Trial Outcomes & Findings for Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Subjects With Advanced Cancer or Multiple Myeloma. (NCT NCT00330759)

Last Updated: 2022-11-07

Results Overview

Time to the first on-study skeletal-related event (SRE) using a non-inferiority analysis. Median was estimated using the Kaplan-Meier method.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1779 participants

Primary outcome timeframe

up to 33 months

Results posted on

2022-11-07

Participant Flow

Participants were enrolled from 21 June 2006 through 16 May 2008

A total of 1779 participants were enrolled in the study. Three participants from one site were excluded from all analyses because Institutional Review Board (IRB) review activities and oversight were not ensured.

Participant milestones

Participant milestones
Measure	Zoledronic Acid Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab Denosumab 120 mg by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Overall Study STARTED	890	886
Overall Study Received Investigational Product	878	878
Overall Study COMPLETED	178	180
Overall Study NOT COMPLETED	712	706

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab Denosumab 120 mg by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Overall Study Death	316	310
Overall Study Disease progression	104	126
Overall Study Withdrawal by Subject	143	124
Overall Study Adverse Event	48	36
Overall Study Participant request	31	22
Overall Study Lost to Follow-up	16	22
Overall Study Noncompliance	15	17
Overall Study Physician Decision	1	2
Overall Study Protocol deviation	0	2
Overall Study Ineligibility determined	2	1
Overall Study Other	36	44

Baseline Characteristics

Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Subjects With Advanced Cancer or Multiple Myeloma.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid n=890 Participants Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab n=886 Participants Denosumab 120 mg by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks	Total n=1776 Participants Total of all reporting groups
Age, Continuous	60.6 Years STANDARD_DEVIATION 10.7 • n=5 Participants	59.3 Years STANDARD_DEVIATION 11.4 • n=7 Participants	59.9 Years STANDARD_DEVIATION 11.1 • n=5 Participants
Sex: Female, Male Female	338 Participants n=5 Participants	298 Participants n=7 Participants	636 Participants n=5 Participants
Sex: Female, Male Male	552 Participants n=5 Participants	588 Participants n=7 Participants	1140 Participants n=5 Participants
Race/Ethnicity, Customized White or Caucasian	770 Participants n=5 Participants	770 Participants n=7 Participants	1540 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	29 Participants n=5 Participants	20 Participants n=7 Participants	49 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	36 Participants n=5 Participants	49 Participants n=7 Participants	85 Participants n=5 Participants
Race/Ethnicity, Customized Asian	44 Participants n=5 Participants	36 Participants n=7 Participants	80 Participants n=5 Participants
Race/Ethnicity, Customized Japanese	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Other	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Tumor Type Stratification Factor Multiple myeloma	93 Participants n=5 Participants	86 Participants n=7 Participants	179 Participants n=5 Participants
Tumor Type Stratification Factor Other	452 Participants n=5 Participants	457 Participants n=7 Participants	909 Participants n=5 Participants
Tumor Type Stratification Factor Non-small cell lung cancer	345 Participants n=5 Participants	343 Participants n=7 Participants	688 Participants n=5 Participants
Previous Skeletal-Related Event Stratification Factor Yes	446 Participants n=5 Participants	440 Participants n=7 Participants	886 Participants n=5 Participants
Previous Skeletal-Related Event Stratification Factor No	444 Participants n=5 Participants	446 Participants n=7 Participants	890 Participants n=5 Participants
Systematic Anti-Cancer Therapy Stratification Factor Yes	747 Participants n=5 Participants	746 Participants n=7 Participants	1493 Participants n=5 Participants
Systematic Anti-Cancer Therapy Stratification Factor No	143 Participants n=5 Participants	140 Participants n=7 Participants	283 Participants n=5 Participants

PRIMARY outcome

Timeframe: up to 33 months

Population: Full Analysis Set, composed of all randomized participants.

Time to the first on-study skeletal-related event (SRE) using a non-inferiority analysis. Median was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=890 Participants Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab n=886 Participants Denosumab 120 mg by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Time to the First On-Study Skeletal-Related Event (Non-Inferiority)	496.0 Days Interval 371.0 to 589.0	625.0 Days Interval 456.0 to Upper limit could not be estimated due to the low number of events

SECONDARY outcome

Timeframe: up to 33 months

Population: Full Analysis Set, composed of all randomized participants.

