From a physiological point of view, ADT induces a state of iatrogenic menopause. For men with high‑risk localised or metastatic disease, long‑term castration, increasingly combined with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, enzalutamide, darolutamide, or apalutamide, is a cornerstone of modern systemic treatment strategies.2 This approach has significantly improved survival, but its cost in terms of side effects is substantial. The toxicities of prolonged androgen suppression are well documented: sexual dysfunction, sarcopenia, weight gain, metabolic syndrome, osteoporosis, and increased cardiovascular risk, along with mood changes and cognitive complaints.5,6 Among these, hot flushes are often the most visible and intrusive daily symptom – yet paradoxically they remain one of the least systematically addressed.
Several older studies make clear that vasomotor symptoms are both common and long‑lasting in this setting. Hot flushes were frequent during and after neoadjuvant hormonal therapy for localised prostate cancer, and are reported as a long‑term side effect of orchiectomy. Hot flushes often persist for many years after surgical or medical castration, with a substantial proportion of men still symptomatic 5–8 years after starting ADT.7 Men describe stereotypical attacks of sudden heat, flushing, and sweating, occurring multiple times a day and night, often accompanied by palpitations, anxiety, and sleep disruption. In systematic reviews, a large proportion of men report moderate to severe distress due to vasomotor symptoms, with significant impact on quality of life and, in some cases, on willingness to continue therapy.7,8,9
Despite this, hot flushes in men are still often trivialised. The clinic visit is dominated by prostate‑specific antigen trends, imaging reports and decisions on treatment intensification or sequencing. Vasomotor symptoms may not even appear in the clinical notes. Yet from a mechanistic standpoint, there is nothing benign about what these men are experiencing. The same hypothalamic KNDy (kisspeptin–neurokinin B–dynorphin) neurons and narrowed thermoneutral zone that drive hot flushes in menopausal women are perturbed in men who have undergone castration.
What has (and has not) worked so far in men
Historically, management of hot flushes in men on ADT has been empirical and off‑label. Estrogens and progestogens can be effective in reducing flushes but carry their own safety concerns, particularly thromboembolic and cardiovascular risks, as well as gynecomastia and breast tenderness. Behavioural interventions and complementary approaches have shown mixed and often modest benefits.10
Non‑hormonal pharmacologic strategies such as gabapentin, venlafaxine, and clonidine have all been studied in small trials or extrapolated from the breast cancer and menopausal literature, with variable results and frequent side effects like dizziness, somnolence, or hypotension.10 The N00CB trial, a randomised, double‑blind, placebo‑controlled phase III study of gabapentin in men with hot flushes, demonstrated some benefit but also highlighted tolerability issues, including dizziness and fatigue, that limit long‑term use.11
Systematic reviews have concluded that although several interventions may help, there is no “gold standard” therapy for hot flushes in men under prostate cancer treatment.12 In parallel, our understanding of the neurobiology of hot flushes – especially the central role of NK3 receptors on KNDy neurons – has advanced mainly in the context of female menopause.
Fezolinetant: proof of concept that NK3 antagonism works
Fezolinetant, a selective NK3 receptor antagonist, was the first drug from this mechanistic class to move convincingly from hypothesis to clinical reality in women. Drawing on foundational work on thermoregulatory circuits in the hypothalamus, fezolinetant was developed to directly target KNDy neurons rather than to replace estrogen.13
Large randomised, placebo‑controlled phase III trials in postmenopausal women with bothersome vasomotor symptoms demonstrated that fezolinetant significantly reduced both the frequency and severity of moderate to severe hot flushes within days to weeks, with improvements maintained over time.13 The magnitude of effect was clinically meaningful, often exceeding a 50% reduction in daily episodes, and crucially was accompanied by improvements in sleep and quality of life. Safety data from these and earlier‑phase trials showed a favourable profile, with most adverse events being mild to moderate and manageable, and without the classical estrogen‑related safety concerns.
