Metastatic Castration-Resistant Prostate Cancer
Conditions
Keywords
abiraterone acetate, prednisone, enzalutamide, cancer, prostate, MDV3100
Brief summary
The purpose of this study was to explore the safety and tolerability of enzalutamide in combination with abiraterone acetate plus prednisone. Subjects diagnosed with cancer of the prostate that was getting worse and spreading to the bone despite receiving hormone treatment were enrolled and received study treatment until disease progression.
Detailed description
For the study duration, all subjects maintained androgen deprivation with a gonadotropin releasing hormone (GnRH) agonist or antagonist or orchiectomy. Study drug was administered until disease progression. Disease progression was defined as a composite endpoint consisting of either clinical deterioration, radiographic progression or prostate-specific antigen (PSA) progression according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria.
Interventions
DRUGenzalutamide
Participants received 160 mg of enzalutamide orally once daily (4 capsules, 40 mg each).
DRUGabiraterone acetate
Participants received 1000 mg of abiraterone acetate orally once daily (4 tablets, 250 mg each).
DRUGprednisone
Participants received 5 mg of prednisone orally twice daily (2 tablets, 5 mg each).
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
MALE
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features * Presence of metastatic disease to the bone * Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical castration) * Subject receiving bisphosphonate or denosumab therapy must have been on stable doses for at least 4 weeks prior to Day 1 * Progressive disease defined as one or more of the following three criteria (Note: subjects who received an antiandrogen must demonstrate disease progression following discontinuation of antiandrogen): * PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2 ng/mL * Soft tissue disease progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) * Bone disease progression defined by PCWG2 criteria (two or more new lesions on bone scan compared with prior scan) * Subject previously treated with chemotherapy must have no more than two prior chemotherapy regimens for the treatment of metastatic prostate cancer * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Agree to use a double-barrier method of contraception which involves the use of a condom in combination with one of the following: contraceptive sponge, diaphragm, or cervical ring with spermicidal gel or foam, if having sex with a woman of child-bearing potential during the length of the study and for one week after abiraterone is discontinued and for at least three months after enzalutamide is discontinued * Subject agrees not to participate in another interventional study while on treatment
Exclusion criteria
* Known or suspected metastases in the brain * Absolute neutrophil count \< 1,000/μL, platelet count \< 75,000/μL, and hemoglobin \< 9 g/dL (NOTE: subject may not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at the Screening visit) * Total bilirubin (TBL), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5 times the upper limit of normal * Creatinine (Cr) \> 2 mg/dL * Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide), 5-α reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or biologic therapy within 4 weeks of Day 1 visit * Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 weeks) of Day 1 visit, or radionuclide therapy within 8 weeks of Day 1 * Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery * Structurally unstable bone lesions suggesting impending fracture * History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumors, brain metastases, or alcoholism. Also, history of loss of consciousness or transient ischemic attack within 12 months of enrollment (Day 1 visit) * Clinically significant cardiovascular disease including: * Myocardial infarction within 6 months of Screening visit; * Uncontrolled angina within 3 months of Screening visit; * Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months of the Screening visit results in a left ventricular ejection fraction that is ≥ 45% * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes) * Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the Electrocardiogram (ECG) \> 470 msec. * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place * Hypotension (systolic blood pressure \< 86 mmHg or bradycardia with a heart rate of \<50 beats per minute on the ECG., unless pharmaceutically induced and thus reversible (i.e. beta blockers). * Uncontrolled hypertension as indicated by a resting systolic blood pressure \>170 mmHg or diastolic blood pressure \>105 mmHg * Prior use of ketoconazole, abiraterone acetate or enzalutamide, or participation in a previous clinical trial of ketoconazole, abiraterone acetate or enzalutamide * History of significant bleeding disorder unrelated to cancer, including: * Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) * Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) of Screening visit * History of GI bleeding within 6 months of Screening visit * Active or symptomatic viral hepatitis or chronic liver disease * Known history of pituitary or adrenal dysfunction
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | From the first dose of study drug administration up 30 days following the last dose of study drug date, with a median duration of treatment of 10.1 months. | A treatment-emergent adverse event (TEAE) was defined as an adverse event occurring or worsening between the start of study treatment date and the latest date of 30 days after the last dose date or the 30-day follow-up visit date, and not later than the data cut-off date or the date of death. AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines (V4.03). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Testosterone Concentration in Bone Marrow Aspirate | Baseline and Week 9 | Testosterone concentration in bone marrow aspirate was measured by laboratory results derived from bone marrow samples processed through liquid chromatography mass spectrometry. |
