Metastatic ER+ Her2- Breast Cancer, Postmenopausal
Conditions
Keywords
Breast cancer, Abiraterone, Postmenopausal, Metastatic
Brief summary
The purpose of this study is to assess the safety and efficacy of oral abiraterone acetate plus oral prednisone and oral abiraterone acetate plus oral prednisone plus oral exemestane, each compared with oral exemestane alone, in postmenopausal women with estrogen receptor-positive (ER+) metastatic (spreading) breast cancer that has relapsed after treatment with letrozole or anastrozole.
Detailed description
This is a randomized (study drug assigned by chance), open-label (all participants will know the identity of the assigned study drug) study divided into three phases, screening, treatment, and follow-up. During screening, potential patients will be assessed for study eligibility after providing signed informed consent. The treatment phase will comprise a series of 28-day cycles with continuous study treatment until breast cancer progression, when an end-of-treatment visit will be completed before the follow-up phase begins. The duration of participation in the study for an individual patient may be up to approximately 7 years, including follow-up evaluations. Patients will be evaluated for the safety and effectiveness of study treatments. During the treatment phase, patients will take the following study drugs by mouth once daily: abiraterone acetate, 1 g/day, as four 250-mg tablets, on an empty stomach, and patients must not eat for at least 1 hour after abiraterone acetate; prednisone (prednisolone when prednisone is not available), 5 mg/day; and exemestane, 25 mg/day, as a single tablet. The treatment phase will consist of a series of 28-day cycles with continuous study treatment until breast cancer progression. At the planned interim analysis, the Data Review Committee has recommended that further randomization to the abiraterone acetate alone group be stopped and that the study is to be continued otherwise.
Interventions
DRUGExemestane
Abiraterone acetate, type=equal, unit=mg, number=250, form=tablet, route=oral use, 4 tablets
DRUGAbiraterone acetate + Prednisone/ Prednisolone + Exemestane
Prednisone or Prednisolone, type=equal, unit=mg, number=5, form=tablet, route=oral use. All drugs are taken once daily.
Abiraterone acetate, type=equal, unit=mg, number=250, form=tablet, route=oral use, 4 tablets
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients must be postmenopausal * ER+, Human epidermal growth factor receptor 2 (Her2) negative metastatic breast cancer * Disease must have been sensitive to anastrozole or letrozole therapy prior to disease progression * No more than two prior lines of therapy in the metastatic setting, of which no more than one was chemotherapy * Eastern Cooperative Oncology Group (ECOG) performance status score of \<=1 * Patients with disease confined only to bone may be included, but patients with purely sclerotic lesions may not participate in the study
Exclusion criteria
* Prior treatment with exemestane, ketoconazole, aminoglutethimide, or a CYP17 inhibitor. Prior treatment with ketoconazole for \<= 7 days is permitted and topical formulations of ketoconazole are permitted * Potential patients must not have taken anastrozole, letrozole, fulvestrant, or any chemotherapy for at least 2 weeks (bevacizumab for at least 3 weeks) before randomization * Anticancer immunotherapy or investigational agent within 4 weeks before randomization, or anticancer radiotherapy (except palliative) or anticancer endocrine therapy within 2 weeks before randomization * Serious or uncontrolled nonmalignant disease, including active or uncontrolled infection * Clinical or biochemical evidence of hyperaldosteronism or hypopituitarism * Any condition that, in the opinion of the investigator, would compromise the well-being of the patient or that could prevent, limit, or confound the protocol-specified assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Approximately 2 years | Progression-free survival was defined as the time from randomization to first occurrence of disease progression (either radiographic or clinical), or death from any cause. PFS was determined using radiographic progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) on measurable lesions captured by computed tomography (CT) or magnetic resonance imaging (MRI). Clinical disease progression was considered only when disease progression could not be confirmed by CT or MRI, such as when the disease site is skin, bone marrow, or central nervous system. |
| Overall Survival (OS) | Approximately 3 years | OS was calculated as the time from randomization to death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Approximately 2 years | Duration of objective response was measured from the first time that the CR or PR was achieved to the first observation of disease progression (either radiographic or clinical) based on the RECIST criteria. |
