance and menopause-related QoL.

Over 52 weeks, treatment-related adverse events were reported in 30.4% of participants receiving elinzanetant compared with 14.6% in the placebo group. The most common adverse events were somnolence, fatigue, and headache, which were predominantly mild to moderate in severity. No serious treatment-related adverse events, hepatotoxicity, endometrial hyperplasia, or other new safety signals were identified during long-term follow-up [28].

Collectively, OASIS-1, OASIS-2, and OASIS-3 established elinzanetant as an effective and well-tolerated non-hormonal therapy for VMS in postmenopausal women, providing a robust clinical foundation for its subsequent evaluation in breast cancer–specific populations.

2.2.3. OASIS-4: breast cancer–dedicated phase III trial

The OASIS-4 trial (NCT05587296; Table 3) represents a landmark in the management of VMS among women receiving endocrine treatments for hormone receptor-positive breast cancer [35]. It is the first large, dedicated phase III study to evaluate a neurokinin receptor antagonist specifically in patients experiencing VMS during adjuvant endocrine therapy.

Table 3.

Clinical trials of neurokinin receptor antagonists in women with breast cancer.

Trial	NK antagonist	Population	Design	Primary endpoints	Key results (Week 12)	Status
OASIS-4	Elinzanetant	Women with hormone receptor-positive breast cancer receiving endocrine therapy (± ovarian suppression)	Phase III, randomized, double-blind, placebo-controlled	Change in moderate–severe VMS frequency	LS mean difference −3.4 events/day vs placebo; significant improvements in sleep and QoL	Results published [35]
HIGHLIGHT (NCT06440967)	Fezolinetant	Women with hormone receptor-positive early breast cancer on adjuvant endocrine therapy (including CDK4/6 inhibitors)	Phase III, randomized, double-blind, placebo-controlled	Change in VMS frequency and severity	Efficacy and safety results pending	Ongoing
FLASH-Breast (NCT06917313)	Fezolinetant	Women with early-stage hormone receptor-positive breast cancer on endocrine therapy	Phase II, randomized, placebo-controlled	Change in VMS frequency and severity	Proof-of-concept study	Ongoing
VENT (NCT06617455)	Fezolinetant	Women with early-stage hormone receptor-positive breast cancer on adjuvant endocrine therapy	Phase II, randomized, double-blind, placebo-controlled	Change in VMS frequency	Exploratory efficacy and safety data pending	Ongoing

Abbreviations: VMS, vasomotor symptoms; LS, least squares; QoL, quality of life; CDK4/6, cyclin-dependent kinase 4 and 6.

This multicenter, randomized, double-blind, placebo-controlled study enrolled 474 women aged 18-70 years with a history of hormone receptor-positive breast cancer (or at elevated risk for hormone receptor–positive disease) receiving adjuvant endocrine therapy (i.e., tamoxifen (n = 265, 56.0%), or aromatase inhibitors (n = 209, 44.0%) with or without ovarian function suppression), who reported at least 35 moderate-to-severe VMS per week. Participants were randomized 2:1 to once-daily oral elinzanetant 120 mg for 52 weeks or placebo for 12 weeks followed by elinzanetant for 40 weeks. Co-primary endpoints were changes from baseline in mean daily VMS frequency at weeks 4 and 12 [35].

At baseline, participants experienced approximately 11 VMS episodes per day. A rapid onset of action was observed by week 1, with mean reductions of −4.0 events/day with elinzanetant versus −1.8 with placebo. By week 4, mean changes were −6.5 (SD 6.1) versus −3.0 (SD 5.0) events/day, yielding an LS mean difference of −3.5 (95% CI -4.4 to −2.6; P < 0.0001). Treatment effects were maintained through week 12 (LS mean difference −3.4; 95% CI -4.2 to −2.5; P < 0.0001). Similar benefits were observed for VMS severity, confirming both the magnitude and consistency of effect [35].

Improvements extended beyond vasomotor control: at week 12, PROMIS Sleep Disturbance T-scores improved by −10.6 with elinzanetant versus −4.1 with placebo (LS mean difference −6.1; 95% CI -7.5 to −4.8; P < 0.0001), and MENQOL total scores decreased by −1.3 versus −0.5 (LS mean difference −0.7; 95% CI -0.9 to −0.5; P < 0.0001). These benefits persisted throughout the 52-week treatment period, indicating sustained efficacy [35].