| Change From Baseline in Dihydrotestosterone (DHT) Concentration in Bone Marrow Aspirate | Baseline and Week 9 | DHT concentration in bone marrow aspirate was to be measured by laboratory results derived from bone marrow samples processed through liquid chromatography mass spectrometry. DHT bone data were not collected. |
| Change From Baseline in Cortisol in Bone Marrow Aspirate | Baseline and Week 9 | Cortisol in bone marrow aspirate was measured by laboratory results derived from bone marrow samples. |
| Change From Baseline in Androstenedione in Bone Marrow Aspirate | Baseline and Week 9 | Androstenedione in bone marrow aspirate was measured by laboratory results derived from bone marrow samples. |
| Change From Baseline in Progesterone in Bone Marrow Aspirate | Baseline and Week 9 | Progesterone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples. |
| Change From Baseline in Pregnenolone in Bone Marrow Aspirate | Baseline and Week 9 | Pregnenolone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples. |
| Change From Baseline in Testosterone Concentration in Blood | Baseline and Week 9 | Testosterone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. |
| Change From Baseline in DHT Concentration in Blood | Baseline and Week 9 | DHT concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. The endpoint could not be analyzed since no participants had DHT levels over the lower limit of quantification (LLOQ). |
| Change From Baseline in Cortisol Concentration in Blood | Baseline and Week 9 | Cortisol concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. |
| Change From Baseline in Progesterone Concentration in Blood | Baseline and Week 9 | Progesterone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. |
| Change From Baseline in Pregnenolone Concentration in Blood | Baseline and Week 9 | Pregnenolone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. |
| Change From Baseline to End-of-Treatment (EoT) in Prostate-Specific Antigen (PSA) Levels | Baseline and EoT; the median duration of treatment was 10.1 months. | Prostate-specific antigen progression by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) was defined as a PSA increase ≥25% and ≥2 ng/ml above the post-baseline nadir, and which was confirmed by the first subsequent value of 3 or more weeks later. |
| Progression Free Survival (PFS) | Up to 1849 days | PFS was measured as the time from the date of first dose of any drug of the study combination treatment until the first evidence of documented progression (a composite endpoint consisting of radiographic progression or PSA progression by PCWG2 or clinical deterioration) or death in the absence of progression (whichever came first) or the date last known to be progression free. The Kaplan-Meier (KM) 95% CI was based on Brookmeyer and Crowley robust non-parametric method. |
| Percentage of Participants With Objective Response for Soft Tissue Lesions According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) | Up to 1849 days | Objective response was based on RECIST version 1.1 for soft tissue lesion on Magnetic resonance imaging (MRI) / Computerized tomography (CT) and the PCWG2 guidelines for bone lesions on bone scans and was defined as partial response (PR) or complete response (CR) based on the investigators' assessments of target, non-target and new lesions while on study treatment. The 95% for objective response rate was based on exact binomial 95% confidence interval (Clopper-Pearson). |
| Bone Scan Response at EoT | EoT; the median duration of treatment was 10.1 months. | PD: ≥1 of 3 criteria: PSA progression: ≥2 rising PSA levels, interval of ≥1 week between each determination. Soft tissue disease progression: RECIST 1.1. Bone disease progression: PCWG2 criteria (≥2 or new lesions on bone scan compared with prior scan). Target lesion CR: disappearance of all target lesions, PR as ≥30% decrease in sum of longest diameter (LD) of target lesions, referencing baseline sum LD, SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, referencing smallest sum LD since treatment start, PD ≥20% increase in sum of LD of target lesions, referencing smallest sum LD recorded since treatment start or appearance of ≥1 new lesions. Non-target lesions CR: disappearance of all non-target lesions and normalization of tumor marker level, SD: persistence of ≥1 non-target lesions and/or maintenance of tumor marker level above normal limits, PD: appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. |
| Change From Baseline to EoT in Bone Specific Alkaline Phosphatase | Baseline and EoT; the median duration of treatment was 10.1 months. | Bone metabolism marker bone specific alkaline phosphatase levels were derived from blood samples collected. |
| Change From Baseline in Urine N-Telopeptide | Baseline and Week 9 | Bone metabolism marker urine N-telopeptide levels were derived from urine samples collected. |
| Change From Baseline in Androstenedione Concentration in Blood | Baseline and Week 9 | Androstenedione concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Androgen Receptor Signaling Assessed by Expression and Localization of Androgen Receptor (AR), CYP17 Expression, Splice Variants, and Pathways Linked With Non-classical AR Signaling and Bone Development | Baseline and Week 9 | The endpoint was considered exploratory and no analysis was planned. |
Countries
United States
Participant flow
Recruitment details
All participants in this all male study were enrolled at 1 site in the United States (US).