| Overall Response Rate (ORR) | Approximately 2 years | Overall response rate was defined as the percentage of participants with measurable disease achieving a best overall response of either complete response (CR) or partial response (PR) based on RECIST. CR: disappearance of all target lesions and non-target lesions. PR: at least a 30 percent (%) decrease in the sum of longest diameter (LD) of target lesions or persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. |
| Change From Baseline in Serum Endocrine Biomarkers (Progesterone and Testosterone) at End of Treatment | Baseline and End of treatment (approximately 2 years) | Change from baseline in serum endocrine biomarkers (Progesterone and Testosterone) was summarized by treatment at end of treatment. |
| Change From Baseline in Serum Endocrine Biomarkers (Estradiol and Estrone) at End of Treatment | Baseline and End of treatment (approximately 2 years) | Change from baseline in serum endocrine biomarkers (estradiol and estrone) was summarized by treatment at end of treatment. |
| Clinical Benefit Rate | Approximately 2 years | Clinical benefit rate was defined as the percentage of participants with measurable disease achieving a best overall response of a CR, PR, or stable disease (SD) for at least 6 months based on RECIST. Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits. |
Countries
Belgium, France, Ireland, Luxembourg, Netherlands, Poland, Russia, South Korea, Spain, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exemestane Participants received exemestane tablet as oral dose of 25 milligram (mg) per day in 28-day treatment cycles until disease progression, unacceptable toxicity, or death (up to 3 years). | 102 |
| Abiraterone Acetate + Prednisone Participants received abiraterone acetate tablet at a total oral dose of 1000 milligram (mg) along with 5 mg capsule of prednisone/prednisolone per day in 28-day treatment cycles until disease progression, unacceptable toxicity, or death (up to 3 years). | 89 |
| Abiraterone Acetate + Exemestane + Prednisone Participants received abiraterone acetate tablet at a total oral dose of 1000 mg and 5 mg capsule of prednisone/prednisolone along with exemestane tablet 25 mg per day in 28-day treatment cycles until disease progression, unacceptable toxicity, or death (up to 3 years). | 106 |
| Total | 297 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 | 0 |
| Overall Study | Other | 67 | 52 | 67 |
| Overall Study | Withdrawal by Subject | 9 | 10 | 9 |
Baseline characteristics
| Characteristic | Exemestane | Abiraterone Acetate + Prednisone | Abiraterone Acetate + Exemestane + Prednisone | Total |
|---|---|---|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 8.55 | 63.1 years STANDARD_DEVIATION 9.17 | 63.8 years STANDARD_DEVIATION 10.91 | 62.9 years STANDARD_DEVIATION 9.63 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 84 Participants | 72 Participants | 95 Participants | 251 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 15 Participants | 10 Participants | 43 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 11 Participants | 4 Participants | 24 Participants |
| Race (NIH/OMB) White | 92 Participants | 76 Participants | 96 Participants | 264 Participants |
| Region of Enrollment Belgium | 18 Participants | 21 Participants | 21 Participants | 60 Participants |
| Region of Enrollment France | 17 Participants | 13 Participants | 11 Participants | 41 Participants |
| Region of Enrollment Italy | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Region of Enrollment Korea, Republic Of | 1 Participants | 0 Participants | 5 Participants | 6 Participants |
| Region of Enrollment Netherlands | 8 Participants | 5 Participants | 8 Participants | 21 Participants |
| Region of Enrollment Russia | 20 Participants | 12 Participants | 19 Participants | 51 Participants |
| Region of Enrollment Spain | 11 Participants | 7 Participants | 12 Participants | 30 Participants |
| Region of Enrollment Ukraine | 11 Participants | 7 Participants | 7 Participants | 25 Participants |
| Region of Enrollment United Kingdom | 7 Participants | 12 Participants | 11 Participants | 30 Participants |
| Region of Enrollment USA | 9 Participants | 11 Participants | 8 Participants | 28 Participants |
| Sex: Female, Male Female | 102 Participants | 89 Participants | 106 Participants | 297 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 102 | 0 / 87 | 2 / 104 |
| other Total, other adverse events | 79 / 102 | 76 / 87 | 84 / 104 |
| serious Total, serious adverse events | 12 / 102 | 18 / 87 | 28 / 104 |
Outcome results
Primary
Overall Survival (OS)
OS was calculated as the time from randomization to death from any cause.