Elinzanetant was generally well tolerated. During the placebo-controlled phase, treatment-emergent adverse events were balanced between the two arms and occurred in 69.8% of elinzanetant-treated patients versus 62.0% of patients treated with placebo; the most common events were headache, somnolence, and fatigue. Serious adverse events were infrequent (2.5% vs. 0.6%). Over 52 weeks, 16.7% of participants discontinued the study for any reason, with discontinuations due to adverse events occurring in 8.0% of elinzanetant-exposed patients, most often early during treatment. No clinically meaningful hepatotoxicity was observed, and breast cancer recurrences during follow-up showed no apparent association with elinzanetant. Among participants completing 52 weeks, 91.6% elected to continue treatment in the long-term extension [35].

Overall, OASIS-4 demonstrates that elinzanetant is an effective, evidence-based, non-hormonal pharmacologic option for managing VMS in women with breast cancer receiving endocrine therapy. Its rapid onset, clinically meaningful symptom reduction, and sustained improvements in sleep and QoL support its potential to enhance treatment adherence and survivorship outcomes.

2.3. Fezolinetant: selective NK3 receptor antagonist

Fezolinetant (formerly ESN364) is an orally administered, highly selective NK3R antagonist, with minimal activity at NK1 or NK2 receptors [36]. Pharmacokinetic studies indicate rapid absorption, with peak plasma concentrations reached within 1-4 h and an elimination half-life of approximately 10 h, supporting once-daily oral dosing. Fezolinetant is primarily metabolized by cytochrome P450 1A2 (CYP1A2), and co-administration with strong CYP1A2 inhibitors is contraindicated due to increased systemic exposure (Table 1) [36,37].

2.4. Clinical evidence - fezolinetant (SKYLIGHT program)

Based on the results of the phase III SKYLIGHT clinical program, fezolinetant received regulatory approval from both FDA and EMA for the treatment of moderate-to-severe VMS associated with menopause, at a dose of 45 mg once daily.

2.4.1. SKYLIGHT-1 and SKYLIGHT-2: postmenopausal women from the general population

SKYLIGHT-1 and SKYLIGHT-2 were identically designed, multicenter, randomized, double-blind, placebo-controlled phase III trials evaluating fezolinetant 30 mg and 45 mg once daily in postmenopausal women experiencing at least seven moderate-to-severe VMS per day [29,30]. In both studies, participants were randomized to fezolinetant 30 mg, fezolinetant 45 mg, or placebo for 12 weeks, followed by a blinded active-treatment extension of up to 40 weeks, yielding a total study duration of 52 weeks. Co-primary endpoints were the mean change from baseline in VMS frequency and severity at weeks 4 and 12.

Across both trials, fezolinetant demonstrated rapid, dose-dependent, and sustained reductions in VMS frequency and severity. In SKYLIGHT-1 (n = 527), placebo-adjusted LS mean reductions in daily VMS frequency at week 4 were −1.87 events/day for the 30-mg dose and −2.07 events/day for the 45-mg dose (both P < 0.001), with effects maintained through week 12 (LS mean differences −2.39 and −2.55 events/day, respectively) [29]. Similar findings were observed in SKYLIGHT-2 (n = 501), where placebo-adjusted LS mean reductions at week 4 were −1.82 events/day for 30 mg and −2.55 events/day for 45 mg (both P < 0.001), with sustained efficacy through week 12 (LS mean differences −1.86 and −2.53 events/day, respectively) [30]. Improvements in VMS severity paralleled reductions in frequency at both time points, with consistently greater effects observed with the 45-mg dose.

Beyond vasomotor control, fezolinetant demonstrated additional clinically relevant benefits, particularly at the 45-mg dose. Improvements in sleep disturbance, assessed using the PROMIS Sleep Disturbance Short Form, reached statistical significance with fezolinetant 45 mg but not with the 30-mg dose in SKYLIGHT-2 [30]. Consistent with these findings, significant improvements in menopause-specific QoL, measured by the MENQOL total score, were observed by week 12 across the SKYLIGHT program with the 45-mg dose, whereas effects with 30 mg were more modest and less consistent. These benefits were maintained descriptively during the extension phase, supporting sustained symptomatic benefit beyond VMS reduction [30].

