NCT01077154

Study of Denosumab as Adjuvant Treatment for Women With High Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE)

Terminated Phase 3 Results posted Last updated 28 September 2021

What this trial tests

Phase 3 trial testing Placebo in Breast Cancer in 4,509 participants. Terminated before completion.

Timeline

2 June 2010

Primary endpoint
31 August 2017

26 March 2018

Quick facts

Lead sponsor	Amgen
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	4,509
Start date	2 June 2010
Primary completion	31 August 2017
Estimated completion	26 March 2018
Sites	459 locations across Hong Kong, Italy, Japan, Malaysia, Taiwan, Ireland, Poland, South Korea

Drugs / interventions tested

• Placebo
• Denosumab (DENOSUMAB) — full drug profile →

Conditions studied

• Breast Cancer — all drugs for Breast Cancer →

Sponsor

Amgen — full company profile →

Who can join

18 and older, female only, with Breast Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Bone Metastasis-free Survival (BMFS) Primary · From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

BMFS time was defined as the time interval from the randomization date to the first occurrence of bone metastasis or death from any cause, whichever came first. Participants last known to be alive with no bone metastasis were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first occurrence of bone metastasis before randomization were censored at their randomization date. Bone metastasis must have been confirmed by central imaging analysis or by biopsy, Evidence of disseminated tumor cells in bone marrow was not su

Group	Value	95% CI
Placebo	13.5	12.1 – 15.0
Denosumab	12.9	11.6 – 14.3

Disease-free Survival (DFS) Secondary · From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Develop

Group	Value	95% CI
Placebo	19.2	17.6 – 20.8
Denosumab	19.6	18.0 – 21.2

Disease-free Survival (DFS) in the Postmenopausal Subset Secondary · From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Develop

Group	Value	95% CI
Placebo	18.6	16.3 – 20.9
Denosumab	20.3	17.8 – 22.7

Overall Survival Secondary · From randomization until the end of study; median (minimum, maximum) time on study was 72.7 (0, 92) and 72.3 (0, 92) months in each treatment group respectively.

Overall survival (OS) time was defined as the time interval from the randomization date to the date of death from any cause. Participants last known to be alive were censored at their last contact date. Since the median time to overall survival could not be estimated at the time of the final analysis due to low numbers of events, the percentage of participants with an event (i.e., death) is reported.

Group	Value	95% CI
Placebo	9.5	8.3 – 10.8
Denosumab	9.5	8.3 – 10.7

Distant Recurrence-free Survival Secondary · From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Distant recurrence-free survival (DRFS) was defined as the time interval from the randomization date to the date of first observation of distant disease recurrence or death from any cause, whichever came first. Participants last known to be alive, who had not experienced distant disease recurrence, were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first distant recurrence before randomization were censored at their randomization date. Distant disease recurrence includes confirmed bone metastasis and extraosseou

Group	Value	95% CI
Placebo	18.0	16.4 – 19.6
Denosumab	18.7	17.1 – 20.3

Adverse events — posted to ClinicalTrials.gov

Time frame: All-cause mortality includes deaths from first dose of study drug to the end of study date; median (min, max) time on study was 72.7 (0, 92) and 72.3 (0, 92) months for Placebo/Denosumab respectively. Adverse Events are from first dose of study drug to 30 days after last dose; median (min, max) time on treatment was 59.4 (0.7, 67) and 59.3 (0.7, 67) months for Placebo/Denosumab respectively.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 675/2218 (30%)

Deaths: 215/2218

Denosumab

Serious: 702/2241 (31%)

Deaths: 215/2241

Serious adverse events (706 terms)

Reaction	System	Placebo	Denosumab
Febrile neutropenia	Blood and lymphatic system disorders	—	—
Pyrexia	General disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Cellulitis	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Osteonecrosis of jaw	Musculoskeletal and connective tissue disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Breast cellulitis	Infections and infestations	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Metastases to central nervous system	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Neutropenic sepsis	Infections and infestations	—	—
Erysipelas	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Mastitis	Infections and infestations	—	—
Deep vein thrombosis	Vascular disorders	—	—
Sepsis	Infections and infestations	—	—
Device related infection	Infections and infestations	—	—
Headache	Nervous system disorders	—	—
Postoperative wound infection	Infections and infestations	—	—
Upper respiratory tract infection	Infections and infestations	—	—

Other adverse events (68 terms — click to expand)

Reaction	System	Placebo	Denosumab
Nausea	Gastrointestinal disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—
Fatigue	General disorders	—	—
Hot flush	Vascular disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Headache	Nervous system disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Insomnia	Psychiatric disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Neuropathy peripheral	Nervous system disorders	—	—
Asthenia	General disorders	—	—
Stomatitis	Gastrointestinal disorders	—	—
Oedema peripheral	General disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Lymphoedema	Vascular disorders	—	—
Radiation skin injury	Injury, poisoning and procedural complications	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Dysgeusia	Nervous system disorders	—	—
Pyrexia	General disorders	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Bone pain	Musculoskeletal and connective tissue disorders	—	—
Mucosal inflammation	General disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Nail disorder	Skin and subcutaneous tissue disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Dizziness	Nervous system disorders	—	—
Erythema	Skin and subcutaneous tissue disorders	—	—
Lacrimation increased	Eye disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Anxiety	Psychiatric disorders	—	—
Paraesthesia	Nervous system disorders	—	—
Hypertension	Vascular disorders	—	—

Most-reported serious reactions: Febrile neutropenia, Pyrexia, Neutropenia, Cellulitis, Pneumonia, Osteonecrosis of jaw, Diarrhoea, Vomiting.

Data from ClinicalTrials.gov NCT01077154 adverse events section.

Sponsor's own description

This randomized phase 3 trial is studying the effect of denosumab to see if it can prevent disease recurrence in the bone or in any other part of the body, when it is given as adjuvant therapy for women with early-stage breast cancer, who are at high risk of disease recurrence.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial.
   Coleman R, Finkelstein DM, Barrios C, Martin M, et al · · 2020 · cited 176× · PMID 31806543 · DOI 10.1016/s1470-2045(19)30687-4
2. Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance.
   Dudas J, Ladanyi A, Ingruber J, Steinbichler TB, et al · · 2020 · cited 148× · PMID 32059478 · DOI 10.3390/cells9020428
3. RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives.
   Infante M, Fabi A, Cognetti F, Gorini S, et al · · 2019 · cited 127× · PMID 30621730 · DOI 10.1186/s13046-018-1001-2
4. Bisphosphonates and other bone agents for breast cancer.
   O'Carrigan B, Wong MH, Willson ML, Stockler MR, et al · · 2017 · cited 113× · PMID 29082518 · DOI 10.1002/14651858.cd003474.pub4
5. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways.
   Hosford SR, Miller TW. · · 2014 · cited 109× · PMID 25206307 · DOI 10.2147/pgpm.s52762
6. Therapeutic targets for bone metastases in breast cancer.
   Clézardin P. · · 2011 · cited 79× · PMID 21586099 · DOI 10.1186/bcr2835
7. Trial Watch: Monoclonal antibodies in cancer therapy.
   Galluzzi L, Vacchelli E, Fridman WH, Galon J, et al · · 2012 · cited 77× · PMID 22720209 · DOI 10.4161/onci.1.1.17938
8. Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04).
   Coleman RE, Collinson M, Gregory W, Marshall H, et al · · 2018 · cited 75× · PMID 30591866 · DOI 10.1016/j.jbo.2018.09.008