Impact of Atorvastatin on Prostate Cancer Progression During ADT

Metastatic Prostate Cancer Clinical Trial

— ESTO2  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04026230
• Other study ID #: 2016-004774-17
• Status: Recruiting
• Phase: Phase 3
• Start date: August 15, 2019
• Est. completion date: December 31, 2025

Study information

• Verified date: October 2022
• Source: Tampere University Hospital
• Contact: Teemu Murtola, MD, PhD
• Phone: +358-3 311 65015
• Email: teemu.murtola[@]uta.fi
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Disease Progression
• Metastatic Prostate Cancer
• Prostatic Neoplasms
• Recurrent Prostate Cancer

Intervention

Drug:
• Atorvastatin 80mg
Capsules including 80 mg of atorvastatin
• Placebo oral capsule
Similar capsules as in the atorvastatin arm, but without the active ingredient

Locations

Country	Name	City	State
Denmark	Herlev and Gentofte Hospital	Herlev
Estonia	Tartu University Hospital	Tartu
Finland	Helsinki University Hospital, Department of Urology	Helsinki
Finland	Central Finland central hospital	Jyväskylä
Finland	Kuopio University Hospital, Department of Urology	Kuopio
Finland	Seinäjoki Central Hospital, Department of Surgery	Seinäjoki
Finland	Tampere University Hospital	Tampere
Finland	Turku University Hospital	Turku
Norway	The Hospital of Telemark	Skien
Norway	The Hospital of Vestfold	Tønsberg

Sponsors (12)

Lead Sponsor	Collaborator
Tampere University Hospital	Central Finland Hospital District, Fimlab laboratories, Helsinki University Central Hospital, Kuopio University Hospital, Oulu University Hospital, Seinajoki Central Hospital, Tartu University Hospital, Telemark Hospital Trust, The Hospital of Vestfold, Turku University Hospital, University of Aarhus

Countries where clinical trial is conducted

Denmark,  Estonia,  Finland,  Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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