Pre-assignment details
All eligible participants who met inclusion criteria and none of the exclusion criteria were enrolled. A total of 64 participants were screened for eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Enzalutamide + Abiraterone + Prednisone Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Miscellaneous | 10 |
| Overall Study | Progressive Disease (PD) | 35 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Enzalutamide + Abiraterone + Prednisone |
|---|---|
| Age, Continuous | 65.4 Years STANDARD_DEVIATION 9.37 |
| Ethnicity Hispanic or Latino | 3 Participants |
| Ethnicity Not Hispanic or Latino | 57 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 51 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 60 |
| other Total, other adverse events | 60 / 60 |
| serious Total, serious adverse events | 9 / 60 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
A treatment-emergent adverse event (TEAE) was defined as an adverse event occurring or worsening between the start of study treatment date and the latest date of 30 days after the last dose date or the 30-day follow-up visit date, and not later than the data cut-off date or the date of death. AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines (V4.03).
Time frame: From the first dose of study drug administration up 30 days following the last dose of study drug date, with a median duration of treatment of 10.1 months.
Population: The analysis population consisted of the safety analysis set (SAF) which consisted of all participants who received at least 1 dose of any drug of the study combination treatment (i.e., enzalutamide, abiraterone and prednisone).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Any TEAE | 60 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Enzalutamide-related TEAEs | 56 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Abiraterone-related TEAEs | 58 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Prednisone-related TEAEs | 16 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Deaths | 0 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Serious TEAEs | 10 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Enzalutamide-related serious TEAEs | 0 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Abiraterone-related serious TEAEs | 2 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Prednisone-related serious TEAEs | 0 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | TEAEs leading to discontinuation of enzalutamide | 3 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Enza-related TEAEs leading to disc. of enza | 0 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Abiraterone-related TEAEs leading to disc. of enza | 0 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Prednisone-related TEAEs leading to disc. of enza | 0 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | TEAEs leading to discontinuation of abiraterone | 1 Participants |
| Enzalutamide + Abiraterone + Prednisone | Number of Participants With Adverse Events (AEs) | Abiraterone-related TEAEs leading to disc. of abi | 1 Participants |
Secondary
Bone Scan Response at EoT
PD: ≥1 of 3 criteria: PSA progression: ≥2 rising PSA levels, interval of ≥1 week between each determination. Soft tissue disease progression: RECIST 1.1. Bone disease progression: PCWG2 criteria (≥2 or new lesions on bone scan compared with prior scan). Target lesion CR: disappearance of all target lesions, PR as ≥30% decrease in sum of longest diameter (LD) of target lesions, referencing baseline sum LD, SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, referencing smallest sum LD since treatment start, PD ≥20% increase in sum of LD of target lesions, referencing smallest sum LD recorded since treatment start or appearance of ≥1 new lesions. Non-target lesions CR: disappearance of all non-target lesions and normalization of tumor marker level, SD: persistence of ≥1 non-target lesions and/or maintenance of tumor marker level above normal limits, PD: appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: EoT; the median duration of treatment was 10.1 months.
