Cancer, Hematologic Malignancies, Multiple Myeloma, Oncology, Bone Metastases, Multiple Myeloma Bone Lesions
Conditions
Keywords
zoledronic acid, hematologic malignancies, SRE, skeletal-related event, blood cancer, lytic bone lesions, bone metastases, myeloma, fractures, spinal cord compression, radiation to bone, surgery to bone, bisphosphonates, Neoplasms, Plasma Cell, Paraproteinemias, Neoplasms, Neoplasm Metastasis, Bone Neoplasms, Bone Marrow Diseases, Blood Protein Disorders, Hematologic Diseases, multiple myeloma, denosumab, Neoplastic Processes, Bone Diseases, Diphosphonates, Bone Density Conservation Agents
Brief summary
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone disease from multiple myeloma.
Interventions
DRUGDenosumab
Administered by subcutaneous injection once every 4 weeks.
DRUGZoledronic acid
Administered by intravenous infusion over 15 minutes once every 4 weeks
Administered by subcutaneous injection once every 4 weeks.
Administered by intravenous infusion over 15 minutes once every 4 weeks
DRUGDenosumab (for the open-label treatment phase)
Administered by subcutaneous injection once every 4 weeks.
Sponsors
Daiichi Sankyo
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented evidence of multiple myeloma (per local assessment): * Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma, and * Monoclonal protein present in the serum and/or urine * Radiographic (X-ray, or computer tomography \[CT\]) evidence of at least 1 lytic bone lesion (or at least 1 focal lesion per magnetic resonance imaging \[MRI\]) * Plan to receive or is receiving primary frontline anti-myeloma therapies * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Age ≥ 18 years * Adequate organ function, as defined by the following criteria (per central or local laboratory values): * Serum aspartate aminotransferase (AST) ≤ 2.0 x upper limit of normal (ULN) * Serum alanine aminotransferase ≤ (ALT) 2.0 x ULN * Serum total bilirubin ≤ 2.0 x ULN * Creatinine clearance ≥ 30 mL/min * Serum calcium or albumin-adjusted serum calcium 2.0 mmol/L (8.0 mg/dL) and 2.9 mmol/L (11.5 mg/dL) * Written informed consent before any study-specific procedure is performed
Exclusion criteria
* Nonsecretory multiple myeloma based upon standard M-component criteria (ie, measurable serum/urine M-component) unless the baseline serum free light chain level is elevated * POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) * Plasma cell leukemia * More than 30 days of previous treatment (before screening) with anti-myeloma therapy (does not include radiotherapy or a single short course of steroid \[ie, less than or equal to the equivalent of dexamethasone 60 mg/day for 4 days\]). * Planned radiation therapy or surgery to the bone (does not include procedures performed before randomization) * Prior administration of denosumab * Use of oral bisphosphonates with a cumulative exposure of more than 1 year * More than 1 previous dose of IV bisphosphonate administration * Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw * Active dental or jaw condition which requires oral surgery, including tooth extraction * Non-healed dental/oral surgery, including tooth extraction * Planned invasive dental procedures * Evidence of any of the following conditions per subject self-report or medical chart review: * Any prior invasive malignancy within 5 years before randomization * Any non-invasive malignancy not treated with curative intent or with knownactive disease within 5 years before randomization * Major surgery or significant traumatic injury occurring within 4 weeks before randomization * Active infection with Hepatitis B virus or Hepatitis C virus * Known infection with human immunodeficiency virus (HIV) * Active infection requiring IV anti-infective therapy * Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after end of treatment * Female subject of child bearing potential is not willing to use highly effective contraception during treatment and for 5 months after the end of treatment (see section 6.3) * Known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium or vitamin D) * Subject is receiving or is less than 30 days since ending other experimental device or drug (no marketing authorization for any indication) * Subject will not be available for follow-up assessment * Any major medical or psychiatric disorder that in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First On-study Skeletal Related Event | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first. |
| Percentage of Participants With an On-study Skeletal Related Event | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. |
| Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. The Kaplan-Meier estimate at weeks 25, 49 and 109 is reported. | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | Overall survival was defined as the time interval (in days) from the randomization date to the date of death. If a participant was still alive at the primary analysis data cut-off date or was lost to follow-up by the primary analysis data cut-off date, survival time was censored at their last contact date or the primary analysis data cut-off date, whichever was first. |
| Time to First On-study Skeletal Related Event - Superiority Analysis | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first. |
| Percentage of Participants Who Died | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | — |
| Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE. A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The average number of events per patient is reported. |
| Time to First and Subsequent On-Study Skeletal Related Event - Number of Events | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE. A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The total number of events is reported. |
Countries
Australia, Austria, Bulgaria, Canada, Czechia, France, Germany, Greece, Hong Kong, Hungary, Ireland, Italy, Japan, Lithuania, Malaysia, New Zealand, Poland, Portugal, Russia, Singapore, Slovakia, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 259 centers across 29 countries in Europe, North America, Asia, Australia/New Zealand, and Japan. Participants were enrolled from 17 May 2012 to 29 March 2016.
