A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer

• Sponsor: Terence Friedlander, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT01637402
• Collaborator: Janssen Biotech, Inc. (Industry)
• Enrollment: 41
• Locations: 2
• Arms: 2
• Actual Duration (Months): 47.5
• Patients Per Site: 20.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects, good and/or bad,an increased dose of Abiraterone Acetate in combination with prednisone has on patients and their prostate cancer. This study will investigate whether an increased-dose (2,000mg daily) is safe and potentially effective when given to patients whose cancer has grown while taking the standard dose.

Condition or Disease	Intervention/Treatment	Phase
Castration Resistant Prostate Cancer	Drug: Abiraterone Acetate; Drug: Prednisone	Phase 2

Detailed Description

This is a phase II multicenter trial of Abiraterone Acetate (AA) in patients with progressive prostate cancer despite androgen deprivation with a particular focus on the pharmacokinetic, pharmacodynamic, and pharmacogenomic events occurring at the time of apparent drug resistance. All eligible patients will have baseline (prior to taking the first dose of Abiraterone Acetate 1000mg/daily) measures of routine clinical variables along with measurements of baseline and treatment related changes in testosterone, androgen, and endocrine levels, genotyping of single-nucleotide polymorphisms (SNP) in the selected enzymes known to be directly inhibited by Abiraterone Acetate, and collection of circulating tumor cells. All patients will be requested to consent for biopsies which will be performed prior to treatment and at the time of disease progression on standard dose Abiraterone Acetate therapy. These biopsies will be analyzed for expression of an androgen receptor (AR)-signature as well as for microarray analysis to explore changes in methylation, and expression of CYP17A1 and other androgen synthesis genes.

Subjects will then begin daily oral therapy with Abiraterone Acetate 1000mg po daily with physiologic prednisone 5mg BID replacement. No food should be consumed for at least 2 hours before the dose of Abiraterone Acetate and for at least 1 hour after the dose of Abiraterone Acetate is taken. Prostate-specific antigen (PSA) will be followed monthly. Abiraterone Acetate will be supplied by Janssen Services. At the end of the first month, the third month, and then every three months thereafter, Abiraterone Acetate, testosterone, and androgen levels will be followed. Subjects not achieving a greater than or equal to 30% PSA decline at 12 weeks will be taken off study. At the time of progression (defined by RECIST criteria OR by the Prostate Cancer Working Group 2 (PCWG) criteria as a 25% increase in PSA above the nadir and an increase in the absolute value PSA of at least 2ng/dl or back to baseline confirmed at least 2 weeks afterward) for subjects who achieved an initial greater than or equal to 30% PSA decline (referred to as Progressive Disease (PD) #1), subjects will begin taking Abiraterone Acetate 1000 mg po BID. Patients will continue to take prednisone 5mg twice a day (BID) and will continue this therapy until a second progression at which point they will be withdrawn from the study. While 1000 mg po BID is not the FDA recommended dose, it is the dose to be investigated in this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Simon's 2 stage minimax design for accrual.Simon's 2 stage minimax design for accrual.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer (CRPC)
• Actual Study Start Date: Mar 13, 2013
• Actual Primary Completion Date: Feb 27, 2017
• Actual Study Completion Date: Feb 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Standard Dose 1000 milligrams (mg) abiraterone acetate in combination with prednisone taken once a day until progression defined by RECIST criteria OR by the Prostate Cancer Working Group 2 (PCWG) criteria	Drug: Abiraterone Acetate; Standard dose participants: 1,000 mg, once daily, oral administration. Dose escalation participants: 1,000 mg, twice daily, oral administration; Other Names: Zytiga ; Drug: Prednisone; 5 mg, twice daily, oral administration
Experimental: Escalated Dose Participants who progressed on the standard dose will be assigned 1000 milligrams (mg) abiraterone acetate in combination with prednisone taken twice a day for at least 12 weeks until progression as defined by RECIST criteria OR by the Prostate Cancer Working Group 2 (PCWG) criteria	Drug: Abiraterone Acetate; Standard dose participants: 1,000 mg, once daily, oral administration. Dose escalation participants: 1,000 mg, twice daily, oral administration; Other Names: Zytiga ; Drug: Prednisone; 5 mg, twice daily, oral administration

Outcome Measures

Primary Outcome Measures

1. Number of Patients With PSA Response From Dose Escalation [Up to 12 weeks from start of dose escalation]

   A PSA response for the dose escalation group is defined as a participant with a documented PSA decline after 12 weeks of therapy with standard-dose, then had disease progression, and then achieved a ≥30% PSA decline after 12 weeks from the start of dose escalation therapy.

