ORLANDO — Toremifene citrate, an estrogen blocker approved for the treatment of advanced breast cancer, significantly reduced the incidence of prostate cancer in high-risk patients enrolled in a double-blind, randomized, phase IIb trial.
Investigator David Price, M.D., reported a 48% reduction in prostate cancer risk for high-grade prostatic intraepithelial neoplasia (PIN) patients who took 20 mg of toremifene each day for a full year. Prostate cancer was diagnosed over the course of the 12-month trial in 31.2% of patients in a placebo group, and 24.4% of those on the 20-mg dose.
Cohorts that completed a year of therapy at higher doses of toremifene also showed lower incidence of cancer, but the differences compared with placebo were not statistically significant. The proportion of 12-month biopsies showing prostate cancer was 9% of 88 men still taking 20 mg of toremifene, 14.3% of 91 men taking 40 mg, and 13% of 77 men treated with 60 mg. The highest cancer rate, 17%, was found among 86 men still taking placebo.
Dr. Price, director of urologic oncology and clinical research at Regional Urology, LLC, in Shreveport, La., presented data at the American Society of Clinical Oncology's annual meeting. He identified himself as a consultant to GTx Inc. in Memphis, which sponsored the trial. The company sells the drug, a selective estrogen receptor modulator, under the brand name Fareston for breast cancer and is developing it for prostate cancer under the name Acapodene.
The study enrolled 514 PIN patients at 64 sites across the United States. Researchers randomized 130 men to placebo, 125 to 20 mg of toremifene, 134 to 40 mg, and 125 to 60 mg. Age and prostate-specific antigen levels were similar across the cohorts.
At 6 months, rates of prostate cancer diagnoses were comparable for the 20-mg and placebo groups: 15.7% and 15.9%, respectively. Dr. Price said he believed the 6-month biopsies detected cancers missed at baseline. Consequently, he proposed that the 12-month biopsy data are more reflective of toremifene's effectiveness.
PIN patients are at substantially higher risk for prostate cancer than are men with high prostate-specific antigen levels, according to Dr. Price. He described PIN as a precancerous condition, comparable with colon polyps, in which abnormal cells are moving toward a malignant state.
“Right now we do not recommend any aggressive treatment for PIN,” he said at a press briefing, describing an anxiety-generating watch-and-wait strategy with repeated biopsies as the only option.
“This study documents the natural history of PIN,” he added, noting that prior estimates of cancer progression were based on retrospective data. “For the first time in a large prospective fashion, we demonstrated that these patients are truly at risk—that one in three is going to develop prostate cancer [within a year].”
Toremifene was well tolerated, with comparable proportions of patients on the drug (7%–9%) and the placebo (11%) reporting at least one serious adverse event. Its most common side effect, fatigue, occurred in 5% of the group taking 20 mg, the most effective dose, according to the presentation.
Gleason scores in men who developed prostate cancer were slightly lower (6.1%) in the 20-mg group than in the placebo group (7.4%). Dr. Price interpreted this as evidence that chemoprevention did not make cancers worse than they would have been without the trial.
The preventive effect demonstrated so far is 10-fold greater than that of tamoxifen against breast cancer, according to Dr. Price. Based on the phase IIb data, he estimated daily toremifene use could prevent 6.8 prostate cancers per 100 patients treated per year. He contrasted this with the National Surgical Adjuvant Breast and Bowel Project B-24 trial, in which tamoxifen use prevented 0.71 cancers per 100 patients with ductal carcinoma in situ after 1 year of treatment.
Audience members challenged him to state the actual numbers, and not just percentages, of patients who developed prostate cancer in the trial. He said 16 patients were diagnosed in the placebo group and 12 in the 20-mg cohort.
In a discussion of the trial, Otis W. Brawley, M.D, associate director of the Winship Cancer Institute at Emory University in Atlanta, noted that the absolute difference was only four fewer men developing prostate cancer: “A reduction of four—total.”