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    Clinical Trial Results:
    TOPARP: Phase II Trial of Olaparib in Patients with Advanced Castration Resistant Prostate Cancer.

    Summary
    EudraCT number
    		 2011-000601-49
    Trial protocol
    		 GB  
    Global end of trial date
    17 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions
    Summary report(s)
    		 DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer
    DNA Repair Defects and Olaparib in Metastatic Prostate Cancer - Appendix
    Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial
    Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial - Supplementary Materials

    Trial information

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    Trial identification
    Sponsor protocol code
    ICR-CTSU/2011/10030
    Additional study identifiers
    ISRCTN number
    		 ISRCTN15124653
    US NCT number
    		 NCT01682772
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ICR/RMH CCR Number: 3592, CR UK Reference Number: CRUK/C12540/A12354, REC Reference Number: 11/LO/2019
    Sponsors
    Sponsor organisation name
    The Institute of Cancer Research
    Sponsor organisation address
    15 Cotswold Road, London, United Kingdom,
    Public contact
    TOPARP Trial Manager, Institute of Cancer Research - Clinical Trials and Statistics Unit, TOPARP-icrctsu@icr.ac.uk
    Scientific contact
    TOPARP Trial Manager, Institute of Cancer Research - Clinical Trials and Statistics Unit, TOPARP-icrctsu@icr.ac.uk
    Sponsor organisation name
    The Royal Marsden Hospital NHS Foundation Trust
    Sponsor organisation address
    Downs Rd, Sutton, United Kingdom,
    Public contact
    TOPARP Trial Manager, The Royal Marsden Hospital NHS Foundation Trust, TOPARP-icrctsu@icr.ac.uk
    Scientific contact
    TOPARP Trial Manager, The Royal Marsden Hospital NHS Foundation Trust, TOPARP-icrctsu@icr.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Sep 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the activity of olaparib in patients with advanced prostate cancer who have progressed following one or two chemotherapy regimens including docetaxel.
    Protection of trial subjects
    Patients were followed closely for any signs of adverse events of study treatment and the study protocol contains guidance for investigators on how to manage the adverse effects that were expected. The expected adverse effects were also listed in the patient information sheet. Patients had regular blood tests to ensure the safety of patients. Patients were given a verbal explanation of the TOPARP trial and were offered the patient information sheet and any additional information about clinical trials and alternative treatments that would normally be offered to take home and discuss with friends and family. Patients were usually given at least 24 hours to consider the trial information and those who agreed to trial entry were asked to sign the consent form prior to any study specific procedures. The Principal Investigator at each site was responsible for ensuring written informed consent was obtained for each patient. This trial was overseen by an Independent Data Monitoring Committee, which would stop the study if there was any cause of concern with respect to patient safety and patients' oncologists would be notified immediately if this was the case.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 148
    Worldwide total number of subjects
    148
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    50
    From 65 to 84 years
    97
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 TOPARP-A: 50 patients recruited from 04/07/2012 to 22/09/2014, across 8 UK centres. TOPARP-B: 98 patients recruited from 01/04/2015 to 30/08/2015, across 17 UK centres.

    Pre-assignment
    Screening details
    		 TOPARP-A screening: 88 patients assessed for eligibility, 38 excluded from trial entry (37 did not meet inclusion criteria; 1 fractured hip during screening). TOPARP-B screening: Of the 592 patients with at least one sample good enough for analysis, 161 were had alterations in any DNA defect repair gene. Of these, 98 DDRm patients were randomised.

    Period 1
    Period 1 title
    TOPARP-A and TOPARP-B trial entry (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TOPARP-A: Olaparib 400mg
    Arm description
    		 Patients receive single agent olaparib at a dose of 400 mg twice daily, continuously on a 28-day cycle. Olaparib will be administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg orally, BID

    Arm title
    		 TOPARP-B: Olaparib 300mg
    Arm description
    		 Patients randomised to receive 300mg twice daily, continuously on a 28-day cycle. Olaparib is administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason. Patients randomised to the 300mg group are offered the option of dose escalation to 400mg twice daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg orally, BID

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300mg orally, BID

    Arm title
    		 TOPARP-B: Olaparib 400mg
    Arm description
    		 Patients randomised to receive 400mg twice daily, continuously on a 28-day cycle. Olaparib is administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Olaparib 400mg orally, BID

    Number of subjects in period 1
    		TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg
    Started
    50
    49
    49
    Completed
    49
    49
    49
    Not completed
    1
    0
    0
         Patient choice
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TOPARP-A: Olaparib 400mg
    Reporting group description
    		 Patients receive single agent olaparib at a dose of 400 mg twice daily, continuously on a 28-day cycle. Olaparib will be administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason.

    Reporting group title
    TOPARP-B: Olaparib 300mg
    Reporting group description
    		 Patients randomised to receive 300mg twice daily, continuously on a 28-day cycle. Olaparib is administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason. Patients randomised to the 300mg group are offered the option of dose escalation to 400mg twice daily.

    Reporting group title
    TOPARP-B: Olaparib 400mg
    Reporting group description
    		 Patients randomised to receive 400mg twice daily, continuously on a 28-day cycle. Olaparib is administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason.