Time frame: Approximately 3 years
Population: ITT analysis set included all participants randomized into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exemestane | Overall Survival (OS) | NA Months |
| Abiraterone Acetate + Prednisone | Overall Survival (OS) | 26.41 Months |
| Abiraterone Acetate + Exemestane + Prednisone | Overall Survival (OS) | NA Months |
p-value: 0.80795% CI: [0.608, 1.896]stratified log-rank test
p-value: 0.54295% CI: [0.688, 2.036]stratified log-rank test
Primary
Progression-Free Survival (PFS)
Progression-free survival was defined as the time from randomization to first occurrence of disease progression (either radiographic or clinical), or death from any cause. PFS was determined using radiographic progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) on measurable lesions captured by computed tomography (CT) or magnetic resonance imaging (MRI). Clinical disease progression was considered only when disease progression could not be confirmed by CT or MRI, such as when the disease site is skin, bone marrow, or central nervous system.
Time frame: Approximately 2 years
Population: Intent-to-Treat (ITT) analysis set included all participants randomized into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exemestane | Progression-Free Survival (PFS) | 3.68 Months |
| Abiraterone Acetate + Prednisone | Progression-Free Survival (PFS) | 3.65 Months |
| Abiraterone Acetate + Exemestane + Prednisone | Progression-Free Survival (PFS) | 4.47 Months |
p-value: 0.43795% CI: [0.816, 1.603]stratified log-rank test
p-value: 0.79495% CI: [0.695, 1.32]stratified log-rank test
Secondary
Change From Baseline in Serum Endocrine Biomarkers (Estradiol and Estrone) at End of Treatment
Change from baseline in serum endocrine biomarkers (estradiol and estrone) was summarized by treatment at end of treatment.
Time frame: Baseline and End of treatment (approximately 2 years)
Population: ITT analysis set with valid baseline value and at least 1 post baseline value. Here n (number analyzed) signifies participants evaluable for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exemestane | Change From Baseline in Serum Endocrine Biomarkers (Estradiol and Estrone) at End of Treatment | Estradiol | 1.53 Picomoles Per Liter (Pmol/L) | Standard Deviation 27.643 |
| Exemestane | Change From Baseline in Serum Endocrine Biomarkers (Estradiol and Estrone) at End of Treatment | Estrone | -34.20 Picomoles Per Liter (Pmol/L) | Standard Deviation 83.77 |
| Abiraterone Acetate + Prednisone | Change From Baseline in Serum Endocrine Biomarkers (Estradiol and Estrone) at End of Treatment | Estradiol | -3.35 Picomoles Per Liter (Pmol/L) | Standard Deviation 13.634 |
| Abiraterone Acetate + Prednisone | Change From Baseline in Serum Endocrine Biomarkers (Estradiol and Estrone) at End of Treatment | Estrone | -28.09 Picomoles Per Liter (Pmol/L) | Standard Deviation 47.779 |
| Abiraterone Acetate + Exemestane + Prednisone | Change From Baseline in Serum Endocrine Biomarkers (Estradiol and Estrone) at End of Treatment | Estradiol | -1.04 Picomoles Per Liter (Pmol/L) | Standard Deviation 20.146 |
| Abiraterone Acetate + Exemestane + Prednisone | Change From Baseline in Serum Endocrine Biomarkers (Estradiol and Estrone) at End of Treatment | Estrone | -30.60 Picomoles Per Liter (Pmol/L) | Standard Deviation 42.385 |
Secondary
Change From Baseline in Serum Endocrine Biomarkers (Progesterone and Testosterone) at End of Treatment
Change from baseline in serum endocrine biomarkers (Progesterone and Testosterone) was summarized by treatment at end of treatment.
