Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy: study protocol

Aino Siltari, Jarno Riikonen, Juha Koskimäki, Tomi Pakarainen, Otto Ettala, Peter Boström, Heikki Seikkula, Andres Kotsar, Teuvo Tammela, Mika Helminen, Paavo V Raittinen, Terho Lehtimäki, Mikkel Fode, Peter Østergren, Michael Borre, Antti Rannikko, Timo Marttila, Arto Salonen, Hanna Ronkainen, Sven Löffeler, Teemu J Murtola, Aino Siltari, Jarno Riikonen, Juha Koskimäki, Tomi Pakarainen, Otto Ettala, Peter Boström, Heikki Seikkula, Andres Kotsar, Teuvo Tammela, Mika Helminen, Paavo V Raittinen, Terho Lehtimäki, Mikkel Fode, Peter Østergren, Michael Borre, Antti Rannikko, Timo Marttila, Arto Salonen, Hanna Ronkainen, Sven Löffeler, Teemu J Murtola

Abstract

Introduction: Blood cholesterol is likely a risk factor for prostate cancer prognosis and use of statins is associated with lowered risk of prostate cancer recurrence and progression. Furthermore, use of statins has been associated with prolonged time before development of castration resistance (CR) during androgen deprivation therapy (ADT) for prostate cancer. However, the efficacy of statins on delaying castration-resistance has not been tested in a randomised placebo-controlled setting.This study aims to test statins' efficacy compared to placebo in delaying development of CR during ADT treatment for primary metastatic or recurrent prostate cancer. Secondary aim is to explore effect of statin intervention on prostate cancer mortality and lipid metabolism during ADT.

Methods and analysis: In this randomised placebo-controlled trial, a total of 400 men with de novo metastatic prostate cancer or recurrent disease after primary treatment and starting ADT will be recruited and randomised 1:1 to use daily 80 mg of atorvastatin or placebo. All researchers, study nurses and patients will be blinded throughout the trial. Patients are followed until disease recurrence or death. Primary outcome is time to formation of CR after initiation of ADT. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and trigyserides) are analysed to test whether changes in serum cholesterol parameters during ADT predict length of treatment response. Furthermore, the trial will compare quality of life, cardiovascular morbidity, changes in blood glucose and circulating cell-free DNA, and urine lipidome during trial.

Ethics and dissemination: This study is approved by the Regional ethics committees of the Pirkanmaa Hospital District, Science centre, Tampere, Finland (R18065M) and Tarto University Hospital, Tarto, Estonia (319/T-6). All participants read and sign informed consent form before study entry. After publication of results for the primary endpoints, anonymised summary metadata and statistical code will be made openly available. The data will not include any information that could make it possible to identify a given participant.

Trial registration number: Clinicaltrial.gov: NCT04026230, Eudra-CT: 2016-004774-17, protocol code: ESTO2, protocol date 10 September 2020 and version 6.

Keywords: clinical trials; prostate disease; urological tumours.

Conflict of interest statement

Competing interests: PØ: honorarium as speaker from Ipsen A/S, Ferring Pharmaceuticals, and Astellas Pharma. MF: consultant fees and honorarium as speaker from Astellas and Ferring. HR: consultant fees from Bayer AB and honorarium as speaker from Sanofi. TJM: Consultant fees from Astellas, Janssen, speaker’s honorarium from Astellas, Janssen and Sanofi, participation in scientific meetings at the expense of Ferring, Pfizer, and Sanofi, stockholder for Arocell AB. PB: consultant fees from Astellas Pharma. All other authors: No competing interests to declare.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Study flow with inclusion and exclusion criteria. ADT, androgen deprivation therapy.
Figure 2
Figure 2
Sample size estimation with power 0.8 as a function of HR. Calculation was made based on study by Harshman et al.

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