Prostate Cancer Prevention: Strategies and Realities

5-α Reductase Inhibitors

It is widely accepted that the development of prostate cancer depends on androgens. Androgens, specifically testosterone and dihydrotestosterone, are essential for growth and development of the prostate gland. When an androgen binds to the androgen receptor, several cellular processes occur, ultimately resulting in the recruitment and activation of gene products. This activation then leads to androgen-receptor-dependent gene transcription and translation which promotes both prostate growth and carcinogenesis. Androgen blockade through medical or surgical castration has been shown to induce apoptosis and slow cancer progression, and has become the standard of care in treatment-naive metastatic prostate cancer.

5-α Reductase inhibitors (5-ARIs) are a class of medications that block the activity of the enzyme 5-α reductase. The conversion of testosterone to dihydrotestosterone (DHT) through 5-α reductase is crucial in accelerating prostate growth, given the greater effects and potency of DHT. 5-α Reductase exists as two different isoenzymes, type I and type II, and the latter has been shown to have high activity in the prostate.

Several landmark clinical trials have critically evaluated the effects of 5-ARIs in treating benign prostatic hyperplasia (BPH). The Finasteride Study Group was a multicentered, double-blinded study where patients with BPH were randomly assigned to receive finasteride (5 mg or 1 mg) or placebo. The primary outcomes in this study were urinary symptoms, urinary flow and volume, and serum levels of DHT. Among patients randomized to 5 mg of finasteride, there was a significant decrease in prostate volume of nearly 20% by the end of 1 year. The Medical Therapy of Prostatic Symptoms (MTOPS) study was another large randomized trial designed to determine whether monotherapy with finasteride or doxazosin (an alpha receptor blocker), or combined medical therapy with both medications was more effective in managing patients with BPH. Similarly, patients who were randomized to receive finasteride had a 20% reduction in prostate volume. These patients also experienced significant improvements in urinary flow, lower rates of urinary retention, and a decreased need for invasive secondary treatments.

Against this backdrop, it is conceivable that 5-ARIs would be successful agents for chemoprevention of prostate cancer, given their biologic role in reducing DHT and their clinical effect on reducing prostate volume. Two large, multicentered clinical trials of 5-ARIs were conducted to critically evaluate the key question – do 5-ARIs reduce the risk of prostate cancer diagnosis and mortality? The Prostate Cancer Prevention Trial (PCPT) was a large, multicentered randomized clinical trial to test whether finasteride, a type II 5-ARI, reduced the risk of prostate cancer among healthy men. Men were eligible for inclusion if they were <55 years, with a normal digital rectal exam (DRE) and with an American Urological Association Symptom Score of <20 at the time of accrual. All patients recruited and enrolled underwent annual PSA testing and DRE for a total of 7 years. PSAs for men randomized to finasteride were adjusted by a factor of 2.3, while PSAs for men on placebo were not adjusted. Indications for transrectal ultrasound (TRUS)-guided prostate biopsy were abnormal DRE or a PSA ≥4 ng/mL. The primary outcome of this clinical trial was the incidence of newly diagnosed men with prostate cancer during the study. In this landmark trial, 18,882 patients were randomized to receive 5 mg finasteride daily or placebo for a period of 7 years. In 2003, Thompson et al. published the initial results from the PCPT. Among patients included in the final analysis, 18.4% of men randomized to finasteride were diagnosed with prostate cancer, while 24.4% of men randomized to placebo were diagnosed with prostate cancer (relative risk or RR 24.8% [95% CI: 18.6–30.6%] p < 0.001). Although the initial results from the PCPT were impressive in terms of decreasing the overall rate of prostate cancer diagnosis, a greater percentage of men randomized to finasteride developed high-grade prostate cancer (Gleason ≥7) compared with those on placebo (6.4% vs. 5.1%; RR: 1.67 [95% CI: 1.44–1.93%] p = 0.005). Furthermore, men on finasteride were more likely to experience erectile dysfunction (67.4% vs. 61.5%; p < 0.001), loss of libido (65.4% vs. 59.6%; p < 0.001), and gynecomastia (4.5% vs. 2.8%; p < 0.001) compared with placebo. Finally, and possibly related to these adverse events, the rate of nonadherence to finasteride was significantly higher than nonadherence to placebo (36.8% vs. 28.9%; p < 0.001).

In a recent update of the PCPT study after 17 years of followup, randomization to finasteride was associated with lower rates of prostate cancer diagnosis compared with placebo (10.5% vs. 14.9%; RR: 0.70 [95% CI: 0.65 to 0.76] p < 0.001). However, patients taking finasteride continued to have a higher rate of high-grade (Gleason 7–10) prostate cancer diagnosis compared with those receiving placebo (3.5% vs. 3.0%; RR: 1.17 [95% CI: 1.00–1.37] p = 0.05). Furthermore, the 15-year survival rates across both arms were nearly identical (78.0% vs. 78.2%; adjusted hazard ratio or HR: 1.03 [95% CI: 0.98–1.09] p = 0.26). Following a diagnosis of prostate cancer, the long-term overall survival remained similar without any significant differences between groups.