    Reporting group values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg Total
    Number of subjects
    		 50 49 49 148
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 18 19 13 50
        From 65-84 years
    		 32 29 36 97
        85 years and over
    		 0 1 0 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 67.5 (60.6 to 72.2) 67.3 (61.2 to 72.1) 67.6 (63.2 to 72.7) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 50 49 49 148
    Primary tumour stage at diagnosis
    Units: Subjects
        T0
    		 3 1 4 8
        T1
    		 1 3 3 7
        T2
    		 10 25 26 61
        T3
    		 21 8 7 36
        T4
    		 8 12 8 28
        Unknown
    		 7 0 1 8
    Lymphadenopathy at diagnosis
    Units: Subjects
        N0
    		 19 17 22 58
        N1
    		 15 17 16 48
        N2
    		 1 1 0 2
        Unknown / NX
    		 15 14 11 40
    Metastatic disease at diagnosis
    Units: Subjects
        Yes
    		 23 24 25 72
        No
    		 27 24 21 72
        Not available
    		 0 1 3 4
    Lung metastases at diagnosis
    Units: Subjects
        Yes
    		 0 1 1 2
        No
    		 23 23 24 70
        No metastatic disease at diagnosis
    		 27 25 24 76
    Lymph nodes metastases at diagnosis
    Units: Subjects
        Yes
    		 9 14 10 33
        No
    		 14 10 15 39
        No metastatic disease at diagnosis
    		 27 25 24 76
    Liver metastases at diagnosis
    Units: Subjects
        Yes
    		 2 1 1 4
        No
    		 21 23 24 68
        No metastatic disease at diagnosis
    		 27 25 24 76
    Bone metastases at diagnosis
    Units: Subjects
        Yes
    		 22 19 22 63
        No
    		 1 5 3 9
        No metastatic disease at diagnosis
    		 27 25 24 76
    Gleason score at diagnosis
    Units: Subjects
        Score=5
    		 1 1 0 2
        Score=6
    		 0 0 3 3
        Score=7
    		 12 3 12 27
        Score=8
    		 14 8 6 28
        Score=9
    		 15 28 22 65
        Score=10
    		 1 6 1 8
        Unknown
    		 7 3 5 15
    Neuroendocrine features present at diagnosis
    Units: Subjects
        Yes
    		 1 1 1 3
        No
    		 44 47 43 134
        Unknown
    		 5 1 5 11
    Diagnosis of small cell prostate cancer
    Units: Subjects
        Yes
    		 1 0 3 4
        No
    		 43 49 42 134
        Unknown
    		 6 0 4 10
    Method of progression at trial entry
    Units: Subjects
        PSA only
    		 12 15 12 39
        Radiographic (with or without PSA progression)
    		 38 34 37 109
    RECIST measurable disease at trial entry
    Units: Subjects
        Target lesions (TOPARP-A)
    		 32 0 0 32
        Non-target lesions only (TOPARP-A)
    		 10 0 0 10
        No target or non-target lesions (TOPARP-A)
    		 8 0 0 8
        Bone lesions only (TOPARP-B)
    		 0 5 5 10
        Non-measurable disease only +/ bone (TOPARP-B)
    		 0 5 8 13
        Measurable disease +/ bone (TOPARP-B)
    		 0 39 36 75
    ECOG performance status at trial entry
    Units: Subjects
        Status 0
    		 9 12 15 36
        Status 1
    		 35 32 25 92
        Status 2
    		 6 5 9 20
    Received prior regimens for CRPC
    Units: Subjects
        2 regimens
    		 3 0 0 3
        3 regimens
    		 7 0 0 7
        >=4 regimens
    		 40 0 0 40
        Not reported (TOPARP-B)
    		 0 49 49 98
    DNA damage response aberration subgroup: BRCA1/2
    Units: Subjects
        Yes
    		 16 15 17 48
        No
    		 33 34 32 99
        Unknown
    		 1 0 0 1
    DNA damage response aberration subgroup: ATM
    Units: Subjects
        Yes
    		 5 10 11 26
        No
    		 44 39 38 121
        Unknown
    		 1 0 0 1
    DNA damage response aberration subgroup: CDK12
    Units: Subjects
        Yes
    		 0 15 6 21
        No
    		 49 34 43 126
        Unknown
    		 1 0 0 1
    DNA damage response aberration subgroup: PALB2
    Units: Subjects
        Yes
    		 1 3 4 8
        No
    		 48 46 45 139
        Unknown
    		 1 0 0 1
    Previous treatments for prostate cancer: Radical radiotherapy
    Units: Subjects
        Yes
    		 18 22 21 61
        No
    		 32 27 28 87
    Previous treatments for prostate cancer: Prostatectomy
    Units: Subjects
        Yes
    		 7 7 6 20
        No
    		 43 42 43 128
    Previous treatments for prostate cancer: Transurethral resection of the prostate
    Units: Subjects
        Yes
    		 2 7 5 14
        No
    		 48 42 44 134
    Previous treatments for prostate cancer: Abiraterone
    Units: Subjects
        Yes
    		 48 24 22 94
        No
    		 2 25 27 54
    Previous treatments for prostate cancer: Enzalutamide
    Units: Subjects
        Yes
    		 14 27 29 70
        No
    		 36 22 20 78
    Previous treatments for prostate cancer: Abiraterone or enzalutamide or both
    Units: Subjects
        Yes
    		 49 43 45 137
        No
    		 1 6 4 11
    Previous treatments for prostate cancer: Docetaxel
    Units: Subjects
        Yes
    		 50 49 49 148
        No
    		 0 0 0 0
    Previous treatments for prostate cancer: Cabazitaxel
    Units: Subjects
        Yes
    		 29 15 22 66
        No
    		 21 34 27 82
    Previous treatments for prostate cancer: Radium-223
    Units: Subjects
        Yes
    		 1 6 8 15
        No
    		 49 43 41 133
    Previous treatments for prostate cancer: Denosumab
    Units: Subjects
        Yes
    		 1 1 0 2
        No
    		 49 48 49 146
    Previous treatments for prostate cancer: Zoledronic acid
    Units: Subjects
        Yes
    		 14 1 2 17
        No
    		 36 48 47 131
    Years since diagnosis of prostate cancer
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 5.0 (3.4 to 7.9) 3.5 (2.4 to 6.4) 5.2 (3.6 to 7.3) -
    Years since confirmed castrate resistant disease
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 2.2 (1.7 to 3.9) 2.4 (1.2 to 3.7) 3.0 (1.8 to 4.0) -
    PSA at diagnosis
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    		 57.0 (17.5 to 637.0) 67.0 (19.0 to 170.5) 62.0 (20.1 to 244.5) -
    CTC count at trial entry
    Units: cells/7.5ml blood
        median (inter-quartile range (Q1-Q3))
    		 37.0 (14.0 to 110) 6.0 (1.0 to 44.0) 6.5 (2.0 to 74.0) -
    PSA at trial entry
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    		 349.5 (153.0 to 806.0) 151.5 (49.0 to 444.9) 158.0 (45.5 to 472.0) -

