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    Clinical Trial Results:
    A Phase 3 Randomized, Open-label Study to Evaluate the Efficacy and Safety of Olaparib Alone or in Combination With Bevacizumab Compared to Bevacizumab with a Fluoropyrimidine in Participants with Unresectable or Metastatic Colorectal Cancer who Have Not Progressed Following First-line Induction (LYNK-003)

    Summary
    EudraCT number
    		 2019-000698-22
    Trial protocol
    		 BE   HU   FR   LT   LV  
    Global end of trial date
    06 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Nov 2024
    First version publication date
    03 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    7339-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04456699
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 jRCT2031200146: jRCT, LYNK-003: MSD
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@msd.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@msd.com
    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
    06 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is an efficacy and safety study of olaparib alone or in combination with bevacizumab being compared to bevacizumab with a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer who have not progressed following first-line induction. The primary hypotheses are: Olaparib + Bevacizumab is superior to a fluoropyrimidine + Bevacizumab with respect to progression-free survival (PFS) using Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR); Olaparib is superior to a fluoropyrimidine + Bevacizumab with respect to PFS using RECIST 1.1 as assessed by BICR. As of amendment 5 study enrollment is being discontinued and study participants randomized to one of the two experimental arms (olaparib plus bevacizumab or olaparib monotherapy) must discontinue study intervention. Participants who are still on study treatment will no longer have tumor response assessments by BICR.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Aug 2020
    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
    Australia: 13
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Japan: 56
    Country: Number of subjects enrolled
    Korea, Republic of: 33
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Türkiye: 40
    Country: Number of subjects enrolled
    Ukraine: 12
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    Chile: 10
    Country: Number of subjects enrolled
    Colombia: 28
    Worldwide total number of subjects
    335
    EEA total number of subjects
    89
    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)
    184
    From 65 to 84 years
    149
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Eligible participants were randomized 1:1:1 to receive either Olaparib + bevacizumab, Olaparib, or Bevacizumab + chemotherapy.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Olaparib + bevacizumab
    Arm description
    		 Participants received olaparib (300 mg twice daily [BID] oral) + Bevacizumab (5 mg/kg intravenous [IV] once every 2 weeks [Q2W]) until progressive disease or end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    MVASI^TM Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg or 7.5 mg/kg Q2W or Q3W IV infusion until progressive disease or end of study

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    LYNPARZA^TM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg BID, oral until progressive disease or end of study

    Arm title
    		 Olaparib
    Arm description
    		 Participants received olaparib (300 mg BID) oral, until progressive disease or end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    LYNPARZA^TM
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg BID, oral until progressive disease or end of study

    Arm title
    		 Bevacizumab + chemotherapy
    Arm description
    		 Participants received investigator's choice of either bevacizumab (7.5 mg/kg IV once every three weeks (Q3W)) + capecitabine (1000 mg/m^2 BID for 14 days, then 7 days off, Q3W) or bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W; bolus 5-FU (400 mg/m2) was added prior to infusional 5-FU, per local standards and at the investigator's discretion). Leucovorin or levoleucovorin 400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) Q2W IV infusion was added per investigator's discretion. Treatment continued until progressive disease or end of study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Fluorouracil Adrucil Efudex
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2400 mg/m^2 over 46 to 48 hours Q2W IV infusion until disease progression or end of study; bolus 5-FU (400mg/m2) can be added prior to infusional 5-FU, per local standards and at the investigator’s discretion

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    XELODA^®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m^2 oral capsule BID for 14 days, then 7 days off, Q3W) until progressive disease or end of study

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    MVASI^TM Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg or 7.5 mg/kg Q2W or Q3W IV infusion until progressive disease or end of study

    Investigational medicinal product name
    Leucovorin/ levoleucovorin
    Investigational medicinal product code
    Other name
    Folinic Acid Fusilev^® Khapzory^TM
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) may be added to Bevacizumab + 5-FU per investigator’s discretion Q2W IV infusion until progressive disease or end of study

