Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy

• Time to Prostate-Specific Antigen Progression According to Prostate Specific Antigen Working Group Criteria [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
  The time interval from the date of randomization to the date of the prostate-specific antigen (PSA) progression as defined in the protocol-specific Prostate Specific Antigen Working Group (PSAWG) criteria, namely, a PSA level of at least 5 ng/ml that has risen on at least 2 successive occasions, at least 2 weeks apart.
• Number of Patients Achieving a Prostate-Specific Antigen Decline >=50% [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
  A prostate-specific antigen (PSA) response was defined as a >=50% decline from baseline.
• Radiographic Progression-free Survival [ Time Frame: Up to 11 months ] [ Designated as safety issue: No ]
  Radiographic progression-free survival is based on imaging studies according to modified Response Evaluation Criteria in Solid Tumors (RECIST): baseline lymph node size must be >=2.0 cm to be considered a target lesion; progression on bone scans with >=2 new lesions not consistent with tumor flare, confirmed on a second scan >=6 weeks later that shows >=1 additional new lesion.

This is a phase 3 study to compare the clinical benefit of abiraterone acetate plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer (CRPC) who have failed one or two chemotherapy regimens. At least one of the previous chemotherapies must have contained docetaxel.

Abiraterone acetate is a steroidal irreversible inhibitor of CYP17 (17α hydroxylase/C17, 20-lyase), blocking 2 important enzymatic activities in the synthesis of testosterone. The goal of this study is to compare the clinical benefit of abiraterone acetate plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer (CRPC) who have failed one or two chemotherapy regimens, one of which contains docetaxel. All patients involved in the study will be randomized (assigned by chance) into one of two arms and will not know what study drug is being given to them. Study drug randomization allocation will be 2:1 (abiraterone acetate: placebo). The study will be conducted in the United States, Canada, Australia, and the EU. The study will consist of screening, treatment, and follow-up. In this study, patients will receive study treatment (abiraterone acetate or placebo) plus prednisone until progression of clinical disease. Follow-up will continue until patient dies, is lost to follow-up, or withdraws informed consent. After providing written informed consent, patients will have screening procedures completed to determine eligibility. Safety evaluations at the screening procedure will include a physical examination, vital signs, and clinical blood laboratory tests, ECG, radiographs, urine tests, and recording of any adverse events including details of current prostate cancer symptoms. Patients will be asked 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 13 weeks after last study drug administration.

Study medication, abiraterone acetate,is an oral (by mouth) medication to be administered as four (4) 250mg abiraterone acetate tablets or 4 placebo tablets to be taken at least one hour before or two hours after a meal anytime up to 10PM everyday. Prednisone will be administered as 5mg orally twice a day for both groups. Each cycle will be 28 days. Study treatment will continue until disease progression as determined by investigator or when the patient meets criteria for withdrawal from study.

• Drug: Placebo
  Four tablets once daily until disease progression
• Drug: Abiraterone acetate
  Four 250-mg tablets once daily until disease progression
• Drug: Prednisone/prednisolone
  5 mg twice daily until disease progression

• Experimental: Abiraterone acetate plus prednisone/prednisolone
  Interventions:

  • Drug: Abiraterone acetate
  • Drug: Prednisone/prednisolone
• Placebo Comparator: Placebo plus prednisone/prednisolone
  Interventions:

  • Drug: Placebo
  • Drug: Prednisone/prednisolone

• Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. doi: 10.1016/S1470-2045(12)70473-4. Epub 2012 Nov 9.
• Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. doi: 10.1016/S1470-2045(12)70379-0. Epub 2012 Sep 18.
• de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005.

Inclusion Criteria:

• Metastatic Castration-Resistant Prostate Cancer Progression after one or two prior cytotoxic chemotherapies
• At least one chemotherapy must have contained docetaxel
• Eastern Cooperative Oncology Group (ECOG) Performance Status <= 2
• Medical or surgical castration with testosterone < 50 ng/dL
• Adequate bone marrow, hepatic and renal function
• Potassium >= 3.5 mmol/L
• Able to swallow the study drug whole as a tablet
• Informed Consent

Exclusion Criteria:

• More than two prior cytotoxic chemotherapy regimens
• Prior Ketoconazole for prostate cancer
• Prior abiraterone acetate or other CYP17 inhibitor or investigational agents targeting the androgen receptor for prostate cancer
• Uncontrolled hypertension
• Active or symptomatic viral hepatitis or chronic liver disease
• History of pituitary or adrenal dysfunction
• Clinically significant heart disease
• Other malignancy
• Known brain metastasis
• GI disorder affecting absorption
• Not willing to use contraception