    End points

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    End points reporting groups
    Reporting group title
    TOPARP-A: Olaparib 400mg
    Reporting group description
    		 Patients receive single agent olaparib at a dose of 400 mg twice daily, continuously on a 28-day cycle. Olaparib will be administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason.

    Reporting group title
    TOPARP-B: Olaparib 300mg
    Reporting group description
    		 Patients randomised to receive 300mg twice daily, continuously on a 28-day cycle. Olaparib is administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason. Patients randomised to the 300mg group are offered the option of dose escalation to 400mg twice daily.

    Reporting group title
    TOPARP-B: Olaparib 400mg
    Reporting group description
    		 Patients randomised to receive 400mg twice daily, continuously on a 28-day cycle. Olaparib is administered until objective disease progression or unacceptable toxicity or patient withdrawal for whatever reason.

    Subject analysis set title
    TOPARP-A biomarker positive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patient was considered to be biomarker-positive if a homozygous deletion or deleterious mutation was identified in a gene reported to be involved either in DNA damage repair or sensitivity to PARP inhibition.

    Subject analysis set title
    TOPARP-A biomarker negative
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patient was considered to be biomarker-negative if a homozygous deletion or deleterious mutation was NOT identified in a gene reported to be involved either in DNA damage repair or sensitivity to PARP inhibition.

    Primary: Composite Response

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    End point title
    		 Composite Response
    End point description
    The primary endpoint is response, which is defined on the basis of the following outcomes; if any of these occur patients will be considered to have responded: • Confirmed objective response by modified RECIST 1.1 (i.e. either complete response (CR) or partial response (PR)) • PSA decline of ≥50% from baseline, confirmed to be sustained by a second PSA value obtained four or more weeks later • Conversion of circulating tumour cell count (CTC) from ≥5 cells/7.5 ml blood at baseline to <5 cells/7.5 ml confirmed by a second consecutive value obtained four or more weeks later. Evaluable patients with no confirmed response as defined above will be classified as non-responders.
    End point type
    Primary
    End point timeframe
    The first disease assessment is performed at 12 weeks post treatment start, then every 12 weeks onwards for RECIST and 4 weeks onwards for PSA and CTC.
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg TOPARP-A biomarker positive TOPARP-A biomarker negative
    Number of subjects analysed
    49 [1]
    46 [2]
    46 [3]
    16 [4]
    33 [5]
    Units: Response
        Composite response
    16
    18
    25
    14
    2
    Notes
    [1] - Evaluable population
    [2] - Evaluable population
    [3] - Evaluable population
    [4] - Within evaluable population
    [5] - Within evaluable population
    Statistical analysis title
    		 TOPARP-B Pick the winner
    Statistical analysis description
    Under the TOPARP-B “pick-the-winner” design, each dose group is assessed independently for antitumour activity. If 19 or more of the planned 44 evaluable patients in one dose group respond (43%), then the dose group is considered successful. In the case where both dose groups are successful, the TOPARP-B SAP describes the strategy to select the successful dose based on response rates and secondary endpoints.
    Comparison groups
    TOPARP-B: Olaparib 300mg v TOPARP-B: Olaparib 400mg
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.144 [7]
    Method
    		 Chi-squared
    Parameter type
    		 Response rate
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [6] - As per the trial “pick-the-winner” design, each dose is assessed separately in the 92 evaluable patients: - 300 mg BID dose group: 18/46 evaluable with confirmed response. RR 39.1% (95%CI 25.1-54.6). - 400 mg BID dose group: 25/46 evaluable with confirmed response. RR 54.3% (95%CI 39.0-69.1).
    [7] - Exploratory - design (pick the winner) not powered for direct comparison of doses.
    Statistical analysis title
    		 TOPARP-A response by BM status
    Comparison groups
    TOPARP-A biomarker positive v TOPARP-A biomarker negative
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.001 [9]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    108.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.8
         upper limit
    		 850.5
    Notes
    [8] - Association between biomarker status and response
    [9] - Fisher's exact p-value

