Advanced Breast Cancer, HER2 Amplified, Human Epidermal Growth Factor Receptor 2 (HER2)
Conditions
Keywords
Enzalutamide, Trastuzumab, Breast cancer, HER2, Androgen receptor positive, Xtandi
Brief summary
The purpose of this study was to evaluate the efficacy of enzalutamide with trastuzumab in patients with HER2+ AR+ metastatic or locally advanced breast cancer.
Interventions
DRUGEnzalutamide
Capsules for oral administration
DRUGTrastuzumab
Intravenous infusion (IV) or subcutaneous injection if it is standard of care within a country
Sponsors
Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Astellas Pharma Global Development, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The subject has histologically or cytologically proven adenocarcinoma of the breast that is HER2+ * The subject has AR+ breast cancer * The subject has metastatic disease or has locally advanced disease that is not amendable to curative treatment * The subject has measurable disease or nonmeasurable, evaluable disease per RECIST 1.1. (NOTE: pleural effusions, ascites or other third fluid space are not evaluable diseases per RECIST 1.1). * The subject has received at least 1 line of therapy in the metastatic or locally advanced disease setting. The subject has been documented to have progressed by determination of the investigator on a regimen containing an anti-HER2 agent as the most recent regimen or the most recent anti-HER2 regimen was discontinued for any toxicity, with the exception of a cardiotoxicity. * The subject has adequately recovered from toxicities due to prior therapy. * The subject has an Eastern Cooperative Oncology Group performance (ECOG) status ≤ 1 at Screening and Day 1 * The subject has available at the site a representative, formalin-fixed, paraffin-embedded, tumor specimen that enabled the definitive diagnosis of breast cancer with adequate viable tumor cells in a tissue block (preferred) or ≥ 10 (20 preferred) freshly cut, unstained, serial slides and the associated pathology report
Exclusion criteria
* The subject has a severe concurrent disease, infection, or comorbidity that would make the subject inappropriate for enrollment. * The subject has current or previously treated brain metastasis or active leptomeningeal disease. Brain imaging is required during screening in all subjects to exclude the presence of unequivocal central nervous system disease. * The subject has a history of a non-breast cancer malignancy with the following exceptions: * The subject with a previous history of a non-invasive carcinoma is eligible if he/she has had successful curative treatment any time prior to Screening. * For all other malignancies, the subject is eligible if they have undergone potentially curative therapy and they have been considered disease free for at least 5 years prior to Screening. * The subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma). * The subject has a history of loss of consciousness, cerebrovascular accident, or transient ischemic attack within 12 months before the Day 1 visit. * The subject has had a hypoglycemic episode requiring medical intervention while on insulin (or other anti-diabetic) treatment within 12 months before Day 1. * The subject had a major surgical procedure, substantial open biopsy, or significant traumatic experience within 28 days before the Day 1 visit, or anticipation of need for major surgical procedure during the course of the study. * The subject has had palliative radiation therapy to bone metastases within 14 days prior to the Day 1 visit (side effects from radiation must be resolved). * The subject has received chemotherapy, immunotherapy, or any other systemic anticancer therapy, with the exception of anti-HER2 therapy (e.g., trastuzumab), within 14 days prior to the Day 1 visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) | Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days. | Clinical benefit rate was defined as the percentage of evaluable participants with best objective response of confirmed complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or prolonged stable disease (≥ 24 weeks). Complete response (CR) was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response (PR) was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions, with persistence of non-target lesions and no new lesions. Stable disease (SD) was defined as \< 30% decrease and \< 20% increase in the size of target lesions, persistence of non-target lesions, and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date that PR or CR was first observed. SD required confirmation with equivalent or improved assessment no less than 8 weeks after enrollment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate | Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days. | Best overall response was the best response across all time points, based on investigator assessments. Best overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) at any time during the study per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed. |
| Progression-free Survival | From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days. | Progression-free survival was defined as the time from the date of first dose of enzalutamide until the date of disease progression per RECIST 1.1, or death from any cause on study, whichever occurred first. Participants who initiated another antitumor therapy before documented progressive disease (PD) or death, or who progressed or died after missing 2 or more consecutive radiological assessments were censored at the date of the last radiological assessment showing no progression. Progressive disease was defined as a ≥ 20% increase in the size of target lesions and at least a 5 mm increase in size of target lesions from smallest size on study, or unequivocal progression of non-target lesions, or any new lesions. |
