Breast Cancer
Conditions
Keywords
Early Stage Breast Cancer, Bone Metastasis, Adjuvant treatment, Neoadjuvant treatment, Denosumab, Stage II breast cancer, Stage III breast cancer, Stage IIA breast cancer, Stage IIB breast cancer, Stage IIIA breast cancer, Stage IIIB breast cancer, Stage IIIC breast cancer, Early breast cancer, Breast Tumors, Breast Neoplasms
Brief summary
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.
Detailed description
Eligible participants were randomized in a 1:1 ratio to receive denosumab 120 mg or placebo subcutaneously (SC) for up to 5 years. Randomization was stratified based on: 1. Breast cancer therapy/lymph node (LN) status: neoadjuvant therapy/any LN status versus adjuvant therapy/LN negative (based on axillary LN dissection, or based on sentinel node status) versus adjuvant therapy/LN positive 2. Hormone receptor (estrogen receptor \[ER\]/progesterone receptor \[PR\]) status: ER and/or PR positive versus ER and PR negative 3. Human epidermal growth factor receptor 2 (HER-2) status: HER-2 positive versus HER-2 negative 4. Age: \< 50 years versus ≥ 50 years 5. Geographic Region: Japan versus Other regions. The primary analysis was conducted after all enrolled participants had the opportunity to complete 5 years of treatment from study day 1.
Interventions
DRUGPlacebo
Administered subcutaneously for up to 5 years
DRUGDenosumab
Administered subcutaneously for up to 5 years
Sponsors
Daiichi Sankyo
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed, American Joint Committee on Cancer (AJCC) stage II or III breast cancer * High risk of breast cancer recurrence, defined as documented evidence of one or more of the following criteria: i) Biopsy evidence of breast cancer in regional lymph node(s) (LN) (node-positive disease); Nodal micrometastases only are not considered node positive ii) Tumor size \> 5 cm (T3) or locally advanced disease (T4) * Documented pathological evaluation of the breast cancer for hormone receptor (estrogen receptor \[ER\] and progesterone receptor \[PR\]) status and HER-2 status * Subjects must be receiving or be scheduled to receive standard of care systemic adjuvant or neoadjuvant chemotherapy and/or endocrine therapy and/or HER-2 targeted therapy * For subjects receiving adjuvant therapy only: * subjects must have undergone complete resection of the primary tumor with clean surgical margins, or subjects must have undergone resection of the primary tumor and be scheduled for further treatment of the primary tumor with curative intent. Definitive treatment must be planned to be completed within approximately 9 months of randomization * Time between definitive surgery and randomization must be ≤ 12 weeks. Definitive surgery may include secondary interventions (e.g. to clear inadequate surgical margins) * Subjects with node positive disease must have undergone treatment of axillary LN with curative intent, or subjects must be scheduled for further treatment of regional lymph nodes with curative intent. Definitive treatment must be planned to be completed within approximately 9 months of randomization * Subjects must not have received prior neoadjuvant treatment. Endocrine treatment for less than 30 days prior to surgery is not considered prior neoadjuvant treatment * For subjects receiving neoadjuvant therapy only: * Time between start of neoadjuvant treatment and randomization must be ≤ 8 weeks and subjects must be scheduled to undergo definitive treatment (including surgery and/or radiotherapy) with curative intent within approximately 9 months of starting neoadjuvant treatment * Female subjects with age ≥ 18 years * Subjects with reproductive potential must have a negative pregnancy test within 14 days before randomization * Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Written informed consent before any study-specific procedure is performed
Exclusion criteria
* Prior or current evidence of any metastatic involvement of any distant site * History of breast cancer (other than ductal carcinoma in situ \[DCIS\] or lobular carcinoma in situ \[LCIS\]) prior to the current diagnosis * Osteoporosis requiring treatment at the time of randomization or treatment considered likely to become necessary within the subsequent six months * Any prior or synchronous malignancy (other than breast cancer), except i) Malignancy treated with curative intent and with no evidence of disease for ≥ 5 years prior to enrollment and considered to be at low risk for recurrence by the treating physician ii) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Active infection with Hepatitis B virus or Hepatitis C virus * Known infection with human immunodeficiency virus (HIV) * Prior history or current evidence of osteomyelitis/osteonecrosis of the jaw * Active dental or jaw condition which requires oral surgery * Planned invasive dental procedure for the course of the study * Non-healed dental or oral surgery * Use of oral bisphosphonates within the past 1 year * Prior or current IV bisphosphonate administration * Prior administration of denosumab * Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or investigational drug study(s), or subject is receiving other investigational agent(s) * Subject is pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment. * Subject is of child bearing potential and is not willing to use, in combination with her partner, 2 highly effective methods of contraception or abstinence during treatment and for 5 months after the end of treatment * Subject has known sensitivity to any of the products to be administered during the study (e.g., mammalian derived products, calcium, or vitamin D) * Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures. * Any major medical or psychiatric disorder that in the opinion of the investigator prevent the subject from completing the study or interfere with the interpretation of the study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bone Metastasis-free Survival (BMFS) | 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 sufficient for determination of disease recurrence. Development of new primary malignancy in bone was not considered as bone metastasis. Since the median BMSF time could not be estimated due to low number of events, the percentage of participants with an event (i.e., bone metastasis or death) is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS) | 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. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported. |
| Disease-free Survival (DFS) in the Postmenopausal Subset | 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. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time in the postmenopausal subset could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported. |
| Overall Survival | 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. |
| Distant Recurrence-free Survival | 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 extraosseous disease other than local-regional disease recurrence. Development of non-breast cancer new primary malignancy was not considered as distant disease recurrence. Since the median time to DRFS could not be estimated due to the low number of events, the percentage of participants with an event (i.e., distant recurrence or death) is reported. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, Denmark, France, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Latvia, Malaysia, Mexico, Netherlands, Peru, Philippines, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, South Africa, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 407 centers in Australia, Western Europe, Eastern Europe, Israel, North America, Asia, South America, South Africa, and Turkey from 02 June 2010 to 24 August 2012.