Across SKYLIGHT-1 and SKYLIGHT-2, fezolinetant was generally well tolerated. During the 12-week placebo-controlled period, treatment-emergent adverse events (TEAEs) occurred in approximately 36–43% of participants receiving fezolinetant and 32–45% receiving placebo. Most events were mild to moderate, with headache being the most frequently reported adverse event (approximately 3-7% with fezolinetant vs 2-4% with placebo). Discontinuations due to adverse events were uncommon (approximately 1-3% with fezolinetant) [29,30].

Hepatic safety signals were infrequent. Across both trials, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations ≥3 × the upper limit of normal (ULN) occurred in approximately 1-2% of participants receiving fezolinetant compared with <1% in placebo groups. Elevations ≥5 × ULN were rare (<0.5%), and no cases fulfilling Hy's law criteria were reported. Liver enzyme elevations were generally asymptomatic, transient, and reversible [29,30].

2.4.2. SKYLIGHT-4: long-term safety and tolerability of fezolinetant

SKYLIGHT-4 was a large, phase III, randomized, double-blind, placebo-controlled trial designed to assess the long-term safety and tolerability of fezolinetant over 52 weeks, with a particular focus on endometrial and hepatic safety [31]. A total of 1830 postmenopausal women with VMS were randomized to placebo, fezolinetant 30 mg, or fezolinetant 45 mg once daily.

Across treatment groups, TEAEs were common but predominantly mild to moderate and occurred at comparable overall frequencies (64.1% with placebo, 67.9% with 30 mg, and 63.9% with 45 mg). Discontinuations due to adverse events and serious TEAEs were infrequent and similar between groups. Endometrial safety criteria were met across all treatment arms, with endometrial hyperplasia or malignancy occurring in ≤0.5% of participants and no clinically meaningful changes in endometrial thickness. Bone mineral density and trabecular bone score remained stable and comparable to placebo over 52 weeks [31].

Hepatic safety findings in SKYLIGHT-4 were consistent with earlier trials. ALT or AST elevations ≥3 × ULN occurred in 1.0% of placebo-treated participants, 1.4% receiving fezolinetant 30 mg, and 2.0% receiving fezolinetant 45 mg. These events were generally asymptomatic and reversible, with no cases meeting Hy's law criteria, confirming the hepatic safety profile observed in earlier studies [31].

Taken together, the SKYLIGHT program established fezolinetant, particularly at the 45-mg dose, as an effective and generally well-tolerated non-hormonal pharmacologic option for the management of menopausal VMS, supported by robust efficacy data and comprehensive long-term safety evaluation.

Following regulatory approval, post-marketing reports of rare but severe drug-induced liver injury prompted enhanced hepatic monitoring recommendations in patients receiving fezolinetant. Current prescribing information advises baseline liver function testing prior to treatment initiation, followed by regular monitoring during the early phase of therapy, with treatment interruption or discontinuation in the event of clinically significant transaminase elevations [37].

2.4.3. Additional phase III studies in the postmenopausal women

The MOONLIGHT program (Table 2), conducted primarily in East Asian populations, included phase III studies evaluating fezolinetant 30 mg for both efficacy (MOONLIGHT-1) and long-term safety (MOONLIGHT-3). While MOONLIGHT-1 did not demonstrate statistically significant superiority over placebo likely due to lower dosing and a high placebo response, MOONLIGHT-3 provided supportive long-term safety data over 52 week [32,33]. Importantly, as in SKYLIGHT trials, these studies were not designed to include women with breast cancer.

Fezolinetant has also been evaluated in other phase III studies enrolling broader menopausal populations. The phase 3b DAYLIGHT trial (Table 2) assessed fezolinetant 45 mg in women with moderate-to-severe VMS considered unsuitable for MHT, including those with formal contraindications such as a history of breast cancer. Fezolinetant significantly reduced VMS frequency and severity and was associated with improvements in sleep disturbance and menopause-related QoL over 24 weeks. However, although women with a prior breast cancer diagnosis were eligible for inclusion, the proportion of such participants was not reported, limiting subgroup-specific interpretation of these findings [34].

