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

• ClinicalTrials.gov Identifier: NCT01972217
• Recruitment Status: Completed
• First Posted: October 30, 2013
• Results First Posted: October 2, 2018
• Last Update Posted: November 14, 2023
• Sponsor: AstraZeneca
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: October 24, 2013
• First Posted Date: October 30, 2013
• Results First Submitted Date: September 6, 2018
• Results First Posted Date: October 2, 2018
• Last Update Posted Date: November 14, 2023
• Actual Study Start Date: April 1, 2014
• Actual Primary Completion Date: September 22, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 6, 2018)

• Part A: Percentage of Patients Experiencing Adverse Events (AEs) [ Time Frame: Cohort 1 and 2: From baseline in Part A (Day 1 for each cohort) up to 30 days following last dose of study treatment. ]
  The safety and tolerability of olaparib in combination with abiraterone was assessed during Part A of the study. The percentage of patients experiencing AEs, including information on seriousness, severity, study treatment relationship and those leading to discontinuation for all doses of olaparib and for abiraterone are presented. Severity of AEs was assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) v4.0. AEs were assigned to a Grade from 1 through 5 as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. 'c-r' = causally related 'discont' = discontinuation.
• Part A: Number of Patients With Dose Limiting Toxicities (DLTs) [ Time Frame: From Day 1 for Cohort 1 and from Day 4 for Cohort 2 up to 14 days treatment with olaparib + abiraterone for 3 patients. ]
  DLTs were assessed by a Safety Review Committee (SRC) after a minimum of 3 patients had received at least 14 days of treatment in Part A. A DLT was defined as any toxicity which was not a recognised AE of abiraterone or prednisolone, and was not attributable to the disease or disease-related processes under investigation, which occurred during a minimum period of 14 days treatment and which included: 1. haematological toxicity CTCAE v4.0 Grade 4 or higher present for more than 4 days (except anaemia); 2. non-haematological toxicity CTCAE v4.0 Grade 3 or higher including infection, corrected QT interval prolongation; 3. any other toxicity that was greater than that at baseline, was clinically significant and/or unacceptable, did not respond to supportive care, resulted in a disruption of dosing schedule of 7 days or more, or was judged to be a DLT by the SRC. A DLT excluded alopecia and isolated laboratory changes of any grade without clinical sequelae or clinical significance.
• Part B: Median Radiological Progression-Free Survival (rPFS) Time [ Time Frame: From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months. ]
  The efficacy of olaparib when given in combination with abiraterone was assessed by rPFS, defined as the time from randomisation to disease progression using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (for soft tissue disease) and Prostate Cancer Working Group 2 (PCWG-2) (for bone disease) criteria, or death. Progression using RECIST 1.1 criteria was defined as at least 20% increase from baseline in the sum of diameters of target lesions, progression of existing non-target lesions, or the appearance of at least 1 new lesion. Progression using PCWG-2 criteria was determined if 2 or more new metastatic bone lesions were observed (with a total of at least 4 new lesions since baseline assessment if observed at the 12 week scan, or persistence of or increase in number of lesions if observed after the 12 week scan as determined by a confirmatory scan at least 6 weeks later or at next scheduled visit).
• Part B: Percentage of Patients With Progression Events or Death (rPFS) [ Time Frame: From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months. ]
  The efficacy of olaparib when given in combination with abiraterone was assessed by rPFS, defined as the time from randomisation to disease progression using RECIST version 1.1 (for soft tissue disease) and PCWG-2 (for bone disease) criteria, or death. Progression using RECIST 1.1 criteria was defined as at least 20% increase from baseline in the sum of diameters of target lesions, progression of existing non-target lesions, or the appearance of at least 1 new lesion. Progression using PCWG-2 criteria was determined if 2 or more new metastatic bone lesions were observed (with a total of at least 4 new lesions since baseline assessment if observed at the 12 week scan, or persistence of or increase in number of lesions if observed after the 12 week scan as determined by a confirmatory scan at least 6 weeks later or at next scheduled visit). The percentage of patients with progression events is presented overall and according to RECIST 1.1 and/or PCWG-2 criteria, or death.