| Time to Progression | From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days. | Time to progression was defined as the time from the first date of enzalutamide treatment until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, who progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression. |
| Overall Response Rate at Week 24 | 24 weeks | Overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed. |
| Time to Response | From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days. | Time to response was defined as the time from the first date of enzalutamide treatment to initial CR or PR and was calculated for participants with a CR or PR. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From the first dose date of study drug to 30 days after the last dose date of study drug or the start of subsequent treatment or date of death, whichever was first (Up to 3031 days) | An AE was defined as any untoward medical occurrence in a participant administered study drug/who underwent study procedures and did not necessarily have a causal relationship with treatment. Abnormalities identified during medical tests were defined as an AE if they induced clinical signs/symptoms, required active intervention, interruption or discontinuation of study medication, or were clinically significant to the investigator. An AE was defined as serious if any of the following resulted: Death, was life-threatening, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/ birth defect, inpatient hospitalization/prolongation of hospitalization or other medically important event. TEAE was defined as an AE observed during the treatment emergent period, which is from first dose date of study drug to 30 days after last dose date or the start of subsequent treatment or date of death, whichever is first. |
| Duration of Response | Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.. | Duration of response was defined as the time from the date of first documentation of response (CR or PR) until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression. |
Countries
Belgium, Canada, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 35 clinical sites in Belgium, Canada, Italy, Spain, the United Kingdom and the United States.
Pre-assignment details
This study enrolled women with human epidermal growth factor receptor 2 positive (HER2+) and androgen receptor positive (AR+) metastatic or locally advanced breast cancer who progressed on anti-HER2 therapy in the metastatic or advanced setting.
Participants by arm
| Arm | Count |
|---|---|
| Enzalutamide + Trastuzumab Participants received 160 mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met. | 103 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 7 |
| Overall Study | Miscellaneous Reasons | 37 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Enzalutamide + Trastuzumab |
|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 10 |
| Anatomic Stage Stage 0 | 3 Participants |
| Anatomic Stage Stage IA | 6 Participants |
| Anatomic Stage Stage IB | 1 Participants |
| Anatomic Stage Stage IIA | 14 Participants |
| Anatomic Stage Stage IIB | 12 Participants |
| Anatomic Stage Stage IIIA | 5 Participants |
| Anatomic Stage Stage IIIB | 7 Participants |
| Anatomic Stage Stage IIIC | 7 Participants |
| Anatomic Stage Stage IV | 28 Participants |
| Anatomic Stage Unknown | 20 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 | 51 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 | 51 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Histopathology at Diagnosis Ductal | 73 Participants |
| Histopathology at Diagnosis Inflammatory | 5 Participants |
| Histopathology at Diagnosis Intraductal | 6 Participants |
| Histopathology at Diagnosis Lobular | 6 Participants |
| Histopathology at Diagnosis Mixed | 1 Participants |
| Histopathology at Diagnosis Not otherwise specified | 1 Participants |
| Histopathology at Diagnosis Other | 5 Participants |
| Histopathology at Diagnosis Unknown | 6 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaskan Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants |
| Race/Ethnicity, Customized Race Black or African American | 8 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants |
| Race/Ethnicity, Customized Race White | 90 Participants |
| Sex: Female, Male Female | 103 Participants |
| Sex: Female, Male Male | 0 Participants |
| Time from Initial Diagnosis of Primary Cancer to Enrollment | 1199 days |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 103 |
| other Total, other adverse events | 89 / 103 |
| serious Total, serious adverse events | 24 / 103 |
Outcome results
Primary
Clinical Benefit Rate (CBR)
Clinical benefit rate was defined as the percentage of evaluable participants with best objective response of confirmed complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or prolonged stable disease (≥ 24 weeks). Complete response (CR) was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response (PR) was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions, with persistence of non-target lesions and no new lesions. Stable disease (SD) was defined as \< 30% decrease and \< 20% increase in the size of target lesions, persistence of non-target lesions, and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date that PR or CR was first observed. SD required confirmation with equivalent or improved assessment no less than 8 weeks after enrollment.