    Secondary: PSA response

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    End point title
    		 PSA response
    End point description
    PSA partial response is defined as a ≥ 50% decline in PSA value from cycle1 day 1 (baseline). This PSA decline must be confirmed to be sustained by a second PSA value obtained 4 or more weeks later.
    End point type
    Secondary
    End point timeframe
    PSA response is first evaluated at 12 weeks post treatment start and then evaluated at each cycle of treatment (every 4 weeks).
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg
    Number of subjects analysed
    49 [10]
    43 [11]
    46 [12]
    Units: Subjects
        PSA responses
    10
    13
    17
    Notes
    [10] - Evaluable population
    [11] - PSA evaluable
    [12] - PSA evaluable
    No statistical analyses for this end point

    Secondary: Time to PSA progression

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    End point title
    		 Time to PSA progression
    End point description
    PSA progression is defined as follows: • If PSA while on treatment declines from baseline, PSA progression is defined when a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir is documented, which needs to be confirmed by a second consecutive value obtained 3 or more weeks later. • If there is no decline from baseline, PSA progression is defined when a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline is documented after 12 weeks of treatment. Time to PSA progression will be computed from date of start of olaparib to date of PSA progression. Patients who do not experience a PSA progression will be censored at the last PSA assessment date while on allocated treatment. In the TOPARP-B 300mg dose BID, PSA values after dose-escalation to 400mg BID are excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    The first PSA reading is obtained at 12 weeks post treatment start then evaluated at each cycle of treatment (every 4 weeks).
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg
    Number of subjects analysed
    48 [13]
    46 [14]
    49 [15]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    5.7 (2.8 to 11.1)
    5.6 (2.8 to 14)
    3.7 (2.8 to 10.9)
    Notes
    [13] - PSa-progression evaluable
    [14] - PSA evaluable
    [15] - PSA evaluable
    No statistical analyses for this end point

    Secondary: % Change in PSA to 12 weeks

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    End point title
    		 % Change in PSA to 12 weeks
    End point description
    Percentage of change in PSA from baseline to 12 weeks (or earlier for those who discontinue therapy).
    End point type
    Secondary
    End point timeframe
    % Change in PSA from baseline to 12 weeks. Maximum decline in PSA that occurs at any point in treatment.
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg
    Number of subjects analysed
    46
    46 [16]
    48 [17]
    Units: %
        median (inter-quartile range (Q1-Q3))
    38.7 (-29.3 to 136.8)
    -4.6 (-38.1 to 55.3)
    4.6 (-51.9 to 49.3)
    Notes
    [16] - PSA-change evaluable
    [17] - PSA-change evaluable
    No statistical analyses for this end point

    Secondary: CTC response

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    End point title
    		 CTC response
    End point description
    The proportion of patients with a CTC conversion to <5/7.5 ml blood at nadir (confirmed by a second consecutive value four or more weeks later) will be presented along an exact two-sided 95% confidence interval. Waterfall plots of CTC falls will also be presented that show the percentage change in CTC counts from baseline to 12 weeks as well as maximal CTC count declines that occur at any point after treatment. In Part B, the dose group will be displayed using different colours. Longitudinal spaghetti plots of CTC values over time will also be presented to explore the different patterns of response in Part B this will be conducted for each dose group. CTC response’s association with PFS and OS will be examined via landmark analyses (to compare OS or PFS between CTC responders and non-responders at a given time point).
    End point type
    Secondary
    End point timeframe
    The first assessment of CTC response is at 12 weeks post treatment. CTC is then evaluated at every cycle (4 weeks).
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg
    Number of subjects analysed
    49 [18]
    27 [19]
    28 [20]
    Units: Subjects
    14
    13
    15
    Notes
    [18] - Evaluable population
    [19] - CTC evaluable
    [20] - CTC evaluable
    No statistical analyses for this end point

    Secondary: Radiographic progression free survival (rPFS)

