Case Study V Finasteride and Prostate Cancer

The Prostate Cancer Prevention Trial (PCPT) is a doubleblind chemoprevention trial of prostate cancer in 18,882 non-symptomatic, healthy men who were randomized to 5 mg/day of finasteride or placebo for 7 years.79 Finasteride is an inhibitor of (~90% of) 5-a-reductase, an enzyme involved in hormone metabolism of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. Intraprosta-tic DHT is thought to be a major stimulus for prostate cancer cell growth, as evidenced by in vitro and in vivo studies.80,81 Thus, reducing DHT by inhibiting 5-a-reductase activity is a plausible strategy for preventing prostate cancer development.

There was significant preclinical and clinical experience with finasteride before the initiation of the PCPT. Numerous animal model studies suggested finasteride had prostate cancer preventive activity in several rats,82 and finasteride had been approved and was in wide clinical use as treatment for benign prostatic hyperplasia.83 The toxicity profile for finasteride was well characterized as being low and well tolerated by healthy subjects.

At the end of the 7-year trial, an endpoint biopsy was performed in all men, demonstrating a 24.8% lower cumulative incidence of prostate cancer in the finasteride compared to the placebo group.79 However, the finasteride group also had a higher rate of high-grade cancers (higher Gleason scores) than the placebo group. In addition, men in the finasteride group reported more problems with sexual function but fewer urinary problems than men in the placebo group. Thus, this prevention trial identified multiple issues, including (1) a significantly higher detection rate in both arms of the study compared to earlier studies84 and (2) a 27% increase in highgrade Gleason scores in the treatment arm based on central review by pathologists blinded to treatment assignment, whereas the proportion in the placebo group was similar to other series.85 Fortunately, this was a well-designed trial with well-planned tissue collection and storage, so despite the mixed results the trial will certainly yield tremendous information about prostate carcinogenesis. Another large trial (8,000 men) using the 5-a-reductase inhibitor dutasteride for a 4-year intervention is also currently under way.86

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