Time frame: Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
Population: The efficacy evaluable set (EES) included all enrolled participants who had centrally assessed androgen receptor positive (AR+; defined as ≥ 10% of tumor cells with nuclear expression), received at least one dose of study drug, and had at least one available post baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enzalutamide + Trastuzumab | Clinical Benefit Rate (CBR) | 23.6 percentage of participants |
Secondary
Best Overall Response Rate
Best overall response was the best response across all time points, based on investigator assessments. Best overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) at any time during the study per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed.
Time frame: Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
Population: Efficacy evaluable set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enzalutamide + Trastuzumab | Best Overall Response Rate | 4.5 percentage of participants |
Secondary
Duration of Response
Duration of response was defined as the time from the date of first documentation of response (CR or PR) until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression.
Time frame: Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days..
Population: Efficacy evaluable set participants with a best overall response of CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide + Trastuzumab | Duration of Response | NA days |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An AE was defined as any untoward medical occurrence in a participant administered study drug/who underwent study procedures and did not necessarily have a causal relationship with treatment. Abnormalities identified during medical tests were defined as an AE if they induced clinical signs/symptoms, required active intervention, interruption or discontinuation of study medication, or were clinically significant to the investigator. An AE was defined as serious if any of the following resulted: Death, was life-threatening, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/ birth defect, inpatient hospitalization/prolongation of hospitalization or other medically important event. TEAE was defined as an AE observed during the treatment emergent period, which is from first dose date of study drug to 30 days after last dose date or the start of subsequent treatment or date of death, whichever is first.
Time frame: From the first dose date of study drug to 30 days after the last dose date of study drug or the start of subsequent treatment or date of death, whichever was first (Up to 3031 days)
Population: The Safety Analysis Set (SAF) which consisted of all participants who had received at least 1 or partial dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any treatment emergent adverse events (TEAE) | 97 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Enzalutamide Related TEAE | 75 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Trastuzumab Related TEAE | 40 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Drug Related TEAE | 78 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Deaths | 4 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE | 24 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Enzalutamide Related Serious TEAE | 3 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Trastuzumab Related Serious TEAE | 0 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any Drug Related Serious TEAE | 3 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of enzalutamide | 23 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of trastuzumab | 21 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of any study drug | 24 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Discontinuation due to enzalutamide Related TEAE | 5 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Discontinuation due to trastuzumab Related TEAE | 5 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Discontinuation due to Any Drug Related TEAE | 9 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE Leading to Dose Reduction | 7 Participants |
| Enzalutamide + Trastuzumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE Leading to Dose Interruption | 23 Participants |
Secondary
Overall Response Rate at Week 24
Overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed.
Time frame: 24 weeks
Population: Efficacy evaluable set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enzalutamide + Trastuzumab | Overall Response Rate at Week 24 | 3.4 percentage of participants |
Secondary
Progression-free Survival
Progression-free survival was defined as the time from the date of first dose of enzalutamide until the date of disease progression per RECIST 1.1, or death from any cause on study, whichever occurred first. Participants who initiated another antitumor therapy before documented progressive disease (PD) or death, or who progressed or died after missing 2 or more consecutive radiological assessments were censored at the date of the last radiological assessment showing no progression. Progressive disease was defined as a ≥ 20% increase in the size of target lesions and at least a 5 mm increase in size of target lesions from smallest size on study, or unequivocal progression of non-target lesions, or any new lesions.
Time frame: From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
Population: Efficacy evaluable set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide + Trastuzumab | Progression-free Survival | 105.0 days |
Secondary
Time to Progression
Time to progression was defined as the time from the first date of enzalutamide treatment until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, who progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression.
Time frame: From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
Population: Efficacy analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide + Trastuzumab | Time to Progression | 108.0 days |
Secondary
Time to Response
Time to response was defined as the time from the first date of enzalutamide treatment to initial CR or PR and was calculated for participants with a CR or PR.
Time frame: From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
Population: Efficacy evaluable set with a best overall response of CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide + Trastuzumab | Time to Response | 57 days |