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Clinical Trial Results:
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

Summary
EudraCT number	2013-003520-37
Trial protocol	GB BE NL CZ ES IT FR
Global end of trial date	24 Aug 2023

Results information
Results version number	v1(current)
This version publication date	26 Nov 2023
First version publication date	26 Nov 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

D081DC00008

ISRCTN number

US NCT number

NCT01972217

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

One MedImmune Way, Gaithersburg, United States, MD 20878

Public contact

Medical Director, AstraZeneca, +1 3028851180, ClinicalTrialTransparency@astrazeneca.com

Scientific contact

Medical Director, AstraZeneca, +1 3028851180, ClinicalTrialTransparency@astrazeneca.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

22 Sep 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Sep 2017

Global end of trial reached?

Yes

Global end of trial date

24 Aug 2023

Was the trial ended prematurely?

Main objective of the trial

In Part A, to assess the safety and tolerability of olaparib twice daily (bid) administration when given in addition to abiraterone and to recommend, by assessment of dose-limiting toxicities (DLTs) and other safety and tolerability data, a dose of olaparib for further study when given in addition to abiraterone. In Part B, to compare the efficacy of olaparib when given in addition to abiraterone, with placebo given in addition to abiraterone.

Protection of trial subjects

This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council on Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.

Background therapy

Patients received abiraterone 1000 milligrams (mg) once daily. Abiraterone is indicated in combination with prednisone or prednisolone 5 mg once daily for the treatment of patients with metastatic castrate-resistant prostate cancer (mCRPC).

Evidence for comparator

Actual start date of recruitment

01 Apr 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 24

Country: Number of subjects enrolled

United Kingdom: 27

Country: Number of subjects enrolled

Italy: 17

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

Czechia: 13

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Russian Federation: 31

Country: Number of subjects enrolled

Poland: 19

Country: Number of subjects enrolled

United States: 2

Worldwide total number of subjects

158

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

114

85 years and over

Subject disposition

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Recruitment details

In this 2-part study, patients with 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.

Screening 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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Part A Cohort 1: Olaparib 200 mg + abiraterone

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Olaparib

Investigational medicinal product code

AZD2281

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 200 mg olaparib bid, administered as 2 x 100 mg tablets.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

Other name

Prednisone

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 5 mg prednisolone or prednisone once daily as indicated with abiraterone treatment for mCRPC.

Investigational medicinal product name

Abiraterone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 1000 mg abiraterone once daily, administered as 4 x 250 mg tablets.

Part A Cohort 2: Olaparib 300 mg + abiraterone

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Olaparib

Investigational medicinal product code

AZD2281

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 300 mg olaparib bid, administered as 3 x 100 mg tablets or 2 x 150 mg tablets.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

Other name

Prednisone

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 5 mg prednisolone or prednisone once daily as indicated with abiraterone treatment for mCRPC.

Investigational medicinal product name

Abiraterone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 1000 mg abiraterone once daily, administered as 4 x 250 mg tablets.

Part B: Olaparib + abiraterone

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Olaparib

Investigational medicinal product code

AZD2281

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 300 mg olaparib bid, administered as 3 x 100 mg tablets or 2 x 150 mg tablets.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

Other name

Prednisone

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 5 mg prednisolone or prednisone once daily as indicated with abiraterone treatment for mCRPC.

Investigational medicinal product name

Abiraterone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 1000 mg abiraterone once daily, administered as 4 x 250 mg tablets.

Part B: Placebo + abiraterone

Arm description

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.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received placebo to match olaparib 100 mg or 150 mg tablets.

Investigational medicinal product name

Abiraterone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 1000 mg abiraterone once daily, administered as 4 x 250 mg tablets.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

Other name

Prednisone

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 5 mg prednisolone or prednisone once daily as indicated with abiraterone treatment for mCRPC.

Number of subjects in period 1	Part A Cohort 1: Olaparib 200 mg + abiraterone	Part A Cohort 2: Olaparib 300 mg + abiraterone	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Started	3	13	71	71
Completed	2	1	25	24
Not completed	1	12	46	47
Reason not recorded	-	-	1	-
Adverse event, non-fatal	-	1	-	-
Death	-	1	43	44
Condition under investigation worsened	1	9	-	-
Screen failure	-	-	-	1
Lost to follow-up	-	-	2	1
Withdrawal by patient	-	1	-	1

