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CHICAGO -- A widely available anticholinergic significantly improved hot flash symptoms in men taking androgen deprivation therapy (ADT) for their prostate cancer, a researcher reported here.

In a double-blind randomized trial of 81 men, twice-daily oxybutynin significantly reduced hot flash severity -- as measured by patient-reported hot flash scores -- as well as the frequency of the common and bothersome ADT side effect, according to findings presented by Brad Stish, MD, of the Mayo Clinic in Rochester, Minnesota, at the American Society of Clinical Oncology (ASCO) meeting here.

At baseline, patients had hot flash scores of approximately 18 points. At 6 weeks, twice-daily oxybutynin at doses of 5 mg and 2.5 mg led to average reductions of 13.95 and 9.94 points, respectively, as compared with a 4.85-point reduction with placebo (P=0.0019 and P=0.0732). Of note, a prespecified P value <0.1 was considered significant in the study.

And from averages of about 10 hot flashes per day at baseline, patients on the anticholinergic reported 6.89 and 4.77 fewer daily hot flashes at the lower and higher doses, respectively, as compared with 2.15 fewer with placebo (P<0.0001 and P=0.0236).

Furthermore, said Stish, oxybutynin was associated with improved patient quality of life and was well-tolerated.

"We think these results are very compelling and really believe that this demonstrates oxybutynin should be a reasonably considered clinical option for men who have bothersome hot flashes related to their androgen deprivation therapy," he said, adding that the anticholinergic is an attractive agent given that it's been around for decades, is widely available, and is very cost effective.

Hot flashes are the most predominant and commonly addressed problem in the clinic for men taking ADT for prostate cancer, said Stish in his introductory remarks. Used both in the non-metastatic and metastatic settings, ADT is given either temporarily, intermittently, or sometimes as a lifelong therapy in advanced disease.

Previous studies have shown that agents such as megestrol acetate, gabapentin, and venlafaxine can be effective for managing hot flash symptoms in men, but additional options are needed, he said.

Oxybutynin previously demonstrated effectiveness in a randomized placebo-controlled trial for reducing hot flash symptoms and frequency in women, but studies have shown discordant results for men and women treated with the same agents for hot flashes, according to Stish.

Commenting on the new findings, ASCO-designated discussant Clark DuMontier, MD, MPH, of Brigham and Women's Hospital in Boston, noted the apparent dose-response effect with the anticholinergic and said "the data are strong to consider oxybutynin for hot flashes in men on androgen deprivation therapy, especially if venlafaxine is ineffective."

However, DuMontier noted there was low power to detect toxicity in the trial given the small sample size and called for larger head-to-head trials of oxybutynin and venlafaxine that include older and frailer patients to better evaluate the safety and effectiveness of the two agents for this patient population.

Stish presented primary findings of the double-blind , which enrolled 88 men with frequent ADT-associated hot flashes (at least 28 per week) and randomized them 2:1 to 6 weeks of oxybutynin (2.5 mg or 5 mg twice daily) or matching placebo. Six patients withdrew before starting treatment and one was ineligible, leaving 81 for the primary analysis.

Stratification factors included hot flash frequency at baseline, duration of hot flashes, use of prior therapy for hot flashes, and planned radiation therapy during the study. Patients could be on abiraterone acetate (Zytiga) but not other newer androgen receptor pathway inhibitors -- enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) -- that are CYP3A4 metabolized and may affect oxybutynin serum concentrations.

Patients in the study had a median age of 68, with 30% on abiraterone and 80% having an Eastern Cooperative Oncology Group performance status of 0.

The primary endpoint was change in hot flash score, a validated patient-reported scoring system that multiplies the frequency of hot flashes by their severity on a 0 to 4 scale (0 = none; 1 = mild; 2 = moderate; 3 = severe; and 4 = very severe). Secondary endpoints included quality of life on the Hot Flash-Related Daily Interference Scale (HFRDIS; a 0 to 100 scale where lower scores indicate less interference with life) and safety.

The HFRDIS showed significant improvement with both doses of oxybutynin over placebo, with scores decreasing by about 21 points with the 5-mg dose, about 14 points with the 2.5-mg dose, and about 3 points with placebo (P=0.0012 and P=0.0419, respectively).

Grade ≥3 adverse events (AEs) occurred in 7% of patients on 2.5-mg oxybutynin, 4% of those on the 5-mg dose, and 8% of those on placebo (P=0.86). These included decreased lymphocyte count, urinary tract infection, and anemia in the oxybutynin recipients, and tachycardia and syncope in the placebo recipients, with none considered related to treatment.

Dry mouth was the most common oxybutynin-related grade 2 AE (9%), which was not surprising and typically transient, said Stish. The drug is used for bladder symptoms, and dry mouth is a commonly reported side effect.

Grade 2 events of urinary retention (4%), urinary frequency (2%), urinary tract infection (2%), gastroesophageal reflux disease (2%), and fatigue (2%) were also considered possibly or probably related to oxybutynin.

Oxybutynin was delivered in the study via a syrup with a concentration of 1 mg/mL, allowing for easy titrating of dose if tolerance issues emerged, said Stish, though twice-daily pills and long-acting forms are also available.

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