Cancer Prevention Research Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach

Finasteride taken for 7 years in the Prostate Cancer Prevention Trial (PCPT) reduced the risk of prostate cancer by 25%, but with an apparent increased risk of high-grade disease. Subsequent analyses found that finasteride biases toward improved prostate cancer detection and accuracy in prostate cancer grading at biopsy. In our first analysis of the present study, we accounted for these biases in estimating the effect of finasteride on the risk of overall and high-grade prostate cancer. This analysis used PCPT data that included 3-month longer collection of endpoints than in the original report with observed prostate cancer rates of 22.9% (4.8% with high grade; placebo) versus 16.6% (5.8% with high grade; finasteride). Based on these updated results, the bias-adjusted prostate cancer rates are estimated to be 21.1% (4.2% high grade; placebo) and 14.7% (4.8% high grade; finasteride), a 30% risk reduction in prostate cancer [relative risk (RR), 0.70; 95% confidence interval (95% CI), 0.64-0.76; P < 0.0001] and a nonsignificant 14% increase in high-grade cancer (RR, 1.14; 95% CI, 0.96-1.35; P = 0.12) with finasteride. We then estimated rates of high-grade prostate cancer based on an analysis that incorporated grading information from radical prostatectomies in 500 subjects diagnosed with cancer. The resulting estimates were high-grade cancer rates of 8.2% (placebo) versus 6.0% (finasteride), a 27% risk reduction (RR, 0.73; 95% CI, 0.56-0.96; P = 0.02) with finasteride. Our third analysis examined the impact of biopsy sensitivity on the risk relative of high-grade prostate cancer and found that differential sensitivity of biopsy between the treatment arms can have a significant impact on risk ratio estimates. These collective results suggest that the observed, unadjusted higher risk of high-grade disease with finasteride seems to have been due to facilitated diagnosis resulting primarily from increased biopsy sensitivity with finasteride. Therefore, men undergoing regular prostate cancer screening or who express an interest in cancer prevention should be informed of the opportunity to take finasteride for preventing prostate cancer. One in seven men in the United States is expected to be diagnosed with prostate cancer in his lifetime primarily because of aggressive screening. The effect of screening on morbidity and mortality is uncertain; and the human and economic cost of prostate cancer treatment is substantial. These circumstances make preventing this common disease an attractive public health strategy (1–3). The Prostate Cancer Prevention Trial (PCPT) tested the ability of finasteride, a selective inhibitor of 5α-reductase type 2, to reduce the risk of prostate cancer. The independent Data and Safety Monitoring Committee recommended closure of the PCPT 15 months early because of overwhelming evidence that the primary end point had been reached: Finasteride had reduced the risk of prostate cancer by 25% (4). Concurrently, finasteride apparently had increased the risk of high-grade disease. Although high-grade tumors were a relatively small proportion of all detected tumors in the finasteride group, the potentially increased risk of aggressive disease and an unfavorable editorial accompanying the initial publication led to a general lack of acceptance of finasteride for cancer prevention (5). In the United States, early detection and treatment remain the primary focus for controlling this disease. Since the initial publication of primary PCPToutcomes, analyses of these contrasting conclusions have continued, as has a widespread debate on finasteride for prostate cancer prevention. We now know that finasteride enhances the detection of prostate cancer through the following effects on the performance characteristics of for-cause biopsies (see "Materials and Authors' Affiliations: Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pathology, The University of Colorado at Denver, Denver, Colorado; The Southwest Oncology Group; and Department of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas Received 04/25/2008; accepted 05/02/2008. Grant support: NCI grant CA37429. Requests for reprints: Mary W. Redman, Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M3-C102, Seattle, WA 98109. Phone: 206-667-4767; Fax: 206-667-4408; E-mail: [email protected]. ©2008 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0092 OF1 Cancer Prev Res 2008; Online First 2008 www.aacrjournals.org Published Online First on May 18, 2008 as 10.1158/1940-6207.CAPR-08-0092 Cancer Research. on April 2, 2017. © 2008 American Association for cancerpreventionresearch.aacrjournals.org Downloaded from Published OnlineFirst May 18, 2008; DOI: 10.1158/1940-6207.CAPR-08-0092