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Toremifene 80 mg demonstrates reduction in fracture risk in men who are less than 80 years of age on androgen deprivation therapy
Robert Feldman, MD1, Michael Flanagan, MD1, Michael Brawer, MD2.
1Connecticut Clinical Research, Middlebury, CT, USA, 2GTx, Inc, Memphis, TN, USA.

Background
The use of androgen deprivation therapy (ADT) in prostate cancer is associated with increased fracture risk. Previously we demonstrated in a Phase III trial that toremifene, a selective estrogen receptor modulator (SERM), significantly decreased fracture incidence in men receiving ADT. Similar to other SERMs, there was an increase in venous thromboembolic events. This risk appeared to stratify to men ≥80 years of age. VTEs occurred in 1.5% and 2.5% of men <80, ≥80 respectively in the overall study. To identify a patient population with the greatest benefit/risk profile we assessed the effect of toremifene in men <80 years.
Methods
In this analysis of men <80 years of age receiving ADT for prostate cancer, 430 received toremifene 80 mg and 417 received placebo (orally daily). 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 or hip (BMD). The primary endpoint was new vertebral fractures. Secondary endpoints included fragility fractures and bone mineral density (BMD).
Results
Toremifene 80 mg demonstrated a 79.5% relative risk reduction in the incidence of new vertebral fractures (CI0.95: 29.8%-94.0%; P<0.005). The absolute reduction was 3.8% (4.8% placebo, 1.0% toremifene). Toremifene 80 mg significantly increased BMD at all sites measured (P<0.001 for all comparisons). There was a concomitant decrease in markers of bone turnover (P<0.001 for all comparisons). Venous thromboembolic events occurred in 2.1% of the toremifene patients compared to 1.0% (P=0.26) of the placebo patients. Other adverse events were similar between groups.
Conclusions
In men <80 years receiving ADT for prostate cancer, toremifene significantly decreased the incidence of new vertebral fractures. Toremifene also significantly improved BMD, bone turnover markers, and breast pain and tenderness. The risk of VTE was lower than in the overall study population. These results suggest an improved benefit/risk profile in men <80 years receiving ADT.


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