Atorvastatin Before Prostatectomy and Prostate Cancer (ESTO1)

The Impact of Atorvastatin on Prostate Cancer - a Randomized, Pre-surgical Clinical Trial

This single-center, randomized, double-blind trial assesses the impact of short-term atorvastatin administration on proliferation activity, apoptotic rate and histological inflammation in prostate tissue.

Study Overview

• Status: Completed
• Conditions: Prostatic Neoplasms
• Intervention / Treatment: Drug: Placebo; Drug: Atorvastatin

Detailed Description

In this trial 160 men who have been diagnosed with prostate cancer, and whose first-line treatment will be radical prostatectomy (surgical removal of the prostate), are randomized to receive either 80 mg atorvastatin or placebo daily for 2-5 weeks until the operation. Blood cholesterol and serum PSA are measured before starting the study drug use and before the operation.

After the operation change in PSA and histological inflammation, apoptotic rate and Ki-67 staining intensity are compared between atorvastatin-treated and placebo-treated men. The correlation between changes in serum cholesterol or prostate specific antigen (PSA) and the tissue characteristics is evaluated.

After recruiting 60 men we will perform an interim analysis on primary end-points without breaking the blinding to treatment allocation. If we observe a statistically significant difference in all primary end-points, the trial will be stopped early and the results published.

Additionally, atorvastatin concentration in the blood and the prostate tissue is measured with mass spectrometry to determine penetrance of atorvastatin into the prostate. DNA- and RNA-samples are obtained from the prostate tissue and the blood. These will be used to study how gene expression of statin- and cholesterol-modifying enzymes affects the responses observed in prostate tissue.

As a secondary end-point we will measure recovery of erectile function after the operation and compare between the two study arms. Erectile function is measured using IIEF-5 questionnaire once before the operation and again 3, 6, 9 and 12 months from the prostatectomy.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Lahti, Finland
    • Päijät-Häme Central Hospital
  • Pori, Finland
    • Satakunta Central Hospital
  • Tampere, Finland, 33521
    • Tampere University Hospital, Department of Urology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Prostate cancer proven histologically in prostate biopsy
• Radical prostatectomy selected as the first-line treatment
• Willingness to participate and sign informed consent

Exclusion Criteria:

• Previous oncological treatments for any malignancy
• Previous usage of statins, finasteride or dutasteride within a year prior to prostate cancer diagnosis
• Clinically significant liver- or kidney insufficiency (plasma alanine aminotransferase level is twice over the recommended upper limit or serum creatinine level is over 170 µmol/l)
• Previous adverse effects from cholesterol-lowering treatment
• Ongoing use of drugs having interactions with statins (St John's Wort, HIV protease inhibitors, ciclosporin, macrolide antibiotics, fusidic acid, phenytoin, carbamazepine, dronedarone or oral antifungal medication)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Similar capsules as in the atorvastatin arm, but including no active ingredient. Used daily for 3-5 weeks before prostatectomy	Drug: Placebo; Similar capsules as in the atorvastatin arm, but without the active ingredient
Experimental: Atorvastatin; Atorvastatin capsules orally, 80 mg daily for 3-5 weeks before prostatectomy	Drug: Atorvastatin; Capsules including 80 mg of atorvastatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apoptosis	Number of apoptotic cells in prostate tissue. Measured after radical prostatectomy, on average after 4 weeks of recruitment	Four weeks after recruitment
Ki-67 expression	Cellular proliferation activity in prostate tissue as measured by Ki-67 expression. Measured after radical prostatectomy, on average after 4 weeks of recruitment	Four weeks after recruitment
Histological inflammation	Extent of histological inflammation in the prostate tissue as evaluated by study pathologist	After prostatectomy
serum PSA	Change in serum PSA level as measured before starting the study drug and again just before prostatectomy	At recruitment and before prostatectomy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
serum cholesterol	Changes in measured fasting serum cholesterol parameters: total cholesterol, HDL and LDL. First measure is done at recruitment, another right before radical prostatectomy.	At recruitment and again four weeks after
Atorvastatin level in prostate tissue	Measurement of atorvastatin level in prostate tissue with mass spectrometry. Measured after radical prostatectomy, on average four weeks after recruitment	Four weeks after recruitment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genotype of cholesterol-metabolizing enzymes	Genotyping of cholesterol-metabolizing enzymes from blood and tissue samples	Post-hoc analysis, one year after recruitment completes
Genotype of statin-metabolizing enzymes	Genotyping statin-metabolizing enzymes from blood and tissue samples	Post hoc analysis, one year after recruitment completes
Erection function	Erectile function as measured with IIEF-5 questionnaire before prostatectomy and again at 3 month intervals during the first year after prostatectomy	One year after prostatectomy

Collaborators and Investigators

• Sponsor: Tampere University Hospital
• Collaborators: Tampere University; University of Eastern Finland; Finnish Cultural Foundation; Fimlab laboratories
• Investigators: Principal Investigator: Teemu J Murtola, M.D., Ph.D., Tampere University; Study Director: Teuvo LJ Tammela, M.D., Ph.D., Tampere University

Publications and helpful links

General Publications

• Raittinen PVH, Syvala H, Tammela TLJ, Hakkinen MR, Ilmonen P, Auriola S, Murtola TJ. Atorvastatin induces adrenal androgen downshift in men with prostate cancer: A post Hoc analysis of a pilot adaptive Randomised clinical trial. EBioMedicine. 2021 Jun;68:103432. doi: 10.1016/j.ebiom.2021.103432. Epub 2021 Jun 16.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): May 1, 2017
• Study Completion (Actual): May 1, 2017

Study Registration Dates

• First Submitted: March 22, 2013
• First Submitted That Met QC Criteria: March 26, 2013
• First Posted (Estimate): April 1, 2013

Study Record Updates

• Last Update Posted (Actual): May 7, 2018
• Last Update Submitted That Met QC Criteria: May 4, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Inflammation; Prostate cancer; Atorvastatin; Apoptosis; Pre-surgical trial; Proliferation
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: 2011-005438-20