Estrogen receptor modulator prevents PCa in some men

May 1, 2005

Orlando, FL--Testosterone's effect on the development and progression of BPH and prostate cancer is well known, but a group of University of Tennessee researchers has been focusing on testosterone's less frequently studied "partner in crime"—estrogen.

Orlando, FL-Testosterone's effect on the development and progression of BPH and prostate cancer is well known, but a group of University of Tennessee researchers has been focusing on testosterone's less frequently studied "partner in crime"-estrogen.

Men at high risk for prostate cancer developed statistically significantly fewer malignancies when taking toremifene citrate (Acapodene), a selective estrogen re-ceptor modulator, than those taking placebo, the researchers reported here at the Multidisciplinary Prostate Cancer Symposium.

"Many [prostate cancer] strategies to date have revolved around blocking testosterone's action on the prostate," said Mitchell Steiner, MD, lead investigator and professor of urology at the University of Tennessee. "Although probably efficacious, this results in unacceptable side effects in men. We decided to look at blocking estrogen's action, which should have similar efficacy to blocking testosterone but with fewer side effects."

Patients were re-biopsied at 6 and 12 months, with a minimum of eight cores per biopsy.

The 20-mg dose turned out to have the strongest effect. Nearly one-fourth (24.4%) of patients on that dosage had developed prostate cancer at 1-year follow-up, compared with 31.2% on placebo (p<.05). Among the patients who had a negative prostate biopsy for cancer at baseline and 6 months, the reduction in prostate cancer was 48%. The investigators calculated that 6.8 cancers per 100 persons treated per year were avoided using toremifene, 20 mg.

The 40-mg and 60-mg toremifene doses were also efficacious but did not have as much of an effect as the 20-mg dose.

Men with PIN at risk "This study shows not only that prostate cancer is preventable, but also that men who have high-grade PIN are at high risk for developing prostate cancer," said Dr. Steiner, who also serves as chief executive officer of GTx, Inc., the company that owns exclusive U.S. rights to toremifene for all indications.

"Patients with high-grade PIN cannot be ignored. They must undergo periodic prostate biopsies to detect prostate cancer when high-grade PIN progresses. They cannot be followed by serial serum PSAs, since high-grade PIN does not contribute to serum PSA."

As Dr. Steiner explains, the prostate contains at least two receptor types for estrogen: ER alpha and ER beta. ER alpha accelerates prostate growth, while ER beta blocks it. Toremifene acts like estrogen when present in bone or brain, but it blocks estrogen's action in the prostate. More specifically, at low doses it tends to block ER alpha more effectively than it blocks ER beta.

"In other words, it takes the foot off the accelerator while keeping the foot on the brake," Dr. Steiner said. "At higher doses, toremifene stops the brakes from working, too. We expected that it would be more effective at lower doses, and that is what we observed clinically in this large study."

Dr. Steiner and colleagues have already begun a multicenter, placebo-controlled phase III clinical trial comparing toremifene, 20 mg, with placebo in 1,260 men with high-grade PIN. The study, which already has more than 100 participating clinical sites, is actively enrolling patients.

The drug is also being tested at an 80-mg dose for the treatment of the serious side effects of androgen deprivation therapy in men with advanced prostate cancer. Mechanistically, it may be able to prevent bone loss and reduce osteoporotic fractures, block gynecomastia, and reduce hot flashes, according to Dr. Steiner.

Toremifene, given at a 60-mg dose, is FDA-approved for the treatment of metastatic breast cancer in postmenopausal women.