Baseline characteristics

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Reporting group title

Part A Cohort 1: Olaparib 200 mg + abiraterone

Reporting group description

Reporting group title

Part A Cohort 2: Olaparib 300 mg + abiraterone

Reporting group description

Reporting group title

Part B: Olaparib + abiraterone

Reporting group description

Reporting group title

Part B: Placebo + abiraterone

Reporting group description

Reporting group values	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
Number of subjects	3	13	71	71	158
Age Categorical
Units: Subjects
In Utero	0	0	0	0	0
Preterm newborn- gestational age < 37 wk	0	0	0	0	0
Newborns (0-27days)	0	0	0	0	0
Infants and toddlers (28days - 23months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
From 18 - 64 years	0	3	17	22	42
From 65 - 84 years	3	9	53	49	114
Over 85 years	0	1	1	0	2
Sex: Female, Male
Units: Subjects
Female	0	0	0	0	0
Male	3	13	71	71	158
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	1	0	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	0	1	1	2
White	3	13	67	67	150
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	2	3	5
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	0	11	5	17
Not Hispanic or Latino	2	13	58	63	136
Unknown or Not Reported	0	0	2	3	5

End points

Top of page

Reporting group title

Part A Cohort 1: Olaparib 200 mg + abiraterone

Reporting group description

Reporting group title

Part A Cohort 2: Olaparib 300 mg + abiraterone

Reporting group description

Reporting group title

Part B: Olaparib + abiraterone

Reporting group description

Reporting group title

Part B: Placebo + abiraterone

Reporting group description

Subject analysis set title

Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients received olaparib 300 mg bid alone for 3 to 7 days to determine the steady state PK profile for olaparib. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 5 days to determine the PK profiles of both olaparib and abiraterone. Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Subject analysis set title

Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients received abiraterone 1000 mg once daily alone for 5 to 7 days to determine the steady state PK profile for abiraterone. Patients then received olaparib 300 mg bid and abiraterone 1000 mg once daily for at least 3 days to determine the PK profiles of both olaparib and abiraterone. Patients also received prednisone or prednisolone 5 mg bid in combination with the abiraterone treatment.

Primary: Part A: Percentage of Patients Experiencing Adverse Events (AEs)

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End point title

Part A: Percentage of Patients Experiencing Adverse Events (AEs) ^[1] ^[2]

End point description

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. The Part A Safety analysis set consisted of all patients who received at least 1 dose of study treatment in Part A.

End point type

Primary

End point timeframe

Cohort 1 and 2: From Baseline in Part A (Day 1 for each cohort) up to 30 days following last dose of study treatment (up to approximately 3 years).

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Part A was a safety run where safety and tolerability were assessed. Thus, no statistical analyses was required.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part A was a safety run where safety and tolerability were assessed. Thus, no statistical analyses was required.

End point values	Part A Cohort 1: Olaparib 200 mg + abiraterone	Part A Cohort 2: Olaparib 300 mg + abiraterone
Number of subjects analysed	3	13
Units: Percentage of patients
number (not applicable)
Any AE c-r to olaparib + abiraterone	66.7	46.2
Any AE c-r to olaparib only	33.3	7.7
Any AE c-r to abiraterone only	0	15.4
Any AE CTCAE Grade 3 or higher	66.7	23.1
Any AE CTCAE Grade 3 or higher c-r to olaparib	0	7.7
Any AE CTCAE Grade 3 or higher c-r to abiraterone	0	7.7
Any AE with outcome = death	0	0
Any serious AE (SAE)	66.7	23.1
Any SAE c-r to olaparib	0	0
Any SAE c-r to abiraterone	0	0
Any AE causing discont of olaparib	0	7.7
Any AE causing discont c-r to olaparib	0	0
Any AE causing discont c-r to abiraterone	0	0

No statistical analyses for this end point

Primary: Part A: Number of Patients with DLTs

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End point title

Part A: Number of Patients with DLTs ^[3] ^[4]

End point description

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.

End point type

Primary

End point timeframe

From Day 1 for Cohort 1 and from Day 4 for Cohort 2 up to 14 days treatment with olaparib + abiraterone for 3 patients.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Part A was a safety run where safety and tolerability were assessed. Thus, no statistical analyses was required.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part A was a safety run where safety and tolerability were assessed. Thus, no statistical analyses was required.

End point values	Part A Cohort 1: Olaparib 200 mg + abiraterone	Part A Cohort 2: Olaparib 300 mg + abiraterone
Number of subjects analysed	3	13
Units: Patients
number (not applicable)	2	4

No statistical analyses for this end point

Primary: Part B: Median Radiological Progression-Free Survival (rPFS) Time

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End point title

Part B: Median Radiological Progression-Free Survival (rPFS) Time ^[5] ^[6]

End point description

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).

