**2.1 Pharmaceuticals**

Finasteride and dutasteride are both 5-ARI medications used to successfully inhibit prostate growth. These two agents are both currently accepted for treating benign prostatic hypertrophy (BPH). The difference between the two medications is minimal, however potentially significant. 5-α-Reductase has two isoenzymes. Finasteride inhibits the type 2 isoenzyme while dutasteride inhibits both the type 1 and type 2 isoenzymes. Dutasteride thus has more complete inhibition of DHT, roughly 90% as compared to finasteride's 70% reduction of serum DHT.5,6 It has been proposed that expression of the type 1 isoenzyme is increased with prostate cancer while the type 2 isoenzyme is unaffected with prostate cancer.7 5-ARI medications focus on inhibiting androgen receptor (AR) activation. Research on BPH has shown that consistent use of finasteride or dutasteride decreases prostatic volume 30% and reduce PSA levels 50-60%.8 Both 5-ARI medications have been tested for chemopreventative benefits with multicenter, randomized, double blind, placebo controlled trials. The thrust of this paper will discuss the 5-ARI medications and their current role in prostate cancer prevention.

Other pharmaceutical agents potentially used for prostate cancer prevention include statins, nonsteroidal anti-inflammatory drugs (NSAIDS), and toremifene. Statins inhibit HMG-CoA, the rate limiting step of cholesterol synthesis. Statin use over 2 years has been associated with a decrease in prostate specific antigen.9 By inhibiting prostatic cellular growth and promoting apoptosis, statins also decrease cellular growth. No large double blind study has evaluated the effect of statin use on prostate cancer but a meta-analysis did find a protective effect.10 Further studies are needed to substantiate current evidence.

NSAIDS inhibit cyclooxygenase-2 (COX-2), which is a key enzyme found in prostate cancer which converts arachidonic acid to prostaglandins. Experimental evidence demonstrated a regression of PIN after NSAID use, but the planned trial with rofecoxib was withdrawn after safety concerns.11,12

Selective estrogen modulators (SERMs) are best known for their effects on breast cancer. Toremifene has decreased prostate cancer in the TRAMP model. A phase 2b study found that 20mg doses of toremifene resulted in a 48% decrease in prostate cancer at one year.13 However, the phase III trial demonstrated no significant risk reduction.14

### **2.2 Micronutrients**

430 Cancer Prevention – From Mechanisms to Translational Benefits

In December of 2010, the Federal Drug Administration's (FDA) Oncology Drugs Advisory Committee (ODAC) reviewed 5-ARI's indication for the prevention of prostate cancer in men at increased risk for prostate cancer. This committee ruled against the use of 5-ARI's for the use of prostate chemoprevention. Advocacy groups have since issues statements disagreeing with the FDA's ruling, highlighting the fact that controversy continues to exist. The goal of this paper is to examine the available agents and the current environment.

**2. Current chemopreventative agents - pharmaceuticals and micronutrients**  The ideal chemopreventative agent should be minimally expensive, nontoxic and effective. Having multiple preventative benefits is considered a plus; however it should not potentiate other causes of morbidity or mortality. Pharmaceutical agents, most notably 5-ARIs, and micronutrients have been studied to better establish their potential role in cancer

Finasteride and dutasteride are both 5-ARI medications used to successfully inhibit prostate growth. These two agents are both currently accepted for treating benign prostatic hypertrophy (BPH). The difference between the two medications is minimal, however potentially significant. 5-α-Reductase has two isoenzymes. Finasteride inhibits the type 2 isoenzyme while dutasteride inhibits both the type 1 and type 2 isoenzymes. Dutasteride thus has more complete inhibition of DHT, roughly 90% as compared to finasteride's 70% reduction of serum DHT.5,6 It has been proposed that expression of the type 1 isoenzyme is increased with prostate cancer while the type 2 isoenzyme is unaffected with prostate cancer.7 5-ARI medications focus on inhibiting androgen receptor (AR) activation. Research on BPH has shown that consistent use of finasteride or dutasteride decreases prostatic volume 30% and reduce PSA levels 50-60%.8 Both 5-ARI medications have been tested for chemopreventative benefits with multicenter, randomized, double blind, placebo controlled trials. The thrust of this paper will discuss the 5-ARI medications and their current role in