Time frame: Baseline and End of treatment (approximately 2 years)
Population: ITT analysis set with valid baseline value and at least 1 post baseline value. Here n (number analyzed) signifies participants evaluable for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exemestane | Change From Baseline in Serum Endocrine Biomarkers (Progesterone and Testosterone) at End of Treatment | Progesterone | -4.80 Nanomoles Per Liter (nmol/L) | Standard Deviation 18.268 |
| Exemestane | Change From Baseline in Serum Endocrine Biomarkers (Progesterone and Testosterone) at End of Treatment | Testosterone | -0.09 Nanomoles Per Liter (nmol/L) | Standard Deviation 0.416 |
| Abiraterone Acetate + Prednisone | Change From Baseline in Serum Endocrine Biomarkers (Progesterone and Testosterone) at End of Treatment | Progesterone | 8.98 Nanomoles Per Liter (nmol/L) | Standard Deviation 15.113 |
| Abiraterone Acetate + Prednisone | Change From Baseline in Serum Endocrine Biomarkers (Progesterone and Testosterone) at End of Treatment | Testosterone | -0.51 Nanomoles Per Liter (nmol/L) | Standard Deviation 0.459 |
| Abiraterone Acetate + Exemestane + Prednisone | Change From Baseline in Serum Endocrine Biomarkers (Progesterone and Testosterone) at End of Treatment | Progesterone | 12.34 Nanomoles Per Liter (nmol/L) | Standard Deviation 16.967 |
| Abiraterone Acetate + Exemestane + Prednisone | Change From Baseline in Serum Endocrine Biomarkers (Progesterone and Testosterone) at End of Treatment | Testosterone | -0.48 Nanomoles Per Liter (nmol/L) | Standard Deviation 0.323 |
Secondary
Clinical Benefit Rate
Clinical benefit rate was defined as the percentage of participants with measurable disease achieving a best overall response of a CR, PR, or stable disease (SD) for at least 6 months based on RECIST. Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.
Time frame: Approximately 2 years
Population: ITT analysis set with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exemestane | Clinical Benefit Rate | 12.7 Percentage of participants |
| Abiraterone Acetate + Prednisone | Clinical Benefit Rate | 9.6 Percentage of participants |
| Abiraterone Acetate + Exemestane + Prednisone | Clinical Benefit Rate | 22.7 Percentage of participants |
p-value: 0.60395% CI: [0.264, 2.175]Chi-squared
p-value: 0.13795% CI: [0.816, 3.926]Chi-squared
Secondary
Duration of Response
Duration of objective response was measured from the first time that the CR or PR was achieved to the first observation of disease progression (either radiographic or clinical) based on the RECIST criteria.
Time frame: Approximately 2 years
Population: ITT analysis set with measurable disease at baseline with complete or partial response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exemestane | Duration of Response | 6.47 months |
| Abiraterone Acetate + Prednisone | Duration of Response | 4.86 months |
| Abiraterone Acetate + Exemestane + Prednisone | Duration of Response | 6.93 months |
Secondary
Overall Response Rate (ORR)
Overall response rate was defined as the percentage of participants with measurable disease achieving a best overall response of either complete response (CR) or partial response (PR) based on RECIST. CR: disappearance of all target lesions and non-target lesions. PR: at least a 30 percent (%) decrease in the sum of longest diameter (LD) of target lesions or persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.
Time frame: Approximately 2 years
Population: ITT analysis set with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exemestane | Overall Response Rate (ORR) | 6.3 Percentage of participants |
| Abiraterone Acetate + Prednisone | Overall Response Rate (ORR) | 5.8 Percentage of participants |
| Abiraterone Acetate + Exemestane + Prednisone | Overall Response Rate (ORR) | 12.1 Percentage of participants |
p-value: 195% CI: [0.213, 3.878]Fisher Exact
p-value: 0.36695% CI: [0.605, 6.026]Fisher Exact