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    End point title
    		 Radiographic progression free survival (rPFS)
    End point description
    Radiographic progression free survival (rPFS) will be defined by either RECIST progression and /or progression on bone scan. It will be measured from the date of trial entry to the first occurrence of radiographic progression or death from any cause. If no event exists, then rPFS will be censored at the last scheduled disease assessment on study.
    End point type
    Secondary
    End point timeframe
    Trial entry to first occurrence of radiographic progression or death from any cause, or censoring time.
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg TOPARP-A biomarker positive TOPARP-A biomarker negative
    Number of subjects analysed
    49 [21]
    49 [22]
    49 [23]
    16
    33
    Units: Months
        median (inter-quartile range (Q1-Q3))
    2.9 (2.5 to 10.8)
    5.6 (2.8 to 9.9)
    5.5 (2.8 to 14.4)
    10.8 (5.6 to 17.1)
    2.6 (2.4 to 2.9)
    Notes
    [21] - ITT population
    [22] - ITT population
    [23] - ITT population
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    Progression free survival will be measured from the date of trial entry until radiographic progression, unequivocal clinical progression or death. If no event exists, then PFS will be censored at the last scheduled disease assessment on study.
    End point type
    Secondary
    End point timeframe
    Trial entry to radiographic progression, unequivocal clinical progression or death, or censoring time.
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg
    Number of subjects analysed
    49 [24]
    49 [25]
    49 [26]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    2.8 (2.8 to 8.2)
    5.4 (2.7 to 8.5)
    5.5 (2.8 to 11.5)
    Notes
    [24] - ITT population
    [25] - ITT population
    [26] - ITT population
    No statistical analyses for this end point

    Secondary: Duration of PSA response

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    End point title
    		 Duration of PSA response
    End point description
    Duration of PSA response is calculated from the time the PSA value first declines by at least 50% of the cycle 1 day 1 (baseline) value (must be confirmed by a second value) until the time there is an increase of 25% of PSA nadir, provided the absolute increase is at least 2 ng/mL. The increase must be confirmed by a second consecutive measurement that is at least 25% above the nadir. If the PSA never shows a 25% increase over the nadir value, then the patient will be censored at the last PSA measurement. Duration of PSA response will be summarised by the median and presented along its 95% confidence interval. Time to PSA response on the duration of response (e.g. by fitting left-truncated models of adjusting by time to response) may be explored.
    End point type
    Secondary
    End point timeframe
    PSA response is first evaluated at 12 weeks post treatment start and then evaluated at each cycle of treatment (every 4 weeks).
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg TOPARP-A biomarker positive TOPARP-A biomarker negative
    Number of subjects analysed
    16 [27]
    18 [28]
    25 [29]
    14 [30]
    2 [31]
    Units: Months
        median (confidence interval 95%)
    9.1 (6.8 to 13.8)
    6.8 (4.4 to 12.9)
    7.9 (4.4 to 13.7)
    9.1 (7.1 to 14.8)
    6.5 (2.2 to 10.8)
    Notes
    [27] - Responders
    [28] - Responders
    [29] - Responders
    [30] - Responders
    [31] - Responders
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS will be measured from the date of trial entry to the date of death (whatever the cause). Survival time of living patients will be censored on the last date a patient is known to be alive or lost to follow-up.
    End point type
    Secondary
    End point timeframe
    Trial entry to date of death or censoring.
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg TOPARP-A biomarker positive TOPARP-A biomarker negative
    Number of subjects analysed
    49
    49
    49
    16
    33
    Units: Months
        median (confidence interval 95%)
    10.4 (7.5 to 14.5)
    10.1 (9 to 14.7)
    14.8 (10.1 to 18.3)
    15.3 (10.4 to 17.4)
    7.5 (4.6 to 11.1)
    No statistical analyses for this end point

    Secondary: Maximum % decline in PSA during treatment

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    End point title
    		 Maximum % decline in PSA during treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Maximum decline in PSA that occurs at any point in treatment.
    End point values
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 300mg TOPARP-B: Olaparib 400mg
    Number of subjects analysed
    49
    46 [32]
    49 [33]
    Units: %
        median (inter-quartile range (Q1-Q3))
    31.9 (-47.3 to 93.4)
    -12.8 (-69.6 to 30.1)
    -11.8 (-79.6 to 28.0)
    Notes
    [32] - PSA-change evaluable
    [33] - PSA-change evaluable
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AE) were collected on a continuous basis using NCI-CTCAE v4.02 reporting criteria from screening until 30 days after the last dose of olaparib, or until a new anti-cancer therapy is started.
    Adverse event reporting additional description
    TOPARP-A: MedDRA v14, CTCAE v4.02 TOPARP-B: MedDRA v22, CTCAE v4.02
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0, 22.0
    Reporting groups
    Reporting group title
    TOPARP-A: Olaparib 400mg
    Reporting group description
    		 -

    Reporting group title
    TOPARP-B: Olaparib 400mg
    Reporting group description
    		 -

    Reporting group title
    TOPARP-B: Olaparib 300mg
    Reporting group description
    		 -