Meta‑analyses pooling data from trials of NK3 antagonists have confirmed the class effect on vasomotor symptoms is robust, rapid in onset, and supported by very low p‑values for key efficacy endpoints.13
Elinzanetant: dual NK1/NK3 antagonism and potential added value
Elinzanetant builds on this foundation but introduces an important twist. It is a dual NK1 and NK3 receptor antagonist, designed to modulate not only the KNDy pathway but also substance P–mediated signalling through NK1 receptors, which are involved in nausea, mood regulation, and aspects of pain and stress responses.14,15 The rationale is that blocking both NK1 and NK3 may have additive or synergistic effects on vasomotor symptoms and possibly on associated sleep, mood, and sleep disturbances.
In women with vasomotor symptoms, the SWITCH‑1 trial demonstrated substantial reductions in the frequency and severity of hot flushes, and an emerging signal of benefit on sleep and quality of life.16
The pivotal phase III OASIS 1 and 2 trials in menopausal women with moderate to severe vasomotor symptoms confirmed and extended these observations.17 Compared with placebo, elinzanetant produced rapid and durable reductions in both the frequency and severity of hot flushes, with statistically highly significant results and effect sizes that are immediately clinically interpretable for patients. Improvements were also seen in sleep disturbance and menopause‑related quality‑of‑life scales. The drug was generally well tolerated, with a safety profile consistent with prior studies and no emergence of unexpected safety concerns.
OASIS 4 specifically evaluated elinzanetant in women receiving endocrine therapy for breast cancer, a population in which hot flushes are not only common but often severe and long‑lasting. Again, elinzanetant produced rapid and clinically meaningful reductions in vasomotor symptoms, alongside improvements in sleep and functioning, with a favourable safety profile in the context of concomitant cancer therapy. The fact that these benefits were observed in women with treatment‑induced menopause is particularly important when considering extrapolation to men on ADT.
Systematic reviews and meta‑analyses that include both fezolinetant and elinzanetant now provide an overview of this emerging class.18,19 Across thousands of women and multiple trials, NK antagonists consistently show large effect sizes on hot flush frequency and severity, rapid onset of action, modulation of sleep and quality of life, and an overall benign safety profile. For elinzanetant specifically, the dual NK1/NK3 mechanism raises the possibility of additional benefit on sleep quality, mood and global well‑being, dimensions that are highly relevant to men living for years with advanced prostate cancer.
Why a men‑specific trial is still needed – and why it does not need to be huge
Despite the compelling data in women, including those with treatment‑induced menopause, we believe that a dedicated trial in men on ADT is ethically and scientifically necessary. The biology strongly overlaps but is not guaranteed to be identical; men differ in baseline comorbidities, concomitant medications, and patterns of cardiovascular and metabolic risk. A rigorously designed trial is the most reliable way to assess whether the magnitude, speed and durability of effect seen in women can be reproduced in men, and to carefully characterise the safety profile in this specific population.
At the same time, the strength of the signal in women has important implications for trial design in men. In OASIS 1 and 2, and in the breast cancer endocrine therapy trial, the p‑values for primary vasomotor endpoints were extremely low, reflecting large treatment effects and relatively modest variability. Meta‑analytic data confirm substantial and consistent reductions in hot flush frequency, often of the order of several episodes per day, and improvements that appear within one to two weeks.18,19
When we used these data to inform sample size calculations for a phase III trial in men on ADT with a one‑sided alpha of 2.5% and 80% power, approximately 100 men were required to detect the difference at the primary timepoints. An optimal trial could consist of a 54‑week, double‑blind, randomised, placebo‑controlled crossover design, followed by an open‑label NK3 inhibitor extension.
Overall, the design should be intentionally pragmatic. It aims to generate clear, clinically interpretable evidence with a relatively small but well‑characterised cohort, leveraging what we have learned from the menopausal and breast cancer settings.
From inequality to opportunity
The central argument of our European Urology editorial was that the current situation – in which women have access to modern, non‑hormonal, mechanistically targeted therapies for hot flushes, while men on ADT do not – represents a form of therapeutic inequality.1 The science underpinning vasomotor symptoms does not stop at the gender divide, and neither should our therapeutic ambition.