Pre-assignment details
Participants were randomized in a 1:1 ratio to 1 of 2 groups. Randomization was stratified based on breast cancer therapy/lymph node (LN) status, hormone receptor status, human epidermal growth factor receptor 2 (HER-2) status, age, and geographic region.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years. | 2,253 |
| Denosumab Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years. | 2,256 |
| Total | 4,509 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Decision | 1 | 6 |
| Overall Study | Adverse Event | 9 | 9 |
| Overall Study | Death | 215 | 214 |
| Overall Study | Disease Progression | 18 | 20 |
| Overall Study | Ineligibility Determined | 10 | 14 |
| Overall Study | Lost to Follow-up | 43 | 35 |
| Overall Study | Noncompliance | 22 | 20 |
| Overall Study | Other | 14 | 11 |
| Overall Study | Protocol Deviation | 1 | 0 |
| Overall Study | Protocol-specified Criteria: Study Ended | 1,524 | 1,514 |
| Overall Study | Withdrawal by Subject | 369 | 385 |
Baseline characteristics
| Characteristic | Total | Placebo | Denosumab |
|---|---|---|---|
| Age, Continuous | 51.5 years STANDARD_DEVIATION 10.7 | 51.6 years STANDARD_DEVIATION 10.6 | 51.4 years STANDARD_DEVIATION 10.7 |
| Age, Customized 18 - 64 years | 3919 Participants | 1960 Participants | 1959 Participants |
| Age, Customized 65 - 74 years | 519 Participants | 259 Participants | 260 Participants |
| Age, Customized 75 - 84 years | 69 Participants | 33 Participants | 36 Participants |
| Age, Customized ≥ 85 years | 2 Participants | 1 Participants | 1 Participants |
| Age (Strata per Randomization) < 50 years | 2055 Participants | 1026 Participants | 1029 Participants |
| Age (Strata per Randomization) ≥ 50 years | 2454 Participants | 1227 Participants | 1227 Participants |
| Breast Cancer Histopathologic Grade Grade 1 = Low | 431 Participants | 222 Participants | 209 Participants |
| Breast Cancer Histopathologic Grade Grade 2 = Intermediate | 2094 Participants | 1015 Participants | 1079 Participants |
| Breast Cancer Histopathologic Grade Grade 3 = High | 1844 Participants | 938 Participants | 906 Participants |
| Breast Cancer Histopathologic Grade Not Evaluable/Missing | 140 Participants | 78 Participants | 62 Participants |
| Breast Cancer Therapy / Lymph Node Status (Strata per Randomization) Adjuvant therapy / lymph node negative | 133 Participants | 68 Participants | 65 Participants |
| Breast Cancer Therapy / Lymph Node Status (Strata per Randomization) Adjuvant therapy / lymph node positive | 3274 Participants | 1635 Participants | 1639 Participants |
| Breast Cancer Therapy / Lymph Node Status (Strata per Randomization) Neo-adjuvant therapy / any lymph node status | 1102 Participants | 550 Participants | 552 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 3835 Participants | 1913 Participants | 1922 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restricted but ambulatory) | 669 Participants | 340 Participants | 329 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory, unable to work) | 3 Participants | 0 Participants | 3 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 2 Participants | 0 Participants | 2 Participants |
| Geographic Region (Strata per Randomization) Japan | 262 Participants | 131 Participants | 131 Participants |
| Geographic Region (Strata per Randomization) Other | 4247 Participants | 2122 Participants | 2125 Participants |
| Hormone Receptor Status (Strata per Randomization) ER and/or PR positive | 3487 Participants | 1740 Participants | 1747 Participants |
| Hormone Receptor Status (Strata per Randomization) ER and PR negative | 1022 Participants | 513 Participants | 509 Participants |
| Human Epidermal Growth Factor Receptor 2 (HER-2) Status (Strata per Randomization) HER-2 negative | 3527 Participants | 1763 Participants | 1764 Participants |
| Human Epidermal Growth Factor Receptor 2 (HER-2) Status (Strata per Randomization) HER-2 positive | 982 Participants | 490 Participants | 492 Participants |
| Lymph Node Status N0 | 261 Participants | 130 Participants | 131 Participants |
| Lymph Node Status N1 | 2750 Participants | 1369 Participants | 1381 Participants |
| Lymph Node Status N2 | 1011 Participants | 506 Participants | 505 Participants |
| Lymph Node Status N3 | 454 Participants | 230 Participants | 224 Participants |
| Lymph Node Status Nx | 33 Participants | 18 Participants | 15 Participants |
| Menopausal Status Postmenopausal | 2149 Participants | 1088 Participants | 1061 Participants |
| Menopausal Status Premenopausal | 2360 Participants | 1165 Participants | 1195 Participants |
| Molecular Subtypes of Breast Cancer HR negative and HER-2 negative | 684 Participants | 341 Participants | 343 Participants |