2.4.4. Breast cancer specific trials (ongoing)

While fezolinetant has received regulatory approval for the treatment of moderate-to-severe VMS in postmenopausal women of the general population, dedicated phase III trials in women with breast cancer undergoing endocrine therapy are currently ongoing. These studies aim to provide direct evidence of efficacy and safety in a population characterized by iatrogenic estrogen deprivation.

No phase III fezolinetant trial has reported breast cancer-specific outcomes. SKYLIGHT and MOONLIGHT trials excluded women with a malignancy history, while DAYLIGHT permitted inclusion of women with prior breast cancer but did not report their number [[29], [30], [31], [32], [33], [34]]. However, emerging evidence from ongoing research is beginning to address this evidence gap (Table 3).

HIGHLIGHT (NCT06440967) is an ongoing phase III, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of fezolinetant for the treatment of moderate-to-severe VMS in women with hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy. Eligible participants are randomized in a 1:1 ratio to fezolinetant or placebo and followed over a 52-week treatment period, allowing assessment of both short-term efficacy and longer-term safety and tolerability [38].

The co-primary endpoints focus on changes in the frequency and severity of VMS at early time points (weeks 4 and 12), reflecting clinically meaningful symptom relief. Secondary endpoints include patient-reported outcomes related to sleep, QoL, and overall treatment tolerability.

Importantly, the study population is intended to reflect contemporary breast cancer care. Participants must be receiving stable adjuvant endocrine therapy (e.g., tamoxifen or aromatase inhibitors, with or without ovarian function suppression) prior to randomization and are required to continue the same regimen throughout the study. Concomitant adjuvant CDK4/6 inhibitors (such as abemaciclib or ribociclib) are permitted [38].

Complementing this pivotal program, the FLASH-Breast study (NCT06917313) is an ongoing phase II, randomized, placebo-controlled trial assessing fezolinetant 45 mg once daily over 12 weeks in women with early-stage hormone receptor-positive breast cancer receiving endocrine therapy. The study plans to enroll approximately 92 participants and uses daily symptom diaries to evaluate short-term changes in the frequency and severity of VMS, providing early proof-of-concept data in this oncology population.

The VENT study (NCT06617455) is a small, randomized, double-blind, placebo-controlled exploratory trial evaluating fezolinetant 45 mg once daily in women with early-stage hormone receptor-positive breast cancer experiencing moderate-to-severe VMS during adjuvant endocrine therapy. Similar to FLASH-Breast, VENT focuses on short-term changes in VMS frequency and severity over a 12-week treatment period, captured using daily symptom diaries, with secondary assessments of sleep disturbance and menopause-related QoL. Although limited in sample size, VENT provides additional supportive proof-of-concept evidence, complementing data generated by the FLASH-Breast and HIGHLIGHT programs.

Together, these studies represent a stepwise approach to establishing the efficacy and safety of fezolinetant for VMS management in women with breast cancer, progressing from early signal generation to confirmatory phase III evaluation and laying the groundwork for potential evidence-based use in this population. At present, regulatory approval of fezolinetant by both EMA and FDA is restricted to the general menopausal population, and its use in women with breast cancer remains off-label pending results from ongoing phase III trials.

3. Comparative perspective and practical oncology considerations

3.1. Key comparative insights

Elinzanetant and fezolinetant represent novel, non-hormonal pharmacologic strategies targeting neurokinin signaling within hypothalamic pathways implicated in VMS, as described above. Despite differences in receptor selectivity and metabolic profiles, both agents have demonstrated clinically meaningful, placebo-adjusted reductions in VMS frequency of approximately 2-3 episodes per day at 12 weeks, with rapid onset of action and sustained improvements in sleep and menopause-related QoL.

Whether dual NK1/NK3 receptor antagonism with elinzanetant provides incremental benefit over selective NK3 inhibition with fezolinetant remains uncertain. Dual blockade may offer advantages for sleep and affective symptoms through modulation of substance P–mediated NK1 signaling; however, direct comparative data are currently lacking.

Safety profiles further distinguish these agents. Across the OASIS program, elinzanetant has not demonstrated a signal of clinically meaningful hepatotoxicity. In contrast, fezolinetant carries an FDA boxed warning for rare but serious drug-induced liver injury, necessitating routine liver function monitoring. This distinction may be clinically relevant in patients with hepatic comorbidities or those receiving multiple concomitant therapies.