End point type

Primary

End point timeframe

From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months.

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only the Median which is a descriptive measure was presented here. Hence, no statistical analysis is needed here.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only the Median which is a descriptive measure was presented here. Hence, no statistical analysis is needed here.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	71	71
Units: Months
median (confidence interval 95%)	13.8 (10.8 to 20.4)	8.2 (5.5 to 9.7)

No statistical analyses for this end point

Primary: Part B: Percentage of Patients with Progression Events or Death (rPFS)

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End point title

Part B: Percentage of Patients with Progression Events or Death (rPFS) ^[7]

End point description

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.

End point type

Primary

End point timeframe

From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	71	71
Units: Percentage of patients
number (not applicable)	64.8	76.1

Comparison of rPFS

Statistical analysis description

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.

Comparison groups

Part B: Olaparib + abiraterone v Part B: Placebo + abiraterone

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.651

Confidence interval

level

95%

sides

2-sided

lower limit

0.438

upper limit

0.969

Secondary: Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss)

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End point title

Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss)

End point description

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. 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.

End point type

Secondary

End point timeframe

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.

End point values	Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone	Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone
Number of subjects analysed	6	6 ^[8]
Units: micrograms per millilitre (mcg/mL)
geometric mean (geometric coefficient of variation)
Olaparib alone (n=6, n=0)	7.781 ( 25.06 )	9999999 ( 99999999 )
Olaparib + abiraterone (n=5, n=6)	6.504 ( 20.90 )	7.724 ( 28.05 )

Notes
[8] - Cohort 2 Group 2 did not receive olaparib alone.

No statistical analyses for this end point

Secondary: Part A PK: Abiraterone Cmax,ss

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End point title

Part A PK: Abiraterone Cmax,ss

End point description

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. 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.

End point type

Secondary

End point timeframe

End point values	Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone	Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone
Number of subjects analysed	6 ^[9]	6
Units: nanograms per millilitre (ng/mL)
geometric mean (geometric coefficient of variation)
Abiraterone alone (n=0, n=6)	99999999 ( 99999999 )	145.8 ( 135.5 )
Olaparib + abiraterone (n=6, n=4)	130.7 ( 68.87 )	86.12 ( 48.88 )

Notes
[9] - Cohort 2 Group 1 did not receive abiraterone alone.

No statistical analyses for this end point

Secondary: Part A PK: Abiraterone tmax,ss

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End point title

Part A PK: Abiraterone tmax,ss

End point description

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. 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.

End point type

Secondary

End point timeframe

End point values	Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone	Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone
Number of subjects analysed	6 ^[10]	6
Units: Hours
median (full range (min-max))
Abiraterone alone (n=0, n=6)	99999999 (99999999 to 99999999)	2.525 (1.00 to 3.00)
Olaparib + abiraterone (n=6, n=4)	3.000 (1.08 to 3.00)	2.500 (2.00 to 3.02)

Notes
[10] - Cohort 2 Group 1 did not receive abiraterone alone.

No statistical analyses for this end point

Secondary: Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (tmax,ss)

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End point title

Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (tmax,ss)

End point description

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. 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.

End point type

Secondary

End point timeframe

End point values	Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone	Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone
Number of subjects analysed	6	6 ^[11]
Units: Hours (h)
median (full range (min-max))
Olaparib alone (n=6, n=0)	2.000 (1.00 to 2.17)	99999999 (99999999 to 99999999)
Olaparib + abiraterone (n=5, n=6)	2.080 (2.00 to 4.00)	2.000 (0.500 to 3.02)

Notes
[11] - Cohort 2 Group 2 did not receive olaparib alone.

No statistical analyses for this end point

Secondary: Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss)

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End point title

Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss)

End point description

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. 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.

End point type

Secondary

End point timeframe

End point values	Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone	Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone
Number of subjects analysed	6	6 ^[12]
Units: mcg/mL
geometric mean (geometric coefficient of variation)
Olaparib alone (n=6, n=0)	1.264 ( 46.58 )	99999999 ( 99999999 )
Olaparib + abiraterone (n=5, n=6)	0.9170 ( 31.56 )	1.279 ( 65.36 )

Notes
[12] - Cohort 2 Group 2 did not receive olaparib alone.

No statistical analyses for this end point

Secondary: Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss)

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End point title

Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss)

End point description

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. 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.

