Finasteride Use Appears Unlikely to Induce High-Grade Prostate Tumors

Roxanne Nelson

September 17, 2007 — The chemopreventive agent finasteride (Proscar, Merck & Co) does not appear to increase the rate of histologically high-grade prostate carcinomas, a possibility that had been suggested by a previous study showing also that the drug reduces the risk for prostate cancer. According to 2 new studies, published online in the September 11 issue of the Journal of the National Cancer Institute, the elevated rate of high-grade tumors observed in men who received finasteride in the Prostate Cancer Prevention Trial (PCPT) is most likely due to an increased rate of cancer detection.
The PCPT was the first phase 3 clinical trial to evaluate the chemoprevention of prostate cancer. Men who used finasteride had a lower incidence of prostate cancer, but among those who did develop the disease while taking finasteride, a higher incidence of high-grade tumors was observed. This finding raised the possibility that finasteride induces the development of a higher-grade cancer.
"The primary finding of the PCPT was that prostate cancer, overall, was reduced by 25% in men in the finasteride group of the study," said first author M. Scott Lucia, MD, of the University of Colorado Health Sciences Center in Denver. "A secondary finding from the trial was that there was a higher incidence of high-grade cancer in the finasteride group."
Dr. Lucia and colleagues looked at possible explanations for the latter finding, and histologically examined high-grade prostate biopsies with a Gleason score of 8 to 10 for hormonal effects; 90 specimens were from men treated with finasteride and 52 were from the placebo group. They also assessed biopsies with a Gleason score of 7 to 10 (n = 282 for finasteride; n = 244 for placebo) for pathologic surrogates of disease extent.
They found that prostate volumes were lower among men who had received finasteride, but degenerative hormonal changes seen in the high-grade biopsies were similar in both groups. In the finasteride group, pathologic surrogates for tumor extent were also lower with finasteride than with placebo. Among patients who had undergone a prostatectomy, the increased rate of high-grade disease that was initially observed with diagnostic needle biopsy in the finasteride group (42.7% for finasteride vs 25.4% for placebo) was less pronounced at prostatectomy (46.4% for finasteride vs 38.6% for placebo).
A larger proportion of the men who received finasteride were found to have high-grade disease at prostatectomy (69.7% vs 50.5%), but pathologic staging and the proportion of tumors that were low grade at biopsy and upgraded to high-grade cancer at prostatectomy were similar in the 2 groups.
"We found that there was no pathologic evidence that high-grade cancer was more advanced in the finasteride group, and there was no evidence that finasteride induced a hormonal artefact that would have interfered with proper grading of the cancers," Dr. Lucia told Medscape. "There is evidence that finasteride reduced gland volume in men taking the drug, such that high-grade cancer was better detected by biopsy."
The pathologic evidence indicates that it is unlikely that finasteride induces a high-grade cancer, although it cannot be completely ruled out. Hpwever,"the risk of high-grade cancer in men taking finasteride or other 5-alpha reductase inhibitors (5ARIs) is lower than originally believed," Dr. Lucia said. "Physicians should consider discussing prostate-cancer prevention using 5ARIs with their patients."
In the second study, Peter Gann, MD, ScD, director of the division of pathology research at the University of Illinois at Chicago, and colleagues hypothesized that the increase in high-grade tumors seen among finasteride users who participated in the PCPT was caused by the drug's ability to reduce prostate volume, thus allowing a greater detection of high-grade tumors because of sampling density. The researchers used 2 logistic models to assess the role of detection bias as a possible reason for the larger number of high-grade tumors observed in men who received finasteride.
The median prostate volume was 25% lower among patients receiving finasteride than among those receiving placebo, and the logistic model that was developed for the placebo group showed that detection of high-grade tumors would likely decrease as prostate volume increased. Using this model, it was predicted that a total of 239 high-grade tumors would be found in the finasteride group. The actual number of high-grade cancers detected was 243, and the difference was not statistically significant.
"The analyses presented here show that adjustment for changes in gland volume due to the drug could account for essentially all of the observed association between finasteride assignment and high-grade cancer," write the researchers.
In an accompanying editorial, Gerald Andriole, MD, of Washington University School of Medicine in St. Louis, Missouri, and colleagues point out that the results of these 2 studies strengthen the evidence that the increased proportion of high-grade prostate tumors observed in the PCPT is not likely to be clinically relevant.
"In the future, molecular testing of these PCPT tissue samples may be useful [in determining] whether the high-grade carcinomas seen in the finasteride arm have DNA ploidy and gene-expression profiles similar to those of untreated high-grade carcinoma," they write. "Ultimately, analysis of radical prostatectomy specimens and long-term clinical follow-up of the finasteride-treated patients will be necessary to completely ascertain the clinical significance of the increased high-grade cancer on biopsy in the PCPT."
Dr. Lucia's study was supported by National Cancer Institute Public Health Service grants through the Southwest Oncology Group. Dr. Lucia has been a scientific consultant for GlaxoSmithKline. All of Dr. Gann's coauthors except for one are paid employees of Merck & Co Inc, which manufactures finasteride.
J Natl Cancer Inst. 2007;99:1375-1383, 1366-1374, 1355-1356.