Population: The analysis population consisted of the SAF (participants with available data).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Bone Scan Response at EoT | Complete Response (CR) | 1 Participants |
| Enzalutamide + Abiraterone + Prednisone | Bone Scan Response at EoT | Progressive Disease (PD) | 15 Participants |
| Enzalutamide + Abiraterone + Prednisone | Bone Scan Response at EoT | Non-CR/Non-PD | 35 Participants |
| Enzalutamide + Abiraterone + Prednisone | Bone Scan Response at EoT | Not Evaluable | 1 Participants |
Secondary
Change From Baseline in Androstenedione Concentration in Blood
Androstenedione concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the plasma androstenedione evaluable set (PAOS) which consisted of all participants from the SAF with baseline and week 9 androstenedione laboratory results derived from plasma samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Androstenedione Concentration in Blood | -0.24 nmol/L | Standard Deviation 0.206 |
Comparison: Androstenedione blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in Androstenedione in Bone Marrow Aspirate
Androstenedione in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the biomarker androstenedione evaluable set (BAOS) which consisted of all participants from the SAF with baseline and week 9 androstenedione laboratory results derived from bone marrow samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Androstenedione in Bone Marrow Aspirate | -0.32 nmol/L | Standard Deviation 0.342 |
Comparison: Androstenedione biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in Cortisol Concentration in Blood
Cortisol concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the plasma cortisol evaluable set (PCES) which consisted of all participants from the SAF with baseline and week 9 cortisol laboratory results derived from plasma samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Cortisol Concentration in Blood | -48.81 nmol/L | Standard Deviation 43.725 |
Comparison: Cortisol blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in Cortisol in Bone Marrow Aspirate
Cortisol in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the biomarker cortisol evaluable set (BCES) which consisted of all participants from the SAF with baseline and week 9 cortisol laboratory results derived from bone marrow samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Cortisol in Bone Marrow Aspirate | -46.86 nmol/L | Standard Deviation 48.022 |
Comparison: Cortisol biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in DHT Concentration in Blood
DHT concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. The endpoint could not be analyzed since no participants had DHT levels over the lower limit of quantification (LLOQ).
Time frame: Baseline and Week 9
Population: The endpoint could not be analyzed since no participants had DHT levels over the LLOQ.
Secondary
Change From Baseline in Dihydrotestosterone (DHT) Concentration in Bone Marrow Aspirate
DHT concentration in bone marrow aspirate was to be measured by laboratory results derived from bone marrow samples processed through liquid chromatography mass spectrometry. DHT bone data were not collected.
Time frame: Baseline and Week 9
Population: DHT bone data were not collected.
Secondary
Change From Baseline in Pregnenolone Concentration in Blood
Pregnenolone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the plasma pregnenolone evaluable set (PEES) which consisted of all participants from the SAF with baseline and week 9 pregnenolone laboratory results derived from plasma samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Pregnenolone Concentration in Blood | 1507.42 pg/ml | Standard Deviation 1699.335 |
Comparison: Pregnenolone blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in Pregnenolone in Bone Marrow Aspirate
Pregnenolone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the biomarker pregnenolone evaluable set (BEES) which consisted of all participants from the SAF with baseline and week 9 pregnenolone laboratory results derived from bone marrow samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Pregnenolone in Bone Marrow Aspirate | 1381.44 pg/ml | Standard Deviation 1513.324 |
Comparison: Pregnenolone biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in Progesterone Concentration in Blood
Progesterone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the plasma progesterone evaluable set (POES) which consisted of all participants from the SAF with baseline and week 9 progesterone laboratory results derived from plasma samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Progesterone Concentration in Blood | 1.43 nmol/L | Standard Deviation 2.434 |
Comparison: Progesterone blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: 0.0002t-test, 2 sided
Secondary
Change From Baseline in Progesterone in Bone Marrow Aspirate
Progesterone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the biomarker progesterone evaluable set (BOES) which consisted of all participants from the SAF with baseline and week 9 progesterone laboratory results derived from bone marrow samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Progesterone in Bone Marrow Aspirate | 1.16 nmol/L | Standard Deviation 1.104 |
Comparison: Progesterone biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in Testosterone Concentration in Blood
Testosterone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the plasma testosterone evaluable set (PTES) which consisted of all participants from the SAF with baseline and week 9 testosterone laboratory results derived from plasma samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Testosterone Concentration in Blood | -0.06 nmol/L | Standard Deviation 0.068 |
Comparison: Testosterone blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline in Testosterone Concentration in Bone Marrow Aspirate
Testosterone concentration in bone marrow aspirate was measured by laboratory results derived from bone marrow samples processed through liquid chromatography mass spectrometry.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the biomarker testosterone evaluable set (BTES) which consisted of all participants from the SAF with baseline and week 9 testosterone laboratory results derived from bone marrow samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Testosterone Concentration in Bone Marrow Aspirate | -19.48 pmol/L | Standard Deviation 257.923 |
Comparison: Testosterone biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.p-value: 0.615t-test, 2 sided
Secondary
Change From Baseline in Urine N-Telopeptide
Bone metabolism marker urine N-telopeptide levels were derived from urine samples collected.