End point type

Secondary

End point timeframe

End point values	Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone	Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone
Number of subjects analysed	6	6 ^[13]
Units: mcg*h/mL
geometric mean (geometric coefficient of variation)
Olaparib alone (n=6, n=0)	45.27 ( 31.89 )	99999999 ( 99999999 )
Olaparib + abiraterone (n=5, n=6)	40.83 ( 11.47 )	49.51 ( 37.30 )

Notes
[13] - Cohort 2 Group 2 did not receive olaparib alone.

No statistical analyses for this end point

Secondary: Part A PK: Abiraterone Cmin,ss

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End point title

Part A PK: Abiraterone Cmin,ss

End point description

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. 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.

End point type

Secondary

End point timeframe

End point values	Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone	Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone
Number of subjects analysed	6 ^[14]	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Abiraterone alone (n=0, n=6)	99999999 ( 99999999 )	8.376 ( 96.52 )
Olaparib + abiraterone (n=6, n=4)	7.983 ( 163.3 )	6.358 ( 50.96 )

Notes
[14] - Cohort 2 Group 1 did not receive abiraterone alone.

No statistical analyses for this end point

Secondary: Part B: Percentage of Patients Experiencing AEs

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End point title

Part B: Percentage of Patients Experiencing AEs ^[15]

End point description

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 safety analysis set consisted of all patients randomised into Part B of the study who received at least 1 dose of olaparib/placebo.

End point type

Secondary

End point timeframe

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).

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	71	71
Units: Percentage of patients
number (not applicable)
Any AE c-r to ola/pla + abiraterone	45.1	12.7
Any AE c-r to ola/pla only	18.3	9.9
Any AE c-r to abiraterone only	1.4	7.0
Any AE CTCAE Grade 3 or higher	53.5	28.2
Any AE CTCAE Grade 3 or higher c-r to ola/pla	23.9	5.6
Any AE CTCAE Grade 3 or higher c-r to abiraterone	16.9	1.4
Any AE with outcome = death	5.6	1.4
Any AE with outcome = death c-r to ola/pla	1.4	0
Any AE with outcome = death c-r to abiraterone	0	0
Any SAE	35.2	19.7
Any SAE c-r to ola/pla	9.9	1.4
Any SAE c-r to abiraterone	5.6	0
Any AE causing discont of ola/pla	29.6	9.9
Any AE causing discont c-r to ola/pla	16.9	5.6
Any AE causing discont c-r abiraterone	8.5	1.4

No statistical analyses for this end point

Secondary: Part A PK: Abiraterone AUCss

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End point title

Part A PK: Abiraterone AUCss

End point description

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. 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.

End point type

Secondary

End point timeframe

End point values	Part A Cohort 2 Group 1: Olaparib, olaparib + abiraterone	Part A Cohort 2 Group 2: Abiraterone, olaparib + abiraterone
Number of subjects analysed	6 ^[16]	6
Units: ng*h/mL
geometric mean (geometric coefficient of variation)
Abiraterone alone (n=0, n=6)	99999999 ( 99999999 )	825.5 ( 105.5 )
Olaparib + abiraterone (n=6, n=4)	718.9 ( 102.0 )	524.6 ( 37.65 )

Notes
[16] - Cohort 2 Group 1 did not receive abiraterone alone.

No statistical analyses for this end point

Secondary: Part B: Percentage of Patients With PSA Responses

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End point title

Part B: Percentage of Patients With PSA Responses ^[17]

End point description

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. The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.

End point type

Secondary

End point timeframe

From baseline, then every 4 weeks up to Week 52, and then every 12 weeks.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	71	71
Units: Percentage of patients
number (confidence interval 80%)
Single visit response	50.7 (43.10 to 58.31)	47.9 (40.29 to 55.49)
Confirmed response	47.9 (40.29 to 55.49)	42.3 (34.74 to 49.77)

No statistical analyses for this end point

Secondary: Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels

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End point title

Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels ^[18]

End point description

The median 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. 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.

End point type

Secondary

End point timeframe

From baseline, then every 4 weeks up to Week 52, and then every 12 weeks.

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	71	68
Units: Percentage change in PSA level
median (full range (min-max))	-54.16 (-100.0 to 533.2)	-49.85 (-100.0 to 230.1)

No statistical analyses for this end point

Secondary: Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level

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End point title

Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level ^[19]

End point description

The 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. 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.

End point type

Secondary

End point timeframe

From baseline, then every 4 weeks up to Week 52, and then every 12 weeks.

