Effect of Low-dose 500 mg Abiraterone Acetate in Treatment of Metastatic Prostate Cancer Patients

Primary Objectives:

As a preliminary Phase I trial, the primary objective of the study would be to evaluate the percentage change in prostate specific antigen (PSA) from baseline to 12 weeks.

Secondary Objectives:

• determine the proportion of patients achieving PSA response (≥ 50% reduction in PSA after 12 weeks of therapy).
• evaluate the pharmacokinetics associated with the 500 mg dose of abiraterone acetate.
• investigate the correlation between plasma exposure of abiraterone and CP-I or CP-III in order to support their utility as a biomarker of OATP1B1/1B3 function.
• assess the pharmacodynamic effects of the reduced 500 mg dose on the maximal percentage change in serum androgens (dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), testosterone, androstenedione) from baseline.

Inclusion criteria

• Histologically confirmed adenocarcinoma prostate
• Age >21 years
• Diagnosis of metastatic castration-resistant prostate cancer (mCRPC) (chemotherapy naïve and chemotherapy pre-treated patients) or metastatic hormone-sensitive prostate cancer (mHSPC)
• For mCRPC patients, evidence of castration resistance is defined as disease progression despite a testosterone level <50ng/dL (or surgical castration)
• Progressive disease was defined as either

• PSA progression according to Prostate Cancer Working Group (PCWG2) criteria15: PSA evidence for progressive prostate cancer consists of a minimum PSA level of at least 2 ng/ml, which has subsequently risen on at least 2 successive occasions, at least 1 week apart
• Radiographic progression according to RECIST 1.1 guidelines or
• 2 or more new lesions on bone scan
• Newly initiated on abiraterone acetate therapy
• Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1 or 2.
• Adequate hematologic, hepatic, and renal function would include:

• hemoglobin ≥9.0 g/dL independent of transfusions
• neutrophils ≥1.5 x 109/L
• platelets ≥100 x 109/L
• total bilirubin ≤1.5× upper limit of normal (ULN) [except for subjects with documented Gilbert's disease in which case total bilirubin not to exceed 10× ULN]
• alanine (ALT) and aspartate (AST) aminotransferase ≤2.5X ULN
• serum creatinine <1.5× ULN or calculated creatinine clearance ≥30 mL/min
• serum potassium ≥3.5 mmol/L
• Ability to provide informed consent

Exclusion criteria

• Patients with prior use of enzalutamide or other potent androgen pathway targeted therapies
• Concurrent therapy with strong inhibitors or inducers of CYP3A4 due to concerning possible drug-drug interactions with abiraterone.
• Concurrent therapy with strong inhibitors or inducers of OATP transporters (e.g., rifampicin, cyclosporine) due to concerning possible effects on CP-I and CP-III.
• New York Heart Association (NYHA) class II, NYHA class III, or IV congestive heart failure (any symptomatic heart failure)
• Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP ≥95 mmHg). Subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
• Patients who do not voluntarily consent to participate in the study