Secondary Outcome Measures

1. Number of Participants With Worst-grade, Treatment-related Toxicities for Dose Escalation Group [Up to 24 months]

   Frequency of any treatment-related toxicity with increased-dose Abiraterone Acetate by maximum observed grade will be tabulated for the study cohort. Toxicities will be graded for management according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as a measure of patient safety.

2. Time to PSA Progression for Dose Escalation Cohort [up to 24 months]

   Time to PSA progression as defined by RECIST criteria or by the Prostate Cancer Working Group 2 (PCWG) criteria for patients whom were treated with increased dose Abiraterone Acetate.

3. Progression Free Survival for Dose Escalation Cohort [up to 24 months]

   Progression free survival for patients treated with increased dose Abiraterone Acetate

4. Serum Concentration Levels of Abiraterone Acetate Over Time [Up to 24 months]

   Pharmacokinetic assessment at the initiation of standard dose therapy, at the time of initial disease progression, at the time of a response to increased dose of abiraterone acetate and at the time of disease progression on increased-dose therapy.

5. Correlation of Circulating Testosterone Levels at Baseline and Week 12 [Baseline and Week 12]

   Pearson's correlation coefficients ("r") will be calculated to summarize the relationship between testosterone values at baseline and at 12 weeks. Testosterone labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of testosterone levels between the 2 time points, a value of 0 indicating no association between testosterone levels between the two time points, and a value of +1 indicating a positive linear association of testosterone levels between the two time points.

6. Comparison of Circulating Testosterone Levels Between Primary-Resistant Patients and Responders [Baseline and Week 12]

   The distribution of the baseline testosterone levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12.

7. Correlation of Circulating Dehydroepiandrosterone (DHEA) Levels From Baseline to Week 12 [Baseline and Week 12]

   Pearson's correlation coefficients ("r") will be calculated to summarize the relationship between DHEA values at baseline and at 12 weeks. DHEA labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of DHEA levels between the 2 time points, a value of 0 indicating no association between DHEA levels between the two time points, and a value of +1 indicating a positive linear association of DHEA levels between the two time points.

8. Comparison of Circulating DHEA Levels Between Primary-Resistant and Responders [Baseline and Week 12]

   The distribution of the baseline DHEA levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12.

9. Correlation of Circulating Dehydroepiandrosterone-sulfate (DHEA-S) Levels at Baseline and Week 12 [Baseline and Week 12]

   Pearson's correlation coefficients ("r") will be calculated to summarize the relationship between DHEA-S values at baseline and at 12 weeks. DHEA-S labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of DHEA-S levels between the 2 time points, a value of 0 indicating no association between DHEA-S levels between the two time points, and a value of +1 indicating a positive linear association of DHEA-S levels between the two time points.

10. Comparison of Circulating DHEA-S Levels Between Primary-Resistant Patients and Responders [Baseline and Week 12]

    The distribution of the baseline DHEA-S levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12.

11. Correlation of Circulating Androstenedione Levels at Baseline and Week 12 [Baseline and Week 12]

    Pearson's correlation coefficients ("r") will be calculated to summarize the relationship between androstenedione values at baseline and at 12 weeks. Androstenedione labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of androstenedione levels between the 2 time points, a value of 0 indicating no association between androstenedione levels between the two time points, and a value of +1 indicating a positive linear association of androstenedione levels between the two time points.

