Phase III ADT trial demonstrates improvement in gynecomastia in men on toremifene 80 mg compared to placebo
Robert Feldman, MD1, Michael Flanagan, MD1, York P. Moy, MD1, Anthony Kim, MD1, Shontelle Dodson, PharmD2, Domingo Rodriguez, MD2, Ronald A. Morton, MD2.
1Connecticut Clinical Research Center, Middlebury, CT, USA, 2GTx, Inc, Memphis, TN, USA.
Use of androgen deprivation therapy (ADT) has increased over the last decade. The increase in ADT utilization is likely due to more aggressive approaches to prostate cancer (PCa) treatment and improvements in survival. An estrogen deficiency related side effect of ADT in men with prostate cancer is the development of gynecomastia characterized by breast tenderness. This occurs as a result of the change in the estradiol to testosterone ratio. We conducted a double blind, randomized, placebo controlled trial to determine if toremifene 80 mg could prevent fractures in men on ADT. Because of the prevalence of gynecomastia in men on ADT we also assessed the effect of toremifene on the incidence and severity of breast enlargement and tenderness
1389 men with PCa were randomized to receive 80 mg toremifene or placebo orally for up to 24 months. All subjects were on ADT for ≥ 6 months, had a serum PSA ≤4 ng/mL, were >70 years of age or were at, or below, WHO thresholds for spine and hip (BMD). All subjects were maintained on continuous ADT throughout the study. The primary endpoint was new morphometric vertebral fractures (MVF). Key secondary endpoints included gynecomastia, hot flashes and changes in BMD and lipids. The modified intent to treat population (446 toremifene subjects, 467 placebo subjects) was defined as all subjects who received at least 1 dose of study medication and had at least 1 on-study radiograph. Breast tenderness was assessed on physical examination by a physician and was scored as 1st or 2nd degree worsening, unchanged, or 1st or 2nd degree improved. Each assessment was performed at baseline and months 3,6,12,18, and 24.
At the end of study, a positive effect of toremifene on breast tenderness was observed with more subjects scored as improved and fewer subjects scored as worsened in the toremifene treated group compared to placebo using last observation carried forward (LOCF) (p=0.0034). In subjects with documented use of bicalutamide (toremifene=99, placebo=101) there was an equally impressive improvement in breast tenderness using LOCF (p=0.0008). Effects on breast glandular size were not statistically significant.
Toremifene demonstrated a positive effect on the treatment of gynecomastia in men on ADT. Toremifene is a selective estrogen receptor modulator with partial agonist and antagonist activity. Specifically, it is estrogenic in bone and the hypothalamus, and anti-estrogenic in the breast and prostate. These results suggest that treatment with a SERM can reduce breast tenderness in this patient population.