Importantly, elinzanetant currently holds a relative advantage in the oncology setting, supported by level 1 evidence from the breast cancer-dedicated phase III OASIS-4 trial in women receiving endocrine therapy [35]. By contrast, fezolinetant remains under investigation in this population, with ongoing phase III (HIGHLIGHT) and supportive phase II studies (e.g., FLASH-Breast) expected to further define its role.

3.2. Drug-drug interactions and special clinical populations

Management of VMS in women with breast cancer requires careful consideration of drug-drug interactions, as patients often receive complex multidrug regimens, including endocrine therapies, psychotropic agents, bone-modifying drugs, and CDK4/6 inhibitors.

Elinzanetant is primarily metabolized via CYP3A4 and acts as a substrate rather than an inhibitor or inducer. Exposure may therefore be affected by strong CYP3A4 inhibitors or inducers; concomitant use with potent inhibitors, including ribociclib, is not recommended [26]. No clinically meaningful interactions with tamoxifen have been reported, and co-administration is not expected to compromise tamoxifen efficacy, which is largely dependent on CYP2D6-mediated metabolism. Similarly, no relevant interactions with aromatase inhibitors are anticipated [39].

Fezolinetant is predominantly metabolized via CYP1A2 and is contraindicated with strong CYP1A2 inhibitors. Tamoxifen and aromatase inhibitors are unlikely to interact with fezolinetant; however, caution is warranted in patients receiving SSRIs or SNRIs, with fluvoxamine to be avoided and other agents used with clinical monitoring [37].

Clinical applicability also differs across patient subgroups. In OASIS-4, elinzanetant demonstrated consistent efficacy in women aged 18-70 years, including premenopausal patients receiving ovarian function suppression combined with tamoxifen or aromatase inhibitors [35]. In contrast, fezolinetant has been studied primarily in naturally postmenopausal women, with limited data in patients undergoing pharmacologic ovarian suppression.

Hepatic function represents an additional differentiating factor, consistent with the safety profiles described above. Elinzanetant has not shown clinically meaningful hepatotoxicity in completed trials, although data in patients with established hepatic impairment remain limited. Fezolinetant, by contrast, is contraindicated in severe hepatic impairment and requires caution and monitoring in moderate impairment due to its boxed warning [26,37].

Overall, optimal use of NK receptor antagonists in breast cancer care requires individualized assessment of menopausal status, hepatic function, and concomitant therapies. In contemporary oncology practice, where endocrine therapy is frequently combined with CDK4/6 inhibitors, agent selection and monitoring should be tailored to balance effective VMS control with overall treatment safety.

4. Pragmatic pathways for VMS management in breast cancer survivors

Management of VMS in women with breast cancer receiving endocrine therapy should follow an individualized, evidence-based, stepwise approach [3]. Key practical considerations for survivorship care are summarized in Table 4 and Fig. 2.

Table 4.

Integrating NK receptor antagonists into oncology survivorship care.

Domain	Key recommendations	Clinical notes
Assessment	Routinely assess VMS frequency, severity, and impact on quality of life during endocrine therapy visits	Use validated tools (e.g., MENQOL, PROMIS Sleep, EORTC-BR42)
Therapeutic positioning	Consider neurokinin receptor antagonists as a preferred non-hormonal option for moderate-to-severe VMS	Provide rapid and clinically meaningful symptom relief compared with traditional non-hormonal agents
Drug selection	Elinzanetant (preferred where available): supported by OASIS-4 trial; no routine laboratory monitoring. Fezolinetant (alternative): requires liver function monitoring; avoid in hepatic impairment or with strong CYP1A2 inhibitors	Selection should account for drug availability, comorbidities, and concomitant medications
Adherence support	Effective VMS control may improve adherence to tamoxifen or aromatase inhibitors	Emphasize the link between symptom management and long-term treatment persistence during patient counseling
Special populations	Applicable to premenopausal women receiving ovarian suppression (elinzanetant data available)	Breast cancer-specific data for fezolinetant are pending
Safety monitoring	Elinzanetant: no routine laboratory monitoring required. Fezolinetant: liver function tests at baseline and every 3 months during early treatment	Monitor for common adverse events such as headache, fatigue, or somnolence
Multidisciplinary care	Coordinate symptom management among oncology, gynecology, and primary care teams	Supports comprehensive survivorship care
Guideline relevance	Evidence supports consideration of neurokinin receptor antagonists in future survivorship and supportive care guidance	Clarification of sequencing, monitoring, and patient selection is needed

VMS, vasomotor symptoms.

