Proof-of-Concept Trial to Assess the Efficacy and Safety of Fezolinetant in Improving Vasomotor Symptoms in Men With Prostate Cancer Undergoing Androgen Deprivation Therapy

Proof-of-Concept Trial to Assess the Efficacy and Safety of Fezolinetant in Improving Vasomotor Symptoms in Men With Prostate Cancer Undergoing Androgen Deprivation Therapy (Fezo-ADT Trial)

The goal of this clinical trial is to learn if fezolinetant can treat hot flashes (vasomotor symptoms) in men with prostate cancer undergoing androgen deprivation therapy.

The main questions it aims to answer are:

• Does fezolinetant improve the frequency and severity of hot flashes?
• Does fezolinetant cause any harm to the liver?
• Does fezolinetant improve quality of life, sleep quality, fatigue, mood, sexual function, and metabolic parameters?

Researchers will compare how people respond to fezolinetant versus a placebo, which does not contain any active medicine.

Participants will:

• Take fezolinetant or a placebo every day for 4 weeks
• Visit the clinic once every 2 weeks for checkups and tests
• Keep a diary of the number of times and intensity that they experience hot flashes

Prostate cancer is the most common type of cancer in men. At the time of initial diagnosis, most men have disease that is confined to the prostate and are typically managed through surveillance or local treatments, such as prostatectomy or radiation therapy. Since the prostate relies on androgens (male hormones), androgen deprivation therapy is the primary treatment for patients with locally advanced, recurrent, or metastatic prostate cancer.

Androgen deprivation therapy involves suppressing the production of androgens in men, which can be achieved through orchiectomy (removal of the testes) or medications like gonadotropin-releasing hormone agonists or antagonists that lower serum testosterone levels to a castrate range (less than 20 ng/dL). In men, 95% of serum estrogen comes from the aromatization of testosterone. Consequently, androgen deprivation not only leads to androgen deficiency but also results in near-absolute estrogen deficiency. The absence of sex hormones in these patients can cause numerous adverse effects, including sexual dysfunction, and loss of muscle and bone. Among these side effects, vasomotor symptoms (such as hot flashes) are particularly debilitating. These symptoms are characterized by sudden feelings of intense heat that spread throughout the body, prompting the activation of heat-dissipation mechanisms to lower body temperature.

Hot flashes are reported by 70-80% of men undergoing androgen deprivation therapy, typically beginning a few weeks after treatment starts, with most men experiencing more than five episodes daily. These vasomotor symptoms significantly affect the patient's quality of life, sleep quality, concentration, and overall productivity. Despite the burden they impose, effective treatments for hot flashes in men undergoing androgen deprivation therapy are still lacking.

The introduction of neurokinin 3 (NK3) receptor antagonists has brought hope to this area. Fezolinetant is a selective NK3 receptor antagonist that has recently been approved for treating moderate to severe vasomotor symptoms in menopausal women. Given that the underlying cause of vasomotor symptoms in both menopausal women and men on androgen deprivation therapy stems from estrogen deficiency, fezolinetant offers an opportunity to assess its efficacy and safety for male patients.

No previous studies have evaluated the effectiveness of NK3 receptor antagonists on vasomotor symptoms in men undergoing androgen deprivation therapy for prostate cancer. Since prostate cancer is the most prevalent solid tumor in men and vasomotor symptoms are common, distressing, and highly burdensome, a trial demonstrating the safety and efficacy of fezolinetant could provide clinicians and patients with a novel, effective, safe, and easy-to-administer treatment that has the potential to transform care for these patients.

Inclusion Criteria:

• Male sex
• Age 40 years and older
• Diagnosis of prostate cancer
• Androgen deprivation therapy
• Presence of 5 or more moderate-to-severe hot flashes per day or 35 or more moderate-to-severe hot flashes per week
• Ability to sign the inform consent
• Willing to use reliable methods of contraception if partner is of childbearing age
• Ability to record hot flashes electronically

Exclusion Criteria:

• Use of abiraterone acetate
• Use of docetaxel and other chemotherapeutic agents
• Liver cirrhosis
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above the upper limit of normal
• Total bilirubin above the upper limit of normal
• Glomerular filtration rate < 30 mL/min
• Use of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, sedatives, or hypnotics if prescribed for the treatment of hot flashes
• Use of over-the-counter hormonal agents or herbal compounds
• Current use of CYP1A2 inhibitors
• Ingestion of alcohol within 2 weeks prior to the baseline visit
• Inability to abstain from alcohol use during the study period.