Phase III trial in men on ADT demonstrates a reduction in hot flashes in men on toremifene 80 mg compared to placebo
Robert Feldman, MD1, Michael Flanagan, MD1, Anthony Kim, MD1, York P. Moy, 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. ADT results in castrate levels of testosterone and estrogen that leads to estrogen deficiency side effects such as hot flashes. In a randomized, double blind, placebo-controlled trial to determine if toremifene 80 mg could prevent fractures in men on ADT, we also assessed the effect of toremifene on the incidence and severity of hot flashes.
METHODS: 1389 men with prostate cancer were randomized to receive 80 mg toremifene orally or placebo 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. Hot flashes were reported by patients using a 7 day diary at baseline and every 3 months on study. Severe hot flashes and flushing were recorded as adverse events and analyzed between treatment groups based on the ITT population
Only US subjects with at least 6 hot flashes/day at baseline and not on Megace® were included in the analysis (toremifene=18 subjects, placebo=19 subjects). In this subgroup, toremifene 80 mg reduced the incidence of hot flashes from baseline at 6 months by 42% compared to a 26% decrease in the placebo group with a trend in favor of toremifene (p=0.0597). At 9 months, toremifene significantly reduced the incidence of hot flashes from baseline by 42% compared to an 18% decrease in the placebo group (p=0.0457). The effect was maintained through the end of the study. The incidence of hot flashes and flushing reported as adverse events (reported by the patient as severe) was lower in the toremifene group (3.9%) compared to the placebo group (5.8%). This incidence showed a statistical trend in favor of toremifene (p=0.1188).
In this randomized placebo controlled trial toremifene 80 mg demonstrated the ability to reduce hot flashes in a subset population that experienced on average a higher number of hot flashes at baseline than that observed in the ITT population. Additionally, fewer subjects reported severe hot flashes and flushing as adverse events.