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	65	61
Units: Percentage change in CTC level
median (full range (min-max))	-1.0 (-478 to 613)	-1.0 (-1279 to 414)

No statistical analyses for this end point

Secondary: Part B: Percentage of Patients With At Least One Objective Response (Objective Response Rate [ORR])

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End point title

Part B: Percentage of Patients With At Least One Objective Response (Objective Response Rate [ORR]) ^[20]

End point description

The overall radiological ORR was calculated to assess the anti-tumour activity of olaparib when given in combination with abiraterone, compared with placebo given in addition to 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. The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received, and only patients with measurable disease at baseline are included.

End point type

Secondary

End point timeframe

From baseline, then every 4 weeks up to Week 52, and then every 12 weeks.

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	33	38
Units: Percentage of patients
number (not applicable)	27.3	31.6

Comparison of ORR

Comparison groups

Part B: Olaparib + abiraterone v Part B: Placebo + abiraterone

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.309 ^[21]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.813

Confidence interval

level

95%

sides

2-sided

lower limit

0.285

upper limit

2.261

Notes
[21] - The p value was calculated with a 1-sided significance level of 2.5%.

Secondary: Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST)

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End point title

Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST) ^[22]

End point description

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. The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.

End point type

Secondary

End point timeframe

From randomisation until analysis cut-off date (up to approximately 3 years).

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	71	71
Units: Months
median (confidence interval 95%)
TFST	13.5 (11.1 to 17.2)	9.7 (7.3 to 12.9)
TSST	19.6 (16.5 to 25.1)	18.0 (16.9 to 20.6)

Comparison of TSST

Comparison groups

Part B: Olaparib + abiraterone v Part B: Placebo + abiraterone

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.147 ^[23]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.809

Confidence interval

level

95%

sides

2-sided

lower limit

0.545

upper limit

1.201

Notes
[23] - The p value was calculated with a 1-sided significance level of 2.5%.

Comparison of TFST

Comparison groups

Part B: Olaparib + abiraterone v Part B: Placebo + abiraterone

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.095 ^[24]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.781

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.13

Notes
[24] - The p value was calculated with a 1-sided significance level of 2.5%.

Secondary: Part B: Median Overall Survival (OS)

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End point title

Part B: Median Overall Survival (OS) ^[25]

End point description

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. The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.

End point type

Secondary

End point timeframe

From baseline, every 12 weeks up to Week 72, then every 24 weeks up to 24 months.

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	71	71
Units: Months
median (confidence interval 95%)	22.7 (17.4 to 29.4)	20.9 (17.6 to 26.3)

Comparison of OS

Comparison groups

Part B: Olaparib + abiraterone v Part B: Placebo + abiraterone

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.331 ^[26]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.911

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

1.384

Notes
[26] - The p value was calculated with a 1-sided significance level of 2.5%.

Secondary: Part B: Median Time to Second Progression or Death (PFS2)

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End point title

Part B: Median Time to Second Progression or Death (PFS2) ^[27]

End point description

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. The Full analysis set consisted of all randomised patients in Part B, regardless of treatment actually received.

End point type

Secondary

End point timeframe

From randomisation until analysis cut-off date (up to approximately 3 years).

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms are reported for this cohort/part.

End point values	Part B: Olaparib + abiraterone	Part B: Placebo + abiraterone
Number of subjects analysed	71 ^[28]	71
Units: Months
median (confidence interval 95%)	23.3 (17.4 to 99999999)	18.5 (16.1 to 23.8)

Notes
[28] - Too few patients with events to allow calculation of upper limit for 95% confidence interval.

Comparison of PFS2

Comparison groups

Part B: Olaparib + abiraterone v Part B: Placebo + abiraterone

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.14 ^[29]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.788

Confidence interval

level

95%

sides

2-sided

lower limit

0.511

upper limit

1.215

Notes
[29] - The p value was calculated with a 1-sided significance level of 2.5%.

Adverse events

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Timeframe for reporting adverse events

Part A: From baseline (Day 1 for each cohort) up to 30 days following last dose of study treatment. Part B: From first dose of study treatment following randomisation up to 30 days following last dose of study treatment (up to approximately 3 years).