Other pharmaceutical agents potentially used for prostate cancer prevention include statins, nonsteroidal anti-inflammatory drugs (NSAIDS), and toremifene. Statins inhibit HMG-CoA, the rate limiting step of cholesterol synthesis. Statin use over 2 years has been associated with a decrease in prostate specific antigen.9 By inhibiting prostatic cellular growth and promoting apoptosis, statins also decrease cellular growth. No large double blind study has evaluated the effect of statin use on prostate cancer but a meta-analysis did find a protective

NSAIDS inhibit cyclooxygenase-2 (COX-2), which is a key enzyme found in prostate cancer which converts arachidonic acid to prostaglandins. Experimental evidence demonstrated a regression of PIN after NSAID use, but the planned trial with rofecoxib was withdrawn

Selective estrogen modulators (SERMs) are best known for their effects on breast cancer. Toremifene has decreased prostate cancer in the TRAMP model. A phase 2b study found that 20mg doses of toremifene resulted in a 48% decrease in prostate cancer at one year.13

effect.10 Further studies are needed to substantiate current evidence.

However, the phase III trial demonstrated no significant risk reduction.14

prevention.

**2.1 Pharmaceuticals** 

prostate cancer prevention.

after safety concerns.11,12

Micronutrients have long been sought after to provide a chemotherapeutic benefit for the development or prevention of prostate cancer. Antioxidants in vitro can inhibit cellular proliferation, induce apoptosis and modulate genes leading to the suppression of prostatic tumor. 15,16 The largest scale trial on micronutrients was for selenium and vitamin E in the Selenium and Vitamin E Cancer Prevention Trial *(*SELECT).

The interest in selenium began with the Nutritional Prevention of Cancer Trial, which used oral selenium for nonmelanoma skin cancer. Men were randomized to selenium versus placebo and were found to have a 65% reduction in prostate cancer incidence after a 4.5 year follow up. Vitamin E interest developed after a 32% reduction in prostate cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC) trial, which was a double blind randomized placebo controlled trial for lung cancer incidence and mortality.

These studies paved the way for the SELECT trial, published in 2009, which was a randomized, placebo controlled population based primary prevention trial focused on the effects of selenium and vitamin E on preventing prostate cancer. SELECT randomized 35,533 men to four treatment arms: selenium with placebo, selenium with vitamin E, Vitamin E with placebo, placebo with placebo. Study supplements included 200 micrograms l-selenomethionine, 400mg racemic alpha-tocopherol and an optional multivitamin containing no selenium or vitamin E. Eligible men were at least 50 years of age for African-Americans, at least 55 for Caucasians, negative DRE, PSA less than 4ng/mL, and normal blood pressure.

The primary endpoint was the presence of prostate cancer found on for cause biopsies. The indications for biopsy were not indicated in the protocol and were at the discretion of the physician.

During the second interim analysis seven years after initiation of the trial, the independent Data and Safety Monitoring Committee recommended discontinuation of the SELECT because the data demonstrated no significant differences between groups. No statistically significant effects were reported on primary or secondary analyses of the data, suggesting no prostate cancer prevention benefits from selenium or vitamin E.17 Unfortunately, selenium and vitamin E, which initially demonstrated promise, was eventually found to not have a significant effect on preventing prostate cancer. 17-19

Other chemopreventative micronutrients include lycopene, green tea, soy, DIM and curcumin. Molecular targets these agents affect include nuclear factor-KB, AKt, Wnt, Hedgehog and Notch.20

Lycopene is a biologically occurring carotenoid that is a potent antioxidant. It has been shown to be associated with lower prostate cancer risk in a number of epidemiologic studies.21 Using the preclinical TRAMP mouse model, prostate cancer was significantly decreased 60% vs. 95% (P=.01). However, no correlation was found with prostate cancer in a PLCO trial examining 29,000 men.

Green tea contains several catechins believed to inhibit oncogenesis and provide antioxidants. Epidemiologic studies between Asian men with a high intake of green tea first suggested that green tea may provide a protective benefit against prostate cancer. Three

The Changing Landscape of Prostate

biopsies were reviewed by a blinded pathologist.

reduced the risk of HGPIN compared to placebo.

given a new indication for prostate cancer prevention.

