Impact of Atorvastatin on Prostate Cancer Progression During ADT

Study Overview
=================
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.

Official Title
-----------------
Impact of Atorvastatin on Prostate Cancer Progression After Initiation of Androgen Deprivation Therapy - Lipid Metabolism as a Novel Biomarker to Predict Prostate Cancer Progression

Conditions
-----------------
Metastatic Prostate Cancer, Recurrent Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Atorvastatin 80mg
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atorvastatin<br>Capsules of atorvastatin. Daily dose of 80 mg for max. 10 years or until development of castration resistance. | Drug: Atorvastatin 80mg<br>* Capsules including 80 mg of atorvastatin<br>* Other names: Lipitor;|
| Placebo Comparator: Placebo<br>Identical capsules as in the atorvastatin arm, but including no active ingredient. Used daily for max. 10 years or until development of castration resistance | Drug: Placebo oral capsule<br>* Similar capsules as in the atorvastatin arm, but without the active ingredient<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From date of randomization until the date of first occurrence of castration resistance, assessed up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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 | 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 | At enrollment and at occurrence of castration resistance, assessed up to 60 months | 
| Fasting blood glucose | To see how ADT affects glucose tolerance and whether atorvastatin intervention has any effect on it | 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. | 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) | 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) | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prostate cancer, Castration resistance, Cholesterol lowering drug, Cholesterol, Atorvastatin, Survival, Mortality