Selective ER Modulators
Both the prostatic stroma and the epithelium express estrogen receptors (ERs), and estrogens are important for prostate growth. Selective ER modulators are structurally diverse non-steroidal compounds that functionally mimic estradiol in their action but also possess cancer-suppressing activity.
Toremifene
Toremifene is an oral selective ER modulator. In a double-blind, placebo-controlled phase III study, Smith et al. assigned 1284 men receiving ADT for PC to toremifene (80 mg by mouth daily) vs placebo. The primary study end point was new vertebral fractures. In this double-blind, placebo-controlled phase III study, 646 men receiving ADT for PC were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI=−1.5–75.0, P=0.05) with number needed to treat 41 to prevent one vertebral fracture. Toremifene significantly increased BMD at lumbar spine, hip and femoral neck vs placebo (P<0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (P<0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group yielding number needed to harm 66. Other adverse events were similar between the groups. Toremifene is not approved by the FDA in men with PC. The FDA has requested additional information before approving a New Drug Application for this drug as a treatment to reduce fractures in men with PC which would include an adequate and well-controlled phase III trial demonstrating the safety and efficacy of toremifene to reduce fractures in men with PC on ADT while not having a detrimental effect on either time-to-disease progression or OS.