Original Primary Outcome Measures (submitted: October 24, 2013)

• Part A. • To evaluate the safety, tolerability of daily olaparib when given in addition to abiraterone and prednisolone. [ Time Frame: 12 months ]
  The parameters describing the safety and tolerability of olaparib will include: - The percentage of patients with DLTs; -The percentage of patients with adverse events by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) (version 4.03) grade; - The percentage of patients with serious adverse events; - The percentage of patients who discontinue olaparib due to adverse events or serious adverse events. Adverse events will be assessed by graded Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Clinical chemistry and haematology laboratory tests, and vital signs will also be measured. The number of adverse events that constitute dose limiting toxicities will be derived and used to select a dose to evaluate further in Part B of the study.
• Part B. Radiologic Progression-Free Survival (rPFS). [ Time Frame: 24 months ]
  rPFS will be assessed from randomization, every 12 weeks, until disease progression or death. Progression-free survival is defined as the time from randomisation until the date of objective disease progression according to RECIST 1.1 (for soft tissue disease) and/or PCWG-2 criteria (for bone disease), or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.

Current Secondary Outcome Measures (submitted: September 6, 2018)

• Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss) [ Time Frame: PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone. ]
  Following multiple dosing to steady state of olaparib 300 mg bid, the Cohort 2 olaparib Cmax,ss is presented for olaparib monotherapy and for olaparib given in combination with abiraterone. Only patients with data available for analysis at each time point are presented.
• Part A PK: Abiraterone Cmax,ss [ Time Frame: PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone. ]
  Following multiple dosing to steady state of abiraterone 1000 mg once daily, the Cohort 2 abiraterone Cmax,ss is presented for abiraterone monotherapy and for olaparib given in combination with abiraterone. Only patients with data available for analysis at each time point are presented.
• Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (Tmax,ss) [ Time Frame: PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone. ]
  Following multiple dosing to steady state of olaparib 300 mg bid, the Cohort 2 olaparib tmax,ss is presented for olaparib monotherapy and for olaparib given in combination with abiraterone. Only patients with data available for analysis at each time point are presented.
• Part A PK: Abiraterone Tmax,ss [ Time Frame: PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone. ]
  Following multiple dosing to steady state of abiraterone 1000 mg once daily, the Cohort 2 abiraterone tmax,ss is presented for abiraterone monotherapy and for olaparib given in combination with abiraterone. Only patients with data available for analysis at each time point are presented.
• Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss) [ Time Frame: PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone. ]
  Following multiple dosing to steady state of olaparib 300 mg bid, the Cohort 2 olaparib Cmin,ss is presented for olaparib monotherapy and for olaparib given in combination with abiraterone. Only patients with data available for analysis at each time point are presented.
• Part A PK: Abiraterone Cmin,ss [ Time Frame: PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone. ]
  Following multiple dosing to steady state of abiraterone 1000 mg once daily, the Cohort 2 abiraterone Cmin,ss is presented for abiraterone monotherapy and for olaparib given in combination with abiraterone. Only patients with data available for analysis at each time point are presented.
• Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss) [ Time Frame: PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone. ]
  Following multiple dosing to steady state of olaparib 300 mg bid, the Cohort 2 olaparib AUCss is presented for olaparib monotherapy and for olaparib given in combination with abiraterone. Only patients with data available for analysis at each time point are presented.
• Part A PK: Abiraterone AUCss [ Time Frame: PK sampling for Cohort 2 Group 1 was between Days 3 and 7 for olaparib, and Days 4 and 8 for olaparib and abiraterone. PK sampling for Cohort 2 Group 2 was between Days 5 and 7 for abiraterone, and Days 6 and 8 for olaparib and abiraterone. ]
  Following multiple dosing to steady state of abiraterone 1000 mg once daily, the Cohort 2 abiraterone AUCss is presented for abiraterone monotherapy and for olaparib given in combination with abiraterone. Only patients with data available for analysis at each time point are presented.
