Cellular Effect of Cholesterol-Lowering Prior to Prostate Removal

BACKGROUND AND RATIONALE

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer
death among men in North America. In the US, there are more than 200,000 newly diagnosed
cases and nearly 40,000 deaths from prostate cancer (CaP) annually. Although elevated lipid
levels are understood to increase risk of coronary heart disease, their importance for CaP is
not understood. Epidemiologic studies consistently show an association between lipid lowering
interventions and decreased risk of advanced CaP. There are no reports of prospective studies
of lipid-lowering interventions directed at CaP.

Epidemiologic studies and preclinical observations suggest that interventions to lower
cholesterol will decrease the risk of developing lethal CaP. However, a definitive, phase III
study of cholesterol-lowering effects on advanced CaP development is needed prior to clinical
implementation of this intervention. Such a trial will require a massive commitment of
resources for the large number of patients needing long follow-up. A rational intermediate
step is to conduct a presurgical intervention study to lower cholesterol in men undergoing
radical prostatectomy. Molecular evidence of treatment effect will provide a sound rationale
for definitive clinical trials, and may provide predictive biomarkers that can be validated
in these future trials.

The investigators propose a prospective trial to assess the effects on the human prostate of
a maximal cholesterol lowering strategy using dual agents in men already scheduled to undergo
radical prostatectomy for prostate cancer.

Simvastatin is a cholesterol-lowering drug approved by the FDA in 1991 and is now
commercially available as Zocor (Merck) or as a generic agent. After ingestion, it is
converted from an inactive lactone to the corresponding β-hydroxyacid, which inhibits HMG-CoA
reductase and the conversion of HMG-CoA to mevalonate. Ezetimibe is a cholesterol-lowering
agent that operates by a distinct mechanism from HMG-CoA reductase inhibitors. It was FDA
approved in 2002 and is commonly administered alone or in combination with a statin. It
specifically inhibits a cholesterol transporter in the small intestines and selectively
inhibits the absorption of cholesterol and related sterols.

A single pill that combines simvastatin and ezetimibe is available from Merck (Vytorin). This
commercially available agent at its standard dose is used in this trial. This study uses the
combination of simvastatin and ezetimibe to achieve maximal cholesterol lowering prior to
prostatectomy.

Inclusion Criteria:

- Biopsy containing ≥ 10 tissue cores sampled

- Biopsy positive for adenocarcinoma of the prostate containing any quantity of Gleason
3 component (e.g. Gleason score 3+3, 3+4, 4+3)

- Scheduled to undergo robotic radical prostatectomy

- Serum PSA <20 ng/ml

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- Pharmacologic therapy (e.g. statins or ezetimibe) to lower cholesterol within 30 days
prior to registration.

- Prior treatment for CaP by surgery, irradiation, local ablative (e.g. cryosurgery or
high intensity focused ultrasound) or androgen deprivation therapy.

- 5-alpha reductase inhibitors (e.g. finasteride or dutasteride) within 180 days prior
to registration.

- Hypersensitivity to simvastatin or ezetimibe.

- Pharmacologic therapy with agents reported to produce adverse drug-drug interactions.
(Table 2)