A Study to Determine Safety and Tolerability of Enzalutamide (MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients

• Sponsor: Astellas Pharma Global Development, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01650194
• Collaborator: Medivation LLC, a wholly owned subsidiary of Pfizer Inc. (Industry)
• Enrollment: 60
• Location: 1
• Arm: 1
• Actual Duration (Months): 65.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration-Resistant Prostate Cancer	Drug: enzalutamide; Drug: abiraterone acetate; Drug: prednisone	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study Determining Safety and Tolerability of Enzalutamide (Formerly MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients
• Actual Study Start Date: Jul 9, 2012
• Actual Primary Completion Date: Jan 4, 2018
• Actual Study Completion Date: Jan 4, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzalutamide + Abiraterone + Prednisone Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.	Drug: enzalutamide; Participants received 160 mg of enzalutamide orally once daily (4 capsules, 40 mg each).; Other Names: MDV3100 ; Drug: abiraterone acetate; Participants received 1000 mg of abiraterone acetate orally once daily (4 tablets, 250 mg each).; Drug: prednisone; Participants received 5 mg of prednisone orally twice daily (2 tablets, 5 mg each).

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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).

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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).

16. 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.

17. 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.

18. Change From Baseline in Urine N-Telopeptide [Baseline and Week 9]

    Bone metabolism marker urine N-telopeptide levels were derived from urine samples collected.

Other Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Male
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site US2492 MD Anderson Cancer Ctr	Houston	Texas	United States	77030

Sponsors and Collaborators

• Astellas Pharma Global Development, Inc.
• Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Investigators

• Study Director: Associate Medical Director, Astellas Pharma Global Development

Study Documents (Full-Text)

• Study Protocol - Jun 18, 2014
• Statistical Analysis Plan - Jan 4, 2016

More Information

Additional Information:

• Link to results on the Astellas Clinical Study Results website

Publications

None provided.

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT01650194
• Other Study ID Numbers: 9785-CL-0011
• First Posted: Jul 26, 2012
• Last Update Posted: Feb 5, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Astellas Pharma Global Development, Inc.: abiraterone acetate; prednisone; enzalutamide; cancer; prostate; MDV3100
• Additional relevant MeSH terms: Prostatic Neoplasms; Prednisone; Abiraterone Acetate

Study Results

Participant Flow

Recruitment Details	All participants in this all male study were enrolled at 1 site in the United States (US).
Pre-assignment Detail	All eligible participants who met inclusion criteria and none of the exclusion criteria were enrolled. A total of 64 participants were screened for eligibility.

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Period Title: Overall Study
STARTED	60
Treated	60
COMPLETED	13
NOT COMPLETED	47

Baseline Characteristics

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Overall Participants	60
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.4 (9.37)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	60 100%
Race/Ethnicity, Customized (Count of Participants)
White	51 85%
Black or African American	6 10%
Asian	2 3.3%
Other	1 1.7%
Ethnicity (Count of Participants)
Not Hispanic or Latino	57 95%
Hispanic or Latino	3 5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	60
Any TEAE	60 100%
Enzalutamide-related TEAEs	56 93.3%
Abiraterone-related TEAEs	58 96.7%
Prednisone-related TEAEs	16 26.7%
Deaths	0 0%
Serious TEAEs	10 16.7%
Enzalutamide-related serious TEAEs	0 0%
Abiraterone-related serious TEAEs	2 3.3%
Prednisone-related serious TEAEs	0 0%
TEAEs leading to discontinuation of enzalutamide	3 5%
Enza-related TEAEs leading to disc. of enza	0 0%
Abiraterone-related TEAEs leading to disc. of enza	0 0%
Prednisone-related TEAEs leading to disc. of enza	0 0%
TEAEs leading to discontinuation of abiraterone	1 1.7%
Abiraterone-related TEAEs leading to disc. of abi	1 1.7%

2. Secondary Outcome

Title	Change From Baseline in Testosterone Concentration in Bone Marrow Aspirate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	45
Geometric Mean (Standard Deviation) [pmol/L]	-19.48 (257.923)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Testosterone biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6150
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Change From Baseline in Dihydrotestosterone (DHT) Concentration in Bone Marrow Aspirate
Description	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

Outcome Measure Data

Analysis Population Description

DHT bone data were not collected.