    Number of subjects in period 1
    		Olaparib + bevacizumab Olaparib Bevacizumab + chemotherapy
    Started
    111
    115
    109
    Treated
    111
    113
    108
    Completed
    0
    0
    0
    Not completed
    111
    115
    109
         Adverse event, serious fatal
    48
    50
    52
         Consent withdrawn by subject
    8
    4
    5
         Physician decision
    -
    -
    2
         Sponsor Decision
    55
    61
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Olaparib + bevacizumab
    Reporting group description
    		 Participants received olaparib (300 mg twice daily [BID] oral) + Bevacizumab (5 mg/kg intravenous [IV] once every 2 weeks [Q2W]) until progressive disease or end of study.

    Reporting group title
    Olaparib
    Reporting group description
    		 Participants received olaparib (300 mg BID) oral, until progressive disease or end of study.

    Reporting group title
    Bevacizumab + chemotherapy
    Reporting group description
    		 Participants received investigator's choice of either bevacizumab (7.5 mg/kg IV once every three weeks (Q3W)) + capecitabine (1000 mg/m^2 BID for 14 days, then 7 days off, Q3W) or bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W; bolus 5-FU (400 mg/m2) was added prior to infusional 5-FU, per local standards and at the investigator's discretion). Leucovorin or levoleucovorin 400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) Q2W IV infusion was added per investigator's discretion. Treatment continued until progressive disease or end of study.

    Reporting group values
    		 Olaparib + bevacizumab Olaparib Bevacizumab + chemotherapy Total
    Number of subjects
    		 111 115 109 335
    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)
    		 68 66 50 184
        From 65-84 years
    		 42 49 58 149
        85 years and over
    		 1 0 1 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.5 ( 12.8 ) 61.1 ( 10.7 ) 63.2 ( 11.3 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 50 49 44 143
        Male
    		 61 66 65 192
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 10 5 4 19
        Asian
    		 25 40 30 95
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 1 1
        White
    		 71 64 66 201
        More than one race
    		 2 3 4 9
        Unknown or Not Reported
    		 3 3 4 10
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 18 16 10 44
        Not Hispanic or Latino
    		 88 93 94 275
        Unknown or Not Reported
    		 5 6 5 16
    Response to Prior Induction
    Participants last scan prior to folinic acid/fluorouracil/oxaliplatin (FOLFOX) + bevacizumab or capecitabine and oxaliplatin (CAPOX) + bevacizumab treatment was assessed by blinded independent central review (BICR) per (Response Evaluation Criteria in Solid Tumors RECIST) 1.1 criteria to evaluate presence of stable disease (SD; Neither sufficient shrinkage to qualify for partial response [PR] nor sufficient increase to qualify for progressive disease), complete response (CR; Disappearance of all target lesions) or PR (At least a 30% decrease in sum of diameters of target lesions).
    Units: Subjects
        CR/PR
    		 49 48 47 144
        Stable Disease (SD)
    		 62 67 62 191
    Number of Induction Cycles
    Number of induction cycles received was assessed at the baseline and categorized as: 1) 6-8 cycles for FOLFOX + bevacizumab or 4-6 cycles for CAPOX + bevacizumab and 2) >8 cycles for FOLFOX + bevacizumab or >6 cycles for CAPOX + bevacizumab.
    Units: Subjects
        6-8cycles of FOLFOX+Bev or 4-6cycles of CAPOX+Bev
    		 53 57 53 163
        >8cycles of FOLFOX+Bev or >6cycles for CAPOX+Bev
    		 58 58 56 172
    Mutation Status
    Participants were assessed for BRAF and/or Ras mutations versus wild type for both (BRAFwt + RASwt) at baseline.
    Units: Subjects
        BRAF and RAS all wild type
    		 32 33 29 94
        BRAF or RAS Mutation
    		 79 82 80 241

    End points

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    End points reporting groups
    Reporting group title
    Olaparib + bevacizumab
    Reporting group description
    		 Participants received olaparib (300 mg twice daily [BID] oral) + Bevacizumab (5 mg/kg intravenous [IV] once every 2 weeks [Q2W]) until progressive disease or end of study.

