NEW YORK (Reuters Health) – Men with isolated high-grade prostatic intraepithelial neoplasia (HGPIN) are at relatively high risk for developing prostate cancer, and treatment with toremifene does not reduce that risk, based on the results of a phase III RCT.

In fact, “Exploration of multiple covariates, including the volume of HGPIN at baseline, did not reveal a therapeutic effect in any subgroup,” the researchers report in the Journal of Clinical Oncology online January 7.

Dr. Samir S. Taneja, with New York University Langone Medical Center in New York, and colleagues explain that estrogen receptor alpha mediates growth of prostate cancer epithelium. Toremifene at low doses selectively inhibits estrogen receptor alpha, and it reduced progression of HGPIN to prostate cancer in preclinical studies and in a phase IIB clinical trial.

The team therefore conducted a phase III trial in which 1590 men with HGPIN were randomly assigned to receive 20 mg toremifene or placebo daily for 3 years. “Efficacy analysis was performed in 1,467 men who underwent at least one on-study biopsy.”

During the study, prostate cancer was diagnosed in 34.7% of the placebo group and in 32.3% of the treatment group, the investigators report. Estimated 3-year prostate cancer-free survival rates in the two groups were 54.9% versus 59.5%, respectively — a nonsignificant difference (p=0.39).

Among men in the placebo arm, cancer was detected in 17.9% in the first year, 12.9% in the second year, and 13.2% in the third. “This is distinct from screening cohorts in which a serial decline in cancer detection rate is typically noted on sequential sampling of men with elevated PSA and benign biopsy,” Dr. Taneja and colleagues point out.

They therefore conclude that, while toremifene does not lower the risk of prostate cancer (PCa), “men with isolated HGPIN have a high likelihood of eventual PCa diagnosis, demonstrating they are ideal candidates for inclusion in chemoprevention trials and require surveillance by periodic prostate biopsy.”

In an accompanying editorial, Dr. Ian M. Thompson Jr. and Dr. Robin Leach, with the University of Texas Health Science Center at San Antonio, note that the “overwhelming majority” of tumors detected after a diagnosis of HGPIN are low grade, and are unlikely to be ultimately fatal.

“Instead of PIN as a target of prevention therapies,” they write, “we would strongly encourage development of biomarkers that predict the development of high-grade tumors, the tumors that are most likely to lead to morbidity and mortality.”

SOURCE: Prostate Cancer Diagnosis Among Men With Isolated High-Grade Intraepithelial Neoplasia Enrolled Onto a 3-Year Prospective Phase III Clinical Trial of Oral Toremifene

SOURCE: Prostate Cancer and Prostatic Intraepithelial Neoplasia: True, True, and Unrelated?

J Clin Oncol 2013.