Adverse event reporting additional description

The Part A Safety analysis set consisted of all patients who received at least 1 dose of study treatment in Part A. 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Part A Cohort 1: Olaparib 200 mg + abiraterone

Reporting group description

Reporting group title

Part A Cohort 2: Olaparib 300 mg + abiraterone

Reporting group description

Reporting group title

Part B: Olaparib + abiraterone

Reporting group description

Reporting group title

Part B: Placebo + abiraterone

Reporting group description

Serious adverse events	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 subjects affected by serious adverse events
subjects affected / exposed	2 / 3 (66.67%)	3 / 13 (23.08%)	25 / 71 (35.21%)	14 / 71 (19.72%)
number of deaths (all causes)	0	1	43	45
number of deaths resulting from adverse events	0	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of the tongue
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Internal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	2 / 71 (2.82%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Urinary tract stoma complication
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	2 / 71 (2.82%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	2 / 71 (2.82%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cognitive disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombotic stroke
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	5 / 71 (7.04%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	4 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Eye haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Proctitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	4 / 71 (5.63%)	3 / 71 (4.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mediastinitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis chronic
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Bacterial infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	2 / 71 (2.82%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	2 / 71 (2.82%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	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 subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	7 / 13 (53.85%)	63 / 71 (88.73%)	52 / 71 (73.24%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	3 / 71 (4.23%)	4 / 71 (5.63%)
occurrences all number	0	0	3	5
Hot flush
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	3 / 71 (4.23%)	2 / 71 (2.82%)
occurrences all number	1	1	3	2
Haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	4 / 71 (5.63%)	0 / 71 (0.00%)
occurrences all number	0	0	5	0
General disorders and administration site conditions
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	2 / 13 (15.38%)	3 / 71 (4.23%)	1 / 71 (1.41%)
occurrences all number	0	3	3	1
Oedema peripheral
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	14 / 71 (19.72%)	8 / 71 (11.27%)
occurrences all number	1	0	16	8
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	15 / 71 (21.13%)	9 / 71 (12.68%)
occurrences all number	1	1	16	11
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	16 / 71 (22.54%)	10 / 71 (14.08%)
occurrences all number	0	0	22	11
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	10 / 71 (14.08%)	1 / 71 (1.41%)
occurrences all number	1	0	11	1
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	2 / 71 (2.82%)	1 / 71 (1.41%)
occurrences all number	1	0	2	1
Pneumonitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences all number	1	0	1	0
Nasal congestion
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	10 / 71 (14.08%)	4 / 71 (5.63%)
occurrences all number	2	1	12	4
Cough
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	11 / 71 (15.49%)	2 / 71 (2.82%)
occurrences all number	0	2	17	2
Psychiatric disorders
Euphoric mood
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Depression
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	2 / 71 (2.82%)	1 / 71 (1.41%)
occurrences all number	1	0	2	1
Depressed mood
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Affect lability
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	6 / 71 (8.45%)	2 / 71 (2.82%)
occurrences all number	0	0	7	2
Investigations
Blood urea increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences all number	3	0	1	0
Blood potassium decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	2 / 71 (2.82%)	1 / 71 (1.41%)
occurrences all number	1	2	3	2
Blood glucose increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Blood creatinine increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	3 / 71 (4.23%)	1 / 71 (1.41%)
occurrences all number	3	1	3	1
Blood calcium decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	1 / 71 (1.41%)	1 / 71 (1.41%)
occurrences all number	1	0	1	1
Alanine aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	1 / 71 (1.41%)	1 / 71 (1.41%)
occurrences all number	1	0	1	1
Body temperature increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences all number	1	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	2	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	2	0	0
Heart rate irregular
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Urine output increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	4 / 71 (5.63%)	4 / 71 (5.63%)
occurrences all number	0	0	4	4
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	3 / 71 (4.23%)	2 / 71 (2.82%)
occurrences all number	1	0	3	2
Fall
subjects affected / exposed	2 / 3 (66.67%)	1 / 13 (7.69%)	5 / 71 (7.04%)	1 / 71 (1.41%)
occurrences all number	2	1	5	2
Humerus fracture
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Laceration
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences all number	2	1	1	0
Lower limb fracture
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Rib fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	1	0	1
Thermal burn
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Wound secretion
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Nervous system disorders
Tremor
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	1 / 71 (1.41%)	1 / 71 (1.41%)
occurrences all number	0	1	1	1
Headache
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	6 / 71 (8.45%)	5 / 71 (7.04%)