Fig. 2.

Clinical algorithm for management of vasomotor symptoms in patients with breast cancer. Fezolinetant is not currently approved for use in breast cancer and is shown as a potential option only if regulatory approval is granted.

4.1. Step 1: lifestyle and behavioral interventions

Non-pharmacological strategies form the foundation of VMS management and should be offered to all patients. Behavioral and environmental measures such as maintaining a cool ambient temperature, wearing layered clothing, avoiding known triggers (e.g., alcohol, spicy foods), and using relaxation or paced-breathing techniques, may provide modest symptom relief with minimal risk. Cognitive-behavioral therapy adapted for VMS has demonstrated clinically meaningful reductions in symptom distress and improvements in QoL and may be considered as an adjunctive intervention [40]. Acupuncture has also been shown to provide modest but clinically meaningful reductions in VMS frequency and severity in some breast cancer populations [41].

4.2. Step 2: non-hormonal pharmacological therapy

In patients with persistent or clinically significant symptoms, non-hormonal pharmacologic therapy is recommended. NK receptor antagonists, including elinzanetant and fezolinetant, currently represent the most effective and best-tolerated pharmacologic options, providing rapid symptom relief without interfering with endocrine therapies. Where NK receptor antagonists are unavailable, alternative agents include venlafaxine, gabapentin, clonidine, or low-dose paroxetine [42]. Paroxetine, although approved for VMS, should be avoided in patients receiving tamoxifen because of CYP2D6 inhibition and potential reduction in endoxifen exposure [43].

4.3. Step 3: selection of NK receptor antagonists

When available, elinzanetant is the preferred option for women with hormone receptor-positive breast cancer receiving endocrine therapy, supported by phase III evidence from OASIS-4 demonstrating efficacy, safety, and compatibility with endocrine agents. It may be particularly suitable for patients requiring long-term symptom control or receiving complex concomitant therapies, and routine laboratory monitoring is not required [26].

Fezolinetant, approved for menopausal VMS in the general population, may be considered in selected situations when elinzanetant is unavailable or unsuitable. However, its use requires baseline and periodic liver function testing, and it should be avoided in patients with hepatic impairment or those receiving strong CYP1A2 inhibitors [37].

4.4. Step 4: monitoring and adherence support

For elinzanetant, clinical monitoring should focus on mild adverse effects such as somnolence or fatigue, without the need for routine laboratory testing. For fezolinetant, liver function tests should be performed regularly during therapy, with treatment discontinuation recommended for clinically significant transaminase elevations [37].

Effective management of VMS is essential to support adherence to adjuvant endocrine therapy, as uncontrolled symptoms are a leading cause of premature treatment discontinuation [44]. Early identification of symptoms and prompt intervention within survivorship care pathways can improve both QoL and long-term treatment persistence.

5. Clinical implications, knowledge gaps and future directions

The introduction of NK receptor antagonists represents a meaningful advance in the management of VMS in women with hormone receptor-positive breast cancer receiving adjuvant endocrine therapy. By targeting hypothalamic thermoregulatory dysregulation rather than hormonal pathways, these agents provide a non-estrogenic, mechanism-based approach to one of the most prevalent and burdensome treatment-related toxicities in this population. Importantly, effective VMS control extends beyond symptom relief, with potential implications for endocrine therapy adherence and treatment persistence.

From a clinical perspective, NK receptor antagonists offer a valuable alternative to traditional non-hormonal therapies such as SSRIs/SNRIs or gabapentin, which are often limited by modest efficacy, tolerability concerns, or drug-drug interactions. Supported by phase III evidence in breast cancer, elinzanetant currently represents the most advanced non-hormonal option for VMS management in this setting, whereas the clinical positioning of fezolinetant will depend on the results of ongoing breast cancer-specific studies.

