Metastatic Castration-resistant Prostate Cancer
Conditions
Keywords
Olaparib, castration-resistant, metastatic prostate cancer, Prior Docetaxel Chemotherapy
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.
Interventions
DRUGOlaparib
Olaparib bid
DRUGPlacebo
Placebo bid
DRUGAbiraterone
Abiraterone 1000 mg
Prednisone or prednisolone 5 mg bid will be co-administered with the abiraterone in this study.
Sponsors
Merck Sharp & Dohme LLC
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 130 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Percentage of Patients Experiencing Adverse Events (AEs) | 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) | 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 | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A PK: Abiraterone Cmax,ss | 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) | 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 | 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) | 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 | 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) | 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 | 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 | 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 | 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 | 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 | 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]) | 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) | 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) | 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) | 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. |
| Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss) | 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. |
Countries
Belgium, Canada, Czechia, France, Italy, Netherlands, Poland, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
In this 2-part study, patients with metastatic castrate-resistant prostate cancer (mCRPC) were recruited at 41 sites in Europe, Russia and North America. Part A had 2 cohorts for olaparib dose selection when given with approved treatment abiraterone. Part B compared olaparib versus placebo both with abiraterone in post-chemotherapy mCRPC patients.
Pre-assignment details
Patients dosed in open-label Part A could not participate in Part B which was a randomised, double-blind, placebo-controlled comparison of olaparib + abiraterone versus placebo + abiraterone in patients who had received prior chemotherapy containing docetaxel.
Participants by arm
| Arm | Count |
|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone Patients received olaparib 200 mg bid and abiraterone 1000 mg once daily. Patients were assessed at Weeks 1, 2 and 4, then every 4 weeks up to Week 52, and every 12 weeks thereafter.
Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment. | 3 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone If the combination of olaparib 200 mg + abiraterone 1000 mg was well tolerated (determined after a minimum of 14 days treatment in Cohort 1), patients were recruited into Cohort 2.
Cohort 2 Group 1: patients received olaparib 300 mg bid alone for 3 to 7 days. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 5 days.
Cohort 2 Group 2: patients received abiraterone 1000 mg once daily alone for 5 to 7 days. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 3 days.
Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment. | 13 |
| Part B: Olaparib + Abiraterone Patients received the selected dose of olaparib 300 mg bid + abiraterone 1000 mg once daily. Patients were assessed every 4 weeks up to Week 52, and every 12 weeks thereafter.
Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment. | 71 |
| Part B: Placebo + Abiraterone Patients received placebo bid + abiraterone 1000 mg once daily. Patients were assessed every 4 weeks up to Week 52, and every 12 weeks thereafter.
Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment. | 71 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A: Open-label Safety Run-in Period | Adverse Event | 0 | 1 | 0 | 0 |
| Part A: Open-label Safety Run-in Period | Condition under investigation worsened | 1 | 9 | 0 | 0 |
| Part A: Open-label Safety Run-in Period | Death | 0 | 1 | 0 | 0 |
| Part A: Open-label Safety Run-in Period | Withdrawal by Subject | 0 | 1 | 0 | 0 |
| Part B Double-blind, Randomised Period | Death | 0 | 0 | 43 | 44 |
| Part B Double-blind, Randomised Period | Lost to Follow-up | 0 | 0 | 2 | 1 |
| Part B Double-blind, Randomised Period | Reason not recorded | 0 | 0 | 1 | 0 |
| Part B Double-blind, Randomised Period | Screen failure | 0 | 0 | 0 | 1 |
| Part B Double-blind, Randomised Period | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Olaparib + Abiraterone | Part B: Placebo + Abiraterone | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 10 Participants | 54 Participants | 49 Participants | 116 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 3 Participants | 17 Participants | 22 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 11 Participants | 5 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 13 Participants | 58 Participants | 63 Participants | 136 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) White | 3 Participants | 13 Participants | 67 Participants | 67 Participants | 150 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 13 Participants | 71 Participants | 71 Participants | 158 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 13 | 43 / 71 | 45 / 71 |
| other Total, other adverse events | 3 / 3 | 7 / 13 | 63 / 71 | 52 / 71 |
| serious Total, serious adverse events | 2 / 3 | 3 / 13 | 25 / 71 | 14 / 71 |
Outcome results
Primary
Part A: Number of Patients With Dose Limiting Toxicities (DLTs)
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.
