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CompletedNCT00286091Updated Oct 17, 2018Results posted

Study on Prolonging Bone Metastasis-Free Survival in Men With Hormone Refractory Prostate Cancer

A Phase 3 interventional study of Denosumab and Placebo in Hormone Refractory Prostate Cancer, sponsored by Amgen. Completed. Open to male participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-10-17.

Sponsored by Amgen · Phase 3, Interventional, and Prevention

Phase
Phase 3
Study type
Interventional
Enrollment
1,435
Allocation
Randomized
Ages
18 Years and older
Sex
Male
01

Study 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.

Read the 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).

02

Conditions studied

  • Hormone Refractory Prostate Cancer

Keywords

  • Hormone refractory prostate cancer
  • androgen independent
  • ADT
  • bone metastasis
03

In context

Prostatic Neoplasms

6,370 studies on the registry are indexed under Prostatic Neoplasms; 1,400 are open to participants now.

This study's enrollment of 1,435 is above the median of 58 across 4,822 interventional studies indexed under Prostatic Neoplasms.

Browse Prostatic Neoplasms studies →

Lead sponsor

Amgen is the lead sponsor of 1,015 studies on the registry; 49 are open to participants now.

Of its 245 completed or terminated interventional studies of FDA-regulated products, 159 (65%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
Male
Accepts 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

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
05

Study design

Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
1,435 participants (actual)

Study arms

  • Placebo comparator
    Placebo

    Participants received placebo subcutaneous injections every 4 weeks during the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injection every 4 weeks during the open-label extension phase.

    Biological: Placebo

  • Experimental
    Denosumb

    Participants received 120 mg denosumab administered by subcutaneous injection every 4 weeks during the double-blind treatment phase. Participants then received open-label denosumab 120 mg by subcutaneous injection every 4 weeks during the open-label extension phase.

    Biological: Denosumab

Interventions

  • BiologicalDenosumab

    Administered by subcutaneous injection

    Also known as: XGEVA®

  • BiologicalPlacebo

    Same volume subcutaneous injection

06

What researchers measure

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. 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.

07

Results

Posted Apr 6, 2015

Participant flow

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.

Double-blind Treatment Phase
Participant flow — Double-blind Treatment Phase
MilestonePlaceboDenosumab
Started716716
Received treatment709716
On study at primary data analysis cutoff164174
Completed132123
Not completed584593
Withdrew: Withdrawal by subject103113
Withdrew: Protocol-specified criteria307269
Withdrew: Death5865
Withdrew: Adverse event2840
Withdrew: Disease progression2235
Withdrew: Other2533
Withdrew: Administrative decision2021
Withdrew: Noncompliance88
Withdrew: Lost to follow-up114
Withdrew: Protocol deviation13
Withdrew: Ineligibility determined12
Open-label Treatment Phase
Participant flow — Open-label Treatment Phase
MilestonePlaceboDenosumab
Started110104
Received treatment109101
Completed3333
Not completed7771
Withdrew: Physician decision2421
Withdrew: Adverse event516
Withdrew: Other1111
Withdrew: Withdrawal by subject1410
Withdrew: Death107
Withdrew: Disease progression93
Withdrew: Noncompliance31
Withdrew: Lost to follow-up01
Withdrew: Protocol-specified criteria10
Withdrew: Missing end of study information01

Outcome measures

PrimaryBone 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.
Reported as:
Median · days
Bone Metastasis-free Survival
daysPlaceboDenosumab
Bone Metastasis-free Survival768.0 (675.00 to 897.00)897.00 (773.00 to 1014.00)
Statistical analysis
  • Placebo vs Denosumab · Wald test · p = 0.0284 · Hazard ratio (hr): 0.85 · 95% CI 0.73 to 0.98Based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio \< 1 favors denosumab.
SecondaryTime 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.
Reported as:
Median · days
Time to First Bone Metastasis
daysPlaceboDenosumab
Time to First Bone Metastasis897.0 (683.00 to 1009.00)1010.0 (897.00 to 1156.00)
Statistical analysis
  • Placebo vs Denosumab · Wald test · p = 0.0317 · Hazard ratio (hr): 0.84 · 95% CI 0.71 to 0.98Based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio \< 1 favors denosumab.
SecondaryOverall 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.
Reported as:
Median · days
Overall Survival
daysPlaceboDenosumab
Overall Survival1365.0 (1220.00 to NA)1335.0 (1221.00 to NA)
Statistical analysis
  • Placebo vs Denosumab · Wald test · p = 0.9125 · Hazard ratio (hr): 1.01 · 95% CI 0.85 to 1.20Based on the Cox proportional hazards model stratified by PSA ≥ 8.0 ng/mL, PSA doubling time ≤ 10 months and previous or current chemotherapy for prostate cancer. A hazard ratio \< 1 favors denosumab.

