Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer.

This is a 2-part study in patients with metastatic CRPC. Part A is an open-label safety
run-in study to assess the safety, tolerability and PK of olaparib when given in addition to
abiraterone 1000 mg once daily. Part B is a randomised, double-blind, placebo-controlled
comparison of the efficacy, safety and tolerability of the dose of olaparib selected from
Part A when given in addition to abiraterone, versus placebo in addition to abiraterone.

Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of
patients with metastatic CRPC. Prednisone or prednisolone 5 mg bid will be administered with
the abiraterone in this study, but throughout this protocol the treatment will be referred to
simply as abiraterone.

For Part A of the study, 15 to 18 evaluable patients (Cohorts 1 and 2) are planned to be
enrolled from approximately 4 sites in approximately 1 or 2 countries, and a further 12
patients may be recruited into a 3rd cohort if necessary.

For Part B of the study, approximately 140 patients who have received prior chemotherapy
containing docetaxel will be randomised from approximately 40 sites in North America and
Europe. Patients who have been dosed in Part A of the study may not participate in Part B.

Inclusion Criteria:

1. Provision of signed and dated written informed consent prior to any study specific
procedures.

2. Male aged 18 years and older.

3. Histologically or cytologically proven diagnosis of prostate cancer.

4. Candidate for abiraterone therapy with documented evidence of metastatic
castration-resistant prostate cancer. Metastatic status is defined as at least one
documented metastatic lesion on either bone scan or CT/MRI scan. Castration resistant
prostate cancer is defined as rising PSA or other signs of disease progression despite
treatment with androgen deprivation therapy and the presence of a castrate level of
testosterone (≤50 ng/dL).

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 with no
deterioration over the previous 2 weeks.

6. Patients must have a life expectancy ≥12 weeks.

7. Patients are willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations, and
completing PRO instruments.

8. Patients must be on a stable concomitant medication regimen, defined as no changes in
medication or in dose within 2 weeks prior to start of olaparib dosing, except for
bisphosphonates, denosumab and corticosteroids, which should be stable for at least 4
weeks prior to start of olaparib dosing.

9. For the randomised phase only, patients must have received chemotherapy in the form of
docetaxel treatment for metastatic castration-resistant prostate cancer. Note:
patients who discontinued docetaxel for toxicity reasons and without completing the
full course will still be eligible to enter this study provided they received at least
2 cycles of chemotherapy.

Provide informed consent for the pharmacogenetic sampling and analyses.

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.