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.
Population: The Part A Safety analysis set consisted of all patients who received at least 1 dose of study treatment in Part A. Treatment group comparisons were based on the initial dose of olaparib actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Number of Patients With Dose Limiting Toxicities (DLTs) | 2 Patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Number of Patients With Dose Limiting Toxicities (DLTs) | 4 Patients |
Primary
Part A: Percentage of Patients Experiencing Adverse Events (AEs)
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.
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.
Population: The Part A Safety analysis set consisted of all patients who received at least 1 dose of study treatment in Part A. Treatment group comparisons were based on the initial dose of olaparib actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE CTCAE Grade 3 or higher c-r to olaparib | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE CTCAE Grade 3 or higher c-r to abiraterone | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE with outcome = death | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any serious AE (SAE) | 66.7 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any SAE c-r to olaparib | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any SAE c-r to abiraterone | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE causing discont of olaparib | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE causing discont of olaparib c-r to olaparib | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE causing discont olaparib c-r to abiraterone | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE c-r to olaparib + abiraterone | 66.7 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE c-r to olaparib only | 33.3 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE c-r to abiraterone only | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE CTCAE Grade 3 or higher | 66.7 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE c-r to olaparib only | 7.7 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE causing discont of olaparib c-r to olaparib | 0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE CTCAE Grade 3 or higher c-r to abiraterone | 7.7 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE CTCAE Grade 3 or higher | 23.1 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE with outcome = death | 0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE causing discont olaparib c-r to abiraterone | 0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any serious AE (SAE) | 23.1 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE c-r to abiraterone only | 15.4 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any SAE c-r to olaparib | 0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE c-r to olaparib + abiraterone | 46.2 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any SAE c-r to abiraterone | 0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE CTCAE Grade 3 or higher c-r to olaparib | 7.7 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A: Percentage of Patients Experiencing Adverse Events (AEs) | Any AE causing discont of olaparib | 7.7 Percentage of patients |
Primary
Part B: Median Radiological Progression-Free Survival (rPFS) Time
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).
Time frame: From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months.
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Median Radiological Progression-Free Survival (rPFS) Time | 13.8 Months |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Median Radiological Progression-Free Survival (rPFS) Time | 8.2 Months |
Primary
Part B: Percentage of Patients With Progression Events or Death (rPFS)
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.
Time frame: From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months.
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients With Progression Events or Death (rPFS) | 64.8 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients With Progression Events or Death (rPFS) | 76.1 Percentage of patients |
Comparison: The 1-sided p-value provides a test for rejecting the null hypothesis of no treatment effect versus the superiority alternative that patients on olaparib have a lower risk of progression compared with placebo.p-value: 0.01795% CI: [0.438, 0.969]Log Rank
Secondary
Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST)
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.
Time frame: From randomisation until analysis cut-off date (up to approximately 3 years).
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST) | TFST | 13.5 Months |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST) | TSST | 19.6 Months |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST) | TFST | 9.7 Months |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST) | TSST | 18.0 Months |
Comparison: Olapatib + abiraterone versus placebo + abiraterone: TFSTp-value: 0.09595% CI: [0.54, 1.13]Log Rank
Comparison: Olaparib + abiraterone versus placebo + abiraterone: TSSTp-value: 0.14795% CI: [0.545, 1.201]Log Rank
Secondary
Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss)
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.
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.
