title: Can atorvastatin with metformin change the natural history of prostate cancer as characterized by molecular, metabolomic, imaging and pathological variables? A randomized controlled trial protocol.
abstract: Atorvastatin and metformin are known energy restricting mimetic agents that act synergistically to produce molecular and metabolic changes in advanced prostate cancer (PCa). This trial seeks to determine whether these drugs favourably alter selected parameters in men with clinically-localized, aggressive PCa.
  
  
  
  This prospective phase II randomized, controlled window trial is recruiting men with clinically significant PCa, confirmed by biopsy following multiparametric MRI and intending to undergo radical prostatectomy. Ethical approval was granted by the Royal Brisbane and Women's Hospital Human and The University of Queensland Medical Research Ethics Committees. Participants are being randomized into four groups: metformin with placebo; atorvastatin with placebo; metformin with atorvastatin; or placebo alone. Capsules are consumed for 8weeks, a duration selected as the most appropriate period in which histological and biochemical changes may be observed while allowing prompt treatment with curative intent of clinically significant PCa. At recruitment and prior to RP, participants provide blood, urine and seminal fluid. A subset of participants will undergo 7Tesla magnetic resonance spectroscopy to compare metabolites in-vivo with those in seminal fluid and biopsied tissue. The primary end point is biochemical evolution, defined using biomarkers (serum prostate specific antigen; PCA3 and citrate in seminal fluid and prostatic tissue). Standard pathological assessment will be undertaken.
  
  
  
  This study is designed to assess the potential synergistic action of metformin and atorvastatin on PCa tumour biology. The results may determine simple methods of tumour modulation to reduce disease progression.
authors.affiliation: The University of Queensland, Centre for Clinical Research, Building 71/918, RBWH, Herston, Brisbane, Qld 4029, Australia; Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia; School of Medicine, The University of Queensland, Herston, Qld 4006, Australia; The Centre for Advanced Imaging, The University of Queensland, St. Lucia, Brisbane, Qld 4072, Australia. Electronic address: m.roberts2@uq.edu.au.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Roberts
authors.affiliation: Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia. Electronic address: dryaxley@wesleyurologyclinic.com.au.
authors.forename: John W
authors.initials: JW
authors.lastname: Yaxley
authors.affiliation: Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia. Electronic address: geoff_coughlin@me.com.
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Coughlin
authors.affiliation: Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia; School of Medicine, The University of Queensland, Herston, Qld 4006, Australia. Electronic address: troygianduzzo@gmail.com.
authors.forename: Troy R J
authors.initials: TR
authors.lastname: Gianduzzo
authors.affiliation: Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia. Electronic address: rachel.esler@gmail.com.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Esler
authors.affiliation: Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia. Electronic address: nigeldunglison@gmail.com.
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Dunglison
authors.affiliation: The University of Queensland, Centre for Clinical Research, Building 71/918, RBWH, Herston, Brisbane, Qld 4029, Australia; Griffith Health Institute, Griffith University, Gold Coast, Qld 4222, Australia. Electronic address: suzanne.chambers@griffith.edu.au.
authors.forename: Suzanne K
authors.initials: SK
authors.lastname: Chambers
authors.affiliation: The University of Queensland, Centre for Clinical Research, Building 71/918, RBWH, Herston, Brisbane, Qld 4029, Australia; Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia. Electronic address: r.medcraft@uq.edu.au.
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Medcraft
authors.affiliation: The University of Queensland, Centre for Clinical Research, Building 71/918, RBWH, Herston, Brisbane, Qld 4029, Australia. Electronic address: c.chow3@uq.edu.au.
authors.forename: Clement W K
authors.initials: CW
authors.lastname: Chow
authors.affiliation: The Centre for Advanced Imaging, The University of Queensland, St. Lucia, Brisbane, Qld 4072, Australia. Electronic address: horst.schirra@cai.uq.edu.au.
authors.forename: Horst Joachim
authors.initials: HJ
authors.lastname: Schirra
authors.affiliation: The University of Queensland, Centre for Clinical Research, Building 71/918, RBWH, Herston, Brisbane, Qld 4029, Australia. Electronic address: r.richards@uq.edu.au.
authors.forename: Renee S
authors.initials: RS
authors.lastname: Richards
authors.affiliation: Department of Medical Imaging, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia. Electronic address: nicholas.kienzle@health.qld.gov.au.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kienzle
authors.affiliation: Department of Medical Imaging, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia. Electronic address: macy.lu@health.qld.gov.au.
authors.forename: Macy
authors.initials: M
authors.lastname: Lu
authors.affiliation: The Centre for Advanced Imaging, The University of Queensland, St. Lucia, Brisbane, Qld 4072, Australia. Electronic address: i.brereton@uq.edu.au.
authors.forename: Ian
authors.initials: I
authors.lastname: Brereton
authors.affiliation: School of Medicine, The University of Queensland, Herston, Qld 4006, Australia; Aquesta Pathology, PO Box 1878, Toowong DC, Brisbane, Qld 4066, Australia. Electronic address: hema@acquesta.com.au.
authors.forename: Hema
authors.initials: H
authors.lastname: Samaratunga
authors.affiliation: Anatomical Pathology, Pathology Queensland, Herston, Brisbane, Qld 4029, Australia. Electronic address: Joanna.Perry-Keene@health.qld.gov.au.
authors.forename: Joanna
authors.initials: J
authors.lastname: Perry-Keene
authors.affiliation: Anatomical Pathology, Pathology Queensland, Herston, Brisbane, Qld 4029, Australia. Electronic address: Diane.Payton@health.qld.gov.au.
authors.forename: Diane
authors.initials: D
authors.lastname: Payton
authors.affiliation: Department of Urology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki 036-8562, Japan. Electronic address: coyama@cc.hirosaki-u.ac.jp.
authors.forename: Chikara
authors.initials: C
authors.lastname: Oyama
authors.affiliation: Research School of Population Health, The Australian National University, Canberra, ACT, Australia; School of Agricultural, Computational and Environmental Sciences, University of Southern Queensland, Toowoomba, Australia; College of Medicine, Qatar University, Doha, Qatar. Electronic address: sardoi@gmx.net.
authors.forename: Suhail A
authors.initials: SA
authors.lastname: Doi
authors.affiliation: The University of Queensland, Centre for Clinical Research, Building 71/918, RBWH, Herston, Brisbane, Qld 4029, Australia. Electronic address: m.lavin@uq.edu.au.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
authors.affiliation: The University of Queensland, Centre for Clinical Research, Building 71/918, RBWH, Herston, Brisbane, Qld 4029, Australia; Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld 4029, Australia; School of Medicine, The University of Queensland, Herston, Qld 4006, Australia; Edith Cowan University, Joondalup, WA 6027, Australia. Electronic address: f.gardiner@uq.edu.au.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Gardiner
mesh_terms: D000951:Antigens, Neoplasm / Q000032:analysis; D000069059:Atorvastatin / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D019343:Citric Acid / Q000032:analysis; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D012107:Research Design
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C479341:prostate cancer antigen 3, human; D019343:Citric Acid; D008687:Metformin; D000069059:Atorvastatin; D017430:Prostate-Specific Antigen
keywords: Atorvastatin; Biomarkers; Clinical trial; Metabolomics; Metformin; Prostate cancer