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily. DHT bone data were not collected.
Measure Participants	0

4. Secondary Outcome

Title	Change From Baseline in Cortisol in Bone Marrow Aspirate
Description	Cortisol in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	47
Geometric Mean (Standard Deviation) [nmol/L]	-46.86 (48.022)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Cortisol biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Change From Baseline in Androstenedione in Bone Marrow Aspirate
Description	Androstenedione in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	37
Geometric Mean (Standard Deviation) [nmol/L]	-0.32 (0.342)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Androstenedione biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Change From Baseline in Progesterone in Bone Marrow Aspirate
Description	Progesterone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	41
Geometric Mean (Standard Deviation) [nmol/L]	1.16 (1.104)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Progesterone biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Change From Baseline in Pregnenolone in Bone Marrow Aspirate
Description	Pregnenolone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	42
Geometric Mean (Standard Deviation) [pg/ml]	1381.44 (1513.324)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Pregnenolone biomarker results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Change From Baseline in Testosterone Concentration in Blood
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	49
Geometric Mean (Standard Deviation) [nmol/L]	-0.06 (0.068)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Testosterone blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Change From Baseline in DHT Concentration in Blood
Description	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

Outcome Measure Data

Analysis Population Description

The endpoint could not be analyzed since no participants had DHT levels over the LLOQ.

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	0

10. Secondary Outcome

Title	Change From Baseline in Cortisol Concentration in Blood
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	52
Geometric Mean (Standard Deviation) [nmol/L]	-48.81 (43.725)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Cortisol blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

11. Secondary Outcome

Title	Change From Baseline in Androstenedione Concentration in Blood
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	37
Geometric Mean (Standard Deviation) [nmol/L]	-0.24 (0.206)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Androstenedione blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

12. Secondary Outcome

Title	Change From Baseline in Progesterone Concentration in Blood
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	48
Geometric Mean (Standard Deviation) [nmol/L]	1.43 (2.434)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Progesterone blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	t-test, 2 sided
	Comments

13. Secondary Outcome

Title	Change From Baseline in Pregnenolone Concentration in Blood
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	47
Geometric Mean (Standard Deviation) [pg/ml]	1507.42 (1699.335)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Abiraterone + Prednisone
	Comments	Pregnenolone blood results collected at baseline and at Week 9 were compared using the paired t-test to evaluate the effect of enzalutamide.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	t-test, 2 sided
	Comments

14. Secondary Outcome

Title	Change From Baseline to End-of-Treatment (EoT) in Prostate-Specific Antigen (PSA) Levels
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the SAF (participants with available data).

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	59
Geometric Mean (Standard Deviation) [ug/L]	36.35 (444.355)

15. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the SAF.

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	60
Median (95% Confidence Interval) [days]	251

16. Secondary Outcome

Title	Percentage of Participants With Objective Response for Soft Tissue Lesions According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST)
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the SAF (participants with measurable soft tissue disease per RECIST 1.1 at baseline with available data).

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	16
Median (95% Confidence Interval) [percentage of participants]	68.8 114.7%

17. Secondary Outcome

Title	Bone Scan Response at EoT
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the SAF (participants with available data).

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	52
Complete Response (CR)	1 1.7%
Progressive Disease (PD)	15 25%
Non-CR/Non-PD	35 58.3%
Not Evaluable	1 1.7%

18. Secondary Outcome

Title	Change From Baseline to EoT in Bone Specific Alkaline Phosphatase
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the SAF (participants with available data).

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	49
Geometric Mean (Standard Deviation) [ug/L]	-5.18 (43.626)

19. Secondary Outcome

Title	Change From Baseline in Urine N-Telopeptide
Description	Bone metabolism marker urine N-telopeptide levels were derived from urine samples collected.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the SAF (participants with available data).

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	34
Geometric Mean (Standard Deviation) [nmolBCE/mmolcreat]	29.35 (85.927)

20. Other Pre-specified Outcome

Title	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
Description	The endpoint was considered exploratory and no analysis was planned.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

Data for these endpoints were not collected.

Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Measure Participants	0

Adverse Events

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.
Arm/Group Title	Enzalutamide + Abiraterone + Prednisone
Arm/Group Description	Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
All Cause Mortality
	Enzalutamide + Abiraterone + Prednisone
	Affected / at Risk (%)	# Events
Total	0/60 (0%)
Serious Adverse Events
	Enzalutamide + Abiraterone + Prednisone
	Affected / at Risk (%)	# Events
Total	9/60 (15%)
Cardiac disorders
Angina pectoris	1/60 (1.7%)	1
Atrial fibrillation	1/60 (1.7%)	1
Eye disorders
Macular oedema	1/60 (1.7%)	1
Retinal vein occlusion	1/60 (1.7%)	1
Infections and infestations
Urosepsis	1/60 (1.7%)	1
Injury, poisoning and procedural complications
Femur fracture	1/60 (1.7%)	1
Hip fracture	1/60 (1.7%)	1
Spinal compression fracture	1/60 (1.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/60 (1.7%)	1
Nervous system disorders
Spinal cord compression	1/60 (1.7%)	1
Vascular disorders
Hypotension	1/60 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Enzalutamide + Abiraterone + Prednisone
	Affected / at Risk (%)	# Events
Total	60/60 (100%)
Blood and lymphatic system disorders
Anaemia	21/60 (35%)	40
Cardiac disorders
Sinus bradycardia	3/60 (5%)	3
Ear and labyrinth disorders
Vertigo	6/60 (10%)	8
Gastrointestinal disorders
Abdominal pain upper	5/60 (8.3%)	5
Constipation	7/60 (11.7%)	10
Diarrhoea	9/60 (15%)	14
Dry mouth	3/60 (5%)	3
Nausea	14/60 (23.3%)	28
Vomiting	6/60 (10%)	20
General disorders
Asthenia	4/60 (6.7%)	4
Fatigue	43/60 (71.7%)	62
Influenza like illness	3/60 (5%)	4
Non-cardiac chest pain	3/60 (5%)	3
Oedema peripheral	9/60 (15%)	13
Pyrexia	7/60 (11.7%)	8
Infections and infestations
Herpes zoster	3/60 (5%)	3
Sinusitis	3/60 (5%)	4
Injury, poisoning and procedural complications
Fall	9/60 (15%)	12
Joint injury	3/60 (5%)	4
Investigations
Activated partial thromboplastin time prolonged	8/60 (13.3%)	10
Alanine aminotransferase increased	18/60 (30%)	70
Aspartate aminotransferase increased	22/60 (36.7%)	54
Blood albumin decreased	3/60 (5%)	3
Blood alkaline phosphatase increased	32/60 (53.3%)	64
Blood bilirubin increased	12/60 (20%)	26
Blood creatinine increased	3/60 (5%)	5
Blood glucose increased	5/60 (8.3%)	7
Blood magnesium decreased	6/60 (10%)	8
Blood potassium decreased	4/60 (6.7%)	4
Lymphocyte count decreased	6/60 (10%)	12
Neutrophil count decreased	7/60 (11.7%)	8
Platelet count decreased	7/60 (11.7%)	12
White blood cell count decreased	14/60 (23.3%)	22
Metabolism and nutrition disorders
Anorexia	8/60 (13.3%)	10
Dehydration	3/60 (5%)	3
Hypercalcaemia	3/60 (5%)	3
Hyperglycaemia	41/60 (68.3%)	96
Hypernatraemia	7/60 (11.7%)	10
Hypoalbuminaemia	5/60 (8.3%)	6
Hypocalcaemia	6/60 (10%)	8
Hypokalaemia	10/60 (16.7%)	16
Hypomagnesaemia	12/60 (20%)	20
Hypophosphataemia	6/60 (10%)	7
Musculoskeletal and connective tissue disorders
Arthralgia	19/60 (31.7%)	26
Back pain	20/60 (33.3%)	28
Bone pain	6/60 (10%)	19
Muscle spasms	4/60 (6.7%)	4
Musculoskeletal chest pain	7/60 (11.7%)	8
Musculoskeletal pain	9/60 (15%)	13
Neck pain	4/60 (6.7%)	8
Pain in extremity	13/60 (21.7%)	18
Nervous system disorders
Balance disorder	3/60 (5%)	4
Cognitive disorder	5/60 (8.3%)	5
Dizziness	4/60 (6.7%)	4
Dysgeusia	8/60 (13.3%)	9
Headache	11/60 (18.3%)	17
Memory impairment	6/60 (10%)	7
Paraesthesia	5/60 (8.3%)	5
Peripheral sensory neuropathy	3/60 (5%)	4
Tremor	3/60 (5%)	5
Psychiatric disorders
Depression	4/60 (6.7%)	4
Insomnia	6/60 (10%)	7
Renal and urinary disorders
Nephrolithiasis	3/60 (5%)	3
Pollakiuria	10/60 (16.7%)	12
Respiratory, thoracic and mediastinal disorders
Cough	10/60 (16.7%)	11
Dyspnoea	5/60 (8.3%)	7
Productive cough	4/60 (6.7%)	5
Rhinitis allergic	4/60 (6.7%)	4
Skin and subcutaneous tissue disorders
Alopecia	9/60 (15%)	9
Pruritus	3/60 (5%)	4
Rash maculo-papular	3/60 (5%)	3
Vascular disorders
Hot flush	27/60 (45%)	39
Hypertension	19/60 (31.7%)	21

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.