• Part B: Percentage of Patients Experiencing AEs [ Time Frame: From first dose of study treatment following randomisation in Part B up to 30 days following last dose of study treatment (up to approximately 3 years). ]
  The safety and tolerability of olaparib when given in combination with abiraterone was assessed during Part B of the study. The percentage of patients experiencing AEs, including information on seriousness, severity, study treatment relationship and those leading to discontinuation for all doses of olaparib and for abiraterone are presented. Severity of AEs was assessed using the NCI Common Terminology CTCAE v4.0. AEs were assigned to a Grade from 1 through 5 as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. 'c-r' = causally related. 'discont' = discontinuation. 'ola/pla' = olaparib/placebo.
• Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels [ Time Frame: From baseline, then every 4 weeks up to Week 52, and then every 12 weeks. ]
  The best percentage change from baseline in PSA levels was determined to assess the anti-tumour activity of olaparib when given in addition to abiraterone, compared with placebo given in addition to abiraterone. The best percentage change was defined as the biggest reduction in PSA level compared with baseline or smallest increase in the absence of a decrease.
• Part B: Percentage of Patients With PSA Responses [ Time Frame: From baseline, then every 4 weeks up to Week 24, and then every 12 weeks. ]
  The percentages of patients with single visit responses and with confirmed responses are presented to assess the anti-tumour activity of olaparib when given in addition to abiraterone, compared with placebo given in addition to abiraterone. A single visit response was defined as any post-dose visit PSA level reduced by 50% or more compared with baseline. A confirmed response was defined as a reduction in PSA level of 50% or more on 2 consecutive occasions at least 4 weeks apart compared with baseline. Patients may have had more than 1 single visit response or confirmed response but were counted once.
• Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level [ Time Frame: From baseline, then every 4 weeks up to Week 24, and then every 12 weeks. ]
  The median best percentage change from baseline in CTC levels was determined to assess the anti-tumour activity of olaparib when given in combination with abiraterone, compared with placebo given in addition to abiraterone. The best percentage change was defined as the biggest CTC level reduction compared with baseline or smallest increase in the absence of a decrease.
• Part B: Percentage of Patients With at Least One Objective Response (Objective Response Rate [ORR]) [ Time Frame: From baseline, then every 4 weeks up to Week 52, and then every 12 weeks. ]
  The overall radiological ORR was calculated to assess the anti-tumour activity of olaparib in combination with abiraterone, compared with placebo in combination with abiraterone. The best overall ORR was defined as the percentage of patients with at least 1 visit response of complete response (CR) or partial response (PR) in soft tissue disease assessed by RECIST 1.1 and also bone scan status of non-progressive disease or non-evaluable for their bone scans assessed by PCWG-2. CR: Disappearance of all target lesions. Reduction of pathological lymph nodes to <10 millimetres. PR: At least a 30% decrease in the sum of diameters of target lesions from baseline. The percentage of patients with a response is presented.
• Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST) [ Time Frame: From randomisation until analysis cut-off date (up to approximately 3 years). ]
  The TFST and TSST were determined to assess the anti-tumour activity of olaparib when given in combination with abiraterone, compared with placebo given in addition to abiraterone. TFST was defined as the time from randomisation to the earlier of first subsequent anti-cancer therapy start date following study treatment discontinuation, or death. TSST was defined as the time from randomisation to the earlier of the second subsequent anti-cancer therapy start date following study treatment discontinuation, or death.
• Part B: Median Overall Survival (OS) [ Time Frame: From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months. ]
  OS was determined to assess the efficacy of olaparib when given in addition to abiraterone, compared with placebo given in addition to abiraterone. OS was performed at the time of the analysis of rPFS, and the median OS, calculated using the Kaplan-Meier technique, is presented.
• Part B: Median Time to Second Progression or Death (PFS2) [ Time Frame: From randomisation until analysis cut-off date (up to approximately 3 years). ]
  The efficacy of olaparib when given in combination with abiraterone was assessed by PFS2, defined by local standard clinical practice and included objective radiological progression by RECIST 1.1 (soft tissue), symptomatic progression, rise in PSA level or death in the absence of overall progression.