Population: The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss) | Olaparib alone | 7.781 micrograms per millilitre (mcg/mL) | Geometric Coefficient of Variation 25.06 |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss) | Olaparib + abiraterone | 6.504 micrograms per millilitre (mcg/mL) | Geometric Coefficient of Variation 20.9 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss) | Olaparib + abiraterone | 7.724 micrograms per millilitre (mcg/mL) | Geometric Coefficient of Variation 28.05 |
Secondary
Part A PK: Abiraterone AUCss
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.
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.
Population: The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK: Abiraterone AUCss | Olaparib + abiraterone | 718.9 ng*h/mL | Geometric Coefficient of Variation 102 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK: Abiraterone AUCss | Abiraterone alone | 825.5 ng*h/mL | Geometric Coefficient of Variation 105.5 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK: Abiraterone AUCss | Olaparib + abiraterone | 524.6 ng*h/mL | Geometric Coefficient of Variation 37.65 |
Secondary
Part A PK: Abiraterone Cmax,ss
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.
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.
Population: The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK: Abiraterone Cmax,ss | Olaparib + abiraterone | 130.7 nanograms per millilitre (ng/mL) | Geometric Coefficient of Variation 68.87 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK: Abiraterone Cmax,ss | Abiraterone alone | 145.8 nanograms per millilitre (ng/mL) | Geometric Coefficient of Variation 135.5 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK: Abiraterone Cmax,ss | Olaparib + abiraterone | 86.12 nanograms per millilitre (ng/mL) | Geometric Coefficient of Variation 48.88 |
Secondary
Part A PK: Abiraterone Cmin,ss
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.
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.
Population: The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK: Abiraterone Cmin,ss | Olaparib + abiraterone | 7.983 ng/mL | Geometric Coefficient of Variation 163.3 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK: Abiraterone Cmin,ss | Abiraterone alone | 8.376 ng/mL | Geometric Coefficient of Variation 96.52 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK: Abiraterone Cmin,ss | Olaparib + abiraterone | 6.358 ng/mL | Geometric Coefficient of Variation 50.96 |
Secondary
Part A PK: Abiraterone Tmax,ss
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.
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.
Population: The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK: Abiraterone Tmax,ss | Olaparib + abiraterone | 3.000 Hours |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK: Abiraterone Tmax,ss | Abiraterone alone | 2.525 Hours |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK: Abiraterone Tmax,ss | Olaparib + abiraterone | 2.500 Hours |
Secondary
Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss)
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.
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.
Population: The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss) | Olaparib alone | 45.27 mcg*h/mL | Geometric Coefficient of Variation 31.89 |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss) | Olaparib + abiraterone | 40.83 mcg*h/mL | Geometric Coefficient of Variation 11.47 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss) | Olaparib + abiraterone | 49.51 mcg*h/mL | Geometric Coefficient of Variation 37.3 |
Secondary
Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss)
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.
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.
Population: The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss) | Olaparib alone | 1.264 mcg/mL | Geometric Coefficient of Variation 46.58 |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss) | Olaparib + abiraterone | 0.9170 mcg/mL | Geometric Coefficient of Variation 31.56 |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss) | Olaparib + abiraterone | 1.279 mcg/mL | Geometric Coefficient of Variation 65.36 |
Secondary
Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (Tmax,ss)
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.
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.
Population: The PK analysis set consisted of all patients who received at least 1 dose of olaparib per the protocol, for whom there was at least 1 reportable PK concentration and who had no important protocol deviations or AEs that impacted on PK on all PK sampling days. Only patients with data available for analysis at each time point are presented.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (Tmax,ss) | Olaparib alone | 2.000 Hours (h) |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (Tmax,ss) | Olaparib + abiraterone | 2.080 Hours (h) |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (Tmax,ss) | Olaparib + abiraterone | 2.000 Hours (h) |
Secondary
Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level
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.
Time frame: From baseline, then every 4 weeks up to Week 24, and then every 12 weeks.
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received. Only patients with data available for analysis are presented.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level | -1.0 Percentage change in CTC level |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level | -1.0 Percentage change in CTC level |
Secondary
Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels
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.
