Hormone Refractory Prostate Cancer
Conditions
Keywords
Hormone refractory prostate cancer, androgen independent, ADT, bone metastasis
Brief summary
The purpose of this study is to compare the treatment effect of denosumab with placebo on prolonging bone metastasis-free survival in men with hormone refractory (androgen independent) prostate cancer who have no bone metastasis at baseline.
Detailed description
Participants were randomized to receive denosumab 120 mg or placebo every 4 weeks (Q4W) until approximately 660 participants developed bone metastasis or died and the primary efficacy and safety analyses were completed. All participants undergoing scheduled assessments were offered open-label denosumab 120 mg subcutaneous (SC) until they either developed a bone metastasis, obtained access to commercially available product in this setting, or for up to 3 years, whichever came first. For participants who ended participation before the open-label extension (OLE) phase or withdrew from investigational product during the OLE phase, their survival data was to be collected every 6 months for up to 3 years after their last dose of investigational product. Participants in the Czech Republic and United Kingdom were enrolled under a separate protocol for the OLE phase per Health Authority request, and are reported separately (Study 20080585; NCT01824342).
Interventions
BIOLOGICALDenosumab
Administered by subcutaneous injection
BIOLOGICALPlacebo
Same volume subcutaneous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* men with histologically confirmed prostate cancer * bilateral orchiectomy at least 6 months before randomization or continuous androgen-deprivation therapy (ADT) with a gonadotropin releasing hormone (GnRH) agonist or antagonist for at least 6 months before randomization * total testosterone level less than 50 ng/dL, * hormone refractory (androgen independent) prostate cancer demonstrated during continuous ADT/post-orchiectomy defined as: 3 consecutive prostate-specific antigen (PSA) values with PSA1 \< PSA2 \< PSA3, each PSA value must be separated by at least 2 weeks, PSA2 and PSA3 greater than or equal to 1.0 ng/mL, * high risk for development of bone metastasis defined as PSA value greater than or equal to 8.0 ng/mL, obtained no more than 3 months before randomization OR PSA doubling time less than or equal to 10.0 months
Exclusion criteria
* prior or current evidence of radiographically detectable bone metastasis * known prior or current evidence of any metastatic involvement of distant organs (lymph node metastases in any region is acceptable) * prior or current intravenous bisphosphonate administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bone Metastasis-free Survival | From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months. | The time to the first occurrence of bone metastasis (either symptomatic or asymptomatic) or death from any cause. Participants who did not experience bone metastasis or on-study death were censored at the last on-study contact date or the primary analysis data cutoff date, whichever came first. Median bone metastasis-free survival time was estimated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Bone Metastasis | From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months. | Time from randomization to the date of first occurrence of bone metastasis (either symptomatic or asymptomatic), excluding death. Participants who did not develop bone metastasis were censored at their last on-study bone assessment date or the primary analysis data cut-off date, whichever was first. Median time to first bone metastasis was estimated using the Kaplan-Meier method. |
| Overall Survival | From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months. | Time from randomization to the date of death. Participants who were still alive or lost to follow-up by the primary analysis data cut-off date were censored at their last contact date (on-study or during survival follow-up) or the primary analysis data cut-off date, whichever was first. |
Participant flow
Recruitment details
Eligible subjects were men ≥ 18 years old with histologically-confirmed, castrate-resistant prostate cancer who were chemically or surgically castrated. The first patient was enrolled into the study on 03 February 2006 and the last patient was enrolled on 23 July 2008.
Pre-assignment details
Participants were randomized to denosumab or placebo in the double-blind treatment phase. All participants undergoing scheduled assessments were offered open-label denosumab for up to 3 years in the open-label extension phase. Three enrolled patients were excluded from all datasets per ethics committee's instructions due to eligibility violations.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo subcutaneous injection every 4 weeks (Q4W) in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase. | 716 |
| Denosumab Participants received 120 mg densumab administered by subcutaneous injection every 4 weeks in the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injecton once every 4 weeks for up to 3 years in the open-label extension phase. | 716 |
| Total | 1,432 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Treatment Phase | Administrative Decision | 20 | 21 |
| Double-blind Treatment Phase | Adverse Event | 28 | 40 |
| Double-blind Treatment Phase | Death | 58 | 65 |
| Double-blind Treatment Phase | Disease Progression | 22 | 35 |
| Double-blind Treatment Phase | Ineligibility Determined | 1 | 2 |
| Double-blind Treatment Phase | Lost to Follow-up | 11 | 4 |
| Double-blind Treatment Phase | Noncompliance | 8 | 8 |
| Double-blind Treatment Phase | Other | 25 | 33 |