occurrences all number	1	0	9	7
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	4 / 71 (5.63%)	2 / 71 (2.82%)
occurrences all number	0	0	5	2
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	4 / 71 (5.63%)	2 / 71 (2.82%)
occurrences all number	0	1	5	2
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	8 / 71 (11.27%)	0 / 71 (0.00%)
occurrences all number	0	1	8	0
Lymphopenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences all number	0	2	1	0
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	18 / 71 (25.35%)	1 / 71 (1.41%)
occurrences all number	0	1	23	1
Ear and labyrinth disorders
Tympanic membrane perforation
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Cerumen impaction
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Eye disorders
Ocular hyperaemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	1	0	0
Eyelid oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	4 / 71 (5.63%)	0 / 71 (0.00%)
occurrences all number	0	0	5	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	8 / 71 (11.27%)	1 / 71 (1.41%)
occurrences all number	1	0	9	1
Abdominal discomfort
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences all number	1	0	0	1
Dyspepsia
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	0 / 71 (0.00%)	3 / 71 (4.23%)
occurrences all number	1	1	0	3
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	1 / 71 (1.41%)	1 / 71 (1.41%)
occurrences all number	1	0	1	1
Constipation
subjects affected / exposed	1 / 3 (33.33%)	2 / 13 (15.38%)	17 / 71 (23.94%)	8 / 71 (11.27%)
occurrences all number	1	2	19	10
Diarrhoea
subjects affected / exposed	2 / 3 (66.67%)	3 / 13 (23.08%)	11 / 71 (15.49%)	8 / 71 (11.27%)
occurrences all number	4	3	17	11
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	2 / 13 (15.38%)	14 / 71 (19.72%)	9 / 71 (12.68%)
occurrences all number	4	3	26	12
Rectal haemorrhage
subjects affected / exposed	2 / 3 (66.67%)	0 / 13 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences all number	2	0	1	0
Nausea
subjects affected / exposed	2 / 3 (66.67%)	2 / 13 (15.38%)	27 / 71 (38.03%)	15 / 71 (21.13%)
occurrences all number	5	2	42	16
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	4 / 71 (5.63%)	0 / 71 (0.00%)
occurrences all number	0	0	4	0
Frequent bowel movements
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	5 / 71 (7.04%)	2 / 71 (2.82%)
occurrences all number	0	0	5	2
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	1	0	1
Skin lesion
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Skin atrophy
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Rash
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	1 / 71 (1.41%)	1 / 71 (1.41%)
occurrences all number	1	0	1	1
Purpura
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	2 / 71 (2.82%)	0 / 71 (0.00%)
occurrences all number	1	0	2	0
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	1	0	1
Blister
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Renal and urinary disorders
Hypertonic bladder
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Urinary retention
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	2 / 71 (2.82%)	1 / 71 (1.41%)
occurrences all number	0	1	2	1
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	1	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	8 / 71 (11.27%)	4 / 71 (5.63%)
occurrences all number	1	1	8	4
Back pain
subjects affected / exposed	3 / 3 (100.00%)	1 / 13 (7.69%)	17 / 71 (23.94%)	14 / 71 (19.72%)
occurrences all number	5	1	21	18
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	11 / 71 (15.49%)	9 / 71 (12.68%)
occurrences all number	0	1	12	9
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	1 / 71 (1.41%)	0 / 71 (0.00%)
occurrences all number	0	1	1	0
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	1 / 71 (1.41%)
occurrences all number	0	1	0	1
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	4 / 71 (5.63%)	2 / 71 (2.82%)
occurrences all number	0	1	4	2
Musculoskeletal chest pain
subjects affected / exposed	2 / 3 (66.67%)	0 / 13 (0.00%)	1 / 71 (1.41%)	5 / 71 (7.04%)
occurrences all number	4	0	1	7
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	7 / 71 (9.86%)	6 / 71 (8.45%)
occurrences all number	0	0	8	7
Spinal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	2 / 71 (2.82%)	3 / 71 (4.23%)
occurrences all number	0	1	2	3
Pain in extremity
subjects affected / exposed	1 / 3 (33.33%)	2 / 13 (15.38%)	5 / 71 (7.04%)	4 / 71 (5.63%)
occurrences all number	2	3	6	4
Osteoporosis
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	1	0	0	0
Osteopenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 13 (15.38%)	2 / 71 (2.82%)	3 / 71 (4.23%)
occurrences all number	0	2	2	3
Infections and infestations
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	2 / 71 (2.82%)	1 / 71 (1.41%)
occurrences all number	0	1	2	2
Lower respiratory tract infection
subjects affected / exposed	2 / 3 (66.67%)	0 / 13 (0.00%)	0 / 71 (0.00%)	3 / 71 (4.23%)
occurrences all number	2	0	0	3
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	4 / 71 (5.63%)	1 / 71 (1.41%)
occurrences all number	0	0	4	1
Furuncle
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	3	0	0
Arthritis infective
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Sinusitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	1 / 71 (1.41%)	1 / 71 (1.41%)
occurrences all number	1	0	2	1
Viral upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	8 / 71 (11.27%)	3 / 71 (4.23%)
occurrences all number	0	0	10	3
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 13 (0.00%)	8 / 71 (11.27%)	2 / 71 (2.82%)
occurrences all number	0	0	9	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	12 / 71 (16.90%)	5 / 71 (7.04%)
occurrences all number	1	1	12	5
Fluid retention
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	0 / 71 (0.00%)	0 / 71 (0.00%)
occurrences all number	0	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 13 (7.69%)	1 / 71 (1.41%)	1 / 71 (1.41%)
occurrences all number	0	1	1	2
Hypocalcaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 13 (0.00%)	1 / 71 (1.41%)	2 / 71 (2.82%)
occurrences all number	1	0	1	2
Hypokalaemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 13 (7.69%)	5 / 71 (7.04%)	4 / 71 (5.63%)
occurrences all number	3	3	7	6