Pre-assignment details
Randomization was stratified according to: * intent to undergo autologous peripheral blood stem cell (PBSC) transplantation * the antimyeloma agent being utilized/planned to be utilized in first-line therapy * stage (International Staging System \[ISS\]) at diagnosis * previous SRE (yes or no) * region (Japan yes or no)
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Participants randomized to receive zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaneously once every 4 weeks in the double-blind treatment phase. | 859 |
| Denosumab Participants randomized to receive denosumab 120 mg subcutaneously plus placebo to zoledronic acid intravenously once every 4 weeks in the double-blind treatment phase. | 859 |
| Total | 1,718 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Blinded Treatment Phase | Administrative Decision | 10 | 8 |
| Blinded Treatment Phase | Adverse Event | 6 | 13 |
| Blinded Treatment Phase | Completed Survival Follow-up | 21 | 9 |
| Blinded Treatment Phase | Death | 147 | 137 |
| Blinded Treatment Phase | Disease Progression | 12 | 10 |
| Blinded Treatment Phase | Ineligibility Determined | 1 | 6 |
| Blinded Treatment Phase | Lost to Follow-up | 6 | 3 |
| Blinded Treatment Phase | Noncompliance | 5 | 3 |
| Blinded Treatment Phase | Other, Not Specified | 2 | 3 |
| Blinded Treatment Phase | Protocol Deviation | 5 | 0 |
| Blinded Treatment Phase | Withdrawal by Subject | 103 | 112 |
| Open Label Treatment Phase | Administrative Decision | 30 | 15 |
| Open Label Treatment Phase | Adverse Event | 30 | 51 |
| Open Label Treatment Phase | Death | 49 | 48 |
| Open Label Treatment Phase | Disease Progression | 17 | 18 |
| Open Label Treatment Phase | Lost to Follow-up | 1 | 2 |
| Open Label Treatment Phase | Noncompliance | 5 | 4 |
| Open Label Treatment Phase | Other, Not Specified | 9 | 7 |
| Open Label Treatment Phase | Pregnancy | 1 | 0 |
| Open Label Treatment Phase | Protocol Violation | 0 | 1 |
| Open Label Treatment Phase | Withdrawal by Subject | 49 | 47 |
Baseline characteristics
| Characteristic | Zoledronic Acid | Denosumab | Total |
|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 10.5 | 63.5 years STANDARD_DEVIATION 10.6 | 63.4 years STANDARD_DEVIATION 10.6 |
| Age, Customized < 65 years | 464 Participants | 472 Participants | 936 Participants |
| Age, Customized ≥ 65 years | 395 Participants | 387 Participants | 782 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 259 Participants | 263 Participants | 522 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restricted but ambulatory) | 413 Participants | 400 Participants | 813 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work) | 187 Participants | 196 Participants | 383 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 35 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 819 Participants | 823 Participants | 1642 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 101 Participants | 107 Participants | 208 Participants |
| Race/Ethnicity, Customized Black or African American | 36 Participants | 29 Participants | 65 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiracial | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 19 Participants | 10 Participants | 29 Participants |
| Race/Ethnicity, Customized White | 699 Participants | 711 Participants | 1410 Participants |
| Sex: Female, Male Female | 386 Participants | 397 Participants | 783 Participants |
| Sex: Female, Male Male | 473 Participants | 462 Participants | 935 Participants |
| Skeletal Related Event History Any Skeletal Related Event | 577 participants | 567 participants | 1144 participants |
| Skeletal Related Event History Pathological fracture | 463 participants | 479 participants | 942 participants |
| Skeletal Related Event History Radiation therapy to bone | 139 participants | 118 participants | 257 participants |
| Skeletal Related Event History Spinal cord compression | 115 participants | 92 participants | 207 participants |
| Skeletal Related Event History Surgery to bone | 144 participants | 142 participants | 286 participants |
| Summary of Randomization Stratifications Anti-myeloma agent utilized/planned: Non-novel | 38 participants | 40 participants | 78 participants |
| Summary of Randomization Stratifications Anti-myeloma agent utilized/planned: Novel | 821 participants | 819 participants | 1640 participants |
| Summary of Randomization Stratifications Intent to undergo PBSC transplantation: No | 394 participants | 394 participants | 788 participants |
| Summary of Randomization Stratifications Intent to undergo PBSC transplantation: Yes | 465 participants | 465 participants | 930 participants |
| Summary of Randomization Stratifications ISS stage at diagnosis: I | 268 participants | 263 participants | 531 participants |
| Summary of Randomization Stratifications ISS stage at diagnosis: II | 313 participants | 319 participants | 632 participants |
| Summary of Randomization Stratifications ISS stage at diagnosis: III | 278 participants | 277 participants | 555 participants |
