{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T08:01:02Z","timestamp":1779264062205,"version":"3.51.4"},"reference-count":38,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T00:00:00Z","timestamp":1651190400000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Finnish Cancer Foundation","award":["024194"],"award-info":[{"award-number":["024194"]}]},{"name":"Finnish Cancer Foundation","award":["16112016"],"award-info":[{"award-number":["16112016"]}]},{"name":"Finnish Cancer Foundation","award":["3122800563"],"award-info":[{"award-number":["3122800563"]}]},{"DOI":"10.13039\/501100004212","name":"P\u00e4ivikki and Sakari Sohlberg Foundation","doi-asserted-by":"crossref","award":["31228005901"],"award-info":[{"award-number":["31228005901"]}],"id":[{"id":"10.13039\/501100004212","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009960","name":"Pirkanmaa hospital district","doi-asserted-by":"crossref","award":["9X032"],"award-info":[{"award-number":["9X032"]}],"id":[{"id":"10.13039\/501100009960","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009960","name":"Pirkanmaa hospital district","doi-asserted-by":"crossref","award":["X51001"],"award-info":[{"award-number":["X51001"]}],"id":[{"id":"10.13039\/501100009960","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["3121330724"],"award-info":[{"award-number":["3121330724"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["322098"],"award-info":[{"award-number":["322098"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032253","name":"Nordic Cancer Union","doi-asserted-by":"crossref","award":["MS793"],"award-info":[{"award-number":["MS793"]}],"id":[{"id":"10.13039\/100032253","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2022,2,9]]},"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>This study aims to test statins\u2019 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>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\u2009mg 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      Clinicaltrial.gov:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04026230\">NCT04026230<\/jats:ext-link>\n                      , Eudra-CT: 2016-004774-17, protocol code: ESTO2, protocol date 10 September 2020 and version 6.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-050264","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T08:19:02Z","timestamp":1652775542000},"page":"e050264","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy: study protocol"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct04026230","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04026230","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7814-427X","authenticated-orcid":false,"given":"Aino","family":"Siltari","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland"},{"name":"Faculty of Medicine, Pharmacology, University of Helsinki, Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jarno","family":"Riikonen","sequence":"additional","affiliation":[{"name":"Department of Urology, TAYS Cancer Center, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juha","family":"Koskim\u00e4ki","sequence":"additional","affiliation":[{"name":"Department of Urology, TAYS Cancer Center, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomi","family":"Pakarainen","sequence":"additional","affiliation":[{"name":"Department of Urology, TAYS Cancer Center, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1011-4602","authenticated-orcid":false,"given":"Otto","family":"Ettala","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Turku, Turku, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Bostr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Turku, Turku, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heikki","family":"Seikkula","sequence":"additional","affiliation":[{"name":"Department of Surgery, Central Finland Central Hospital, Jyvaskyla, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andres","family":"Kotsar","sequence":"additional","affiliation":[{"name":"Department of Urology, Tartu University Hospital, Tartu, Tartumaa, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teuvo","family":"Tammela","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Helminen","sequence":"additional","affiliation":[{"name":"Health Sciences, Tampere University, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paavo V","family":"Raittinen","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Systems Analysis, Aalto University School of Science and Technology, Espoo, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terho","family":"Lehtim\u00e4ki","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Tampere University, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikkel","family":"Fode","sequence":"additional","affiliation":[{"name":"Department of Urology, Herlev and Gentofte University Hospital, Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"\u00d8stergren","sequence":"additional","affiliation":[{"name":"Department