12. Comparison of Circulating Androstenedione Levels Between Primary-Resistant Patients and Responders [Baseline and Week 12]

    The distribution of the baseline androstenedione levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have signed an informed consent document indicating that the subjects understands the purpose of and procedures required for the study and are willing to participate in the study

• Be willing/able to adhere to the prohibitions and restrictions specified in this protocol

• Written Authorization for Use and Release of Health and Research Study Information has been obtained

• Male aged 18 years and above

• Able to swallow the study drug whole as a tablet

• Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken

• Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 1 week after last study drug administration.

• Have a baseline serum potassium of ≥ 3.5 milliequivalents per litre (mEq/L)

• Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels < 1.5 x upper limit of normal (ULN)

• Have a serum albumin of ≥ 3.0 g/dL

• Total bilirubin ≤ 1.5 x ULN (In patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN is acceptable)

• Have a platelet count of ≥ 100,000/μL

• Have an absolute neutrophil count of > 1500 cell/mm3

• Have a calculated creatinine clearance ≥ 60 mL/min

• Have a hemoglobin of ≥ 9.0 g/dL

• Have histologically confirmed adenocarcinoma of the prostate.

• No prior therapy with chemotherapy for metastatic prostate cancer.

• Have metastatic disease based on a positive bone scan or objective imaging on CT scan.

• Have ongoing gonadal androgen deprivation therapy with Luteinizing hormone-releasing hormone (LHRH) analogues or orchiectomy. Patients who have not had an orchiectomy must be maintained on effective LHRH analogue therapy for the duration of the trial.

• Testosterone < 50 ng/dL.

• Progressive disease after androgen deprivation: PSA evidence for progressive prostate cancer consists of a PSA level of at least 2 ng/ml which has risen on at least 2 successive occasions, at least 2 weeks apart. If the confirmatory PSA value is less than the screening PSA value, then an additional test for rising PSA will be required to document progression.

• Antiandrogen Withdrawal (AAWD): Patients who are receiving an antiandrogen as part of primary androgen ablation must demonstrate disease progression following discontinuation of antiandrogen.

• Disease progression after antiandrogen withdrawal is defined as 2 consecutive rising PSA values, obtained at least 2 weeks apart, or documented osseous or soft tissue progression.

• For patients receiving flutamide, at least one of the PSA values must be obtained 4 weeks or more after flutamide discontinuation.

• For patients receiving bicalutamide or nilutamide, at least one of the PSA values must be obtained 6 weeks or more after antiandrogen discontinuation.

• No antiandrogen withdrawal response is expected in patients in whom antiandrogen therapy did NOT result in a decline in PSA or in those patients in whom the response to antiandrogens was < 3 months. Therefore, it is not necessary to wait for AAWD in patients without PSA decline on an anti-androgen or in those in whom a PSA response lasted < 3 months.

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

• Life expectancy of ≥ 12 weeks.

Exclusion Criteria:

• Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated

• Known brain metastasis

• Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg) Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment

• Active or symptomatic viral hepatitis or chronic liver disease

• History of pituitary or adrenal dysfunction

• Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50 % at baseline

• Atrial Fibrillation, or other cardiac arrhythmia requiring medical therapy

• Administration of an investigational therapeutic within 30 days of screening

• Have poorly controlled diabetes

• Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents

• Have a pre-existing condition that warrants long-term corticosteroid use in excess of study dose

• Have known allergies, hypersensitivity, or intolerance to abiraterone acetate or prednisone or their excipients

• Any condition which, in the opinion of the investigator, would preclude participation in this trial.

• Pure small cell carcinoma of the prostate or any mixed histology cancer of the prostate (eg: neuroendocrine) which contains < 50% adenocarcinoma.

• Therapy with other hormonal therapy, including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) any herbal product known to decrease PSA levels (e.g., Saw Palmetto and PC-SPES), or any systemic corticosteroid within 4 weeks prior to first dose of study drug.

• Prior therapy with Abiraterone Acetate or other CYP17 inhibitor(s) including TAK-700 or TOK-001, or investigational agent(s) targeting the androgen receptor for metastatic prostate cancer.

• Prior therapy with ketoconazole for > 2 weeks for prostate cancer.