    Serious adverse events
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 400mg TOPARP-B: Olaparib 300mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 50 (40.00%)
    24 / 49 (48.98%)
    22 / 49 (44.90%)
         number of deaths (all causes)
    49
    49
    48
         number of deaths resulting from adverse events
    0
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
    Additional description: Acute myeloid leukaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pancreatic carcinoma
    Additional description: Pancreatic carcinoma
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
    Additional description: Circulatory collapse
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
    Additional description: Embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: Pulmonary embolism
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pain
    Additional description: Pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    Additional description: Pulmonary embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
    Additional description: Cough
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
    Additional description: Pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
    Additional description: Confusional state
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
    Additional description: C-reactive protein increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
    Additional description: Platelet count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
    Additional description: Fall
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
    Additional description: Femoral neck fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
    Additional description: Femur fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
    Additional description: Fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
    Additional description: Hip fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
    Additional description: Humerus fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
    Additional description: Joint injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
    Additional description: Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
    Additional description: Myocardial infarction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
    Additional description: Transient ischaemic attack
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cauda equina syndrome
    Additional description: Cauda equina syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
    Additional description: Facial paresis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
    Additional description: Radiculopathy
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
    Additional description: Spinal cord compression
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    5 / 50 (10.00%)
    4 / 49 (8.16%)
    4 / 49 (8.16%)
         occurrences causally related to treatment / all
    6 / 6
    4 / 5
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
    Additional description: Neutrophil count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
    Additional description: Febrile neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
    Additional description: Large intestine perforation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
    Additional description: Intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
    Additional description: Rectal haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
    Additional description: Small intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
    Additional description: Jaundice
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
    Additional description: Haematuria
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
    Additional description: Hydronephrosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pollakiuria
    Additional description: Pollakiuria
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
    Additional description: Renal colic
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
    Additional description: Renal failure acute
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
    Additional description: Urinary retention
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
    Additional description: Arthritis bacterial
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
    Additional description: Bone pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin pain
    Additional description: Groin pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
    Additional description: Mobility decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
    Additional description: Muscular weakness
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    4 / 49 (8.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
    Additional description: Pyelonephritis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
    Additional description: Neutropenic sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
    Additional description: Lung infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
    Additional description: Infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
    Additional description: Cellulitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
    Additional description: Abdominal infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
    Additional description: Respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    Additional description: Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 17
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
    Additional description: Urosepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
    Additional description: Hyperkalaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TOPARP-A: Olaparib 400mg TOPARP-B: Olaparib 400mg TOPARP-B: Olaparib 300mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    49 / 49 (100.00%)
    47 / 49 (95.92%)
    Vascular disorders
    Lymphoedema
    Additional description: Lymphoedema
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences all number
    4
    3
    4
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    3 / 50 (6.00%)
    9 / 49 (18.37%)
    11 / 49 (22.45%)
         occurrences all number
    20
    11
    20
    General disorders and administration site conditions
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    9 / 50 (18.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    19
    0
    0
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    45 / 50 (90.00%)
    33 / 49 (67.35%)
    22 / 49 (44.90%)
         occurrences all number
    246
    58
    46
    Hot flush
    Additional description: Hot flush
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    33
    0
    0
    Musculoskeletal chest pain
    Additional description: Musculoskeletal chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
         occurrences all number
    0
    4
    0
    Oedema
    Additional description: Oedema
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    8
    0
    0
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    11 / 50 (22.00%)
    9 / 49 (18.37%)
    8 / 49 (16.33%)
         occurrences all number
    42
    15
    10
    Pain
    Additional description: Pain
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
         occurrences all number
    13
    11
    1
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
         occurrences all number