| Summary of Randomization Stratifications Previous SRE : No | 375 participants | 378 participants | 753 participants |
| Summary of Randomization Stratifications Previous SRE : Yes | 484 participants | 481 participants | 965 participants |
| Summary of Randomization Stratifications Region: Japan | 18 participants | 24 participants | 42 participants |
| Summary of Randomization Stratifications Region: Non-Japan | 841 participants | 835 participants | 1676 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 | 778 / 852 | 757 / 850 | 313 / 418 | 312 / 426 |
| serious Total, serious adverse events | 447 / 852 | 434 / 850 | 159 / 418 | 156 / 426 |
Outcome results
Primary
Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. The Kaplan-Meier estimate at weeks 25, 49 and 109 is reported.
Population: All randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid | Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event | At Week 49 | 43.2 percentage of participants |
| Zoledronic Acid | Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event | At Week 25 | 36.5 percentage of participants |
| Zoledronic Acid | Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event | At Week 109 | 50.6 percentage of participants |
| Denosumab | Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event | At Week 49 | 43.7 percentage of participants |
| Denosumab | Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event | At Week 25 | 35.9 percentage of participants |
| Denosumab | Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event | At Week 109 | 50.5 percentage of participants |
Primary
Percentage of Participants With an On-study Skeletal Related Event
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Percentage of Participants With an On-study Skeletal Related Event | 44.6 percentage of participants |
| Denosumab | Percentage of Participants With an On-study Skeletal Related Event | 43.8 percentage of participants |
Primary
Time to First On-study Skeletal Related Event
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Time to First On-study Skeletal Related Event | 730.0 days |
| Denosumab | Time to First On-study Skeletal Related Event | 695.0 days |
p-value: 0.0195% CI: [0.85, 1.14]Cox proportional hazards model
Secondary
Overall Survival
Overall survival was defined as the time interval (in days) from the randomization date to the date of death. If a participant was still alive at the primary analysis data cut-off date or was lost to follow-up by the primary analysis data cut-off date, survival time was censored at their last contact date or the primary analysis data cut-off date, whichever was first.
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Overall Survival | NA days |
| Denosumab | Overall Survival | 1507.0 days |
Comparison: The survival function of time to death for each treatment group was estimated using Kaplan-Meier method and the hazard ratio of denosumab compared with zoledronic acid and its 2-sided 95% CI were estimated using a Cox proportional hazards model stratified by the randomization stratification factors and including treatment groups, age, race group, geographic region, baseline creatinine clearance, baseline risk per cytogenetic based prognosis, and baseline ECOG as independent variables.p-value: 0.4195% CI: [0.7, 1.16]Cox proportional hazards model
Secondary
Percentage of Participants Who Died
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Percentage of Participants Who Died | 15.0 percentage of participants |
| Denosumab | Percentage of Participants Who Died | 14.1 percentage of participants |
Secondary
Time to First and Subsequent On-Study Skeletal Related Event - Number of Events
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE. A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The total number of events is reported.
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Time to First and Subsequent On-Study Skeletal Related Event - Number of Events | 565 skeletal-related events |
| Denosumab | Time to First and Subsequent On-Study Skeletal Related Event - Number of Events | 565 skeletal-related events |
Secondary
Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE. A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The average number of events per patient is reported.
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient | 0.66 events/patient |
| Denosumab | Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient | 0.66 events/patient |
p-value: 0.8495% CI: [0.89, 1.15]Andersen-Gill model
Secondary
Time to First On-study Skeletal Related Event - Superiority Analysis
A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.
Time frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively.
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Time to First On-study Skeletal Related Event - Superiority Analysis | 730.0 days |
| Denosumab | Time to First On-study Skeletal Related Event - Superiority Analysis | 695.0 days |
p-value: 0.82Log Rank