• Therapy with supplements or complementary medicines/botanicals within 4 weeks of first dose of study drug, except for any combination of the following:

• Conventional multivitamin supplements

• Selenium

• Lycopene

• Soy supplements

• Prior radiation therapy completed < 4 weeks prior to enrollment

• Prior chemotherapy for castration resistant prostate cancer. Patients who have received chemotherapy for early stage prostate cancer (e.g. as part of a neoadjuvant or adjuvant trial) or for other malignancies are eligible provided that >1 year has passed since the administration of the last chemotherapy dose.

• Any "currently active" second malignancy, other than non-melanoma skin cancer. Patients are not considered to have a "currently active" malignancy, if they have completed therapy and are considered by their physician to be at least less than 30% risk of relapse over next year.

• Active psychiatric illnesses/social situations that would limit compliance with protocol requirements.

• Patients in whom urgent chemotherapy, in the opinion of the treating physician, is indicated should not be enrolled in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143
2	Oregon Health and Science University	Portland	Oregon	United States	79239

Sponsors and Collaborators

• Terence Friedlander, MD
• Janssen Biotech, Inc.

Investigators

• Study Chair: Terence Friedlander, MD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 17, 2014

More Information

Publications

None provided.

• Responsible Party: Terence Friedlander, MD, Assistant Clinical Professor, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01637402
• Other Study ID Numbers: 12551; NCI-2012-02079
• First Posted: Jul 11, 2012
• Last Update Posted: Aug 17, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Terence Friedlander, MD, Assistant Clinical Professor, University of California, San Francisco: CRPC; Prostate; Cancer
• Additional relevant MeSH terms: Prostatic Neoplasms; Prednisone; Abiraterone Acetate

Study Results

Participant Flow

Recruitment Details	Participants were recruited through the Urologic Oncology Program at University of California, San Francisco
Pre-assignment Detail	All participants were prescribed the standard dose(STD). Participants who did not exhibit prostate-specific antigen (PSA) decline at 12 weeks were deemed 'primary-resistant' and taken off study. Participants continued STD until progression, at which time, they were assigned to the escalated dose was for a minimum of 12 weeks.

Arm/Group Title	Standard Dose	Escalated Dose
Arm/Group Description	Abiraterone 1000 mg once daily Prednisone 5 mg twice daily	Abiraterone 1000 mg twice daily Prednisone 5 mg twice daily
Period Title: Standard Dose Regimen
STARTED	41	0
COMPLETED	38	0
NOT COMPLETED	3	0
Period Title: Standard Dose Regimen
STARTED	38	0
COMPLETED	32	0
NOT COMPLETED	6	0
Period Title: Standard Dose Regimen
STARTED	14	18
COMPLETED	5	14
NOT COMPLETED	9	4

Baseline Characteristics

Arm/Group Title	All Patients Who Received Treatment
Arm/Group Description	Abiraterone Acetate: Standard dose: 1,000 mg, once daily, oral administration Increased dose offered after week 12 evaluation to participants who progressed after decline on standard dose: 1,000 mg, twice daily, oral administration Prednisone: 5 mg, twice daily, oral administration
Overall Participants	41
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	67.4
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	41 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.4%
Not Hispanic or Latino	37 90.2%
Unknown or Not Reported	3 7.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	17 41.5%
Unknown or Not Reported	1 2.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 7.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	30 73.2%
More than one race	0 0%
Unknown or Not Reported	8 19.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	16 39%
More than one race	0 0%
Unknown or Not Reported	2 4.9%
Region of Enrollment (participants) [Number]
United States	41 100%
Prior Therapies (Count of Participants)
Radical Prostatectomy	12 29.3%
Definitive Radiotherapy	15 36.6%
Metastatic at Diagnosis	14 34.1%
Prostate Specific Antigen levels (ng/dl) [Median (Full Range) ]
Median (Full Range) [ng/dl]	23.18

