Ph II Study to evaluate Olaparib with Abiraterone in treating metastatic castration resistant prostate cancer.

Exclusion Criteria

• 1) Involvement in the planning and/or conduct of the study (applies to both
• AstraZeneca staff, its agents and/or staff at the study site).
• 2) Previous treatment in the present study.
• 3) Treatment with any of the following:
• - Previous exposure to any 2nd generation anti-hormonal including abiraterone and enzalutamide
• - More than 2 prior courses of chemotherapy for metastatic prostate cancer
• - Previous use of immunotherapy or radium-223 for the treatment of metastatic prostate cancer
• - Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study treatment;
• - Any previous exposure to a CYP17 (17α-hydroxylase/C17,20-lyase) inhibitor;
• - Substrates of CYP2D6 with a narrow therapeutic index (eg, thioridazine);
• - Potent inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort).
• - Any previous treatment with a PARP inhibitor, including olaparib.
• 4) With the exception of alopecia or toxicities related to the use of gonadotropinreleasing hormone agonists, any unresolved toxicities from prior therapy greater than CTCAE Grade 2 at the time of starting study treatment.
• 5) Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
• 6) As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• 7) Any of the following cardiac criteria:
• − Mean resting QTc >470 msec obtained from 3 ECGs
• − Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block
• − Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.
• 8) Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years.
• 9) Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
• − Absolute neutrophil count (ANC) <1.5 x 109/L
• − Platelet count <100 x 109/L
• − Haemoglobin (Hb) <100 g/L
• − Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
• >2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or
• >5 x ULN in the presence of liver metastases
• − Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence of liver metastases (except in the case of Gilbert’s disease)
• − Creatinine >1.5 x ULN concurrent with creatinine clearance <50 mL/min
• (measured or calculated by Cockcroft and Gault equation); confirmation of
• creatinine clearance is only required when creatinine is >1.5 x ULN
• − If bone metastases are present and liver function is otherwise considered
• adequate by the Investigator then elevated alkaline phosphatase (ALP) will not exclude the patient.
• 10) Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of olaparib or abiraterone.
• 11) History of hypersensitivity to active or inactive excipients of olaparib or abiraterone or drugs with a similar chemical structure or class to olaparib or abiraterone.
• 12) Patients with myelodysplastic syndrome/acute myeloid leukaemia.
• 13) Current disease or condition known to interfere with absorption, distribution, metabolism, or excretion of drugs, at the Investigator’s discretion.
• 14) Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
• 15) Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Exclusion from the genetic research may be for any of the exclusion criteria specified in the main study or any of the following:
• 16) Previous allogeneic bone marrow transplant.
• 17) Non-leukocyte depleted whole blood transfusion within 120 days of the date of the pharmacogenetic sample collection.