    3
    3
    5
    Reproductive system and breast disorders
    Pelvic pain
    Additional description: Pelvic pain
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
         occurrences all number
    5
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    4
    0
    0
    Cough
    Additional description: Cough
         subjects affected / exposed
    9 / 50 (18.00%)
    8 / 49 (16.33%)
    3 / 49 (6.12%)
         occurrences all number
    22
    8
    3
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    5 / 50 (10.00%)
    9 / 49 (18.37%)
    3 / 49 (6.12%)
         occurrences all number
    14
    11
    6
    Productive cough
    Additional description: Productive cough
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    2
    5
    0
    Psychiatric disorders
    Depression
    Additional description: Depression
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    20
    3
    0
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 49 (4.08%)
    4 / 49 (8.16%)
         occurrences all number
    15
    2
    4
    Investigations
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 50 (16.00%)
    5 / 49 (10.20%)
    4 / 49 (8.16%)
         occurrences all number
    10
    9
    4
    Blood alkaline phosphatase increased
    Additional description: Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 49 (12.24%)
    3 / 49 (6.12%)
         occurrences all number
    3
    10
    3
    Blood bilirubin increased
    Additional description: Blood bilirubin increased
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 49 (8.16%)
    1 / 49 (2.04%)
         occurrences all number
    1
    10
    2
    Blood creatinine increased
    Additional description: Blood creatinine increased
         subjects affected / exposed
    9 / 50 (18.00%)
    6 / 49 (12.24%)
    9 / 49 (18.37%)
         occurrences all number
    29
    17
    20
    Gamma-glutamyltransferase increased
    Additional description: Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 49 (10.20%)
    3 / 49 (6.12%)
         occurrences all number
    3
    12
    5
    Neutrophil count decreased
    Additional description: Neutrophil count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences all number
    0
    1
    3
    Platelet count decreased
    Additional description: Platelet count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    5 / 49 (10.20%)
    3 / 49 (6.12%)
         occurrences all number
    0
    5
    3
    Weight decreased
    Additional description: Weight decreased
         subjects affected / exposed
    12 / 50 (24.00%)
    16 / 49 (32.65%)
    10 / 49 (20.41%)
         occurrences all number
    28
    22
    12
    White blood cell count decreased
    Additional description: White blood cell count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 49 (8.16%)
    2 / 49 (4.08%)
         occurrences all number
    0
    13
    2
    Alanine aminotransferase increased
    Additional description: Alanine aminotransferase increased
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 49 (10.20%)
    2 / 49 (4.08%)
         occurrences all number
    6
    8
    3
    Cardiac disorders
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    10 / 50 (20.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    23
    0
    0
    Nervous system disorders
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
         occurrences all number
    10
    3
    5
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 49 (8.16%)
    6 / 49 (12.24%)
         occurrences all number
    19
    6
    6
    Headache
    Additional description: Headache
         subjects affected / exposed
    7 / 50 (14.00%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
         occurrences all number
    26
    4
    2
    Neuropathy peripheral
    Additional description: Neuropathy peripheral
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    13
    0
    1
    Paraesthesia
    Additional description: Paraesthesia
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 49 (2.04%)
    1 / 49 (2.04%)
         occurrences all number
    7
    1
    1
    Peripheral sensory neuropathy
    Additional description: Peripheral sensory neuropathy
         subjects affected / exposed
    10 / 50 (20.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences all number
    38
    1
    0
    Spinal cord compression
    Additional description: Spinal cord compression
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    0
    6
    0
    Blood and lymphatic system disorders
    Platelet count decreased
    Additional description: Platelet count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    12 / 49 (24.49%)
    13 / 49 (26.53%)
         occurrences all number
    0
    38
    29
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    7 / 50 (14.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    13
    0
    0
    White blood cell count decreased
    Additional description: White blood cell count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
         occurrences all number
    0
    3
    2
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    45 / 50 (90.00%)
    37 / 49 (75.51%)
    32 / 49 (65.31%)
         occurrences all number
    198
    160
    130
    Leukopenia
    Additional description: Leukopenia
         subjects affected / exposed
    7 / 50 (14.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    30
    0
    0
    Lymphocyte count decreased
    Additional description: Lymphocyte count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 49 (8.16%)
    2 / 49 (4.08%)
         occurrences all number
    0
    9
    2
    Neutropenia
    Additional description: Neutropenia
         subjects affected / exposed
    9 / 50 (18.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    17
    0
    0
    Neutrophil count decreased
    Additional description: Neutrophil count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    7 / 49 (14.29%)
    7 / 49 (14.29%)
         occurrences all number
    0
    26
    13
    Gastrointestinal disorders
    Abdominal distension
    Additional description: Abdominal distension
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    5
    0
    0
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    2 / 50 (4.00%)
    10 / 49 (20.41%)
    5 / 49 (10.20%)
         occurrences all number
    2
    16
    5
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    13 / 50 (26.00%)
    8 / 49 (16.33%)
    7 / 49 (14.29%)
         occurrences all number
    34
    11
    7
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 49 (0.00%)
    5 / 49 (10.20%)
         occurrences all number
    2
    0
    5
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    28 / 50 (56.00%)
    15 / 49 (30.61%)
    18 / 49 (36.73%)
         occurrences all number
    69
    23
    29
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    12 / 50 (24.00%)
    15 / 49 (30.61%)
    9 / 49 (18.37%)
         occurrences all number
    22
    19
    11
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    11 / 50 (22.00%)
    11 / 49 (22.45%)
    9 / 49 (18.37%)
         occurrences all number
    27
    15
    10
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    23
    0
    0
    Nail disorder
    Additional description: Nail disorder
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    13
    0
    0
    Renal and urinary disorders
    Haematuria
    Additional description: Haematuria