    Reporting group title
    Olaparib
    Reporting group description
    		 Participants received olaparib (300 mg BID) oral, until progressive disease or end of study.

    Reporting group title
    Bevacizumab + chemotherapy
    Reporting group description
    		 Participants received investigator's choice of either bevacizumab (7.5 mg/kg IV once every three weeks (Q3W)) + capecitabine (1000 mg/m^2 BID for 14 days, then 7 days off, Q3W) or bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W; bolus 5-FU (400 mg/m2) was added prior to infusional 5-FU, per local standards and at the investigator's discretion). Leucovorin or levoleucovorin 400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) Q2W IV infusion was added per investigator's discretion. Treatment continued until progressive disease or end of study.

    Primary: Progression Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Progression Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 as Assessed by Blinded Independent Central Review (BICR)
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS using RECIST 1.1 as assessed by BICR is presented. The analysis population included all randomized participants.
    End point type
    Primary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Olaparib + bevacizumab Olaparib Bevacizumab + chemotherapy
    Number of subjects analysed
    111
    115
    109
    Units: Months
        median (confidence interval 95%)
    3.7 (3.4 to 5.3)
    3.6 (2.0 to 3.7)
    5.5 (3.8 to 5.6)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior FOLFOX/CAPOX + Bev induction response, number of induction cycles and mutation status.
    Comparison groups
    Olaparib + bevacizumab v Bevacizumab + chemotherapy
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9774 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.97
    Notes
    [1] - One-sided p-value based on log-rank test stratified by prior FOLFOX/CAPOX + Bev induction response, number of induction cycles and mutation status.
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior FOLFOX/CAPOX + Bev induction response, number of induction cycles and mutation status.
    Comparison groups
    Olaparib v Bevacizumab + chemotherapy
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9993 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 2.49
    Notes
    [2] - One-sided p-value based on log-rank test stratified by prior FOLFOX/CAPOX + Bev induction response, number of induction cycles and mutation status.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause. The OS is presented. A value of 9999 indicates that no data were calculated. The analysis population consists of all randomized participants.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Olaparib + bevacizumab Olaparib Bevacizumab + chemotherapy
    Number of subjects analysed
    111
    115
    109
    Units: Months
        median (confidence interval 95%)
    21.2 (15.1 to 9999)
    21.6 (17.2 to 9999)
    19.9 (13.8 to 22.5)
    Statistical analysis title
    		 Hazard Ratio
    Comparison groups
    Olaparib v Bevacizumab + chemotherapy
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.2491 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.3
    Notes
    [3] - Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior FOLFOX/CAPOX + Bev induction response, number of induction cycles and mutation status.
    [4] - One-sided p-value based on log-rank test stratified by prior FOLFOX/CAPOX + Bev induction response, number of induction cycles and mutation status.
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior FOLFOX/CAPOX + Bev induction response, number of induction cycles and mutation status.
    Comparison groups
    Olaparib + bevacizumab v Bevacizumab + chemotherapy
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1527 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.21
    Notes
    [5] - One-sided p-value based on log-rank test stratified by prior FOLFOX/CAPOX + Bev induction response, number of induction cycles and mutation status.

    Secondary: Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR

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    End point title
    		 Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR
    End point description
    ORR was defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The analysis population consisted of all randomized participants who had a measurable disease.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Olaparib + bevacizumab Olaparib Bevacizumab + chemotherapy
    Number of subjects analysed
    104
    107
    105
    Units: Percentage of Participants
        number (confidence interval 95%)
    4.8 (1.6 to 10.9)
    1.9 (0.2 to 6.6)
    4.8 (1.6 to 10.8)
    Statistical analysis title
    		 Hazards Ratio
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by prior FOLFOX/CAPOX + Bev induction response, cycles and mutation status.
    Comparison groups
    Olaparib v Bevacizumab + chemotherapy
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.902 [6]
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.7
         upper limit
    		 2.3
    Notes
    [6] - Based on stratified Miettinen & Nurminen method. One-sided p-value for testing H0: difference in % = 0 versus H1: difference in % > 0.
    Statistical analysis title
    		 Difference in Percentage
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by prior FOLFOX/CAPOX + Bev induction response, cycles and mutation status.
    Comparison groups
    Olaparib + bevacizumab v Bevacizumab + chemotherapy
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5272 [7]
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 6.5
    Notes
    [7] - Based on stratified Miettinen & Nurminen method. One-sided p-value for testing H0: difference in % = 0 versus H1: difference in % > 0.

