ESTO2: Impact of Atorvastatin on Prostate Cancer Progression During ADT

Sponsor

Tampere University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04026230

Collaborator

Turku University Hospital (Other), Central Finland Hospital District (Other), Tartu University Hospital (Other), University of Aarhus (Other), Fimlab laboratories (Other), Helsinki University Central Hospital (Other), Kuopio University Hospital (Other)

400

Enrollment

Locations

Arms

76.6

Anticipated Duration (Months)

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Prostate Cancer Recurrent Prostate Cancer	Drug: Atorvastatin 80mg Drug: Placebo oral capsule	Phase 3

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 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 five 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 Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Aug 15, 2019

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atorvastatin Capsules of atorvastatin. Daily dose of 80 mg for max. 5 years or until development of castration resistance.	Drug: Atorvastatin 80mg Capsules including 80 mg of atorvastatin Other Names: Lipitor
Placebo Comparator: Placebo Identical capsules as in the atorvastatin arm, but including no active ingredient. Used daily for max. 5 years or until development of castration resistance	Drug: Placebo oral capsule Similar capsules as in the atorvastatin arm, but without the active ingredient

Arm

Intervention/Treatment

Experimental: Atorvastatin

Capsules of atorvastatin. Daily dose of 80 mg for max. 5 years or until development of castration resistance.

Drug: Atorvastatin 80mg

Capsules including 80 mg of atorvastatin

Other Names:

Lipitor

Placebo Comparator: Placebo

Identical capsules as in the atorvastatin arm, but including no active ingredient. Used daily for max. 5 years or until development of castration resistance

Drug: Placebo oral capsule

Similar capsules as in the atorvastatin arm, but without the active ingredient

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	Country
1	Herlev and Gentofte Hospital	Herlev	Denmark
2	Tartu University Hospital	Tartu	Estonia
3	Helsinki University Hospital, Department of Urology	Helsinki	Finland
4	Central Finland central hospital	Jyväskylä	Finland
5	Kuopio University Hospital, Department of Urology	Kuopio	Finland
6	Seinäjoki Central Hospital, Department of Surgery	Seinäjoki	Finland
7	Tampere University Hospital	Tampere	Finland
8	Turku University Hospital	Turku	Finland