TOPARP: A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer
TOPARP: A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer
This is an open-label, single arm, two part adaptive design phase II trial of Olaparib in
 patients with advanced castration resistant prostate cancer.

 The trial aims to evaluate the the anti-tumour activity of Olaparib in metastatic castration
 resistant prostate cancer, identify molecular signatures of tumour cells in responding and
 non-responding patients, and to identify predictive biomarkers of Olaparib response.
Patients with advanced castration resistant prostate cancer will receive single agent
 Olaparib at a dose of 400mg twice daily, continuously on a 28 day cycle. Olaparib will be
 administered until objective disease progression or unacceptable toxicity or patient
 withdrawal for whatever reason
Inclusion Criteria:

 1. Subject capable of understanding & complying with protocol requirements & signed the
 informed consent form

 2. Minimum age 18 years

 3. Histologically confirmed adenocarcinoma of the prostate with tumour tissue available
 for molecular analyses

 4. At least one but no more than two previous taxane-based chemotherapy regimens. If
 docetaxel chemotherapy is used more than once, this will be considered as one regime.
 Patients may have had prior exposure to cabazitaxel treatment

 5. At least 28 days since the completion of prior therapy, including major surgery,
 chemotherapy & other investigational agents. Clinically relevant sequelae should have
 resolved to grade 1 or less prior to recommencing treatment. For hormonal treatment &
 radiotherapy refer to the protocol guidelines

 6. Documented prostate cancer progression as described in the protocol.

 7. Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM).
 If the patient is being treated with LHRH agonists this must have been initiated at
 least 4 weeks prior to Cycle 1 Day 1 & must be continued throughout the study.

 8. Eastern Cooperative Oncology Group Performance Status of 0, 1, 2

 9. Life expectancy > 12 weeks

 10. Able to swallow a whole tablet

 11. Patient & the patient's partner of childbearing potential, must agree to use medically
 accepted methods of contraception during the course of the study & for 3 months after
 the last dose of study drug

 12. Agreeable to have all the biomarker studies including the paired fresh tumour
 biopsies.

 13. CTC count of 5 cells/7.5mls blood or more at screening. Note: For Part B, CTC count >5
 cells/7.5mls blood is not mandatory if patient has measurable disease by modified
 RECIST and a lesion >2cm and PSA greater than or equal to 2ng/ml at screening.

 14. Adequate bone marrow, hepatic & renal function as defined in the protocol

 15. For Part B only, patients must have genomic defects associated with olaparib
 sensitivity identified by NGS by the central lab.

 Exclusion Criteria:

 1. Surgery, or local prostatic intervention (excluding a prostatic biopsy) less than 28
 days of Cycle 1 Day 1

 2. Less than 28 days from any active anticancer therapy or investigational agents. For
 hormonal treatment & radiotherapy refer to the guidelines outlined in the inclusion
 criteria

 3. Prior treatment with a PARP inhibitor, platinum, cyclophosphamide or mitoxantrone
 chemotherapy

 4. Uncontrolled intercurrent illness including, but not limited to, active infection,
 symptomatic congestive heart failure (New York Heart Association Class III or IV heart
 disease), unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or
 psychiatric illness/social situations that would limit compliance with study
 requirements

 5. Any acute toxicities due to prior chemotherapy & / or radiotherapy that have not
 resolved to a NCI-CTCAE v4.02 grade 0 or 1 with the exception of chemotherapy induced
 alopecia & grade 2 peripheral neuropathy

 6. Malignancy within the previous 2-years with a > 30% probability of recurrence within
 12 months with the exception of non-melanoma skin cancer, in-situ or superficial
 bladder cancer

 7. Patients with myelodysplastic syndrome/acute myeloid leukaemia

 8. Patients with known symptomatic brain metastasis are not suitable for enrollment.
 Patients with asymptomatic, stable, treated brain metastases are eligible for study
 entry

 9. Patients with symptomatic or impending cord compression unless appropriately treated
 beforehand & clinically stable & asymptomatic

 10. Patients who have experienced a seizure or seizures within 6 months of study treatment
 or who are currently being treated with cytochrome P450 enzyme inducing anti-epileptic
 drugs for seizures

 11. Patients receiving any of the following classes of inhibitors of CYP3A4 (see protocol
 for guidelines & wash out periods)

 12. Patients with gastrointestinal disorders likely to interfere with absorption of the
 study medication

 13. Initiating bisphosphonate therapy or adjusting bisphosphonate dose/regimen within 30
 days prior to Cycle 1 Day 1. Patients on a stable bisphosphonate regimen are eligible
 & may continue

 14. Presence of a condition or situation, which, may put the patient at significant risk,
 confound the study results, or interfere significantly with participation in the study