Endometrial safety of ospemifene: results of the phase 2/3 clinical development program

Ospemifene, an estrogen receptor agonist/antagonist with tissue-selective effects that is sometimes referred to as a selective estrogen receptor modulator (SERM), was recently approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause.1 Although SERMs lack the steroidal structure of estrogens, certain SERMs have been reported to elicit tissue-specific responses, such as positive effects on the vaginal epithelium, prevention of breast cancer, and treatment and prevention of osteoporosis with an acceptable benefit/risk profile.2 However, SERMs have been reported to have a spectrum of effects on the endometrium. Tamoxifen, a first-generation SERM, increases the risk of endometrial cancer; this finding is not associated with raloxifene, a second-generation SERM.3,4 Clinical development of other SERMs, such as levormeloxifene and idoxifene, was discontinued because of unacceptable safety profiles, where adverse effects on gynecologic tissues and elsewhere outweighed the benefits. Thus, gynecologic evaluation of a SERM is an essential component for establishing its overall benefit/risk profile in postmenopausal women.5 Ospemifene has been shown in preclinical and clinical studies to exert positive effects on the vaginal epithelium and minimal effects on the endometrium.6-8 The only other approved prescription medications for the treatment of VVA include systemic estrogens, estrogen plus progestogen, and local vaginal estrogens.1 The endometrial effects of unopposed systemic estrogens have long been known.9 The Postmenopausal Estrogen/Progestin Interventions trial found that, after 12 months, 25 of 119 women (21.0%) receiving conjugated equine estrogens (CEE) alone had endometrial hyperplasia, 12 women (10.1%) had complex hyperplasia, and 3 women (2.5%) had hyperplasia with atypia. Three women treated with CEE/medroxyprogesterone acetate (MPA) were reported to have simple hyperplasia (n = 2) or complex hyperplasia (n = 1) at 12 months; there were no reports of hyperplasia with atypia.10 Progestin has been added to oral estrogens to protect against endometrial proliferation. Endometrial outcomes in the Women’s Health, Osteoporosis, Progestin, Estrogen trial were reported for women receiving CEE alone (0.3-0.625mg/d) or a CEE/MPA combination (0.3/1.5 to 0.625/2.5 mg/d). Thirty-two of 2,153 women (1.5%) predominantly in the CEE-alone 0.45- and 0.625-mg treatment groups, developed endometrial hyperplasia by the 12-month evaluation. The incidence of hyperplasia was low (≤0.4%) in all CEE/MPA groups. One case of endometrial hyperplasia was identified in each of the CEE 0.3 mg/MPA 1.5 mg and CEE 0.45 mg/MPA 1.5 mg groups. Groups treated with CEE/MPA had a significantly lower (P ≤ 0.05) incidence of endometrial hyperplasia than the groups treated with corresponding doses of CEE alone, with the exception of the lowest dose (CEE 0.3 mg/MPA 1.5 mg and CEE 0.3 mg), where there was one case of hyperplasia in each group.11 Vaginally administered estrogens have been shown to be effective and well-tolerated for the treatment of VVA. Symptom relief is achieved with low doses of estrogen; however, systemic effects have been reported.12 In a recent study of 10-μg estradiol vaginal tablets,13 one case of endometrial hyperplasia (without atypia) and one case of endometrioid carcinoma were reported among women who were treated for up to 52 weeks, resulting in an incidence rate of 0.52% among 386 women who were reported to have undergone an endometrial biopsy. The mean endometrial thickness was not reported to have increased with treatment in this study. The endometrial safety of conjugated estrogens vaginal cream 0.3 mg applied once daily or twice weekly was evaluated in 155 participants with endometrial biopsies and revealed no endometrial hyperplasia or carcinoma. Transvaginal ultrasound (TVUS) results obtained at week 52 or at early termination showed endometrial thickness of at least 5 mm in approximately 10% of participants.14 The Food and Drug Administration (FDA) draft guidance for vasomotor symptoms and VVA clinical trials recommends evaluating the incidence rate of endometrial hyperplasia at 12 months: “We recommend that the results from the clinical trial demonstrate a hyperplasia rate that is ≤1% with an upper bound of the one-sided 95 percent confidence interval for that rate that does not exceed 4 percent. The frequency of atypical hyperplasia and cancer are important additional factors to be considered in determining approvability of the drug product.” The FDA guidance also advises that “the incidence of hyperplastic polyps and associated atypia would be considered in the safety review.”15 This report will present and discuss the gynecologic effects of a recently approved nonestrogen oral product, ospemifene 60 mg/day.