    Secondary: Number of Participants with One or More Adverse Events (AE)

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    End point title
    		 Number of Participants with One or More Adverse Events (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced at least one AE was reported for each arm. The analysis population included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Olaparib + bevacizumab Olaparib Bevacizumab + chemotherapy
    Number of subjects analysed
    111
    113
    108
    Units: Participants
    101
    91
    96
    No statistical analyses for this end point

    Secondary: Number of Participants Discontinuing Study Intervention Due to an AE

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    End point title
    		 Number of Participants Discontinuing Study Intervention Due to an AE
    End point description
    An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued study intervention due to an AE was reported for each arm. The analysis population included all randomized participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Olaparib + bevacizumab Olaparib Bevacizumab + chemotherapy
    Number of subjects analysed
    111
    113
    108
    Units: Participants
    6
    4
    7
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR

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    End point title
    		 Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR
    End point description
    For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least 30% decrease in the sum of diameters [SD] of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis will be censored at the date of their last tumor assessment. Per RECIST 1.1, PD is defined as at least 20% increase in SD of target lesions and an absolute increase of at least 5 mm in SD. The appearance of one or more new lesions is also considered PD. DOR assessments were based on BICR with confirmation. The DOR as assessed using RECIST 1.1 for all participants who experience a confirmed CR or PR will be presented. A value of 9999 indicates that no data were calculated. The analysis population included all randomized participants who received at least one dose of treatment and had either a CR or a PR.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Olaparib + bevacizumab Olaparib Bevacizumab + chemotherapy
    Number of subjects analysed
    5
    2
    5
    Units: Months
        median (confidence interval 95%)
    9999 (3.6 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 38 months
    Adverse event reporting additional description
    All-cause mortality=all randomized participants (n=335) & adverse events (AEs)=participants who received ≥1 dose of study treatment. MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" unrelated to study treatment were excluded as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Olaparib + Bevacizumab
    Reporting group description
    		 Participants received olaparib (300 mg twice daily [BID] oral) + Bevacizumab (5 mg/kg intravenous [IV] once every 2 weeks [Q2W]) until progressive disease or end of study.

    Reporting group title
    Bevacizumab + Chemotherapy
    Reporting group description
    		 Participants received investigator's choice of either bevacizumab (7.5 mg/kg IV once every three weeks (Q3W)) + capecitabine (1000 mg/m^2 BID for 14 days, then 7 days off, Q3W) or bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W; bolus 5-FU (400 mg/m2) was added prior to infusional 5-FU, per local standards and at the investigator's discretion). Leucovorin or levoleucovorin 400 mg/m^2 (leucovorin) or 200 mg/m^2 (levoleucovorin) Q2W IV infusion was added per investigator's discretion. Treatment continued until progressive disease or end of study.

    Reporting group title
    Olaparib
    Reporting group description
    		 Participants received olaparib (300 mg BID) oral, until progressive disease or end of study.