**3.2 The Reduction by Dutasteride of Prostate Cancer Events (REDUCE)** 

comparing finasteride to dutasteride for the prevention of prostate cancer.

Dutasteride, then, theoretically could enhance the anti-tumor effect.

Cancer Chemoprevention: Current Strategies and Future Directions 433

study site every six months for side effect evaluation and medication refills. Annual PSA and DRE were performed. Biopsy was recommended if the DRE was abnormal or PSA was greater than 4.0ng/ml in the placebo arm or 2.0 times PSA (adjusted to 2.3x in year 4) in the finasteride arm. At the completion of the trial in year seven, all participants were recommended to undergo an end of study prostate biopsy with at least six cores. All

The primary endpoint of the study was the prevalence of prostate cancer as diagnosed by biopsy for cause or end of study biopsies. Prostate cancer was found in 24.4% of the placebo group (1,147/4,692) and 18.4% of the finasteride group (803/4,368), representing a 24.8% risk reduction (CI 19-31, p<0.001). Finasteride's relative benefit was found across all groups including age, race/ethnicity, family history and entry PSA. In addition, Finasteride also

Interestingly, tumors with a Gleason grade of 7-10, high grade tumors, were found to be more prevalent in the finasteride group (37%), 280 of 757 graded tumors, as compared to the placebo group (22%), 237 of 1,068 graded tumors. This was statistically significant (P<.001). The increased prevalence of high grade tumors in the treatment group has generated tremendous speculation and sub-analysis. Forty of the excess high grade tumors were found in the "for cause" biopsies, clinically indicated due to increasing PSA or changes in the DRE. Secondary analyses have found a detection bias demonstrating a net reduction in highgrade cancers and a 53% reduction in low grade cancers.26 However, due disagreement in the medical community regarding finasteride's effect on high-grade cancers, it was not

Published in the *New England Journal of Medicine* in April of 2010, the REDUCE trial, was a 4 year multicenter, randomized, double-blind, placebo-controlled, parallel-group study. 8,231 men were randomized equally to dutasteride 0.5mg daily versus placebo. This trial was begun prior to the completion of the PCPT trial. Eligible patients were randomized to receive either Dutasteride or placebo. There has never been a large randomized trial

An important distinction between dutasteride and finasteride is the effect on 5-alpha reductase. Unlike finasteride, dutasteride affects the expression of both type 1 and type 2 isoenzymes of 5-alpha reductase inhibitors. Animal studies demonstrate that compared to finasteride, dutasteride has an increased reduction in both DHT and tumor growth.27

Eligible participants were required to be 50-75 years old, have a serum PSA between 2.5ng/mL-10mg/mL for men aged 50-60 years or 3.0-10ng/mL for men aged >60 years, and had undergone a prostate biopsy within six months of enrollment. Men were excluded if they had more than one biopsy, had prostate cancer of any grade, HGPIN, atypical small acinar proliferation, or a prostate volume of more than 80 grams, had previous prostate surgery of any kind, or had an international prostate symptom score (IPSS) of 25 or higher. During the trial 6726 men (82.6%) underwent at least 1 biopsy and 1516 men (22.5%) were diagnosed with prostate cancer. The primary endpoint was the presence of prostate cancer

clinical trials suggest a benefit.22 A small clinical trial (n=60) using oral green tea catechins (GTC) found that patients with HGPIN randomized to GTC vs. placebo had no change in PSA levels, but did have less progression of prostate cancer: 1 patient vs. 9 patients progress.23

Soy, like green tea, was also found to demonstrate lower prostate cancer in epidemiologic studies between diets high in soy versus western diets. The benefit is potentially a 70% reduction of prostate cancer.24 Soy affects signaling pathways, specifically Wnt and Hh signaling. Randomized studies are currently being performed.

DIM (the dimeric product of indole-3-carbinol) is found in a variety of plants and has been shown to inhibit alpha reductase suggesting that it may have an inhibitory role in prostate cancer. Curcumin is a bioavailable agent in turmeric and is also an alpha reductase inhibitor. Other regulators along the tumor pathway are inhibited by these two substances. Clinical trials are required to evaluate their effects.

Currently no biologically available micronutrients have been proven to provide chemoprevention benefits of prostate cancer. As such, current patient recommendations are to eat healthy foods and pursue healthy lifestyle changes.25
