Prostate Cancer Study In Men Who Have Failed First-Line Androgen Deprivation Therapy

Study Overview
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Brief Summary
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Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT) the male hormone that leads to benign prostate growth. By blocking the conversion of testosterone to DHT, dutasteride could allow bicalutamide to be a more effective anti-androgen thus prolonging bicalutamide's efficacy.

Official Title
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A Randomized Double-Blind Parallel Group Study Comparing Casodex (or Generic Equivalent) 50mg Plus Placebo to Casodex (or Generic Equivalent) 50mg Plus Dutasteride 3.5mg Administered for 18 Months to Men With Prostate Cancer Who Have Failed First-Line Androgen Deprivation Therapy (Assessed by Rising PSA) Followed by a Two-Year Extension Phase

Conditions
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Neoplasms, Prostate

Intervention / Treatment
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* Drug: dutasteride
* Drug: placebo
* Drug: bicalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Men ≥40 and ≤90 years of age Must have asymptomatic prostate cancer that has progressed during androgen deprivation therapy (rising PSA). PSA progression must have occurred after first-line treatment with GnRH analogues ( e.g. leuprolide, goserelin) or orchiectomy. PSA progression is defined by three rises in PSA each measured at least 4 weeks apart within the previous year. Serum PSA ≥2 and ≤20ng/ml from central laboratory. One PSA retest from central laboratory is allowed if the value is <2 or >20ng/ml; or if the PSA value is not consistent with the previous rising PSA values that determined progression while on a GnRH analogue. Serum Testosterone <50ng/ml from central laboratory. Non-metastatic prostate cancer as confirmed on prior bone scan performed within 8 weeks of screening. Expected survival ≥ 2 years ECOG Performance status 0, 1, or 2 Exclusion criteria: Additional hormonal therapy (excluding the current use of a GnRH analogue) within the past 6 months of: Estrogens (e.g. megestrol, medroxyprogesterone, cyproterone, DES) Drugs with antiandrogenic properties (e.g., spironolactone if >50mg/day, flutamide, bicalutamide*, ketoconazole**, progestational agents) *The use of an antiandrogen during GnRH analogue induction for <6 weeks is acceptable, but none within the 3 months prior to study entry. **The use of topical ketoconazole is permitted prior to and during the study. NOTE: Use of dietary and herbal supplements (e.g., selenium, Vitamin E, saw palmetto), excluding daily vitamins, during the study is discouraged, but not prohibited. All dietary and herbal supplement usage will be recorded in the eCRF. Treatment with oral glucocorticoids during the 3 months prior to randomization or expectation of their use during the study. Prior chemotherapy for prostate cancer. (prior prostatectomy or radiotherapy to the prostate are allowed) Prostate surgery including TUNA, TURP, TUIP, laser treatment, thermotherapy, balloon dilatation, prosthesis, and cryosurgical ablation within 2 months prior to enrollment. Current and/or previous use of the following medications: Finasteride (Proscar, Propecia), or Dutasteride (GI198745, AVODART) exposure within 6 months prior to study entry Anabolic steroids (within 6 months prior to study entry) Participation in any investigational or marketed drug trial within the 30 days prior to the first dose of study drug or anytime during the study period. Any unstable serious co-existing medical condition(s) including but not limited to myocardial infarction, coronary bypass surgery, unstable angina, cardiac arrhythmias, clinically evident congestive heart failure, or cerebrovascular accident within 6 months prior to Screening visit; uncontrolled diabetes; or peptic ulcer disease which is uncontrolled by medical management. Abnormal liver function test greater than 1.5 times the upper limit of normal for alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP] or bilirubin. Serum creatinine >2.0 times the upper limit of normal. History of another malignancy within five years that could affect the treatment of prostate cancer or survival of the subject. History or current evidence of drug or alcohol abuse within the last 12 months. History of any illness (including psychiatric) that, in the opinion of the investigator, might confound the results of the study or pose additional risk to the subject. Known hypersensitivity to any 5 alpha-reductase inhibitor or to any drug chemically related to dutasteride.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>50 mg bicalutamide and 3.5 mg Dutasteride (IP) | Drug: dutasteride<br>* 0.5mg dutasteride (Investigation Product)<br>Drug: bicalutamide<br>* 50 mg Casodex or generic equivalent<br>|
| Placebo Comparator: Arm 2<br>50 mg bicalutamide and placebo | Drug: placebo<br>* making placebo<br>Drug: bicalutamide<br>* 50 mg Casodex or generic equivalent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression | Time to disease progression (PD) is defined as the interval of time between the date of the start of treatment and the date of PD. PD is defined as prostate specific antigen (PSA) progression from Baseline (PSA value is 25% and at least 2 nanograms per milliliter [ng/mL] above Baseline, confirmed by a second PSA value); PSA progression from nadir, without a 50% decrease from Baseline (PSA value is 25% and at least 2 ng/mL above nadir, confirmed by a second PSA value); PSA progression from nadir, with a 50% or more decrease from Baseline (PSA value is 50% and at least 2 ng/mL above nadir, confirmed by a second PSA value); metastatic disease (radiographic evidence of metastatic disease); death due to prostate cancer; or the receipt of post-Baseline rescue medication. PSA confirmation was not required if no subsequent PSA values were available. Participants who did not experience an event were censored at the date of the latest follow-up information. | Interval of time between the date of the start of treatment and the date of disease progression (up to Study Month 42) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Failure | Time to treatment failure is defined as the interval of time between the date of the start of treatment and the date of treatment failure. Treatment failure is defined as PSA progression from Baseline (PSA value is 25% and at least 2 ng/mL above Baseline, confirmed by a second PSA value); metastatic disease (radiographic evidence of metastatic disease); death due to prostate cancer; or receipt of post-baseline rescue medications. PSA confirmation was not required if no subsequent PSA values were available. Participants who did not experience an event were censored at the date of the latest follow-up information. | Interval of time between the date of the start of treatment and the date of treatment failure (up to Study Month 42) | 
| Number of Participants With PSA Response | PSA response is defined as a 50% or greater decrease in PSA from Baseline, confirmed by a second PSA measurement. The time of this response was the date of the first PSA measurement that showed a 50% or greater decrease from the Baseline PSA measurement. PSA confirmation was not required if no subsequent PSA values were available. | Time from Baseline PSA measurement until the first PSA measurement with a 50% or greater reduction in PSA values (up to Study Month 42) | 
| Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Change from Baseline in total PSA was measured at each scheduled post-baseline visit using a general linear model with effects for treatment and Baseline total PSA. Analysis was done using the last observation carried forward (LOCF) approach, in which missing post-Baseline values were imputed with earlier non-missing values. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline and Months 6, 12, 18, 21, and 42 | 
| Number of Participants With Metastatic Disease | Metastatic disease is that evidenced by a radiographic assessment. The time of metastatic disease was the date of radiographic evidence. | Interval of time between the date of the start of treatment and the date of radiographic evidence of metastatic disease (up to Study Month 42) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, androgen deprivation therapy