A multi-center Phase III study was discussed at the 2009 meeting of the American Urological Association.
Men, fighting advanced prostate cancer, often receive long-term ADT, which along with other side effects will increase their incidence of osteoporosis, obesity, and cardiovascular complications. Bone loss leads to osteoporosis, bone fracture, pain, hospitalization, immobility all of which will increase medical costs and inflict negative quality of life issues.
Trying to monitor and combat this problem many physicians simply add calcium supplementation along with bone density scans prior to and during therapy with ADT. However, this has had only minimal positive effects. Bisphosphonates such as Zometa® (zolendronic acid) and a new agent, denosumab, are also prescribed to prevent bone loss.
Toremifene is a selective estrogen receptor modulator, similar to tamoxifen (Nolvadex®), which is approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced breast cancer. Some researchers looking at Toremifene to prevent prostate cancer in men with precancerous growths as well as in evaluating the effects of toremifene on bone and lipid metabolism in men receiving ADT.
This multi-center randomized Phase III trial is being carried out to evaluate the effects of toremifene in men who had received ADT for prostate cancer for at least six months. The expected accrual in this study is 3,000 men.
An interim report of this study was published in the Journal of Urology on January 1, 2008. Data on bone mineralization were reported on 1,392 men receiving toremifene or placebo. It was reported that toremifene significantly increased hip and spine bone mineral density. In another analysis, published in the April 10, 2009 issue of the Journal of Clinical Oncology, data on the effects of toremifene on lipid profiles were published. This study found that toremifene significantly lowered triglycerides, cholesterol, and LDL cholesterol and increased HDL cholesterol. Patients in the placebo group had a significant decrease in HDL cholesterol and significant increases in triglycerides, cholesterol, and LDL cholesterol.
The purpose of the current study was to report the effects of toremifene on bone fractures in men on ADT. This analysis included 1,389 men randomly allocated to receive toremifene or placebo. New vertebral fractures were the primary endpoint, while secondary endpoints were bone mineral density, worsening vertebral fractures, lipid changes, breast pain, hot flashes, and clinical fragility fractures.
At two years new vertebral fractures occurred in 4.93% of controls, and this was reduced by greater than 50% in the toremifene group. These authors also reported that patients in the control group had a much higher incidence of bone complications than expected. They also reported that fracture rates were higher than reported in the literature. Most of the secondary endpoints in this study were positively affected by toremifene administration.
Comments: The final report of this study will be very useful in defining the role of toremifene in preventing bone complications in men receiving ADT for prostate cancer. The effect on lipids could also help decrease the incidence of cardiac complications associated with ADT.
Reference: Lin DW, Marks LS, Morton RA, et al. Positive fracture reduction trial of toremifene 80 mgin men on ADT demonstrates significant fracture risks in untreated placebo group. American Urologic Association Meeting 2009;abstract 639.  Smith MR, Malkowitz, SB, Chu F, et al. Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. Journal of Urology. 2008;179:152-155.  Smith MR, Malkowitz, Chu F, et al. Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study. Journal of Clinical Oncology. 2008;26:1824-1829.
Joel T Nowak MA, MSW
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