Atorvastatin induces adrenal androgen downshift in men with prostate cancer: A post Hoc analysis of a pilot adaptive Randomised clinical trial

Abstract

Background: Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa.

Methods: This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms.

Findings: Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value <0.0001, median difference -342.5; 95% CI -505.23 - -188.98). In the prostatic tissue, atorvastatin was associated with plausible downshift in 11- ketodihydrotestosterone (placebo 25.0pM in 100 mg tissue/1 mL saline, atorvastatin 18.5pM in 100 mg tissue/1 mL saline, p-value 0.027, median difference -6.53; 95% CI -12.8 - -0.29); however, this association diminished after adjusting for multiple testing. No serious harms were reported.

Interpretation: Atorvastatin was associated with adrenal androgen downshift in the serum and possibly in the prostate. The finding warrants further investigation whether atorvastatin could improve androgen deprivation therapy efficacy.

Funding: Funded by grants from the Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and the Expert Responsibility Area of the Tampere University Hospital. CLINICALTRIALS.

Gov identifier: NCT01821404.

Keywords: Clinical trial; Prostate cancer; Prostatic tissue adrenal androgens; Serum adrenal androgens; Statins.

Conflict of interest statement

Declaration of Competing Interest Financial disclosures: Teemu J. Murtola certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr. Murtola reports grants from Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and Expert Responsibility Area of the Tampere University Hospital during the conduct of the study; personal fees from Astellas and Janssen, and other from Astellas and Bayer, outside the submitted work. Dr. Tammela reports grants from Expert Responsibility Area of the Tampere University Hospital, during the conduct of the study; personal fees from Astellas, Bayer, and Roche, outside the submitted work. Other authors have nothing to disclose.

Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Flowchart of the patient recruitment, randomization, and allocation scheme.

Fig. 2

Out-of-bag classification error (black points) and 95% confidence intervals (bars) for random forest classification models as a forest plot. Grey and white points are classification errors for atorvastatin and placebo arm, respectively; the bars are 95% confidence intervals. The confidence interval is for the Monte Carlo error. The vertical dotted line represents the 50% classification error, i.e., as-good-as-coin-flip; Out-of-bag classification error below 50% can be considered better model than random. Serum steroidomic hormone profile after the intervention classifies the treatment arms well. In the prostatic tissue, reduced model, with 11KDHT, DHEA, Estrone, and Testosterone as classifiers, classified the treatment arms with moderately low prediction error, whereas using all features failed in the classification task. For the serum, the sample sizes are n = 52 placebo and n = 56 atorvastatin. For the tissue, the sample sizes are n = 48 placebo and n = 51 atorvastatin.

Fig. 3

Random forest proximity plots for the serum and prostatic tissue hormone profiles. Grey dots represent men who received atorvastatin intervention and white dots represent patients who received placebo. The large grey and white dots are the mean centroids of atorvastatin and placebo arms, respectively. More densely clustered patients demonstrate similar within-group hormone profiles. Fig. 3a) serum profile after intervention shows densely clustered atorvastatin (n = 56) users indicating similarity in their hormone profiles whereas placebo (n = 52) users are randomly scattered indicating that no harmonic changes occurred in placebo arm. Fig. 3b) prostatic tissue profile after intervention does not show as clear clustering amongst atorvastatin (n = 51) users compared to serum hormone profiles, and no clustering of placebo arm (n = 48). The mean centroids are separated which indicates overall difference between the study arms.