Fezolinetant has provided definitive proof that NK3 antagonism can transform the management of hot flushes in women. Elinzanetant, by targeting both NK3 and NK1, offers the possibility of not only matching that benefit but potentially extending it, particularly concerning sleep and global quality of life. Both drugs have reassuring safety and tolerability profiles in large, well‑conducted trials, including in women with treatment‑induced menopause due to endocrine therapy for breast cancer.
In light of these data, maintaining a situation in which men on ADT are expected to rely primarily on older, off‑label, and often poorly tolerated options is increasingly difficult to defend. A focused, efficient phase III trial of elinzanetant in men on ADT is therefore not only scientifically justified but ethically necessary.
As we move into a post‑Movember period, publishing an editorial on this topic in December underscores that attention to the quality of life of men with prostate cancer is not confined to campaigns and awareness months. Hot flushes are not a cosmetic or secondary issue; they are a major driver of distress, insomnia, impaired functioning, and, in some cases, compromised adherence to potentially life‑prolonging therapy.
I would like to thank UroToday for the opportunity to discuss such a delicate and often overlooked topic in more depth, and I am particularly grateful to my mentor, Silke Gillessen, and to my editorial co‑authors, Erik Briers, Pierre Blanchard, Anthony M. Joshua, and Bertrand Tombal – who, from their respective institutions (Istituto Oncologico della Svizzera Italiana, Europa Uomo, Gustave‑Roussy, the Kinghorn Cancer Centre/UNSW, and Cliniques Universitaires Saint‑Luc), have consistently and convincingly advocated for, and helped to implement, programmes and clinical trials that deliver truly clinically meaningful benefits for men living with prostate cancer.
Written by: Martino Pedrani, Istituto Oncologico della Svizzera Italiana, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
References:
- Pedrani M, Gillessen S, Briers E, Blanchard P, Joshua AM, Tombal B. Beyond Menopause: Ending the Inequality—Why Men with Prostate Cancer Still Lack Therapies for Hot Flushes. Eur Urol. 2025 Dec 1. doi:10.1016/j.eururo.2025.12.004.
- Gillessen S, Turco F, Davis ID, Efstathiou JA, Fizazi K, James ND, et al. Management of Patients with Advanced Prostate Cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC). Eur Urol. 2025;87:157–216.
- Nguyen PL, Alibhai SM, Basaria S, D'Amico AV, Kantoff PW, Keating NL, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol. 2015;67:825–36.
- Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Smith MR. Estrogenic side effects of androgen deprivation therapy. Rev Urol. 2007;9:163–80.
- Guttuso T, Jr., DiGrazio WJ, Reddy SY. Review of hot flash diaries. Maturitas. 2012;71:213–6.
- Schow DA, Renfer LG, Rozanski TA, Thompson IM. Prevalence of hot flushes during and after neoadjuvant hormonal therapy for localized prostate cancer. South Med J. 1998;91:855–7.
- Charig CR, Rundle JS. Flushing. Long-term side effect of orchiectomy in treatment of prostatic carcinoma. Urology. 1989;33:175–8.
- Freedman RR. Hot flashes: behavioral treatments, mechanisms, and relation to sleep. Am J Med. 2005;118 Suppl 12B:124–30.
- Karling P, Hammar M, Varenhorst E. Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. J Urol. 1994;152:1170–3.
- Hutton B, Hersi M, Cheng W, Pratt M, Barbeau P, Mazzarello S, et al. Comparing Interventions for Management of Hot Flashes in Patients With Breast and Prostate Cancer: A Systematic Review With Meta-Analyses. Oncol Nurs Forum. 2020;47:E86–E106.
- Loprinzi CL, Dueck AC, Khoyratty BS, Barton DL, Jafar S, Rowland KM, Jr., et al. A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB). Ann Oncol. 2009;20:542–9.
- Frisk J. Managing hot flushes in men after prostate cancer—A systematic review. Maturitas. 2010;65:15–22.
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