Neoplasms, Prostate
Conditions
Keywords
prostate cancer, androgen deprivation therapy
Brief summary
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.
Interventions
DRUGdutasteride
0.5mg dutasteride (Investigation Product)
DRUGplacebo
making placebo
DRUGbicalutamide
50 mg Casodex or generic equivalent
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
40 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression | Interval of time between the date of the start of treatment and the date of disease progression (up to Study Month 42) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure | Interval of time between the date of the start of treatment and the date of treatment failure (up to Study Month 42) | 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. |
| Number of Participants With PSA Response | Time from Baseline PSA measurement until the first PSA measurement with a 50% or greater reduction in PSA values (up to Study Month 42) | 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. |
| Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Baseline and 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. |
| Number of Participants With Metastatic Disease | 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) | Metastatic disease is that evidenced by a radiographic assessment. The time of metastatic disease was the date of radiographic evidence. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bicalutamide 50 mg/Placebo Participants were randomly assigned to receive oral bicalutamide 50 milligrams (mg) and matching placebo once daily for 18 months. Participants who completed the 18-month treatment period with either stabilization or a positive response to their prostate cancer were offered participation in the 2-year extension phase , during which they would remain on their current treatment. A safety follow-up was conducted 16 weeks (+/-7 days) after withdrawal from investigational product (end of treatment or early withdrawal). | 65 |
| Bicalutamide 50 mg/Dutasteride 3.5 mg Participants were randomly assigned to receive oral bicalutamide 50 mg and dutasteride 3.5 mg once daily for 18 months. Participants who completed the 18-month treatment period with either stabilization or a positive response to their prostate cancer were offered participation in the 2-year extension phase, during which they would remain on their current treatment. A safety follow-up was conducted 16 weeks (+/-7 days) after withdrawal from investigational product (end of treatment or early withdrawal). | 62 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension Period (24 Months) | Adverse Event | 3 | 4 |
| Extension Period (24 Months) | Disease Progression | 0 | 1 |
| Extension Period (24 Months) | Lost to Follow-up | 0 | 1 |
| Extension Period (24 Months) | Non-compliance | 0 | 1 |
| Extension Period (24 Months) | Physician Decision | 4 | 3 |
| Extension Period (24 Months) | Protocol-defined Stopping Criteria | 6 | 7 |
| Extension Period (24 Months) | Sponsor Terminated Study | 0 | 1 |
| Extension Period (24 Months) | Withdrawal by Subject | 2 | 5 |
| Treatment Period (18 Months) | Adverse Event | 7 | 6 |
| Treatment Period (18 Months) | Lack of Efficacy | 1 | 0 |
| Treatment Period (18 Months) | Lost to Follow-up | 1 | 0 |
| Treatment Period (18 Months) | Non-compliance | 1 | 0 |
| Treatment Period (18 Months) | Physician Decision | 4 | 4 |
| Treatment Period (18 Months) | Protocol-defined Stopping Criteria | 16 | 14 |
| Treatment Period (18 Months) | Protocol Violation | 3 | 1 |
| Treatment Period (18 Months) | Sponsor Terminated Study | 1 | 1 |
| Treatment Period (18 Months) | Withdrawal by Subject | 4 | 5 |
Baseline characteristics
| Characteristic | Bicalutamide 50 mg/Placebo | Bicalutamide 50 mg/Dutasteride 3.5 mg | Total |
|---|---|---|---|
| Age, Continuous | 77.6 Years STANDARD_DEVIATION 7.9 | 78.9 Years STANDARD_DEVIATION 5.94 | 78.3 Years STANDARD_DEVIATION 7.02 |
| Gender Female | 0 Participants | 0 Participants | 0 Participants |
| Gender Male | 65 Participants | 62 Participants | 127 Participants |
| Race/Ethnicity, Customized African American/African Heritage | 11 participants | 10 participants | 21 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Asian-Japanese Heritage | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian-South East Asian Heritage | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White-White/Caucasian/European Heritage | 51 participants | 50 participants | 101 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 48 / 65 | 51 / 62 |
| serious Total, serious adverse events | 31 / 65 | 30 / 62 |
Outcome results
Primary
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.
Time frame: Interval of time between the date of the start of treatment and the date of disease progression (up to Study Month 42)
Population: Intent-to-Treat (ITT) Population: all participants randomized to study treatment. Data were not summarized for censored participants (no disease progression).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bicalutamide 50 mg/Placebo | Time to Disease Progression | 376.9 Days | Standard Deviation 333.94 |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Time to Disease Progression | 433.1 Days | Standard Deviation 324.25 |
p-value: 0.79Log Rank
95% CI: [0.61, 1.46]
95% CI: [-46.14, 39.05]
Secondary
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.
Time frame: Baseline and Months 6, 12, 18, 21, and 42
Population: ITT Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bicalutamide 50 mg/Placebo | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 12, n=62, 61 | -1.7 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Placebo | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 21, n=26, 30 | -2.1 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Placebo | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 18, n=62, 61 | -1.2 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Placebo | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 42, n=26, 30 | -0.1 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Placebo | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 6, n=62, 61 | -2.0 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 42, n=26, 30 | 0.6 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 6, n=62, 61 | -2.2 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 12, n=62, 61 | -2.1 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 18, n=62, 61 | -1.7 Nanograms per milliliter (ng/mL) |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Change From Baseline in Total PSA at Months 6, 12, 18, 21, and 42 | Month 21, n=26, 30 | -1.8 Nanograms per milliliter (ng/mL) |
Secondary
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.
Time frame: 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)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bicalutamide 50 mg/Placebo | Number of Participants With Metastatic Disease | Months 1-18, n=65, 62 | 8 participants |
| Bicalutamide 50 mg/Placebo | Number of Participants With Metastatic Disease | Months 19-42, n=26, 30 | 1 participants |
| Bicalutamide 50 mg/Placebo | Number of Participants With Metastatic Disease | Overall (Months 1-42), n=65, 62 | 9 participants |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Number of Participants With Metastatic Disease | Months 1-18, n=65, 62 | 5 participants |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Number of Participants With Metastatic Disease | Months 19-42, n=26, 30 | 1 participants |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Number of Participants With Metastatic Disease | Overall (Months 1-42), n=65, 62 | 6 participants |
Secondary
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 frame: Time from Baseline PSA measurement until the first PSA measurement with a 50% or greater reduction in PSA values (up to Study Month 42)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bicalutamide 50 mg/Placebo | Number of Participants With PSA Response | Months 1-18, n=65, 62 | 37 participants |
| Bicalutamide 50 mg/Placebo | Number of Participants With PSA Response | Months 19-42, n=4, 7 | 0 participants |
| Bicalutamide 50 mg/Placebo | Number of Participants With PSA Response | Overall (Months 1-42), n=65, 62 | 37 participants |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Number of Participants With PSA Response | Months 1-18, n=65, 62 | 38 participants |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Number of Participants With PSA Response | Months 19-42, n=4, 7 | 0 participants |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Number of Participants With PSA Response | Overall (Months 1-42), n=65, 62 | 38 participants |
Secondary
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.
Time frame: Interval of time between the date of the start of treatment and the date of treatment failure (up to Study Month 42)
Population: ITT Population. Data were not summarized for censored participants (no treatment failure).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bicalutamide 50 mg/Placebo | Time to Treatment Failure | 368.4 Days | Standard Deviation 323.94 |
| Bicalutamide 50 mg/Dutasteride 3.5 mg | Time to Treatment Failure | 457.5 Days | Standard Deviation 322.01 |