Phase II proof of concept study of atorvastatin in castration resistant prostate cancer

Rushworth, L. K. et al. (2023) Phase II proof of concept study of atorvastatin in castration resistant prostate cancer. BJU International, 131(2), pp. 236-243. (doi: 10.1111/bju.15851) (PMID:35844167) (PMCID:PMC10087532)

Abstract

Objectives: To test for evidence of statin-mediated effects in patients with castration resistant prostate cancer as post-diagnosis use of statins in patients with prostate cancer is associated with favourable survival outcome. Enhanced tumoral cholesterol uptake can drive castration resistant prostate cancer (CRPC). However, it remains unclear whether these associations result from confounding factors or directly from statin mediated effects. Patients and Methods: The SPECTRE trial was a 6-weeks long proof-of-concept single-arm Phase II treatment trial combining atorvastatin and androgen deprivation therapy in patients with CRPC (regardless of the metastatic status), designed to test for evidence of statin-mediated effects in patients with CRPC. The primary study endpoint was the proportion of patients achieving ≥50% drop from baseline in PSA levels at any time over the 6-week period of atorvastatin medication (PSA response). Exploratory endpoints include PSA velocity and mass spectrometrically identified serum metabolites. Results: At scheduled interim analysis, one of twelve patients experienced a ≥50% drop in PSA levels (primary endpoint), with ≥2 patients satisfying the primary endpoint required for further recruitment. All 12 experienced substantial falls in serum cholesterol levels following statin treatment. While all patients had comparable pre-study PSA velocities, 6 of 12 patients showed decreased PSA velocities following statin treatment, suggestive of disease stablisation. Unbiased metabolomics analysis on serial weekly blood samples identified tryptophan to be the dominant metabolite associated with patient response to statin. Conclusions: Data from the SPECTRE study provides the first evidence of statin mediated effects on CRPC and early sign of disease stabilisation. Our data also highlights the possibility of altered tryptophan metabolism being associated with tumour response.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McCartney, Miss Elaine and Delles, Professor Christian and Leung, Professor Hing and Alexander, Mrs Laura and Loveridge, Dr Carolyn and Neilson, Dr Matthew and Rushworth, Dr Linda and Jones, Professor Robert and Mui, Mr Ernest and MacLeod, Mr Martin and Salji, Dr Mark and Sumpton, Mr David and Patel, Dr Rachana
• Authors: Rushworth, L. K., Loveridge, C., Salji, M., MacLeod, M., Mui, E., Sumpton, D., Neilson, M., Hedley, A., Alexander, L., McCartney, E., Patel, R., Wallace, J., Delles, C., Jones, R., and Leung, H. Y.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: BJU International
• Publisher: Wiley
• ISSN: 1464-4096
• ISSN (Online): 1464-410X
• Published Online: 18 July 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in BJU International 131(2): 236-243
• Publisher Policy: Reproduced under a Creative Commons licence

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172001		Combined Suppression of cholesterol bioavailability and androgen de novo syntheseis to treat castrate resistant prostate cancer	Hing Leung	Prostate Cancer UK (PROSCANU)	PG14-009-TR2	CS - Clinical Trials Research
300392		Cancer Research UK Clinical Trials Unit - Core Programme Funding	Robert Jones	Cancer Research UK (CRUK)	C1348/A25355	CS - Clinical Trials UInit Gartnavel