    Serious adverse events
    		 Olaparib + Bevacizumab Bevacizumab + Chemotherapy Olaparib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 111 (14.41%)
    14 / 108 (12.96%)
    13 / 113 (11.50%)
         number of deaths (all causes)
    49
    52
    51
         number of deaths resulting from adverse events
    2
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Injury, poisoning and procedural complications
    Stoma site haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Acute coronary syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Cardiac failure
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Duodenal stenosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Enteritis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Rectal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    2 / 113 (1.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Large intestinal obstruction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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 perforation
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Intestinal obstruction
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 108 (0.93%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Small intestinal perforation
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Gastric haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Vomiting
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 108 (1.85%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 108 (0.93%)
    0 / 113 (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
    Pathological fracture
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    COVID-19
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 108 (0.93%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         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
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Peritonsillar abscess
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Peritonitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Parotitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Large intestine infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Escherichia sepsis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Pneumonia
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Septic shock
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Skin candida
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 108 (0.93%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Hypervolaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 108 (0.93%)
    0 / 113 (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
    Dehydration
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 108 (0.00%)
    0 / 113 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Olaparib + Bevacizumab Bevacizumab + Chemotherapy Olaparib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    94 / 111 (84.68%)
    86 / 108 (79.63%)
    74 / 113 (65.49%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 111 (4.50%)
    6 / 108 (5.56%)
    6 / 113 (5.31%)
         occurrences all number
    6
    8
    7
    Blood creatinine increased
         subjects affected / exposed
    4 / 111 (3.60%)
    6 / 108 (5.56%)
    2 / 113 (1.77%)
         occurrences all number
    4
    9
    2
    Weight decreased
         subjects affected / exposed
    7 / 111 (6.31%)
    6 / 108 (5.56%)
    2 / 113 (1.77%)
         occurrences all number
    7
    6
    2
    Platelet count decreased
         subjects affected / exposed
    2 / 111 (1.80%)
    7 / 108 (6.48%)
    6 / 113 (5.31%)
         occurrences all number
    3
    8
    7
    Neutrophil count decreased
         subjects affected / exposed
    9 / 111 (8.11%)
    3 / 108 (2.78%)
    7 / 113 (6.19%)
         occurrences all number
    20
    5
    8
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 111 (9.91%)
    10 / 108 (9.26%)
    0 / 113 (0.00%)
         occurrences all number
    12
    13
    0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    3 / 111 (2.70%)
    4 / 108 (3.70%)
    7 / 113 (6.19%)
         occurrences all number
    5
    4
    7
    Headache
         subjects affected / exposed
    7 / 111 (6.31%)
    3 / 108 (2.78%)
    1 / 113 (0.88%)
         occurrences all number
    7
    3
    1
    Dysgeusia
         subjects affected / exposed
    10 / 111 (9.01%)
    3 / 108 (2.78%)
    3 / 113 (2.65%)
         occurrences all number
    12
    4
    4
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    7 / 111 (6.31%)
    2 / 108 (1.85%)
    1 / 113 (0.88%)
         occurrences all number
    8
    2
    1
    Neutropenia
         subjects affected / exposed
    9 / 111 (8.11%)
    1 / 108 (0.93%)
    5 / 113 (4.42%)
         occurrences all number
    14
    3
    6
    Anaemia
         subjects affected / exposed
    32 / 111 (28.83%)
    8 / 108 (7.41%)
    21 / 113 (18.58%)
         occurrences all number
    35
    9
    25
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 111 (14.41%)
    11 / 108 (10.19%)
