Double-Blind, Placebo-Controlled Trial of Toremifene for the Prevention of Prostate Cancer in Men with High-Grade Prostatic Intraepithelial Neoplasia

Authors: D. Price, B. Stein, E. Goluboff, P. Sieber, D. Bostwick, G. Barnette, R. Boger, M. S. Steiner

Background: Toremifene, a selective estrogen receptor modulator (SERM) marketed for the treatment of breast cancer, appears to have promise in preventing prostate cancer. A randomized, double-blind, placebo-controlled study was conducted to determine the incidence of prostate cancer in men with high-grade prostatic intraepithelial neoplasia (PIN) treated with toremifene.

Methods: 514 patients with high-grade PIN and no evidence of prostate cancer at study entry were randomized to oral toremifene 20, 40, or 60 mg or placebo QD for 12 months. Patients were rebiopsied at 6 and 12 months (minimum 8 cores per biopsy). Initial and subsequent biopsies were evaluated by a central pathologist (Bostwick Laboratories) for diagnosis of high-grade PIN and prostate cancer. Cumulative risk reduction and 12-month point-estimate risk reduction were compared between each toremifene group and placebo with Mantel-Cox and Cochran-Mantel-Haenszel, respectively, stratified by study center.

Results: The number of evaluable patients (defined as having one on-study biopsy and being compliant with the protocol) was 447. Prostate cancer was diagnosed among significantly fewer patients taking toremifene 20 mg compared with placebo during the study based upon both 6-month and 12-month biopsy data (24.4% vs. 31.2% cumulative incidence, p<0.05). The cumulative incidence of cancer with 40 mg and 60 mg doses was lower than with placebo but not statistically different (28.2% and 28.1%, respectively). The number of cancers prevented per year with toremifene 20 mg over placebo was 6.8 per 100 persons treated. Among patients with no evidence of prostate cancer on baseline and 6-month biopsies, the incidence of prostate cancer was reduced by 48% with toremifene 20 mg compared with placebo on 12-month biopsy (9.1% vs. 17.4% 12 month point estimate, p<0.05). For the 40-mg and 60-mg doses, cancer incidence at 12 months was reduced by 14.3% and 13.0%, respectively, compared with placebo (not statistically significant).

Conclusions: Toremifene 20 mg significantly reduced the incidence of prostate cancer at 1 year in a high-risk population.