Statin Therapy Versus Placebo Prior to Prostatectomy

Prostate cancer patients that have chosen to undergo a prostatectomy as their primary
treatment option will be recruited to this trial. Forty-four subjects will be randomized to
either placebo or simvastatin (40 mg po/day) for 4 weeks prior to surgery. Serum samples
will be obtained at baseline and immediately prior to prostatectomy. At prostatectomy,
cancerous and benign prostate tissue will be microdissected and cryopreserved. Archival
prostatectomy tissues will be used to construct tissue microarrays containing matched benign
and malignant sections. The effect of HMG-CoA reductase inhibition on lipid raft cholesterol
content and targets of prenylation will be determined. The incidence of apoptosis will be
determined along with protein levels of mediators of apoptosis. Lastly the effect of statin
therapy on cellular markers of proliferation will be determined.

Previously, we studied the effect of statin use on the risk of prostate cancer detection in
a case-control study at the Portland VA Medical Center. Statin use was associated with a
62% reduction in cancer odds-risk (OR = 0.38, 95% CI 0.21-0.69). Although these
epidemiologic and laboratory findings have generated enthusiasm for the study of statins in
prostate cancer, no studies have examined the biologic effects of statins on prostate cancer
in humans.

Hypothesis: Statin therapy prior to prostatectomy will successfully target the mevalonate
pathway in the human prostate and this intervention will favorably alter tumor biomarker
status.

Inclusion Criteria:

- Histologically confirmed prostatic adenocarcinoma with Gleason 5 to 7 (3+4 = 7
accepted, not 4 + 3 = 7)

- Radical prostatectomy chosen as primary treatment for prostate cancer

- Age 18 years or older

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

- Other preoperative or prior treatment directed at prostate cancer (i.e., Radiation,
hormonal therapy, cryotherapy)

- Significant active medical illness which in the opinion of the investigator would
preclude protocol treatment

- History of or active liver disease or abnormal results of the baseline liver function
test (> 2 x normal)

- Current use of:

- simvastatin

- lovastatin

- other HMG-CoA inhibitors

- lipid-lowering agents

- Amiodarone

- Cholestyramine

- Cholestyramine and colestipol (bile acid sequestrants)

- Clofibrate and fenofibrate

- Cyclosporine

- CYP3A4 inhibitors

- Danazol

- Diltiazem

- Gemfibrozil

- Niacin ( 1 g/day)

- Verapamil and Warfarin

- Known allergy or sensitivity to ingredients in simvastatin