Ulipristal versus Leuprolide for Management of Uterine Fibroids

Daily oral ulipristal acetate is noninferior to once-monthly injections of leuprolide acetate in reducing bleeding associated with uterine fibroids, according to a study published in the New England Journal of Medicine [2012;366(5):421-432]. A total of 281 patients were randomized to receive oral ulipristal 5 mg once daily, ulipristal 10 mg once daily, or once-monthly leuprolide injections over a period of 13 weeks. Investigators enrolled premenopausal women 18 to 50 years of age planning surgery to address symptomatic uterine fibroids. All enrollees were experiencing heavy uterine bleeding due to fibroids, and the primary end point of the trial was the proportion of patients with control of uterine bleeding at week 13, prior to planned surgical treatment of fibroids. After 13 weeks of treatment, the proportion of patients with controlled bleeding (a pictorial blood-loss assessment chart [PBAC] score of <75 for the preceding 4 weeks) was 90%, 98%, and 89% with ulipristal 5 mg, ulipristal 10 mg, and leuprolide, respectively. Authors noted an improvement of 1.2% with ulipristal 5 mg versus leuprolide injection, and an improvement of 8.8% with 10 mg ulipristal versus leuprolide injection. These findings met prespecified noninferiority criteria for both doses of ulipristal compared with leuprolide. In addition, ulipristal 10 mg was found to be statistically superior to leuprolide in the control of bleeding. Reductions in bleeding were associated with improvements in hemoglobin and hematocrit in all treatment groups. All treatments reduced the volume of the 3 largest fibroids in enrolled patients. However, leuprolide resulted in a significantly greater 53% reduction in fibroid volume, compared with reductions of 36% with ulipristal 5 mg and 42% with ulipristal 10 mg. Although all treatment groups achieved a mean PBAC score of 0 by 13 weeks, excessive bleeding was controlled at a significantly more rapid rate with either dose of ulipristal, when compared with leuprolide injection. Amenorrhea was also achieved more rapidly with ulipristal 10 mg versus leuprolide injection. Median times to amenorrhea were 7 days with ulipristal 5 mg, 5 days with ulipristal 10 mg, and 21 days with leuprolide injection. Approximately half of enrolled patients underwent surgery at the end of the 13-week treatment. There were no significant differences between treatment groups in the rates of adverse events reporting or treatment discontinuation due to adverse events. Other secondary safety end points were evaluated during the trial, including hematologic parameters, bone turnover markers, and other laboratory assessments. While most of these did not differ remarkably between treatment groups, median levels of 1 bone turnover marker, type I collagen C-telopeptide, were significantly higher in the leuprolide treatment group compared with the ulipristal treatment groups at 13 weeks. Mean endometrial thickness at week 13 was 9.4 mm, 10.7 mm, and 5.1 mm with ulipristal 5 mg, ulipristal 10 mg, and leuprolide injection, respectively. Endometrial biopsy noted no histologic changes of clinical concern in any treatment group. In patients who did not undergo surgery, existing fibroids began to enlarge approximately 1 month after the last leuprolide injection, while fibroid volume reduction was maintained for 6 months after the end of treatment in the majority of patients randomized to ulipristal 5 mg or 10 mg. The authors noted several study limitations. For instance, the study was not designed to assess surgical outcomes, and uterine and fibroid volumes were not confirmed by a central reading. They also noted that treatment only continued for 13 weeks, and longer trials may be needed to fully assess the possible benefits and risk of ulipristal therapy.