Time frame: Baseline and Week 9
Population: The analysis population consisted of the SAF (participants with available data).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline in Urine N-Telopeptide | 29.35 nmolBCE/mmolcreat | Standard Deviation 85.927 |
Secondary
Change From Baseline to End-of-Treatment (EoT) in Prostate-Specific Antigen (PSA) Levels
Prostate-specific antigen progression by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) was defined as a PSA increase ≥25% and ≥2 ng/ml above the post-baseline nadir, and which was confirmed by the first subsequent value of 3 or more weeks later.
Time frame: Baseline and EoT; the median duration of treatment was 10.1 months.
Population: The analysis population consisted of the SAF (participants with available data).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline to End-of-Treatment (EoT) in Prostate-Specific Antigen (PSA) Levels | 36.35 ug/L | Standard Deviation 444.355 |
Secondary
Change From Baseline to EoT in Bone Specific Alkaline Phosphatase
Bone metabolism marker bone specific alkaline phosphatase levels were derived from blood samples collected.
Time frame: Baseline and EoT; the median duration of treatment was 10.1 months.
Population: The analysis population consisted of the SAF (participants with available data).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Change From Baseline to EoT in Bone Specific Alkaline Phosphatase | -5.18 ug/L | Standard Deviation 43.626 |
Secondary
Percentage of Participants With Objective Response for Soft Tissue Lesions According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST)
Objective response was based on RECIST version 1.1 for soft tissue lesion on Magnetic resonance imaging (MRI) / Computerized tomography (CT) and the PCWG2 guidelines for bone lesions on bone scans and was defined as partial response (PR) or complete response (CR) based on the investigators' assessments of target, non-target and new lesions while on study treatment. The 95% for objective response rate was based on exact binomial 95% confidence interval (Clopper-Pearson).
Time frame: Up to 1849 days
Population: The analysis population consisted of the SAF (participants with measurable soft tissue disease per RECIST 1.1 at baseline with available data).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Percentage of Participants With Objective Response for Soft Tissue Lesions According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) | 68.8 percentage of participants |
Secondary
Progression Free Survival (PFS)
PFS was measured as the time from the date of first dose of any drug of the study combination treatment until the first evidence of documented progression (a composite endpoint consisting of radiographic progression or PSA progression by PCWG2 or clinical deterioration) or death in the absence of progression (whichever came first) or the date last known to be progression free. The Kaplan-Meier (KM) 95% CI was based on Brookmeyer and Crowley robust non-parametric method.
Time frame: Up to 1849 days
Population: The analysis population consisted of the SAF.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide + Abiraterone + Prednisone | Progression Free Survival (PFS) | 251 days |
Other Pre-specified
Androgen Receptor Signaling Assessed by Expression and Localization of Androgen Receptor (AR), CYP17 Expression, Splice Variants, and Pathways Linked With Non-classical AR Signaling and Bone Development
The endpoint was considered exploratory and no analysis was planned.
Time frame: Baseline and Week 9
Population: Data for these endpoints were not collected.