Clinical trial NCT04026230: Impact of Atorvastatin on Prostate Cancer Progression 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Metastatic Prostate Cancer
Recurrent Prostate Cancer
Keywords: Prostate cancer
Castration resistance
Cholesterol lowering drug
Cholesterol
Atorvastatin
Survival
Mortality
Lead sponsor: Tampere University Hospital
Sponsor class: OTHER
Collaborators: name: Turku University Hospital
name: Central Finland Hospital District
name: Tartu University Hospital
name: University of Aarhus
name: Fimlab laboratories
name: Helsinki University Central Hospital
name: Kuopio University Hospital
name: Oulu University Hospital
name: Seinajoki Central Hospital
name: The Hospital of Vestfold
name: Telemark Hospital Trust
First posted: 2019-07-19
Enrollment: 400
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Castration resistance
timeFrame: From date of randomization until the date of first occurrence of castration resistance, assessed up to 60 months
Secondary outcomes:
measure: Lipid levels
timeFrame: 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
measure: Prostate cancer mortality
timeFrame: From date of randomization until the date of prostate cancer death, assessed up to 60 months
measure: Overall survival
timeFrame: From date of randomization until the date of death due to any cause, assessed up to 60 months
measure: Circulating cell-free DNA
timeFrame: At enrollment and at occurrence of castration resistance, assessed up to 60 months
measure: Fasting blood glucose
timeFrame: 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
measure: Occurrence of cardiovascular events during ADT
timeFrame: 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
measure: General quality of life (QOL)
timeFrame: 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
measure: Prostate cancer-specific quality of life (QOL)
timeFrame: 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
Other outcomes:
Locations:
city: Herlev
country: Denmark
facility: Herlev and Gentofte Hospital
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Department of Urology
city: Jyväskylä
country: Finland
facility: Central Finland central hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital, Department of Urology
city: Seinäjoki
country: Finland
facility: Seinäjoki Central Hospital, Department of Surgery
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
city: Skien
country: Norway
facility: The Hospital of Telemark
city: Tønsberg
country: Norway
facility: The Hospital of Vestfold
Study officials:
affiliation: Tampere University Hospital
name: Teemu Murtola, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Turku University Hospital
name: Otto Ettala, MD, PhD
role: STUDY_DIRECTOR
affiliation: Central Finland Central Hospital
name: Heikki Seikkula
role: STUDY_DIRECTOR
References:
citation: Siltari A, Riikonen J, Koskimaki J, Pakarainen T, Ettala O, Bostrom P, Seikkula H, Kotsar A, Tammela T, Helminen M, Raittinen PV, Lehtimaki T, Fode M, Ostergren P, Borre M, Rannikko A, Marttila T, Salonen A, Ronkainen H, Loffeler S, Murtola TJ. Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy: study protocol. BMJ Open. 2022 Apr 29;12(4):e050264. doi: 10.1136/bmjopen-2021-050264.