The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was another double-blinded, placebo-controlled, multicenter study that followed patients for 4 years. The investigators chose dutasteride for this study as it inhibits both the type I and II isoforms of 5-α reductase. The study enrolled men thought to be at higher risk of prostate cancer; specifically men aged 50–75 years, with a PSA of 2.5–10.0 ng/mL, and a history of one prior negative prostate biopsy within 6 months of study enrollment. Patients were randomized to dutasteride (0.5 mg/daily) or placebo and both groups underwent prostate biopsy at 2 and 4 years. The primary outcome was detection of prostate cancer after 2 and 4 years of treatment or placebo. In the final analysis, 8231 patients were enrolled, with 4105 randomized to dutasteride and 4126 randomized to placebo. Of these patients, 6729 underwent biopsy during the course of the study and were included in the final analysis. Overall, 19.9% of men randomized to dutasteride and 25.1% of men randomized to placebo were diagnosed with prostate cancer. Treatment with dutasteride conferred a relative risk reduction of 22.8% (95% CI: 15.2–29.8%; p < 0.001) compared with placebo. While there were no significant differences in the number of patients diagnosed with high-grade prostate cancer (Gleason ≥7) during the study, a greater number of patients in the treatment group were diagnosed with high-grade cancer in the final 2 years of the study (12 vs. 1; p = 0.0003). There were no deaths attributed to prostate cancer in either group during the course of the study. Randomization to dutasteride was also associated with lower risks of developing sequelae of BPH compared with placebo, including acute urinary retention (1.6 vs. 6.7%; p < 0.001), urinary tract infections (5.3% vs. 8.8%; p < 0.001), and BPH-related surgeries (1.4% vs. 5.1%; p < 0.001). However, patients treated with dutasteride also demonstrated greater adverse events from the hormonal effects of 5-ARI including decreased libido (3.3% vs. 1.6%; p < 0.001), erectile dysfunction (9.0% vs. 5.7%; p < 0.001), and gynecomastia (1.9% vs. 1.0%; p = 0.002).

Data from both the PCPT and REDUCE trials clearly show a benefit in reducing the incidence of low-grade prostate cancer. However, in the PCPT trial, this decrease in the incidence of low-grade cancer came at the expense of an increased rate of diagnosis of high-grade disease. Similarly, the REDUCE investigators found an increase in the rate of high-grade diagnosis in the treatment group in the last 2 years of their trial. Although both finasteride and dutasteride led to a decreased risk of prostate cancer detection overall, the findings that 5-ARIs were associated with a greater risk of high-grade prostate cancer has led to significant controversy about the use of these medications as preventive agents. Furthermore, even with 17 years of follow-up, treatment with finasteride has not conferred a survival benefit for patients in the PCPT, and several studies have suggested that 5-ARIs have long-term adverse effects, especially loss of libido and erectile dysfunction. Hence, to allow patients to make informed decisions, 5-ARIs should only be used for primary prevention in prostate cancer after thorough discussions about the risks and benefits of treatment. In fact, the American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) recently removed from their websites their joint guideline on the use of 5-ARIs as chemopreventive agents since the FDA has not approved dutasteride for prostate cancer prevention, while 5-ARI labels now include information about the increased risk of developing high-grade prostate cancer while taking these medications.

Selenium and Vitamin E

Essential elements and vitamins have also been investigated for their potential role as chemopreventive agents for prostate cancer. Selenium is critical to the enzymatic pathway for glutathione peroxidase and can act as an anti-oxidant. Similarly, it has been postulated that vitamin E (alpha-tocopherol) can help protect against carcinogenesis and other chronic diseases by reducing oxidative stress. In a clinical setting, secondary analyses of randomized controlled trials had shown a potential protective benefit from selenium and vitamin E on prostate cancer incidence, thus leading to the design of a clinical trial to specifically address the issue.

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a large, multicenter, placebo-controlled, randomized, double-blinded study designed to test whether selenium, alpha-tocopherol, or the combination would confer a protective benefit in lowering the incidence of prostate cancer. Secondary endpoints included overall cancer diagnosis, all-cause mortality, and cardiovascular events. Inclusion criteria included patient age ≥55 years of age (≥50 years for African-Americans), no history of prostate cancer, PSA <4 ng/mL, and a normal DRE. Of note, men were not required to undergo annual PSA screening or DRE, and there were no strict criteria to undergo prostate biopsy. Over 7 years, the SELECT trial enrolled 35,533 men from 427 participating sites. Patients were randomly assigned to study groups including placebo, vitamin E (400 IU/day), selenium (200 μg/day), or both.

In 2008, with a median follow-up of 5.46 years, the independent data safety and review committee ended the trial early since the data demonstrated no differences in any of the primary or secondary endpoints. Compared with patients receiving placebo, the incidence of prostate cancer was similar for those patients randomized to vitamin E (HR: 1.13 [95% CI: 0.95–1.35]), selenium (HR: 1.04 [95% CI: 0.87–1.25]), and both (HR: 1.05 [95% CI: 0.88–1.25]). Patients randomized to vitamin E actually trended to a higher incidence of prostate cancer ( p = 0.06). The SELECT trial clearly demonstrated that among healthy men, supplementation with selenium or vitamin E does not help reduce the incidence of prostate cancer.