SAN ANTONIO—Breast cancer survivors may have a new therapeutic option to manage hot flashes, according to data from a randomized, double-blind, placebo-controlled, phase III clinical trial (NCT02961790) presented at the 2018 San Antonio Breast Cancer Symposium (Abstract GS6-02). The trial showed that patients ineligible for hormone replacement therapy, such as breast cancer survivors, had a larger reduction in hot flash frequency and severity while taking oxybutynin compared with those who received placebo. Oxybutynin is an anticholinergic agent approved by the FDA for the treatment of overactive bladder.
“Hot flashes are a very common problem for breast cancer survivors that can significantly impact quality of life,” Amy Tiersten MD, Clinical Director, Breast Medical Oncology, The Mount Sinai Hospital, told Oncology Times. “Anti-estrogen approaches to treatment frequently further lower the estrogen levels of postmenopausal women and can even cause very young, pre-menopausal women to have very low estrogen levels. It is always refreshing to see research being done to help this serious issue.”
The trial, which was conducted by the group Academic and Community Cancer Research United, enrolled women who had hot flashes at least 28 times per week and for more than 30 days. Eligible patients had a history of breast cancer, ductal breast carcinoma in situ, lobular carcinoma in situ, or a concern about taking hormone replacement therapy for fear of breast cancer. Patients taking tamoxifen, aromatase inhibitors, antidepressants, gabapentin, or pregabalin were allowed on the study. Patients taking potent anticholinergics were not.
Participants were randomized to receive oxybutynin 2.5 mg twice daily, oxybutynin 5.0 mg twice daily, or placebo for 6 weeks. Participants completed three questionnaires at baseline and monthly: hot flash diary, hot flash related daily interference scale (HFRDIS), and a symptom experience questionnaire. The primary endpoint was intra-patient change in weekly hot flash score and frequency. The secondary endpoints were change in HFRDIS and change in self-reported symptoms.
A total of 150 patients were accrued to the study and approximately 50 were randomized to each treatment arm. Fourteen participants withdrew from the study and 23 had no baseline data available, leaving 40 evaluable patients in the oxybutynin 2.5 mg arm, 35 in the oxybutynin 5.0 mg arm, and 38 in the placebo arm.
Participant characteristics at baseline were well-balanced among treatment arms. Most participants had experienced hot flashes for more than 9 months, and two-thirds of participants were also taking tamoxifen or an aromatase inhibitor.
Both arms that received oxybutynin for 6 weeks had a statistically significant reduction in hot flash score and frequency compared to placebo (both p<.01). Participants on the low-dose oxybutynin arm had a mean drop in hot flash score of 10 compared with a 5.1 drop for the placebo arm (p=0.003). The mean change in average weekly number of hot flashes decreased by 4.6 for participants on the low-dose oxybutynin arm compared with a decrease of 2.3 for participants on the placebo arm (p=0.002).
Participants on the high-dose oxybutynin arm had a larger benefit than those on the low-dose arm, with a mean reduction in hot flash score of 16.2 compared with a 5.1 reduction for participants on the placebo arm (p<0.001) and a mean reduction in average weekly number of hot flashes of 7.0 compared with a 2.3 reduction for participants on the placebo arm (p<0.001).
According to the HFRDIS, sleep, overall quality of life, leisure, work, social, and relations were statistically improved for participants who received low- or high-dose oxybutynin compared to placebo (p<.05). Concentration and sexuality, however, were not improved at either dose of oxybutynin. Mood and life enjoyment were improved at the higher dose of oxybutynin, but not the lower dose.
Participants who received either dose of oxybutynin reported dry mouth, abdominal pain, and difficulty urinating. Participants who received the higher dose also reported dry eyes, episodes of confusions, diarrhea, and headaches.
Hot Flash Improvements
“Oxybutynin significantly improves hot flash frequency and severity and, more importantly, it's associated with a positive impact in several quality-of-life metrics,” concluded the study's lead author, Roberto Leon-Ferre, MD, Assistant Professor of Oncology at the Mayo Clinic in Rochester, Minn. “While the two oxybutynin doses were not formally compared in our study, as we were not powered to detect those differences, the patients on 5 mg twice daily experienced more reduction in hot flashes and improvement in more domains of the quality of life.”
He described the side effects associated with oxybutynin as “acceptable.” Tiersten echoed a similar view, saying that the side effects reported in the trial were “extremely mild.”
“It is very exciting to have another drug in our armamentarium to treat hot flashes,” Tiersten said. She did not express concern about the short study duration of 6 weeks. “It is not uncommon for these sorts of interventional studies to only study the intervention for a short period of time in order to get an answer about efficacy, but there is no reason to not extrapolate to longer durations of use.”
The Mayo Clinic has been involved with several phase III randomized clinical trials to assess various agents for hot flashes. To put the current trial in perspective, Leon-Ferre showed a slide of the effect of various agents on hot flashes. The agents included oxybutynin, clonidine, fluoxetine, citalopram, venlafaxine, and pregabalin. He cautioned that these were not head-to-head comparisons, but nonetheless said that high dose of oxybutynin was “arguably” one of the more potent agents.
“Although there was not a direct comparison to other drugs that we use for hot flashes, it appeared that the oxybutynin's effect was possibly greater than others with fewer side effects overall,” Tiersten said. “I started my first patient on it yesterday at the 2.5 mg dose. If it doesn't help her at this dose, there is room to titrate up.”
Christina Bennett is a contributing writer.