Outcome Measures

1. Primary Outcome

Title	Number of Patients With PSA Response From Dose Escalation
Description	A PSA response for the dose escalation group is defined as a participant with a documented PSA decline after 12 weeks of therapy with standard-dose, then had disease progression, and then achieved a ≥30% PSA decline after 12 weeks from the start of dose escalation therapy.
Time Frame	Up to 12 weeks from start of dose escalation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Escalation
Arm/Group Description	Dose Escalation (until PSA decrease of at least 30% after 12 weeks): Abiraterone 1,000 mg, twice daily, Prednisone 5 mg twice daily
Measure Participants	14
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Number of Participants With Worst-grade, Treatment-related Toxicities for Dose Escalation Group
Description	Frequency of any treatment-related toxicity with increased-dose Abiraterone Acetate by maximum observed grade will be tabulated for the study cohort. Toxicities will be graded for management according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as a measure of patient safety.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Escalation (CTCAE Grade 1)	Dose Escalation (CTCAE Grade 2)	Dose Escalation (CTCAE Grade 3)	Dose Escalation (CTCAE Grade 4)
Arm/Group Description	Worst grade adverse event with CTCAE Grade 1 for patients taking Abiraterone 1000 mg twice daily, Prednisone 5 mg twice daily	Worst grade adverse event with CTCAE Grade 2 for patients taking Abiraterone 1000 mg twice daily, Prednisone 5 mg twice daily	Worst grade adverse event with CTCAE Grade 3 for patients taking Abiraterone 1000 mg twice daily, Prednisone 5 mg twice daily	Worst grade adverse event with CTCAE Grade 4 for patients taking Abiraterone 1000 mg twice daily, Prednisone 5 mg twice daily
Measure Participants	18	18	18	18
Dry Mouth	1 2.4%	0 NaN	0 NaN	0 NaN
Hypertension	0 0%	1 NaN	0 NaN	0 NaN
Alanine aminotransferase increase	0 0%	0 NaN	1 NaN	0 NaN
Irritability	0 0%	1 NaN	0 NaN	0 NaN
Aspartate aminotransferase increased	0 0%	1 NaN	0 NaN	0 NaN
Hypokalemia	0 0%	1 NaN	0 NaN	0 NaN
Purpura	1 2.4%	0 NaN	0 NaN	0 NaN
Fatigue	0 0%	1 NaN	0 NaN	0 NaN

3. Secondary Outcome

Title	Time to PSA Progression for Dose Escalation Cohort
Description	Time to PSA progression as defined by RECIST criteria or by the Prostate Cancer Working Group 2 (PCWG) criteria for patients whom were treated with increased dose Abiraterone Acetate.
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Escalation
Arm/Group Description	Abiraterone 1,000 mg, twice daily, Prednisone 5 mg twice daily
Measure Participants	14
Median (Full Range) [months]	12

4. Secondary Outcome

Title	Progression Free Survival for Dose Escalation Cohort
Description	Progression free survival for patients treated with increased dose Abiraterone Acetate
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

Progression-free survival could not be calculated due to the lack of objective response in the dose escalation group (i.e. no patients were progression-free).

Arm/Group Title	Dose Escalation
Arm/Group Description	Abiraterone 1,000 mg, twice daily, Prednisone 5 mg twice daily
Measure Participants	0

5. Secondary Outcome

Title	Serum Concentration Levels of Abiraterone Acetate Over Time
Description	Pharmacokinetic assessment at the initiation of standard dose therapy, at the time of initial disease progression, at the time of a response to increased dose of abiraterone acetate and at the time of disease progression on increased-dose therapy.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Only 26 patients on the standard dose had pharmacokinetic samples available for analysis at time of first blood draw. No patients displayed a response to increased-dose therapy therefore data for concentration at time of response to increased dose was not collected.

