Abstract B69: Trial in progress: The impact of atorvastatin on prostate cancer - A randomized, presurgical clinical trial

Background: A widely used group of cholesterol-lowering drugs, statins, have shown promise in prostate cancer prevention. Statin treatment inhibits growth of prostate cancer cells. Statin users have decreased risk of advanced prostate cancer and possibly improved relapse-free survival after curative-intent treatment. Objectives: This single-center, randomized, double-blind trial will assess the impact of short-term atorvastatin administration on proliferation activity, apoptotic rate and histological inflammation in prostate tissue. Serum PSA and cholesterol level are followed during the intervention, and any changes compared to responses in prostate tissue. Concentration of atorvastatin in blood and tissue is measured. Gene-and protein-expression of cholesterol- and statin-metabolizing enzymes are examined in serum and prostate tissue. Materials and methods: The study will randomize 160 men undergoing radical in a 1:1 ratio to receive either 80 mg atorvastatin or placebo each day until the time of the operation, for the period of 4-5 weeks in average. Physicians, patients and pathologists remain blinded to the study allocation until data analysis. Serum PSA and fasting lipoprotein-profile is determined before initiation of medication use and on the day before the operation. Extra blood samples are taken from each participant to obtaining serum DNA-sample and measurement of atorvastatin concentration with mass spectrometry. After prostatectomy, a piece of fresh prostate tissue is separated for making of tissue RNA-sample and determination of atorvastatin concentration in the tissue. After standard pathological evaluation of the prostate study pathologist picks slides from the tumor and histologically normal tissue for immunohistochemical evaluation of inflammation, Ki-67 proliferation index, apoptotic activity and expression of cholesterol-metabolizing enzymes. Inclusion- and exclusion criteria: Inclusion criteria for the study are: 1) histologically confirmed, previously untreated prostate cancer, 2) radical prostatectomy as the first-line treatment and 3) willingness to participate and signing of informed consent. Exclusion criteria are: 1) previous oncological treatments for any malignancy, 2) previous usage of statins, finasteride or dudasteride 3) clinical liver- or kidney insufficiency 4) previous adverse effects from cholesterol-lowering treatment and 5) ongoing use of drugs interacting with statin drugs. Power calculations: Previously a 4-13% decrease in serum PSA has been reported in statin users. The number of study participants needed do detect a 4% difference (statistical power 0.80, α=0.05) is 962, whereas 117 participants are needed to detect a 13% difference. Statins are expected to lower Ki-67 index in prostate cancer by 12-54%. A total of 50 patients would be needed to detect a 12% difference, and 12 patients needed to detect a 54% difference. The sample size of 160 men was chosen to allow detection of change in Ki-67 proliferation index while leaving good possibility to detect a change in serum PSA even assuming a dropout rate of 10%. Ethical considerations: The study is ethically sound, as it evaluates a commonly used and well-tolerated drug, atorvastatin, in prevention of prostate cancer, a common disease causing significant morbidity and mortality. The participants will give informed consent. The participants are selected to minimize the probability of side-effects; the study drug will be stopped if side-effects occur. The study does not interfere with normal diagnosis and management of prostate cancer. The ethics committee of Pirkanmaa Health Care District has approved the study protocol. Importance and phase of study: The study will show whether atorvastatin has a clinically significant impact on prostate cancer growth. The recruitment of participants starts in August 2012, and is expected to be completed by the end of 2014. Citation Format: Teemu J. Murtola, Jarno Riikonen, Juha Koskimaki, Antti Kaipia, Paula Kujala, Teemu Tolonen, Heimo Syvala, Seppo Auriola, Emma Raitoharju, Terho Lehtimaki, Teuvo LJ Tammela. Trial in progress: The impact of atorvastatin on prostate cancer – A randomized, presurgical clinical trial. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B69.