| Molecular Subtypes of Breast Cancer HR negative and HER-2 positive | 331 Participants | 163 Participants | 168 Participants |
| Molecular Subtypes of Breast Cancer HR positive and HER-2 negative | 2918 Participants | 1460 Participants | 1458 Participants |
| Molecular Subtypes of Breast Cancer HR positive and HER-2 positive | 574 Participants | 288 Participants | 286 Participants |
| Molecular Subtypes of Breast Cancer Missing | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 435 Participants | 222 Participants | 213 Participants |
| Race/Ethnicity, Customized Black | 144 Participants | 70 Participants | 74 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 247 Participants | 112 Participants | 135 Participants |
| Race/Ethnicity, Customized Japanese | 269 Participants | 134 Participants | 135 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 7 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 38 Participants | 18 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 3368 Participants | 1692 Participants | 1676 Participants |
| Sex: Female, Male Female | 4509 Participants | 2253 Participants | 2256 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 215 / 2,218 | 215 / 2,241 |
| other Total, other adverse events | 2,123 / 2,218 | 2,149 / 2,241 |
| serious Total, serious adverse events | 675 / 2,218 | 702 / 2,241 |
Outcome results
Primary
Bone Metastasis-free Survival (BMFS)
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 sufficient for determination of disease recurrence. Development of new primary malignancy in bone was not considered as bone metastasis. Since the median BMSF time could not be estimated due to low number of events, the percentage of participants with an event (i.e., bone metastasis or death) is reported.
Time frame: 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.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Bone Metastasis-free Survival (BMFS) | 13.5 percentage of participants |
| Denosumab | Bone Metastasis-free Survival (BMFS) | 12.9 percentage of participants |
p-value: 0.795% CI: [0.82, 1.14]Stratified Log Rank
Secondary
Disease-free Survival (DFS)
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. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
Time frame: 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.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Disease-free Survival (DFS) | 19.2 percentage of participants |
| Denosumab | Disease-free Survival (DFS) | 19.6 percentage of participants |
p-value: 0.5795% CI: [0.91, 1.19]Stratified Log Rank
Secondary
Disease-free Survival (DFS) in the Postmenopausal Subset
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. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time in the postmenopausal subset could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
Time frame: 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.
Population: Randomized participants postmenopausal at enrollment, defined as:~* Undergone bilateral oophorectomy~* Age ≥ 60 years~* Age 45 to 59 years with 1 of the criteria, ie, either amenorrhea \> 12 months with an intact uterus and ≥ 1 intact ovary; or amenorrhea for ≤ 12 months and follicle-stimulating hormone and estradiol in postmenopausal range.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Disease-free Survival (DFS) in the Postmenopausal Subset | 18.6 percentage of participants |
| Denosumab | Disease-free Survival (DFS) in the Postmenopausal Subset | 20.3 percentage of participants |
p-value: 0.2695% CI: [0.92, 1.36]Stratified Log Rank
Secondary
Distant Recurrence-free Survival
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 extraosseous disease other than local-regional disease recurrence. Development of non-breast cancer new primary malignancy was not considered as distant disease recurrence. Since the median time to DRFS could not be estimated due to the low number of events, the percentage of participants with an event (i.e., distant recurrence or death) is reported.
Time frame: 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.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Distant Recurrence-free Survival | 18.0 percentage of participants |
| Denosumab | Distant Recurrence-free Survival | 18.7 percentage of participants |
p-value: 0.4195% CI: [0.92, 1.21]Stratified Log Rank
Secondary
Overall Survival
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.
Time frame: 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.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Overall Survival | 9.5 percentage of participants |
| Denosumab | Overall Survival | 9.5 percentage of participants |
p-value: 0.9495% CI: [0.83, 1.22]Stratified Log Rank