| Double-blind Treatment Phase | Protocol Deviation | 1 | 3 |
| Double-blind Treatment Phase | Protocol-Specified Criteria | 307 | 269 |
| Double-blind Treatment Phase | Withdrawal by Subject | 103 | 113 |
| Open-label Treatment Phase | Adverse Event | 5 | 16 |
| Open-label Treatment Phase | Death | 10 | 7 |
| Open-label Treatment Phase | Disease Progression | 9 | 3 |
| Open-label Treatment Phase | Lost to Follow-up | 0 | 1 |
| Open-label Treatment Phase | Missing End of Study Information | 0 | 1 |
| Open-label Treatment Phase | Noncompliance | 3 | 1 |
| Open-label Treatment Phase | Other | 11 | 11 |
| Open-label Treatment Phase | Physician Decision | 24 | 21 |
| Open-label Treatment Phase | Protocol-specified Criteria | 1 | 0 |
| Open-label Treatment Phase | Withdrawal by Subject | 14 | 10 |
Baseline characteristics
| Characteristic | Denosumab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 73.2 years STANDARD_DEVIATION 8.8 | 73.2 years STANDARD_DEVIATION 8.3 | 73.2 years STANDARD_DEVIATION 8.6 |
| Eastern Cooperative Oncology Group (ECOG)Pperformance Status Grade 0 | 505 participants | 514 participants | 1019 participants |
| Eastern Cooperative Oncology Group (ECOG)Pperformance Status Grade 1 | 210 participants | 199 participants | 409 participants |
| Eastern Cooperative Oncology Group (ECOG)Pperformance Status Grade 2 | 1 participants | 3 participants | 4 participants |
| Eastern Cooperative Oncology Group (ECOG)Pperformance Status Grade 3 | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG)Pperformance Status Grade 4 | 0 participants | 0 participants | 0 participants |
| Prior Chemotherapy Regimens No | 653 participants | 662 participants | 1315 participants |
| Prior Chemotherapy Regimens Yes | 63 participants | 54 participants | 117 participants |
| Prostate-Specific Antigen (PSA) ≥ 8.0 ng/mL No | 243 participants | 245 participants | 488 participants |
| Prostate-Specific Antigen (PSA) ≥ 8.0 ng/mL Yes | 473 participants | 471 participants | 944 participants |
| Prostate-Specific Antigen (PSA) Doubling Time ≤ 10 months | 574 participants | 580 participants | 1154 participants |
| Prostate-Specific Antigen (PSA) Doubling Time > 10 months | 142 participants | 136 participants | 278 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 17 participants | 18 participants | 35 participants |
| Race/Ethnicity, Customized Black or African American | 41 participants | 35 participants | 76 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 32 participants | 37 participants | 69 participants |
| Race/Ethnicity, Customized Japanese | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 18 participants | 17 participants | 35 participants |
| Race/Ethnicity, Customized Unknown | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White or Caucasian | 606 participants | 604 participants | 1210 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 716 Participants | 716 Participants | 1432 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 585 / 705 | 599 / 720 | 80 / 109 | 74 / 101 |
| serious Total, serious adverse events | 332 / 705 | 341 / 720 | 39 / 109 | 36 / 101 |
Outcome results
Primary
Bone Metastasis-free Survival
The time to the first occurrence of bone metastasis (either symptomatic or asymptomatic) or death from any cause. Participants who did not experience bone metastasis or on-study death were censored at the last on-study contact date or the primary analysis data cutoff date, whichever came first. Median bone metastasis-free survival time was estimated using the Kaplan-Meier method.
Time frame: From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.
Population: Full analysis set (all randomized participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Bone Metastasis-free Survival | 768.0 days |
| Denosumab | Bone Metastasis-free Survival | 897.00 days |
Comparison: Primary and secondary endpoint analyses were conducted hierarchically. To preserve an overall type I error rate of 0.05, a 0.0488 2-sided test of bone metastasis-free survival was performed. If superiority of denosumab over placebo was established, time to first bone metastasis was tested with a 2-sided significance level of 0.050. If superiority of denosumab over placebo was also established, overall survival time was tested at a 2-sided significance level of 0.050.p-value: 0.028495% CI: [0.73, 0.98]Wald test
Secondary
Overall Survival
Time from randomization to the date of death. Participants who were still alive or lost to follow-up by the primary analysis data cut-off date were censored at their last contact date (on-study or during survival follow-up) or the primary analysis data cut-off date, whichever was first.
Time frame: From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival | 1365.0 days |
| Denosumab | Overall Survival | 1335.0 days |
p-value: 0.912595% CI: [0.85, 1.2]Wald test
Secondary
Time to First Bone Metastasis
Time from randomization to the date of first occurrence of bone metastasis (either symptomatic or asymptomatic), excluding death. Participants who did not develop bone metastasis were censored at their last on-study bone assessment date or the primary analysis data cut-off date, whichever was first. Median time to first bone metastasis was estimated using the Kaplan-Meier method.
Time frame: From the first dose of investigational product to the primary data cutoff date of 30 July 2010; median time on study was approximately 20 months.
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Bone Metastasis | 897.0 days |
| Denosumab | Time to First Bone Metastasis | 1010.0 days |
p-value: 0.031795% CI: [0.71, 0.98]Wald test