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 49 (8.16%)
    4 / 49 (8.16%)
         occurrences all number
    15
    5
    4
    Hydronephrosis
    Additional description: Hydronephrosis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences all number
    2
    1
    3
    Nocturia
    Additional description: Nocturia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    3
    0
    1
    Pollakiuria
    Additional description: Pollakiuria
         subjects affected / exposed
    9 / 50 (18.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    49
    0
    0
    Urinary incontinence
    Additional description: Urinary incontinence
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    20
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
    Additional description: Musculoskeletal chest pain
         subjects affected / exposed
    5 / 50 (10.00%)
    8 / 49 (16.33%)
    3 / 49 (6.12%)
         occurrences all number
    8
    12
    4
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    20 / 50 (40.00%)
    15 / 49 (30.61%)
    12 / 49 (24.49%)
         occurrences all number
    84
    24
    17
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    26 / 50 (52.00%)
    14 / 49 (28.57%)
    18 / 49 (36.73%)
         occurrences all number
    103
    21
    26
    Bone pain
    Additional description: Bone pain
         subjects affected / exposed
    17 / 50 (34.00%)
    4 / 49 (8.16%)
    1 / 49 (2.04%)
         occurrences all number
    42
    6
    1
    Groin pain
    Additional description: Groin pain
         subjects affected / exposed
    7 / 50 (14.00%)
    3 / 49 (6.12%)
    3 / 49 (6.12%)
         occurrences all number
    28
    3
    3
    Muscle spasms
    Additional description: Muscle spasms
         subjects affected / exposed
    1 / 50 (2.00%)
    6 / 49 (12.24%)
    3 / 49 (6.12%)
         occurrences all number
    6
    7
    4
    Muscular weakness
    Additional description: Muscular weakness
         subjects affected / exposed
    7 / 50 (14.00%)
    6 / 49 (12.24%)
    4 / 49 (8.16%)
         occurrences all number
    17
    6
    4
    Musculoskeletal pain
    Additional description: Musculoskeletal pain
         subjects affected / exposed
    8 / 50 (16.00%)
    8 / 49 (16.33%)
    7 / 49 (14.29%)
         occurrences all number
    34
    10
    12
    Myopathy
    Additional description: Myopathy
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    12
    0
    0
    Neck pain
    Additional description: Neck pain
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
         occurrences all number
    19
    1
    3
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    14 / 50 (28.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    39
    0
    0
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
         occurrences all number
    7
    3
    1
    Infections and infestations
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    4 / 49 (8.16%)
         occurrences all number
    0
    2
    6
    Influenza like illness
    Additional description: Influenza like illness
         subjects affected / exposed
    0 / 50 (0.00%)
    5 / 49 (10.20%)
    3 / 49 (6.12%)
         occurrences all number
    0
    6
    4
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    5 / 50 (10.00%)
    8 / 49 (16.33%)
    6 / 49 (12.24%)
         occurrences all number
    5
    13
    6
    Metabolism and nutrition disorders
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    23 / 50 (46.00%)
    13 / 49 (26.53%)
    15 / 49 (30.61%)
         occurrences all number
    75
    14
    24
    Hyperglycaemia
    Additional description: Hyperglycaemia
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    4
    0
    1
    Hypoalbuminaemia
    Additional description: Hypoalbuminaemia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    3
    0
    0
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    6 / 50 (12.00%)
    8 / 49 (16.33%)
    3 / 49 (6.12%)
         occurrences all number
    17
    9
    4
    Hyponatraemia
    Additional description: Hyponatraemia
         subjects affected / exposed
    7 / 50 (14.00%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
         occurrences all number
    8
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2012
    Provide clarification to end of treatment and end of study definition, follow up time frames, assessment time frames and removal of data collection not necessary for study analysis.
    12 Nov 2012
    Updates of adverse events in line with Olaparib Investigator Brochure Edition 8. Clarification of the requirement for archival tumour tissue and fresh biopsy. Clarification that CTC count at screening must be confirmed by central laboratory. Additional guidance of fasting requirements prior to some blood sample collection. Addition of sample collection at specified time points
    15 Apr 2014
    Clarification of measurement of CTC conversion. Updated inclusion criteria on how long patients should be independent of transfusions for and albumin value. Clarification of the therapies not permitted after termination of olaparib use and recommended time before commencing a new anticancer treatment. Extension of CTC sample collection window prior to start of olaparib. Update to allow biopsy and blood samples taken prior to consent, within a specified window, to be used at screening. Addition of Coagulation studies at specified time points. Addition of whole genome sequencing.
    26 Jun 2015
    Specification of requirements and procedures for TOPARP A and TOPARP B. Addition of TOPARP B: patients will be randomised to receive 300mg or 400 mg twice daily. Amendment from 44 patients to 88 patients (44 in each group) in TOPARP B. Addition of the dose of 300mg ID to study the tolerability and antitumour activity of both dose level in TOPARP B. Patients receiving 300mg will be allowed to escalate to 400mg upon disease progression in clinically indicated. Amendment to modified RECIST 1.1 from modified RECIST. Removal of objective response (PSA-ORR) as secondary endpoint. Addition of secondary endpoint as percentage change of PSA from baseline to 12 weeks (or earlier if discontinued therapy) and maximise PSA decline while on treatment; TOPARP B only - Cmax and AUC after first dose and at steady state for the 400mg and 300mg BID dose levels. Addition of exploratory endpoint - TOPARP B only - to evaluate the response rate following dose-escalation from 300mg to 400mg BID. Addition of post confirmation of the presence of the putative predictive biomarkers in TOPARP B. Addition of pre-screening stage to confirm presence of biomarker. Addition of 250mg for dose reduction and removal of 100mg dose reduction. Clarification that fresh biopsy is optional in TOPARP B. Clarification that patients can be discontinued on clinical progression as well as radiological progression. Addition of pharmacokinetic analysis for TOPARP B.
    15 Mar 2018
    Updates of adverse events in line with olaparib Investigator Brochure Edition 14. Extension of follow up scans beyond 2 years whilst on study treatment. Clarification and updates of inclusion criteria. Updates to permitted windows and time pointes for study assessments. Updates on pharmacokinetic samples in line with PK sub-study closure. Update to SAE reporting period.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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