Arm/Group Title	Concentration at First Draw on Standard Dose Therapy (4 Weeks)	Concentration at Time of Disease Progression on Standard Dose	Concentration at Time of Response to Increased-dose	Concentration at Time of Disease Progression on Increased Dose
Arm/Group Description	Plasma Abiraterone concentration at 4 weeks for patients on standard dose	Plasma Abiraterone concentration at time of disease progression on standard dose	Plasma Abiraterone concentration at the time of a response to increased-dose Abiraterone Acetate	Plasma Abiraterone concentration at the time of disease progression on increased-dose therapy.
Measure Participants	26	26	0	14
Median (Full Range) [nanograms per millilitre (ng/mL)]	5.5	14.2	31.5

6. Secondary Outcome

Title	Correlation of Circulating Testosterone Levels at Baseline and Week 12
Description	Pearson's correlation coefficients ("r") will be calculated to summarize the relationship between testosterone values at baseline and at 12 weeks. Testosterone labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of testosterone levels between the 2 time points, a value of 0 indicating no association between testosterone levels between the two time points, and a value of +1 indicating a positive linear association of testosterone levels between the two time points.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Testosterone levels were maximally suppressed below the laboratory limit of detection (LOD) at week 12 for patients on standard-dose therapy so no correlation could be performed. There were no responders in dose escalation so evaluation of hormonal changes with dose-escalated group was not pursued.

Arm/Group Title	Standard Dose	Dose Escalation
Arm/Group Description	Standard Dose until progression: Abiraterone 1,000 mg, once daily, Prednisone 5 mg twice daily	Dose Escalation (until PSA decrease of at least 30% after 12 weeks): Abiraterone 1,000 mg, twice daily, Prednisone 5 mg twice daily
Measure Participants	0	0

7. Secondary Outcome

Title	Comparison of Circulating Testosterone Levels Between Primary-Resistant Patients and Responders
Description	The distribution of the baseline testosterone levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Testosterone levels were maximally suppressed below the laboratory limit of detection (LOD) at week 12 for patients on standard-dose therapy so no correlation could be performed. There were no responders in the dose escalation group so evaluation of hormonal changes with dose-escalated group was not pursued.

Arm/Group Title	Testosterone in Primary Resistant (STD)	Testosterone in Responders (STD)
Arm/Group Description	Testosterone levels in patients without > 30% PSA decline during standard dose therapy.	Testosterone levels in patients with > 30% PSA decline during standard dose therapy
Measure Participants	7	19
Mean (Standard Deviation) [Nanograms per decilitre (ng/dL)]	NA (NA)	NA (NA)

8. Secondary Outcome

Title	Correlation of Circulating Dehydroepiandrosterone (DHEA) Levels From Baseline to Week 12
Description	Pearson's correlation coefficients ("r") will be calculated to summarize the relationship between DHEA values at baseline and at 12 weeks. DHEA labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of DHEA levels between the 2 time points, a value of 0 indicating no association between DHEA levels between the two time points, and a value of +1 indicating a positive linear association of DHEA levels between the two time points.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

No DHEA values were collected for week 12 in dose escalation group so correlation of for dose escalation could not be performed.

Arm/Group Title	Standard Dose	Dose Escalation
Arm/Group Description	Standard Dose until progression: Abiraterone 1,000 mg, once daily, Prednisone 5 mg twice daily	Dose Escalation (until PSA decrease of at least 30% after 12 weeks): Abiraterone 1,000 mg, twice daily, Prednisone 5 mg twice daily
Measure Participants	26	0
Number [correlation coefficient (r)]	0

9. Secondary Outcome

Title	Comparison of Circulating DHEA Levels Between Primary-Resistant and Responders
Description	The distribution of the baseline DHEA levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Twenty-six patients had both baseline and follow-up samples available for analysis. There were no responders in dose escalation group so evaluation of hormonal changes with dose-escalated group was not pursued.

Arm/Group Title	DHEA in Primary Resistant (STD)	DHEA in Responders (STD)
Arm/Group Description	DHEA levels in patients without > 30% PSA decline during standard dose therapy.	DHEA levels in patients with > 30% PSA decline during standard dose therapy.
Measure Participants	7	19
Initial draw	56.2	79.4
Progression / Week 12	28.5	13.5

10. Secondary Outcome

Title	Correlation of Circulating Dehydroepiandrosterone-sulfate (DHEA-S) Levels at Baseline and Week 12
Description	Pearson's correlation coefficients ("r") will be calculated to summarize the relationship between DHEA-S values at baseline and at 12 weeks. DHEA-S labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of DHEA-S levels between the 2 time points, a value of 0 indicating no association between DHEA-S levels between the two time points, and a value of +1 indicating a positive linear association of DHEA-S levels between the two time points.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

DHEA-S levels were maximally suppressed below the laboratory limit of detection (LOD) at week 12 for patients on standard-dose therapy so no correlation could be performed. There were no responders in dose escalation so evaluation of hormonal changes with dose-escalated group was not pursued.