Time to first on-study skeletal-related event (SRE) using a test for superiority. Median was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=890 Participants Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab n=886 Participants Denosumab 120 mg by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Time to First On-Study Skeletal-Related Event (Superiority)	496.0 Days Interval 371.0 to 589.0	625.0 Days Interval 456.0 to Upper limit could not be estimated due to the low number of events.

SECONDARY outcome

Timeframe: up to 33 months

Population: Full Analysis Set, composed of all randomized participants

Time to the first-and-subsequent on-study skeletal-related event (SRE) using multiple event analysis. To be considered a subsequent SRE, 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.

Outcome measures

Outcome measures
Measure	Zoledronic Acid n=890 Participants Zoledronic acid 4 mg by intravenous injection with a subcutaneous denosumab placebo once every 4 weeks	Denosumab n=886 Participants Denosumab 120 mg by subcutaneous injection with an intravenous zoledronic acid placebo once every 4 weeks
Time to the First-and-Subsequent On-Study Skeletal-Related Event	436 Events	392 Events

Adverse Events

Zoledronic Acid 4 mg Q4W

Serious events: 581 serious events

Other events: 767 other events

Deaths: 0 deaths

Denosumab 120 mg Q4W

Serious events: 552 serious events

Other events: 751 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results aftercompletion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Zoledronic Acid 4 mg Q4W n=878 participants at risk	Denosumab 120 mg Q4W n=878 participants at risk
Psychiatric disorders Insomnia	10.6% 93/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.1% 89/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Blood and lymphatic system disorders Anaemia	30.1% 264/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	26.7% 234/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Blood and lymphatic system disorders Leukopenia	7.7% 68/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.7% 50/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Blood and lymphatic system disorders Neutropenia	11.4% 100/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.3% 90/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Blood and lymphatic system disorders Thrombocytopenia	9.8% 86/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.3% 90/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Abdominal pain	9.8% 86/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	9.6% 84/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Abdominal pain upper	4.3% 38/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.4% 47/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Constipation	23.8% 209/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	21.4% 188/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Diarrhoea	18.8% 165/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	18.6% 163/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Nausea	29.6% 260/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	27.8% 244/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Gastrointestinal disorders Vomiting	19.0% 167/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	19.8% 174/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Asthenia	19.5% 171/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	17.8% 156/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Chest pain	9.7% 85/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.5% 92/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Fatigue	24.6% 216/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	23.1% 203/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Mucosal inflammation	5.4% 47/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	4.9% 43/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Oedema peripheral	15.4% 135/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	12.1% 106/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Pain	5.4% 47/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.4% 47/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
General disorders Pyrexia	19.4% 170/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	14.2% 125/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Infections and infestations Urinary tract infection	5.0% 44/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	4.3% 38/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Injury, poisoning and procedural complications Rib fracture	5.2% 46/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	4.4% 39/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Injury, poisoning and procedural complications Thoracic vertebral fracture	5.0% 44/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	4.0% 35/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Investigations Weight decreased	12.0% 105/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	11.3% 99/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Metabolism and nutrition disorders Anorexia	21.6% 190/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	18.6% 163/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Metabolism and nutrition disorders Dehydration	5.1% 45/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	4.8% 42/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Metabolism and nutrition disorders Hypocalcaemia	5.4% 47/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.0% 88/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Metabolism and nutrition disorders Hypokalaemia	7.2% 63/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	6.0% 53/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Arthralgia	15.6% 137/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	14.1% 124/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Back pain	20.8% 183/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	19.2% 169/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Bone pain	17.0% 149/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	15.6% 137/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	5.6% 49/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	6.0% 53/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	10.8% 95/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	10.5% 92/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Musculoskeletal and connective tissue disorders Pain in extremity	14.6% 128/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	13.8% 121/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Nervous system disorders Dizziness	8.2% 72/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	7.6% 67/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Nervous system disorders Headache	10.6% 93/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	11.3% 99/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Nervous system disorders Neuropathy peripheral	4.8% 42/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.2% 46/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Nervous system disorders Paraesthesia	6.7% 59/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.1% 45/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Psychiatric disorders Anxiety	6.4% 56/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	8.3% 73/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Psychiatric disorders Depression	6.4% 56/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	7.1% 62/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Respiratory, thoracic and mediastinal disorders Cough	17.2% 151/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	19.6% 172/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Respiratory, thoracic and mediastinal disorders Dyspnoea	19.5% 171/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	22.0% 193/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Skin and subcutaneous tissue disorders Alopecia	7.1% 62/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	5.5% 48/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Skin and subcutaneous tissue disorders Rash	8.5% 75/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.	7.6% 67/878 • up to 2 years 9 months The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.