Bone Metastases
Conditions
Keywords
Bone metastases, Hormone-refractory prostate cancer, Skeletal, Fractures, Compressions, Bisphosphonates
Brief summary
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid (Zometa®) in the treatment of bone metastases in men with hormone-refractory prostate cancer
Interventions
DRUGzoledronic acid
Q4W 4 mg zoledronic acid IV over minimum 15 minutes and 120 mg denosumab placebo SC
BIOLOGICALdenosumab
Q4W 120 mg denosumab SC and 4 mg zoledronic acid placebo IV over a minimum of 15 minutes
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men \>/= 18 years of age with histologically confirmed prostate cancer * Radiographic evidence of at least one bone metastasis * Failure of at least one hormonal therapy as evidenced by a rising PSA * Serum testosterone level of \<50 ng/dL * ECOG PS 0, 1, or 2 * Adequate organ function
Exclusion criteria
* Current or prior IV bisphosphonate administration * Current or prior oral bisphosphonates for bone mets * Life expectancy of less than 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First On-Study SRE (Non-inferiority) | Up to 40.5 months | Time to the first on-study skeletal-related event (SRE) analyzed for non-inferiority. Kaplan-Meier estimates of the median and its dispersion are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First On-Study SRE (Superiority) | Up to 40.5 months | Time to the first on-study skeletal-related event (SRE), analyzed for superiority of denosumab. Kaplan-Meier estimates of the median and its dispersion are reported. |
| Time to the First-And-Subsequent On-Study SRE | Up to 40.5 months | Time to the first-and-subsequent on-study skeletal-related event (SRE), analyzed for superiority of denosumab using multiple event analysis, the event must occur at least 21 days after the previous SRE. This outcome measure utilizes multiple event times, was analyzed based on a proportional mean model, and is therefore more appropriately summarized by the cumulative mean number of events. |
Participant flow
Recruitment details
Participants were enrolled from 12 May 2006 through 18 December 2008.
Pre-assignment details
1904 participants were enrolled, however 3 were excluded from all analyses as Institutional Review Board review activities and oversight were not ensured.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks | 951 |
| Denosumab Denosumab 120 mg subcutaneously with an intravenous zoledronic acid placebo once every 4 weeks | 950 |
| Total | 1,901 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 43 | 56 |
| Overall Study | Death | 269 | 294 |
| Overall Study | Disease progression | 113 | 117 |
| Overall Study | Ineligibility determined | 2 | 3 |
| Overall Study | Lost to Follow-up | 13 | 9 |
| Overall Study | Noncompliance | 14 | 7 |
| Overall Study | Other | 42 | 33 |
| Overall Study | Participant request | 75 | 52 |
| Overall Study | Physician Decision | 4 | 1 |
| Overall Study | Protocol deviation | 4 | 3 |
| Overall Study | Withdrawal by Subject | 164 | 147 |
Baseline characteristics
| Characteristic | Denosumab | Zoledronic Acid | Total |
|---|---|---|---|
| Age, Continuous | 70.5 Years STANDARD_DEVIATION 8.7 | 71.0 Years STANDARD_DEVIATION 8.4 | 70.8 Years STANDARD_DEVIATION 8.6 |
| Current Prostate Cancer Chemotherapy Stratification Factor No | 818 Participants | 819 Participants | 1637 Participants |
| Current Prostate Cancer Chemotherapy Stratification Factor Yes | 132 Participants | 132 Participants | 264 Participants |
| Previous Skeletal-Related Event (SRE) Stratification Factor No | 718 Participants | 720 Participants | 1438 Participants |
| Previous Skeletal-Related Event (SRE) Stratification Factor Yes | 232 Participants | 231 Participants | 463 Participants |
| Prostate-Specific Antigen (PSA) Stratification Factor PSA level < 10 ng/mL | 145 Participants | 145 Participants | 290 Participants |
| Prostate-Specific Antigen (PSA) Stratification Factor PSA level ≥ 10 ng/mL | 805 Participants | 806 Participants | 1611 Participants |
| Race/Ethnicity, Customized Asian | 22 Participants | 26 Participants | 48 Participants |
| Race/Ethnicity, Customized Black or African American | 38 Participants | 35 Participants | 73 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 45 Participants | 57 Participants | 102 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 15 Participants | 22 Participants | 37 Participants |
| Race/Ethnicity, Customized White or Caucasian | 829 Participants | 810 Participants | 1639 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 950 Participants | 951 Participants | 1901 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 853 / 945 | 844 / 943 |
| serious Total, serious adverse events | 568 / 945 | 594 / 943 |
Outcome results
Primary
Time to the First On-Study SRE (Non-inferiority)
Time to the first on-study skeletal-related event (SRE) analyzed for non-inferiority. Kaplan-Meier estimates of the median and its dispersion are reported.
Time frame: Up to 40.5 months
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Time to the First On-Study SRE (Non-inferiority) | 521.0 Days |
| Denosumab | Time to the First On-Study SRE (Non-inferiority) | 629.0 Days |
p-value: 0.000295% CI: [0.71, 0.95]Regression, Cox
Secondary
Time to the First-And-Subsequent On-Study SRE
Time to the first-and-subsequent on-study skeletal-related event (SRE), analyzed for superiority of denosumab using multiple event analysis, the event must occur at least 21 days after the previous SRE. This outcome measure utilizes multiple event times, was analyzed based on a proportional mean model, and is therefore more appropriately summarized by the cumulative mean number of events.
Time frame: Up to 40.5 months
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Time to the First-And-Subsequent On-Study SRE | 584 Events |
| Denosumab | Time to the First-And-Subsequent On-Study SRE | 494 Events |
p-value: 0.008595% CI: [0.71, 0.94]Anderson-Gill model
Secondary
Time to the First On-Study SRE (Superiority)
Time to the first on-study skeletal-related event (SRE), analyzed for superiority of denosumab. Kaplan-Meier estimates of the median and its dispersion are reported.
Time frame: Up to 40.5 months
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Time to the First On-Study SRE (Superiority) | 521.0 Days |
| Denosumab | Time to the First On-Study SRE (Superiority) | 629.0 Days |
p-value: 0.008595% CI: [0.71, 0.95]Regression, Cox