Arm/Group Title	Standard Dose	Dose-Escalation
Arm/Group Description	Standard Dose until progression: Abiraterone 1,000 mg, once daily, Prednisone 5 mg twice daily	Dose Escalation (until PSA decrease of at least 30% after 12 weeks): Abiraterone 1,000 mg, twice daily, Prednisone 5 mg twice daily
Measure Participants	0	0

11. Secondary Outcome

Title	Comparison of Circulating DHEA-S Levels Between Primary-Resistant Patients and Responders
Description	The distribution of the baseline DHEA-S levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

DHEA-S levels were maximally suppressed below the laboratory limit of detection (LOD) at week 12 for patients on standard-dose therapy so no correlation could be performed. There were no responders in dose escalation so evaluation of hormonal changes with dose-escalated group was not pursued.

Arm/Group Title	DHEA-S in Primary Resistant (STD)	DHEA-S in Responders (STD)
Arm/Group Description	DHEA-S levels in patients without > 30% PSA decline during standard dose therapy.	DHEA-S levels in patients with > 30% PSA decline during standard dose therapy.
Measure Participants	7	19
Mean (Standard Deviation) [microgram per deciliter (µg/dL)]	NA (NA)	NA (NA)

12. Secondary Outcome

Title	Correlation of Circulating Androstenedione Levels at Baseline and Week 12
Description	Pearson's correlation coefficients ("r") will be calculated to summarize the relationship between androstenedione values at baseline and at 12 weeks. Androstenedione labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of androstenedione levels between the 2 time points, a value of 0 indicating no association between androstenedione levels between the two time points, and a value of +1 indicating a positive linear association of androstenedione levels between the two time points.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Androstenedione levels were maximally suppressed below the laboratory limit of detection (LOD) at week 12 for patients on standard-dose therapy so no correlation could be performed. There were no responders in dose escalation so evaluation of hormonal changes with dose-escalated group was not pursued.

Arm/Group Title	Standard Dose	Dose Escalation
Arm/Group Description	Standard Dose until progression: Abiraterone 1,000 mg, once daily, Prednisone 5 mg twice daily	Dose Escalation (until PSA decrease of at least 30% after 12 weeks): Abiraterone 1,000 mg, twice daily, Prednisone 5 mg twice daily
Measure Participants	0	0

13. Secondary Outcome

Title	Comparison of Circulating Androstenedione Levels Between Primary-Resistant Patients and Responders
Description	The distribution of the baseline androstenedione levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Androstenedione levels were maximally suppressed below the laboratory limit of detection (LOD) at week 12 for patients on standard-dose therapy so no correlation could be performed. There were no responders in dose escalation so evaluation of hormonal changes with dose-escalated group was not pursued.

Arm/Group Title	Androstenedione in Primary Resistant (STD)	Androstenedione in Responders (STD)
Arm/Group Description	Androstenedione levels in patients without > 30% PSA decline during standard dose therapy.	Androstenedione levels in patients with > 30% PSA decline during standard dose therapy.
Measure Participants	7	19
Mean (Standard Deviation) [ng/dL]	NA (NA)	NA (NA)

