Linzagolix with and without hormonal add-back therapy for symptomatic uterine fibroids: PRIMROSE 1 & 2 long-term extension and withdrawal study.

Abstract

OBJECTIVES To evaluate 1) whether oral linzagolix administered once daily for up to 52 weeks (extension study) at a dose of 100 mg or 200 mg with or without hormonal add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethisterone acetate) can maintain the efficacy and tolerability seen at 6 months of therapy, and 2) whether there is any recurrence of symptoms (bleeding and pain) after cessation of therapy (withdrawal study). STUDY DESIGN PRIMROSE 1 and PRIMROSE 2 were essentially identical, randomized, parallel, double-blind, placebo-controlled phase 3 trials conducted in women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss of more than 80 ml per cycle over 2 menstrual cycles). Eligible women with uterine fibroid-associated heavy menstrual bleeding were randomly assigned at a 1:1:1:1:1 ratio to one of five masked daily treatments: (1)placebo, (2)100 mg linzagolix alone, (3)100 mg linzagolix with hormonal ABT (1 mg estradiol and 0.5 mg norethisterone acetate), (4) 200 mg linzagolix alone (with ABT after 24 weeks), or (5) 200 mg linzagolix with hormonal ABT (1 mg estradiol and 0.5 mg norethisterone acetate). After 24 weeks, patients assigned to the placebo or 200 mg linzagolix alone groups were switched to 200 mg linzagolix with ABT, except in PRIMROSE 1, where 50% of subjects on a placebo continued with the placebo (random selection) until week 52. All other women continued on the original study medication. Efficacy and safety were evaluated at week 52 (extension study) as well as week 64 (withdrawal study). Bone mineral density was also assessed at week 76 (6 months after cessation of therapy). SETTING A total of 94 clinical sites in the USA (PRIMROSE 1) and 95 in Europe and the USA (PRIMROSE 2). PARTICIPANTS In PRIMROSE 1 and 2, 1,012 women were included in the full analysis set. Eligible subjects were women aged 18 years or older with ultrasound-confirmed fibroids and heavy menstrual bleeding of at least 80 ml blood loss per cycle for a minimum of two cycles, as determined by the alkaline haematin method. Eligible participants had to have at least one fibroid measuring 2 cm in diameter or more (or multiple small fibroids with overall uterine volume exceeding 200 cm3), but no fibroids greater than 12 cm in diameter. MAIN OUTCOMES MEASURES The primary endpoint was decreased menstrual blood loss to less than 80 ml and a reduction of more than 50% from baseline. Specifically, this study sought to determine whether the reduction in menstrual blood loss and other secondary outcomes, such as uterine volume and pain, observed at 24 weeks could be maintained over an extended (52 weeks) treatment period and further withdrawal period. MAIN RESULTS In the pooled data from PRIMROSE 1 and PRIMROSE 2 extension studies, the significantly higher proportion of women showing a reduction in heavy menstrual bleeding in all linzagolix (with or without ABT) treatment groups observed at week 24, was maintained until week 52. Percentages of women with reduced menstrual blood loss at week 52 (based on the pooled week 52 full analysis set) were 55.0% in the 100 mg group, 86.1% in the 100 mg with ABT group, 76.7% in the 200 mg group/200 mg with ABT, and 89.9% in the 200 mg with ABT group. Of subjects previously treated with linzagolix and in amenorrhoea by week 52, 88.8% reported their first bleed or heavy bleeding between weeks 52 and 64. In both PRIMROSE studies, the most common adverse events up to week 52 were hot flushes. Their incidence had returned to baseline values by week 64. Bone mineral density was well preserved in all groups at week 52. In women treated with 200 mg linzagolix alone up to week 24, initial BMD loss (lumbar spine) recovered by week 52 after adding ABT from week 24 onwards. CONCLUSIONS Findings at 52 weeks confirmed the benefits of treatment observed at 24 weeks. At 52 weeks, linzagolix (100 mg or 200 mg) with or without ABT was found to reduce heavy menstrual bleeding, which is a burden for women with uterine fibroids. Their quality of life was improved. Risks of bone loss and vasomotor symptoms were minimized as a result of ABT administration. Partial suppression with once daily linzagolix (100 mg) without ABT potentially provides a unique option for chronic treatment of symptomatic uterine fibroids in women who do not wish to have ABT or in whom it is contraindicated. The relatively fast recurrence of uterine fibroid-associated symptoms after cessation of therapy is an argument in favour of long-term continuation of treatment.