Original Secondary Outcome Measures (submitted: October 24, 2013)

• Part A: Olaparib and abiraterone PK parameters: AUCss. Cmax ss, tmax ss, Cmin ss. [ Time Frame: Up to 14 days. ]
  Treatment ratios for abiraterone steady state Cmax and AUC (in combination : alone) and olaparib steady state Cmax and AUC (in combination : alone) will be calculated to assess the drug -drug interaction potential between olaparib and abiraterone.
• Part B: Overall survival (OS). [ Time Frame: 37 months. ]
  Overall survival is defined as the time from the date of randomisation until death due to any cause.
• Part B: The time to second progression (PFS2) [ Time Frame: 37 months. ]
  PFS2. Progression defined by local standard clinical practice. May involve any of: objective radiological progression, symptomatic progression, PSA or death.
• Part B: Response to treatment as shown by Overall Response Rates (ORR), changes in PSA levels, change in CTC levels over time and measurement of time to requiring further prostate cancer treatment [ Time Frame: 37 months ]
  Malignant soft tissue response and overall radiological response [malignant soft tissue response by RECIST 1.1 and overall radiological response by RECIST 1.1 and PCWG-2]).
• Part B: To evaluate the safety, tolerability of daily olaparib when given in addition to abiraterone and prednisolone [ Time Frame: 37 months ]
  The parameters describing the safety and tolerability of olaparib will include:

  • The percentage of patients with adverse events by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) (version 4.03) grade;
  • The percentage of patients with serious adverse events;
  • The percentage of patients who discontinue olaparib due to adverse events or serious adverse events;

  Assessment of AEs graded by CTCAE v4.0. Clinical chemistry and haematological laboratory tests and vital signs also evaluated.
• Part B: ERG expression/fusion status [ Time Frame: 37 months ]
  Where possible patient ERG expression/fusion will be assessed and association between this and treatment efficacy will be examined.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: October 24, 2013)

• Change in HRQL [ Time Frame: 37 months ]
  Assessed using FACT-P.
• Change in pain and other prostate cancer related symptoms [ Time Frame: 37 months ]
  Assessed using FACT-P and BPI-SF.
• Health state utility index [ Time Frame: 37 months ]
  Assessed Using EQ-5D-5L health state utility index.

Descriptive Information

• Brief Title: Ph II Study to Evaluate Olaparib With Abiraterone in Treating Metastatic Castration Resistant Prostate Cancer.
• Official Title: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Phase II Study to Compare the Efficacy, Safety and Tolerability of Olaparib Versus Placebo When Given in Addition to Abiraterone Treatment in Patients With Metastatic Castrate-Resistant Prostate Cancer Who Have Received Prior Chemotherapy Containing Docetaxel
• Brief 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Metastatic Castration-resistant Prostate Cancer

Intervention

• Drug: Olaparib
  Olaparib bid
  Other Name: PARP inhibition
• Drug: Placebo
  Placebo bid
  Other Name: Placebo to PARP inhibition
• Drug: Abiraterone
  Abiraterone 1000 mg
• Drug: Prednisone or prednisolone
  Prednisone or prednisolone 5 mg bid will be co-administered with the abiraterone in this study.

Study Arms

• Active Comparator: Olaparib
  200 mg or 300 mg bid
  Interventions:

  • Drug: Olaparib
  • Drug: Abiraterone
  • Drug: Prednisone or prednisolone
• Placebo Comparator: Placebo
  placebo to match olaparib bid
  Interventions:

  • Drug: Placebo
  • Drug: Abiraterone
  • Drug: Prednisone or prednisolone

Publications *

• Clarke N, Wiechno P, Alekseev B, Sala N, Jones R, Kocak I, Chiuri VE, Jassem J, Flechon A, Redfern C, Goessl C, Burgents J, Kozarski R, Hodgson D, Learoyd M, Saad F. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):975-986. doi: 10.1016/S1470-2045(18)30365-6. Epub 2018 Jun 4.
• Saad F, Thiery-Vuillemin A, Wiechno P, Alekseev B, Sala N, Jones R, Kocak I, Chiuri VE, Jassem J, Flechon A, Redfern C, Kang J, Burgents J, Gresty C, Degboe A, Clarke NW. Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2022 Oct;23(10):1297-1307. doi: 10.1016/S1470-2045(22)00498-3. Epub 2022 Sep 2. Erratum In: Lancet Oncol. 2022 Oct;23(10):e446.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 22, 2019): 158
• Original Estimated Enrollment (submitted: October 24, 2013): 170
• Actual Study Completion Date: August 24, 2023
• Actual Primary Completion Date: September 22, 2017 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Czechia, France, Italy, Netherlands, Poland, Russian Federation, Spain, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01972217
• Other Study ID Numbers: D081DC00008; UVA97934 ( Other Identifier: Quintiles ); 2013-003520-37 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: October 2023