Metastatic Prostate Cancer, Recurrent Prostate Cancer
Conditions
Keywords
Prostate cancer, Castration resistance, Cholesterol lowering drug, Cholesterol, Atorvastatin, Survival, Mortality
Brief summary
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.
Detailed description
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.
Interventions
DRUGAtorvastatin 80mg
Capsules including 80 mg of atorvastatin
DRUGPlacebo oral capsule
Similar capsules as in the atorvastatin arm, but without the active ingredient
Sponsors
Turku University Hospital
Central Finland Hospital District
Tartu University Hospital
University of Aarhus
Fimlab laboratories
Helsinki University Central Hospital
Kuopio University Hospital
Oulu University Hospital
Seinajoki Central Hospital
The Hospital of Vestfold
Telemark Hospital Trust
Tampere University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histopathologically confirmed metastatic (radiologically confirmed bone or soft tissue metastasis or enlarged lymph nodes at minimum 15 mm in diameter beyond the pelvic lymph nodes) or recurrent (requiring treatment after curative-intent surgery or radiotherapy) adenocarcinoma of the prostate for which androgen deprivation or antiandrogen therapy (GnRH agonist/antagonist, bicalutamide/flutamide, surgical castration or enzalutamide/abiraterone monotherapy) is initiated as definitive treatment no longer than 3 months before recruitment * previous prostatectomy and radiation therapy allowed * ADT/antiandrogen therapy for neoadjuvant hormone therapy is not included * Willingness to participate and signing of informed consent
Exclusion criteria
* Statin use at the time of recruitment or within 6 months of it * Previous adverse effects during statin therapy * Familial hypercholesterolemia or very high total cholesterol (9.3 mmol/l or above) * Clinically significant renal insufficiency (serum creatinine above 170 µmol/l) or liver insufficiency (serum alanine aminotransferase more than 2x above the upper limit of normal range) * Use of drugs that may interact with statins (St John's Wort, HIV protease inhibitors, ciclosporin, macrolide antibiotics, fucidic acid, phenytoin, carbamazepine, dronedarone or oral antifungal medication).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Castration resistance | From date of randomization until the date of first occurrence of castration resistance, assessed up to 60 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lipid levels | 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 | 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 |
| Prostate cancer mortality | From date of randomization until the date of prostate cancer death, assessed up to 60 months | Followed through Finnish national registries after reaching the primary end-point |
| Overall survival | From date of randomization until the date of death due to any cause, assessed up to 60 months | Followed through Finnish national registries after reaching the primary end-point |
| Circulating cell-free DNA | At enrollment and at occurrence of castration resistance, assessed up to 60 months | Occurrence of adverse tumor traits predicting development of castration resistance in circulating cell free DNA |
| Fasting blood glucose | 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 | To see how ADT affects glucose tolerance and whether atorvastatin intervention has any effect on it |
| Occurrence of cardiovascular events during ADT | 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 | 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. |
| General quality of life (QOL) | 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 | Score from validated QOL questionnaire EORTC QLQ-C30 (range 0-100, with 100 denoting highest quality of life) |
| Prostate cancer-specific quality of life (QOL) | 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 | Score from validated QOL questionnaire EORTC QLQ-PR25 (range 0-100, with 100 denoting highest quality of life) |
Countries
Denmark, Estonia, Finland, Norway
Contacts
Primary ContactTeemu Murtola, MD, PhD
Backup ContactAino Siltari, PhD
Outcome results
None listed