5-alpha reductase inhibitors reduce prostate cancer risk, but not all experts are ready to support their chemopreventive role

Chemoprevention with dutasteride (a 5-alpha reductase inhibitor or 5-ARI), given at a dose of 0.5 mg daily, reduced the risk of incident prostate cancer detected on biopsy and improved outcomes related to benign prostatic hyperplasia, according to the results published in the April 1, 2010, edition of the New England Journal of Medicine.

Key Points

Chemoprevention with dutasteride (a 5-alpha reductase inhibitoror 5-ARI), given at a dose of 0.5 mg daily, reduced the risk of incident prostate cancer detected on biopsy and improved outcomes related to benign prostatic hyperplasia, according to the results published in the April 1, 2010, edition of the New England Journal of Medicine.

The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study was a 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel group study that included men aged 50 to 75 with a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng/mL and at least 1 negative prostate biopsy within 6 months before enrollment. Among 6,729 men who underwent a biopsy or prostate surgery, cancer was detected in only 19.9% of men in the dutasteride group, as compared with 25.1% of men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% CI, 15.2–29.8) and an absolute risk reduction of 5.1% over the 4-year study period (P<.001). Furthermore, dutasteride therapy resulted in a reduction in the rate of acute urinary retention (1.6% vs 6.7%, a 77.3% relative risk reduction), as compared with placebo.

Recently, the American Society of Clinical Oncology (ASCO) and American Urological Association (AUA) released clinical practice guidelines supporting the use of 5-ARIs for chemoprevention of prostate cancer in asymptomatic men with a PSA ≤3.0 ng/mL who are regularly screened with PSA or are anticipating undergoing annual PSA screening.

Dr Walsh further cautioned that the use of these drugs for prevention may be risky. "Because PSA levels are suppressed, men may have a false sense of security, and if prostate cancer ever develops, the diagnosis may be delayed until they have high-grade disease that may be difficult to cure," Dr Walsh wrote.

Dr Walsh's concerns are not unsupported. During follow-up years 3 and 4 of REDUCE, there were 12 highly aggressive tumors with a Gleason score of 8 to 10 (the Gleason score is the sum of the 2 most common grades of prostate tumor, each of which is graded on a scale of 1 to 5, with 5 most aggressive) in the dutasteride group, as compared with only 1 in the placebo group (P=.003). Similar concerns were found in a recent meta-analysis, which was used as the basis for current clinical treatment guidelines.

ASCO and AUA note in their jointly published guideline document, "Although the majority of the Panel judged that the observed higher incidence of high-grade (Gleason score 8 to 10) cancer [with chemoprevention] ... is likely due to confounding factors, the increased incidence of high-grade cancer as a result of induction by the drug cannot be excluded with certainty."

SOURCES

1. Andriole GL, Bostwick DG, Brawley OW, et al; REDUCE Study Group. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:1192–1202.

2. Walsh PC. Chemoprevention of prostate cancer. N Engl J Med. 2010;362:1237–1238.