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Were there any global substantial amendments to the protocol? Yes

15 Aug 2014

-Frequency of clinic visits increased to every 4 weeks for first 52 weeks. -Log rank test replaced Cox proportional hazrd model as primary analysis for time-to-event endpoints. -Inclusion of additional Eastern Cooperative Oncology Group assessments to Part B. -Removed text relating to a separate study for chemotherapy-naive CRPC patients as study was not planned; and text relating to closure of Part A database. -Amendment of text relating to Hy's law cases.

13 Oct 2015

-Secondary endpoints amended to include investigation of Ataxia telangiectasia mutated gene and Breast cancer gene mutations as candidate predictors of response to olaparib. -Changes to text relating to contraception during study. -Updated text regarding olaparib drug-drug interactions to reflect recent findings. -Added text to state once olaparib/placebo dose had been reduced, escalation was not permitted to clarify dose reduction management. -Text regarding olaparib anaemia management was updated.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

'99999999' in the end points section indicates data is not available.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A: Percentage of Patients Experiencing Adverse Events (AEs)

Primary: Part A: Percentage of Patients Experiencing Adverse Events (AEs)

Primary: Part A: Number of Patients with DLTs

Primary: Part A: Number of Patients with DLTs

Primary: Part B: Median Radiological Progression-Free Survival (rPFS) Time

Primary: Part B: Median Radiological Progression-Free Survival (rPFS) Time

Primary: Part B: Percentage of Patients with Progression Events or Death (rPFS)

Primary: Part B: Percentage of Patients with Progression Events or Death (rPFS)

Secondary: Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss)

Secondary: Part A Pharmacokinetics (PK): Olaparib Maximum Plasma Concentration at Steady State (Cmax,ss)

Secondary: Part A PK: Abiraterone Cmax,ss

Secondary: Part A PK: Abiraterone Cmax,ss

Secondary: Part A PK: Abiraterone tmax,ss

Secondary: Part A PK: Abiraterone tmax,ss

Secondary: Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (tmax,ss)

Secondary: Part A PK Analysis: Olaparib Time to Reach Maximum Plasma Concentration at Steady State (tmax,ss)

Secondary: Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss)

Secondary: Part A PK Analysis: Olaparib Minimum Plasma Concentration at Steady State (Cmin,ss)

Secondary: Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss)

Secondary: Part A PK Analysis: Olaparib Area Under the Plasma Concentration-Time Curve at Steady State (AUCss)

Secondary: Part A PK: Abiraterone Cmin,ss

Secondary: Part A PK: Abiraterone Cmin,ss

Secondary: Part B: Percentage of Patients Experiencing AEs

Secondary: Part B: Percentage of Patients Experiencing AEs

Secondary: Part A PK: Abiraterone AUCss

Secondary: Part A PK: Abiraterone AUCss

Secondary: Part B: Percentage of Patients With PSA Responses

Secondary: Part B: Percentage of Patients With PSA Responses

Secondary: Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels

Secondary: Part B: Median Best Percentage Change From Baseline in Prostate Specific Antigen (PSA) Levels

Secondary: Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level

Secondary: Part B: Median Best Percentage Change From Baseline in Circulating Tumour Cell (CTC) Level

Secondary: Part B: Percentage of Patients With At Least One Objective Response (Objective Response Rate [ORR])

Secondary: Part B: Percentage of Patients With At Least One Objective Response (Objective Response Rate [ORR])

Secondary: Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST)

Secondary: Median Time to First Subsequent Therapy (TFST) and Median Time to Second Subsequent Therapy (TSST)

Secondary: Part B: Median Overall Survival (OS)

Secondary: Part B: Median Overall Survival (OS)

Secondary: Part B: Median Time to Second Progression or Death (PFS2)

Secondary: Part B: Median Time to Second Progression or Death (PFS2)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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