of Urology, Herlev and Gentofte University Hospital, Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Borre","sequence":"additional","affiliation":[{"name":"Department of Urology, Aarhus Universitetshospital, Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antti","family":"Rannikko","sequence":"additional","affiliation":[{"name":"Department of Urology, Helsinki University and Helsinki University Hospital, Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timo","family":"Marttila","sequence":"additional","affiliation":[{"name":"Department of Urology, Sein\u00e4joki Central Hospital, Sein\u00e4joki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arto","family":"Salonen","sequence":"additional","affiliation":[{"name":"Department of Urology, Kuopio University Hospital, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna","family":"Ronkainen","sequence":"additional","affiliation":[{"name":"Department of Urology, Oulu University Hospital, Oulu, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3553-2491","authenticated-orcid":false,"given":"Sven","family":"L\u00f6ffeler","sequence":"additional","affiliation":[{"name":"Section of Urology, Vestfold Hospital Trust, Tonsberg, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2932-9590","authenticated-orcid":false,"given":"Teemu J","family":"Murtola","sequence":"additional","affiliation":[{"name":"Department of Urology, TAYS Cancer Center, Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"2025121221580972000_12.4.e050264.1","unstructured":"Finnish cancer registry statistics. Available: http:\/\/stats.cancerregistry.fi\/stats\/eng\/veng0003m0.html"},{"key":"2025121221580972000_12.4.e050264.2","unstructured":"M\u00e4klin S , Rissanen P . Cancer expenses in Finland. Available: http:\/\/www.cancer.fi\/@Bin\/47734\/Sy\u00f6pien+aiheuttamat+kustannukset.pdf"},{"key":"2025121221580972000_12.4.e050264.3","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.23304"},{"key":"2025121221580972000_12.4.e050264.4","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0157660","article-title":"Efficacy and safety of combined androgen deprivation therapy (ADT) and docetaxel compared with ADT alone for metastatic hormone-naive prostate cancer: a systematic review and meta-analysis","volume":"11","author":"Botrel","year":"2016","journal-title":"PLoS One"},{"key":"2025121221580972000_12.4.e050264.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1503747"},{"key":"2025121221580972000_12.4.e050264.6","doi-asserted-by":"crossref","first-page":"159","DOI":"10.5534\/wjmh.2014.32.3.159","article-title":"Primary androgen deprivation therapy for prostate cancer in Koreans: a retrospective multicenter study","volume":"32","author":"Seo","year":"2014","journal-title":"World J Mens Health"},{"key":"2025121221580972000_12.4.e050264.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2012.11120.x"},{"key":"2025121221580972000_12.4.e050264.8","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1002\/cam4.665","article-title":"Association between baseline serum glucose, triglycerides and total cholesterol, and prostate cancer risk categories","volume":"5","author":"Arthur","year":"2016","journal-title":"Cancer Med"},{"key":"2025121221580972000_12.4.e050264.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.10.022"},{"key":"2025121221580972000_12.4.e050264.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039445"},{"key":"2025121221580972000_12.4.e050264.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2014.06.001"},{"key":"2025121221580972000_12.4.e050264.12","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2172"},{"key":"2025121221580972000_12.4.e050264.13","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.385"},{"key":"2025121221580972000_12.4.e050264.14","doi-asserted-by":"crossref","DOI":"10.1038\/pcan.2016.3","article-title":"Association between statins and clinical outcomes among men with prostate cancer: a systematic review and meta-analysis","volume":"19","author":"Raval","year":"2016","journal-title":"Prostate Cancer Prostatic Dis"},{"key":"2025121221580972000_12.4.e050264.15","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-13-0515"},{"key":"2025121221580972000_12.4.e050264.16","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1097\/JU.0000000000000494","article-title":"Serum lipids prior to starting androgen deprivation therapy and risk of castration resistant prostate cancer and metastasis: results from the search database","volume":"203","author":"Dambal","year":"2020","journal-title":"J Urol"},{"key":"2025121221580972000_12.4.e050264.17","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.ejca.2018.11.033","article-title":"Prostate cancer incidence and mortality among men using statins and non-statin lipid-lowering medications","volume":"112","author":"Van Rompay","year":"2019","journal-title":"Eur J