Finasteride and Prostate Cancer: A Commentary

Abstract

This commentary discusses the risks and benefits of using finasteride to prevent prostate cancer.

Prostate cancer management has focused on early detection and treatment, but the prolonged development cycle of prostate cancer suggests that prevention may be a preferable approach. Finasteride and dutasteride, inhibitors of 5α-reductase, inhibit conversion of testosterone to dihydrotestosterone (a potent androgen) and have low toxicity, which makes them attractive chemopreventive agents. Both drugs have been proven successful in treating benign prostatic hyperplasia (BPH) and have been approved by the U.S. Food and Drug Administration (FDA) for this indication [1]. Lower doses of finasteride have also been approved for treatment of male pattern baldness [2]. There was great hope that they would be safe, easy, and effective chemoprevention agents against prostate cancer, but studies show otherwise.

In this issue of The Oncologist, Kao and colleagues from Taiwan report on the most recent study that shows finasteride use was associated with an actual increase in risk of prostate cancer [3]. They identified 1,489 patients with cancer and BPH in the Taiwanese National Health Insurance registry and carefully matched three patients without cancer. The use of finasteride was associated with an increased risk of prostate and overall cancer (prostate cancer risk increased with an odds ratio of 1.9; overall cancer odds ratio was 1.5). Use of dutasteride was associated with no reduction in risk of prostate cancer and an increased risk of renal cancer. These disappointing results are in line with several other randomized trials investigating the use of these drugs for chemoprevention.

Clinical Trial Results

The Prostate Cancer Prevention Trial (PCPT) randomly assigned 18,882 men who had a prostate-specific antigen level at or below 3.0 ng/mL, were age 55 or older, and had a normal digital rectal examination, to finasteride (5 mg/day) or placebo for 7 years [4]. The study reported a decrease of 24.8% in prevalence of biopsy-proven prostate cancer in the finasteride population (803 of 4,368 men; 18.4%) compared with placebo (1,147 of 4,696 men; 24.4%). Urinary symptoms were less common in the finasteride group. However, there was no documented evidence of increased survival in the finasteride group. In addition, a 27% increased risk of high-grade disease (Gleason score >7) was seen in the finasteride group (280 of 4,368 men; 6.4%) compared with the placebo group (237 of 4,692 men; 5.1%). Despite the increase in high-grade disease, only five men died of prostate cancer in each group. In all, 97.7% of tumors in the finasteride group and 98.4% of tumors in the placebo group were T1 or T2. Finasteride-treated men were more likely to experience more frequent sexual side effects.

In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, 6,729 men were randomly assigned to dutasteride or placebo for 4 years [5]. Men in the dutasteride group experienced 22.8% less incidence of biopsy-proven prostate cancer (659 of the 3,305 men in the dutasteride group, as compared with 858 of the 3,424 in the placebo group). No significant difference was found in the frequency of high-grade disease in patients with Gleason scores ≥7. However, there was a trend toward high-grade disease in patients with Gleason scores ≥8 in the dutasteride group, with a significant increase in high-grade disease in that group in years 3 and 4 of the study.

Based on these results, the FDA did not approve the use of either finasteride or dutasteride for prostate cancer prevention; the advisory committee vote was unanimous (17 to 0). Of note, African-American men are the highest risk group for prostate cancer, but they were underrepresented in both of these studies (2.3% in the PCPT study and 3.7% in the REDUCE study).

Cost Effectiveness of Finasteride

The cost of finasteride compared to the benefits has been a concern given the unsustainable increases in cancer care costs in the United States [6–8]. Increasingly, most health care entities are looking to ensure reasonable value for new expenditures [9]. The current U.S. price to the consumer for 5 mg of finasteride is about $1 a day (drugstore.com, accessed April 10, 2012). Most studies have shown that the cost-effectiveness ratio of finasteride is many times worse than the U.S. standard, whether one uses the traditional $50,000 per additional year of life or more appropriate estimates of $150,000–$200,000 [10].

As shown in Table 1, the cost-effectiveness ratio of finasteride is well over usual thresholds, and the cost would have to be reduced to half the current price to meet the threshold of $100,000 per life year. Reed and colleagues used a 14-single nucleotide polymorphisms and family history prediction model to “target” individuals at highest risk; they derived a value closer to accepted thresholds. However, their model makes several assumptions that are not supported by the current evidence, including the following: (a) there is no increased risk of high-grade cancers: (b) finasteride is equally effective at preventing all grades of cancer (not just low-grade cancers); and (c) finasteride is equally effective in high-risk populations. In summary, the drug lacks sufficient effectiveness at the current price to meet cost-effectiveness thresholds.

Table 1.

Effectiveness and cost-effectiveness of finasteride as the primary prostate cancer preventative agent

Abbreviations: PCPT, Prostate Cancer Prevention Trial; QALY, quality-adjusted life year.

Communication Between Physicians and Patients

The clinical trial results created a dilemma for physicians. Rather than establishing finasteride and dutasteride as safe and effective chemoprevention agents, the trial results demonstrated substantial chemoprevention but at the cost of increased risk of high-grade prostate cancer and a small increased risk of sexual adverse effects. In contrast, the breast cancer chemoprevention drugs tamoxifen [15] and raloxifene [16] were effective chemoprevention agents and did not increase the rate of high-risk cancer. There is no other effective strategy for chemoprevention; vitamin E and selenium are not recommended. None of the available guidelines strongly suggest finasteride or dutasteride use, as shown in Table 2. Additional research is essential to determine if any agent is effective in high-risk populations, such as African American men, individuals with family history, or individuals with genetic risk.

Table 2.

Recommendations for physician communication concerning the use of 5α-reductase inhibitors

Abbreviations: 5-AR, 5α-reductase; 5-ARI, 5α-reductase inhibitor; PCPT, Prostate Cancer Prevention Trial.

Physicians considering the use of 5α-reductase inhibitors should counsel their patients in accordance with guidance from the American Society of Clinical Oncology (Table 2). The ideal candidate for finasteride or dutasteride is a patient with BPH with a family history of prostate cancer and/or other reasons to be concerned about developing prostate cancer; the candidate should be willing to accept the risk of developing a high-grade cancer and remain under close surveillance. Patients concerned about the risk of developing high-grade prostate cancers may be prescribed alternative agents to treat BPH, such as α-blockers. Most patients and physicians will await the development of more effective agents with less potential risk.

See the accompanying article on pages 986–991 of this issue.