Alliance A222001 Phase 2 Trial: Oxybutynin Looks Promising for Hot Flashes in Men Under ADT

The Alliance A222001 study, published in the Journal of Clinical Oncology in January 2026, found that oxybutynin, a drug typically used to treat overactive bladder, significantly reduces hot flashes in men receiving androgen-deprivation therapy (ADT), with improvements occurring within the first week of treatment and sustained throughout the study period.

The findings could reshape how oncologists manage a side effect that affects up to 80 percent of men undergoing ADT and frequently drives patients to abandon otherwise life-saving cancer treatment. For decades, hot flashes in prostate cancer patients have received far less attention than their counterparts in breast cancer or menopausal women, despite causing comparable disruption to sleep, cognition, and quality of life.

The rationale for investigating oxybutynin stems from the mechanism of ADT itself. Androgen-deprivation therapy works by lowering testosterone to starve prostate cancer cells. However, this sudden hormonal shift disrupts the body’s thermoregulatory centers in the hypothalamus, triggering uncontrolled episodes of profuse sweating, flushing, and heat sensation. Existing treatments, venlafaxine (an antidepressant), gabapentin (an anticonvulsant), megestrol acetate (a progesterone analog), and medroxyprogesterone acetate, offer variable relief and carry their own side effects or tolerability concerns. Oxybutynin, an anticholinergic medication, had shown promise in women with breast cancer-related hot flashes but had never been rigorously tested in men with prostate cancer until now.

The trial was a multi-center effort spanning 15 academic and community cancer centers across the United States, including Mayo Clinic, Georgetown-Lombardi Comprehensive Cancer Center, Yale University, Ohio State University, Sidney Kimmel Cancer Center, and others. Researchers enrolled 88 men with prostate cancer experiencing at least 28 hot flashes per week (Note: actual average roughly 10 per day) who were on stable ADT regimens. Eighty-one patients met eligibility criteria for final analysis, with a median age of 68.5 years. Participants were randomly assigned to receive either oxybutynin at 2.5 mg twice daily, oxybutynin at 5 mg twice daily, or matching placebo for six weeks.

The results were striking. Men receiving placebo experienced an average reduction of 2.15 hot flashes per day and a 4.85-point drop in daily hot flash severity scores. Those taking 2.5 mg of oxybutynin twice daily reported reductions of 4.77 hot flashes per day and a 9.94-point decrease in severity. But the most impressive results came from the 5 mg twice-daily dose: 6.89 fewer hot flashes per day and a 13.95-point reduction in severity. Stated differently, the high-dose oxybutynin group achieved approximately a 68 percent reduction in daily hot flashes compared to the placebo group’s 21 percent reduction.

In the 5 mg group, 79 percent of patients experienced at least a 50 percent reduction in hot flash scores. These improvements occurred remarkably quickly, often becoming apparent during the first week of treatment, and remained sustained throughout the six-week study period.

Beyond raw hot flash counts, the trial measured impacts on quality of life using the Hot Flash-Related Daily Interference Scale, which assesses how hot flashes disrupt mood, sleep, work, social activities, and overall well-being. The 2.5 mg dose improved these scores by 14.2 points (compared to a 3.1-point improvement with placebo), while the 5 mg dose improved scores by 20.7 points. These gains translate to tangible improvements in sleep quality, daytime functioning, and psychological well-being—the real-world benefits that matter most to patients struggling with symptoms.

What makes these results particularly compelling is the safety profile. The trial reported no treatment-related Grade 3 or higher adverse events in any group. Serious adverse events occurred in less than 8 percent of patients overall, with no difference between oxybutynin and placebo groups. Dry mouth was the most commonly reported side effect, typically mild and transient. A small number of patients reported urinary retention, urinary frequency, or fatigue, but these were rare and did not lead to treatment discontinuation in the trial population.

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