Cancer"},{"key":"2025121221580972000_12.4.e050264.18","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/s41391-020-0207-5","article-title":"Associations among statins, preventive care, and prostate cancer mortality","volume":"23","author":"Kumar","year":"2020","journal-title":"Prostate Cancer Prostatic Dis"},{"key":"2025121221580972000_12.4.e050264.19","doi-asserted-by":"publisher","DOI":"10.1515\/hsz-2014-0194"},{"key":"2025121221580972000_12.4.e050264.20","doi-asserted-by":"publisher","DOI":"10.2174\/187152012800228715"},{"key":"2025121221580972000_12.4.e050264.21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.12954\/PI.14063","article-title":"Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy","volume":"2","author":"Armandari","year":"2014","journal-title":"Prostate Int"},{"key":"2025121221580972000_12.4.e050264.22","doi-asserted-by":"crossref","first-page":"86","DOI":"10.2174\/1874467209666160112125631","article-title":"Interconnection of Estrogen\/Testosterone metabolism and mevalonate pathway in breast and prostate cancers","volume":"10","author":"Mokarram","year":"2017","journal-title":"Curr Mol Pharmacol"},{"key":"2025121221580972000_12.4.e050264.23","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1001\/jamaoncol.2015.0829","article-title":"Statin use at the time of initiation of androgen deprivation therapy and time to progression in patients with hormone-sensitive prostate cancer","volume":"1","author":"Harshman","year":"2015","journal-title":"JAMA Oncol"},{"key":"2025121221580972000_12.4.e050264.24","doi-asserted-by":"publisher","DOI":"10.4111\/kju.2015.56.9.630"},{"key":"2025121221580972000_12.4.e050264.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.11.021"},{"key":"2025121221580972000_12.4.e050264.26","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/jcpt.13092","article-title":"The effect of statins on advanced prostate cancer patients with androgen deprivation therapy or abiraterone\/enzalutamide: a systematic review and meta-analysis","volume":"45","author":"Yang","year":"2020","journal-title":"J Clin Pharm Ther"},{"key":"2025121221580972000_12.4.e050264.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2014.02.006"},{"key":"2025121221580972000_12.4.e050264.28","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.eururo.2018.06.037","article-title":"Atorvastatin versus placebo for prostate cancer before radical Prostatectomy-A randomized, double-blind, placebo-controlled clinical trial","volume":"74","author":"Murtola","year":"2018","journal-title":"Eur Urol"},{"key":"2025121221580972000_12.4.e050264.29","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/s41391-020-0221-7","article-title":"A pilot window-of-opportunity study of preoperative fluvastatin in localized prostate cancer","volume":"23","author":"Longo","year":"2020","journal-title":"Prostate Cancer Prostatic Dis"},{"key":"2025121221580972000_12.4.e050264.30","doi-asserted-by":"crossref","DOI":"10.1016\/j.eururo.2020.12.031","article-title":"The association between statin use and outcomes in patients initiating androgen deprivation therapy","volume":"79","author":"Hamilton","year":"2021","journal-title":"Eur Urol"},{"key":"2025121221580972000_12.4.e050264.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2008.08.010"},{"key":"2025121221580972000_12.4.e050264.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2019.103208"},{"key":"2025121221580972000_12.4.e050264.33","unstructured":"World Health Organization . WHOQOL-BREF, the world Health organization quality of life, 2021."},{"key":"2025121221580972000_12.4.e050264.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2016.08.037"},{"key":"2025121221580972000_12.4.e050264.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajur.2016.08.003"},{"key":"2025121221580972000_12.4.e050264.36","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-008-9144-9"},{"key":"2025121221580972000_12.4.e050264.37","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1007\/s00259-018-4116-y","article-title":"Longitudinal PET imaging of tumor hypoxia during the course of radiotherapy","volume":"45","author":"Stieb","year":"2018","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"2025121221580972000_12.4.e050264.38","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.cpet.2019.06.007","article-title":"Pet assessment of immune effects from interventional oncology procedures","volume":"14","author":"Hunt","year":"2019","journal-title":"PET Clin"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2021-050264","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T05:58:21Z","timestamp":1765605501000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2021-050264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4,29]]},"published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1136\/bmjopen-2021-050264"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2021-050264","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4]]}}}