Adverse Events

Time Frame	Up to 24 months
Arm/Group Title	Standard Dose Therapy		Dose Escalation
Arm/Group Description	Abiraterone 1000 mg daily, Prednisone 5 mg twice daily		Dose Escalation (until PSA decrease of at least 30% after 12 weeks): Abiraterone 1,000 mg, twice daily, Prednisone 5 mg twice daily
All Cause Mortality
	Standard Dose Therapy		Dose Escalation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/18 (0%)
Serious Adverse Events
	Standard Dose Therapy		Dose Escalation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/41 (17.1%)		1/18 (5.6%)
Cardiac disorders
Atrial fibrillation	1/41 (2.4%)		0/18 (0%)
Gastrointestinal disorders
Constipation	1/41 (2.4%)		0/18 (0%)
Dental caries	1/41 (2.4%)		0/18 (0%)
Nausea	1/41 (2.4%)		0/18 (0%)
Vomiting	1/41 (2.4%)		0/18 (0%)
General disorders
Fatigue	0/41 (0%)		1/18 (5.6%)
Infections and infestations
Lung infection	0/41 (0%)		1/18 (5.6%)
Upper respiratory infection	1/41 (2.4%)		0/18 (0%)
Investigations
Alanine aminotransferase increased	1/41 (2.4%)		0/18 (0%)
Aspartate aminotransferase increased	1/41 (2.4%)		0/18 (0%)
Metabolism and nutrition disorders
Anorexia	0/41 (0%)		1/18 (5.6%)
Hypokalemia	0/41 (0%)		1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/41 (0%)		1/18 (5.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/41 (2.4%)		1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	Standard Dose Therapy		Dose Escalation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/41 (82.9%)		10/18 (55.6%)
Eye disorders
Cataract	0/41 (0%)		1/18 (5.6%)
Gastrointestinal disorders
Diarrhea	4/41 (9.8%)		0/18 (0%)
Nausea	3/41 (7.3%)		1/18 (5.6%)
Dyspepsia	3/41 (7.3%)		0/18 (0%)
Vomiting	3/41 (7.3%)		0/18 (0%)
Oral pain	1/41 (2.4%)		1/18 (5.6%)
Dry mouth	0/41 (0%)		1/18 (5.6%)
General disorders
Fatigue	5/41 (12.2%)		2/18 (11.1%)
Pain	4/41 (9.8%)		1/18 (5.6%)
Edema limbs	3/41 (7.3%)		0/18 (0%)
Irritability	0/41 (0%)		1/18 (5.6%)
Infections and infestations
Upper respiratory infection	5/41 (12.2%)		0/18 (0%)
Skin infection	1/41 (2.4%)		1/18 (5.6%)
Injury, poisoning and procedural complications
Bruising	4/41 (9.8%)		0/18 (0%)
Fall	4/41 (9.8%)		0/18 (0%)
Fracture	4/41 (9.8%)		0/18 (0%)
Investigations
Creatinine increased	5/41 (12.2%)		1/18 (5.6%)
Alanine aminotransferase increased	3/41 (7.3%)		1/18 (5.6%)
Aspartate aminotransferase increased	3/41 (7.3%)		1/18 (5.6%)
Metabolism and nutrition disorders
Hypokalemia	6/41 (14.6%)		2/18 (11.1%)
Hypomagnesemia	4/41 (9.8%)		0/18 (0%)
Anorexia	1/41 (2.4%)		1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Pain in extremity	6/41 (14.6%)		0/18 (0%)
Myalgia	4/41 (9.8%)		0/18 (0%)
Muscle weakness lower limb	1/41 (2.4%)		1/18 (5.6%)
Flank pain	0/41 (0%)		1/18 (5.6%)
Nervous system disorders
Dizziness	3/41 (7.3%)		0/18 (0%)
Peripheral sensory neuropathy	2/41 (4.9%)		1/18 (5.6%)
Psychiatric disorders
Anxiety	0/41 (0%)		1/18 (5.6%)
Renal and urinary disorders
Urinary incontinence	3/41 (7.3%)		1/18 (5.6%)
Cystitis noninfective	0/41 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/41 (0%)		2/18 (11.1%)
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	4/41 (9.8%)		0/18 (0%)
Dry skin	0/41 (0%)		1/18 (5.6%)
Purpura	0/41 (0%)		1/18 (5.6%)
Vascular disorders
Hypertension	5/41 (12.2%)		2/18 (11.1%)
Hot flashes	5/41 (12.2%)		0/18 (0%)
Vascular disorders - Other, specify	0/41 (0%)		1/18 (5.6%)

Limitations/Caveats

Additional accrual to the dose-increased arm was halted early due to lack of efficacy at interim analysis

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.