Adverse events

Collected over Median investigational product exposure was 18.4 and 19.3 months in the placebo and denosumab groups respectively during the double blind phase and 23.7 and 24.9 months during the open-label treatment phase.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
DB: Placebo—332/705 (47.1%)585/705 (83%)
DB: Denosumab 120 mg Q4W—341/720 (47.4%)599/720 (83.2%)
OLE: Placebo/ Denosumab 120 mg Q4W—39/109 (35.8%)80/109 (73.4%)
OLE: Denosumab/ Denosumab 120 mg Q4W—36/101 (35.6%)74/101 (73.3%)
Most frequent serious events
Showing 10 of 526
Most frequent serious events
EventDB: PlaceboDB: Denosumab 120 mg Q4WOLE: Placebo/ Denosumab 120 mg Q4WOLE: Denosumab/ Denosumab 120 mg Q4W
Urinary retentionRenal and urinary disorders33/70556/7206/1095/101
HaematuriaRenal and urinary disorders25/70537/7202/1095/101
Osteonecrosis of jawMusculoskeletal and connective tissue disorders0/70512/7201/1095/101
Myocardial infarctionCardiac disorders10/70512/7204/1091/101
Renal failure acuteRenal and urinary disorders16/70512/7204/1092/101
Prostatic obstructionReproductive system and breast disorders2/7050/7204/1090/101
AnaemiaBlood and lymphatic system disorders12/70525/7202/1093/101
Prostate cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)21/70515/7201/1091/101
Urinary tract infectionInfections and infestations15/70515/7202/1093/101
DehydrationMetabolism and nutrition disorders9/7057/7200/1093/101
Most frequent other events
Showing 10 of 42
Most frequent other events
EventDB: PlaceboDB: Denosumab 120 mg Q4WOLE: Placebo/ Denosumab 120 mg Q4WOLE: Denosumab/ Denosumab 120 mg Q4W
Back painMusculoskeletal and connective tissue disorders159/705166/72024/1098/101
ConstipationGastrointestinal disorders124/705128/72013/10915/101
ArthralgiaMusculoskeletal and connective tissue disorders116/705123/72011/1099/101
HaematuriaRenal and urinary disorders90/70587/72017/10911/101
DiarrhoeaGastrointestinal disorders102/705110/7208/10910/101
Urinary tract infectionInfections and infestations96/705108/72015/10914/101
Pain in extremityMusculoskeletal and connective tissue disorders88/705101/72012/10910/101
NauseaGastrointestinal disorders95/70598/7204/10914/101
FatigueGeneral disorders82/70598/7205/1098/101
Oedema peripheralGeneral disorders88/70594/7205/10911/101

Baseline characteristics

Age, Continuous
Age, Continuous(years)PlaceboDenosumabTotal
Mean73.2 ± 8.373.2 ± 8.873.2 ± 8.6
Sex: Female, Male
Sex: Female, Male(Participants)PlaceboDenosumabTotal
Female000
Male7167161432
Race/Ethnicity, Customized
Race/Ethnicity, Customized(participants)PlaceboDenosumabTotal
White or Caucasian6046061210
Black or African American354176
Hispanic or Latino373269
Asian181735
Japanese202
American Indian or Alaska Native202
Native Hawaiian or Other Pacific Islander101
Other171835
Unknown022
Eastern Cooperative Oncology Group (ECOG)Pperformance Status
Eastern Cooperative Oncology Group (ECOG)Pperformance Status(participants)PlaceboDenosumabTotal
Grade 05145051019
Grade 1199210409
Grade 2314
Grade 3000
Grade 4000
Prostate-Specific Antigen (PSA) Doubling Time
Prostate-Specific Antigen (PSA) Doubling Time(participants)PlaceboDenosumabTotal
≤ 10 months5805741154
> 10 months136142278
Prostate-Specific Antigen (PSA) ≥ 8.0 ng/mL
Prostate-Specific Antigen (PSA) ≥ 8.0 ng/mL(participants)PlaceboDenosumabTotal
Yes471473944
No245243488
Prior Chemotherapy Regimens
Prior Chemotherapy Regimens(participants)PlaceboDenosumabTotal
Yes5463117
No6626531315
08

Study locations

No study locations are listed for this record.

09

References and documents

Publications

  • Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, Miller K, Sieber P, Karsh L, Damiao R, Tammela TL, Egerdie B, Van Poppel H, Chin J, Morote J, Gomez-Veiga F, Borkowski T, Ye Z, Kupic A, Dansey R, Goessl C. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012 Jan 7;379(9810):39-46. doi: 10.1016/S0140-6736(11)61226-9. Epub 2011 Nov 15. PubMed 22093187 ↗
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Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Oct 17, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT00286091
Lead sponsor
Amgen
Responsible party
Sponsor
First posted
Feb 3, 2006
Start date
Jan 24, 2006
Primary completion
Jul 30, 2010
Completion
Apr 9, 2014
Results posted
Apr 6, 2015
Last update
Oct 17, 2018

Study contacts

MD
study director · Amgen

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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