Time frame: From baseline, then every 4 weeks up to Week 52, and then every 12 weeks.
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received. Only patients with data available for analysis are presented.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels | -54.16 Percentage change in PSA level |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels | -49.85 Percentage change in PSA level |
Secondary
Part B: Median Overall Survival (OS)
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.
Time frame: From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months.
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Median Overall Survival (OS) | 22.7 Months |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Median Overall Survival (OS) | 20.9 Months |
p-value: 0.33195% CI: [0.6, 1.384]Log Rank
Secondary
Part B: Median Time to Second Progression or Death (PFS2)
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.
Time frame: From randomisation until analysis cut-off date (up to approximately 3 years).
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Median Time to Second Progression or Death (PFS2) | 23.3 Months |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Median Time to Second Progression or Death (PFS2) | 18.5 Months |
p-value: 0.1495% CI: [0.511, 1.215]Log Rank
Secondary
Part B: Percentage of Patients Experiencing AEs
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.
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).
Population: Part B safety analysis set consisted of all patients randomised into Part B of the study who received at least 1 dose of olaparib/placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE causing discont treatment c-r abiraterone | 8.5 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE c-r to ola/pla + abiraterone | 45.1 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE c-r to ola/pla only | 18.3 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE c-r to abiraterone only | 1.4 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE CTCAE Grade 3 or higher | 53.5 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE CTCAE Grade 3 or higher c-r to ola/pla | 23.9 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE CTCAE Grade 3 or higher c-r to abiraterone | 16.9 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE with outcome = death | 5.6 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE with outcome = death c-r to ola/pla | 1.4 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE with outcome = death c-r to abiraterone | 0 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any SAE | 35.2 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any SAE c-r to ola/pla | 9.9 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any SAE c-r to abiraterone | 5.6 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE causing discont of ola/pla | 29.6 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE causing discont of treatment c-r to ola/pla | 16.9 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE causing discont of ola/pla | 9.9 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any SAE c-r to abiraterone | 0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE causing discont treatment c-r abiraterone | 1.4 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any SAE c-r to ola/pla | 1.4 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE c-r to ola/pla + abiraterone | 12.7 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE with outcome = death c-r to ola/pla | 0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE c-r to ola/pla only | 9.9 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE with outcome = death | 1.4 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE c-r to abiraterone only | 7.0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE with outcome = death c-r to abiraterone | 0 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE CTCAE Grade 3 or higher | 28.2 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE causing discont of treatment c-r to ola/pla | 5.6 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE CTCAE Grade 3 or higher c-r to ola/pla | 5.6 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any SAE | 19.7 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients Experiencing AEs | Any AE CTCAE Grade 3 or higher c-r to abiraterone | 1.4 Percentage of patients |
Secondary
Part B: Percentage of Patients With at Least One Objective Response (Objective Response Rate [ORR])
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.
Time frame: From baseline, then every 4 weeks up to Week 52, and then every 12 weeks.
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received. Only patients with data available for analysis are presented. Only patients with measurable disease at baseline are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients With at Least One Objective Response (Objective Response Rate [ORR]) | 27.3 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients With at Least One Objective Response (Objective Response Rate [ORR]) | 31.6 Percentage of patients |
p-value: 0.30995% CI: [0.285, 2.261]Regression, Logistic
Secondary
Part B: Percentage of Patients With PSA Responses
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.
Time frame: From baseline, then every 4 weeks up to Week 24, and then every 12 weeks.
Population: The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients With PSA Responses | Single visit response | 50.7 Percentage of patients |
| Part A Cohort 1: Olaparib 200 mg + Abiraterone | Part B: Percentage of Patients With PSA Responses | Confirmed response | 47.9 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients With PSA Responses | Single visit response | 47.9 Percentage of patients |
| Part A Cohort 2: Olaparib 300 mg + Abiraterone | Part B: Percentage of Patients With PSA Responses | Confirmed response | 42.3 Percentage of patients |