Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer.
Condition: Metastatic Castration-resistant Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Olaparib; Placebo; Abiraterone; Prednisone or prednisolone
Intervention description: Olaparib bid; Placebo bid; Abiraterone 1000 mg; Prednisone or prednisolone 5 mg bid will be co-administered with the abiraterone in this study.
Intervention MeSH terms: Prednisone; Prednisolone; Olaparib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 158.0
Sex: Male
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Olaparib; castration-resistant, metastatic prostate cancer; Prior Docetaxel Chemotherapy

Summary:

      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 pharmacokinetics (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 given 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 twice daily (bid) will be administered with the abiraterone in this study.
    

Eligibility criteria:

        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.