This randomized double-blind placebo-controlled trial tests whether intervention with atorvastatin delays development of castration resistance compared to placebo during androgen deprivation therapy (ADT) for prostate cancer.
Cholesterol-lowering statin drugs have been reported to lower proliferation activity in prostate cancer, delay occurrence of castration resistance and reduce the risk of prostate cancer death. Therefore, it is important to test statins' efficacy in addition to conventional prostate cancer treatment in a randomized, placebo-controlled trial. This phase 3 randomized double-blind placebo-controlled trial will explore whether intervention with atorvastatin delays prostate cancer progression i.e. development of castration resistance compared to placebo during androgen deprivation therapy (ADT) for metastatic or recurrent prostate cancer. Secondary objectives include exploring whether atorvastatin lowers prostate cancer-specific or overall mortality compared to placebo, and to demonstrate whether changes in serum lipid parameters predict disease recurrence and occurrence of adverse genomic changes predicting castration resistance among prostate cancer patients during ADT. The study recruitment target is 400 participants who start ADT as management of metastatic or recurrent prostate cancer. These men will be randomized 1:1 (200 + 200) to receive blinded study drug, either 80 mg of atorvastatin daily or placebo until disease recurrence i.e. development of castration resistance or for a maximum of five years. The study will be carried out in collaboration between urological departments of University Hospitals in Finland as a project of the national FinnProstata study group, Herlev University Hospital in Denmark, Vestfold and Telemark hospitals in Norway and the Tartu University Hospital in Estonia. Follow-up is continued until the primary end-point, development of castration resistance. After this the participants will be given the opportunity to voluntarily carry on with the blinded intervention for maximum time of ten year to observe effects on survival after development of castration resistance. Blinding will be lifted after the follow-up is complete for all study participants. Castration resistance is defined as prostate-specific antigen (PSA) progression (three consecutive rises of PSA measured at least 1 week apart with two \> 50% increases over the nadir and PSA \> 2 ng/ml) or radiological disease progression (appearance of two or more lesions in bone scan or soft tissue enlargement as per RECIST criteria) with serum testosterone at castrate level (\< 1.73 nmol/l; 50 ng/dl) during ADT.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
400
Capsules including 80 mg of atorvastatin
Similar capsules as in the atorvastatin arm, but without the active ingredient
Herlev and Gentofte Hospital
Herlev, Denmark
NOT_YET_RECRUITINGTartu University Hospital
Tartu, Estonia
RECRUITINGHelsinki University Hospital, Department of Urology
Helsinki, Finland
Castration resistance
Castration resistance is defined as PSA progression (three consecutive PSA rises measured at least 1 week apart with two \> 50% increases over the nadir and PSA \> 2 ng/ml) or radiological disease progression (appearance of two or more lesions in bone scan or soft tissue enlargement as per RECIST criteria) with serum testosterone at castrate level (\< 1.73 nmol/l; 50 ng/dl) during ADT.
Time frame: From date of randomization until the date of first occurrence of castration resistance, assessed up to 60 months
Lipid levels
Change in serum lipid levels during the intervention. Measured at baseline and in every follow-up visit. Results are blinded from the investigators and participants before the final analysis
Time frame: From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 6 month intervals up to 60 months
Prostate cancer mortality
Followed through Finnish national registries after reaching the primary end-point
Time frame: From date of randomization until the date of prostate cancer death, assessed up to 60 months
Overall survival
Followed through Finnish national registries after reaching the primary end-point
Time frame: From date of randomization until the date of death due to any cause, assessed up to 60 months
Circulating cell-free DNA
Occurrence of adverse tumor traits predicting development of castration resistance in circulating cell free DNA
Time frame: At enrollment and at occurrence of castration resistance, assessed up to 60 months
Fasting blood glucose
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Central Finland central hospital
Jyväskylä, Finland
RECRUITINGKuopio University Hospital, Department of Urology
Kuopio, Finland
NOT_YET_RECRUITINGSeinäjoki Central Hospital, Department of Surgery
Seinäjoki, Finland
RECRUITINGTampere University Hospital
Tampere, Finland
RECRUITINGTurku University Hospital
Turku, Finland
RECRUITINGThe Hospital of Telemark
Skien, Norway
RECRUITINGThe Hospital of Vestfold
Tønsberg, Norway
RECRUITINGTo see how ADT affects glucose tolerance and whether atorvastatin intervention has any effect on it
Time frame: From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 6 month intervals up to 60 months
Occurrence of cardiovascular events during ADT
Any cardiovascular events as described by the participant or evident from the patient files during the course of follow-up. Followed via national registries after meeting the primary end-point.
Time frame: From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 6 month intervals up to 60 months
General quality of life (QOL)
Score from validated QOL questionnaire EORTC QLQ-C30 (range 0-100, with 100 denoting highest quality of life)
Time frame: From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 12 month intervals up to 60 months
Prostate cancer-specific quality of life (QOL)
Score from validated QOL questionnaire EORTC QLQ-PR25 (range 0-100, with 100 denoting highest quality of life)
Time frame: From date of randomization until the date of first occurrence of castration resistance or death, whichever came first, assessed at 12 month intervals up to 60 months