    8 / 113 (7.08%)
         occurrences all number
    22
    14
    8
    Fatigue
         subjects affected / exposed
    14 / 111 (12.61%)
    10 / 108 (9.26%)
    15 / 113 (13.27%)
         occurrences all number
    15
    11
    15
    Pyrexia
         subjects affected / exposed
    10 / 111 (9.01%)
    7 / 108 (6.48%)
    5 / 113 (4.42%)
         occurrences all number
    10
    9
    5
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    8 / 111 (7.21%)
    2 / 108 (1.85%)
    4 / 113 (3.54%)
         occurrences all number
    9
    2
    5
    Abdominal pain
         subjects affected / exposed
    19 / 111 (17.12%)
    13 / 108 (12.04%)
    8 / 113 (7.08%)
         occurrences all number
    22
    14
    8
    Vomiting
         subjects affected / exposed
    13 / 111 (11.71%)
    11 / 108 (10.19%)
    7 / 113 (6.19%)
         occurrences all number
    17
    14
    13
    Stomatitis
         subjects affected / exposed
    8 / 111 (7.21%)
    11 / 108 (10.19%)
    4 / 113 (3.54%)
         occurrences all number
    9
    13
    4
    Nausea
         subjects affected / exposed
    31 / 111 (27.93%)
    24 / 108 (22.22%)
    23 / 113 (20.35%)
         occurrences all number
    38
    35
    26
    Diarrhoea
         subjects affected / exposed
    11 / 111 (9.91%)
    15 / 108 (13.89%)
    9 / 113 (7.96%)
         occurrences all number
    16
    15
    9
    Constipation
         subjects affected / exposed
    16 / 111 (14.41%)
    14 / 108 (12.96%)
    11 / 113 (9.73%)
         occurrences all number
    18
    15
    11
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    6 / 111 (5.41%)
    4 / 108 (3.70%)
    0 / 113 (0.00%)
         occurrences all number
    7
    6
    0
    Cough
         subjects affected / exposed
    6 / 111 (5.41%)
    3 / 108 (2.78%)
    3 / 113 (2.65%)
         occurrences all number
    6
    3
    3
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 111 (0.90%)
    8 / 108 (7.41%)
    0 / 113 (0.00%)
         occurrences all number
    1
    8
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 111 (0.90%)
    10 / 108 (9.26%)
    3 / 113 (2.65%)
         occurrences all number
    1
    13
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    6 / 111 (5.41%)
    5 / 108 (4.63%)
    1 / 113 (0.88%)
         occurrences all number
    6
    7
    1
    Back pain
         subjects affected / exposed
    8 / 111 (7.21%)
    8 / 108 (7.41%)
    3 / 113 (2.65%)
         occurrences all number
    8
    9
    3
    Arthralgia
         subjects affected / exposed
    9 / 111 (8.11%)
    8 / 108 (7.41%)
    7 / 113 (6.19%)
         occurrences all number
    13
    9
    8
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    5 / 111 (4.50%)
    6 / 108 (5.56%)
    4 / 113 (3.54%)
         occurrences all number
    6
    9
    4
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    10 / 108 (9.26%)
    1 / 113 (0.88%)
         occurrences all number
    0
    12
    1
    Decreased appetite
         subjects affected / exposed
    15 / 111 (13.51%)
    12 / 108 (11.11%)
    18 / 113 (15.93%)
         occurrences all number
    15
    13
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2019
    The major changes of Amendment 1 (AM1) were addition of routine urinalysis prior to each dose of bevacizumab in Arms 1 & 3 and prior to Day 1 of each cycle in Arm 2, clarified reporting of Myelo Dysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) diagnosis throughout the study, clarified the definition of uncontrolled hypertension and clarified that participants with persistent alopecia and/or Grade ≤3 neuropathy from previous anticancer therapy were no longer excluded.
    19 May 2020
    The major changes of AM2 were addition of blood draws for olaparib pharmacokinetics and added information on participants who began treatment with bevacizumab must remain on bevacizumab throughout the study and participants who began treatment with biosimilar bevacizumab must remain on the same biosimilar throughout the study.
    22 Nov 2021
    The major changes of AM3 were addition of Blinded Independent Central Review (BICR) confirmation of non-PD status prior to randomization and added dose of Bevacizumab for Arm 3.
    05 Jan 2022
    The major changes of AM4 were addition of information related to need for confirmation of non-PD by BICR from induction imaging and the timing of the submission and addition of leucovorin to list of medications whose label must be checked for prohibited concomitant medications.
    26 Oct 2022
    The major changes of AM5 were stopped study enrollment due to futility and study participants discontinued study intervention and no crossover from either experimental arm to Standard of Care (SOC) arm was allowed. Participants on SOC were allowed to continue receiving study intervention until criteria for discontinuation is met at the discretion of the investigator.

    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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