Despite this progress, several key knowledge gaps remain. Longer-term follow-up from OASIS-4 and ongoing fezolinetant trials is needed to confirm durability of efficacy, late-onset safety, and oncologic neutrality, including any potential impact on breast cancer recurrence. While available phase III trials consistently demonstrate rapid and sustained efficacy over 12–52 weeks, longer-term real-world data will be essential to confirm the durability of benefit and long-term safety in breast cancer populations. Direct comparative studies between dual NK1/NK3 and selective NK3 antagonists are also required to determine whether dual blockade confers incremental benefit, particularly for sleep and mood-related symptoms. Mechanistic studies incorporating biomarker or neurophysiologic endpoints may further refine understanding of NK signaling in VMS.

Future research should assess whether improved VMS control with NK antagonists translates into better adherence to tamoxifen or aromatase inhibitors and whether this, in turn, influences disease outcomes. This question is especially relevant as CDK4/6 inhibitors become increasingly integrated into adjuvant therapy, where overlapping toxicities may further challenge adherence. Additional data are also needed in special populations, including premenopausal women receiving ovarian suppression, patients with hepatic impairment, and more diverse cohorts, to ensure broad applicability.

Overall, NK receptor antagonists represent a significant step forward in supportive care for women with breast cancer, with the potential to meaningfully improve symptom burden and quality of survivorship as their role within modern oncology practice continues to be defined.

6. Conclusions

NK receptor antagonists represent a substantial advance in the management of VMS in women with breast cancer receiving endocrine therapy. Elinzanetant, a dual NK1/NK3 antagonist, has demonstrated rapid and durable efficacy with a favorable tolerability profile in the phase III OASIS-4 trial, providing the first high-level evidence supporting NK pathway inhibition specifically in this population.

Fezolinetant, a selective NK3 antagonist approved for menopausal VMS in the general population, has shown comparable efficacy in non-oncologic settings; however, its role in breast cancer survivors remains under active investigation. The requirement for liver function monitoring and the signal for hepatotoxicity highlight the need for careful patient selection, particularly in women with hepatic comorbidities or complex polypharmacy, until breast cancer–specific data become available.

By offering non-hormonal, centrally acting, and rapidly effective symptom control, NK receptor antagonists address a critical unmet need in women with contraindications to estrogen-based therapies. As clinical evidence continues to evolve, these agents are likely to assume an important role in supportive oncology care, with the potential to improve QoL, support adherence to life-prolonging endocrine therapy, and strengthen survivorship outcomes in breast cancer.

CRediT authorship contribution statement

Katarzyna Pogoda: Writing – review & editing, Writing – original draft, Visualization, Methodology, Investigation, Data curation, Conceptualization. Luca Arecco: Writing – review & editing, Visualization, Methodology, Investigation, Data curation. Matteo Lambertini: Writing – review & editing, Methodology, Investigation, Data curation, Conceptualization.

Ethical approval

Not applicable.

Data sharing

This article synthesizes evidence from previously published sources. No new datasets were generated or analyzed. Further information is available from the corresponding author.

Funding

No funding was received for this project.

Declaration of competing interests

KP - honoraria for consultations/lectures/training/clinical trials and payment of conferences fees from AstraZeneca, Gilead, Roche, Novartis, Eli Lilly, Pfizer, MSD, Sandoz, Swixx, Bayer, Astellas, Exact Sciences, Menarini.

LA – Travel grant from AstraZeneca; research funding (to his institution) from Gilead and Pfizer.

ML – advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Gilead, MSD, Pierre Fabre, Menarini, Nordic Pharma, Bayer, Ipsen, Daiichi Sankyo; receiving speaker honoraria from Roche, Lilly, Novartis, Pfizer, AstraZeneca, Takeda, Ipsen, Sandoz, Libbs, Daiichi Sankyo, Gilead, Menarini; receiving travel grants from Gilead, Roche, Daiichi Sankyo; receiving research funding (to his institution) from Gilead; having other financial interests as JCO Consultant Editor, Chair of the ESO Certificate of Competence in Breast Cancer; nonfinancial interests as a member of the executive board of the Breast International Group (BIG), member of Board of the International Society for Fertility Preservation (ISFP) and member of the ASCO Annual Meeting Scientific Program Committee on the Breast Cancer – Local/Regional/Adjuvant Track.