Update on Prostate Cancer Chemoprevention

Jennifer Fisher Lowe, PharmD; Lawrence A. Frazee, PharmD

Disclosures

Pharmacotherapy. 2006;26(3):353-359. 

In This Article

5-α-Reductase Inhibitors

5-α-Reductase inhibitors prevent the con-version of testosterone to dihydrotestosterone—the most active androgen in the prostate. Of the two isoenzymes of 5-α-reductase, type 2 is present in normal and hypertrophic prostate tissue, whereas type 1 is the predominant form in prostate cancer cells and is overexpressed in some prostate cancers.[39] Because androgens are required for the development of prostate cancer,[40] and men with lower 5-α-reductase activity have a lower rate of prostate cancer,[41] 5-α-reductase inhibitors have been considered for chemo-prevention of prostate cancer.

The 5-α-reductase inhibitors available in the United States for treatment of benign prostatic hyperplasia are finasteride and dutasteride. Finasteride selectively inhibits the type 2 isoenzyme of 5-α-reductase, whereas dutasteride inhibits both isoenzymes. Two randomized, controlled trials are assessing the efficacy of a 5-α-reductase inhibitor for prevention of prostate cancer: the Prostate Cancer Prevention Trial (PCPT)[42] and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial[43] ( Table 2 ).

Finasteride

The PCPT was the first large phase III prostate cancer chemoprevention trial in the United States with prostate cancer as the primary outcome.[42] The study subjects were healthy men aged 55 years or older with a normal digital rectal examination and a PSA level of 3 ng/ml or lower. A total of 18,882 men were randomized to receive either finasteride 5 mg/day or placebo for 7 years. Subjects were monitored annually with a digital rectal examination and PSA level measurement. For those receiving finasteride, total PSA level was adjusted for the effect of finasteride before being reported.[7]

The primary end point of the 7-year study was prevalence of prostate cancer as diagnosed by biopsy resulting from an abnormal finding on digital rectal examination or a PSA level exceeding 4 ng/ml (for-cause biopsies), or by end-of-study biopsy. The study was powered to detect a relative reduction of 25% in occurrence of prostate cancer from the expected 6% rate in the placebo group.[44]

In March 2003, the primary goal of the trial had been met, and the Data and Safety Monitoring Committee recommended the trial be stopped 15 months early. The prevalence of prostate cancer was reduced by 24.8% (95% CI 18.6–30.6%), from 24.4% to 18.4%, in those subjects randomized to finasteride versus placebo (p < 0.001). A second finding was a relative increase in the frequency of invasive tumors (Gleason score 7–10) in the finasteride group (6.4% vs 5.1%, p = 0.005). Analysis of the attributable risk, considering all biopsies regardless of cause, revealed that if 1000 men received finasteride for 7 years, 60 cases of prostate cancer could be prevented, at the cost of 13 excess cases of high-grade cancers. The authors of the PCPT provided theoretical reasons to possibly explain the increased occurrence of high-grade tumors: a finasteride treatment effect that promotes high-grade tumors, selective inhibition of low-grade tumors, and a grading bias in patients treated with finasteride.[42]

The placebo group consisted of 9459 men, of whom 4692 were available for end-of-study biopsy. Prostate cancer was diagnosed in 1147 (24.4%) of the men in the placebo group. This rate was much higher than the a priori prediction of 6%. Of the 1147 men diagnosed with prostate cancer, 571 cases were diagnosed by for-cause biopsy. The other 576 were diagnosed by end-of-study biopsy, and the cancer would not have been detected in normal practice. Of interest, when all 9459 men randomized to the placebo group were included, and only the 571 cancers detected by for-cause biopsy were considered, the rate of prostate cancer occurrence was 6%. This suggests either considerable underdetection of prostate cancer using the criteria defined for the for-cause biopsies, or overdetection of clinically insignificant cancer.[45] Based strictly on for-cause biopsy, analysis of the attributable risk revealed that if 1000 men received finasteride for 7 years, 14 cases of prostate cancer could be prevented, at the cost of four excess cases of high-grade cancers.

The authors of the PCPT recently published a review article that addresses choosing the best candidates for finasteride chemoprevention.[46] The authors proposed that men with obstructive urinary symptoms, men at high risk of prostate cancer, and men committed to screening and early detection be considered for chemoprevention. However, without studies that address these subgroups specifically, it is difficult to make a solid recommendation.

Dutasteride

A phase II, double-blind, placebo-controlled, dose-ranging comparative trial clearly demonstrated that serum dihydrotestosterone suppression was significantly greater with the dual (types 1 and 2) 5-α-reductase inhibitor dutasteride 0.5 mg/day than with finasteride 5 mg/day in men with benign prostatic hyperplasia.[47] Mean ± SD reduction in baseline dihydrotestosterone concentration in men receiving dutasteride was 94.7% ± 3.3% versus 70.8% ± 18.3% in those receiving finasteride (p < 0.001). The difference in 5-α-reductase expression in prostate tissue and androgen suppression between the two agents led to the rationale for the design of the REDUCE trial.

The REDUCE trial is a 4-year, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group chemoprevention trial to determine the effect of dutasteride 0.5 mg/day in men with an increased risk for developing prostate cancer.[48] Free and total PSA levels will be assessed every 6 months throughout the study, and prostate biopsy will be performed at 2 and 4 years. Enrollment of 4000 men in each treatment group will provide greater than 90% overall power to detect superiority of dutasteride 0.5 mg over placebo after 4 years. Study enrollment was completed in spring 2005.

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