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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind Study of Pembrolizumab (MK-3475) Plus Docetaxel Plus Prednisone versus Placebo Plus Docetaxel Plus Prednisone in Participants with Chemotherapy naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC) who have Progressed on a Next Generation Hormonal Agent (NHA) (KEYNOTE-921)

    Summary
    EudraCT number
    		 2018-004116-22
    Trial protocol
    		 AT   DE   NL   GB   ES   FR   IE   IT  
    Global end of trial date
    18 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2024
    First version publication date
    06 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-3475-921
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03834506
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck: KEYNOTE-921
    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@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.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
    18 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and docetaxel in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC but have progressed on or are intolerant to Next Generation Hormonal Agent (NHA).
    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
    02 May 2019
    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
    Argentina: 53
    Country: Number of subjects enrolled
    Australia: 33
    Country: Number of subjects enrolled
    Austria: 25
    Country: Number of subjects enrolled
    Brazil: 16
    Country: Number of subjects enrolled
    Canada: 57
    Country: Number of subjects enrolled
    Chile: 20
    Country: Number of subjects enrolled
    China: 21
    Country: Number of subjects enrolled
    Colombia: 55
    Country: Number of subjects enrolled
    France: 135
    Country: Number of subjects enrolled
    Germany: 53
    Country: Number of subjects enrolled
    Ireland: 16
    Country: Number of subjects enrolled
    Israel: 34
    Country: Number of subjects enrolled
    Italy: 51
    Country: Number of subjects enrolled
    Japan: 80
    Country: Number of subjects enrolled
    Korea, Republic of: 34
    Country: Number of subjects enrolled
    Netherlands: 56
    Country: Number of subjects enrolled
    Russian Federation: 71
    Country: Number of subjects enrolled
    Spain: 87
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    United States: 87
    Worldwide total number of subjects
    1030
    EEA total number of subjects
    423
    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)
    225
    From 65 to 84 years
    793
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of the 1030 participants randomized in the MK-3475-921 global study, 21 participants were also included in the China extension study for MK-3475-921 (NCT04907227).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab + Docetaxel
    Arm description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly received dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg via IV infusion

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    TAXOTERE®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    docetaxel 75 mg/m^2 by IV infusion

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg by oral tablets

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    DECADRON®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg by oral tablets

    Arm title
    		 Placebo + Docetaxel
    Arm description
    		 Participants received placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly received dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
    Arm type
    		 Placebo Comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    TAXOTERE®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    docetaxel 75 mg/m^2 by IV infusion

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    DECADRON®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg by oral tablets

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg by oral tablets

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Normal saline or dextrose infusion
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose-matched placebo by IV infusion

    Number of subjects in period 1
    		Pembrolizumab + Docetaxel Placebo + Docetaxel
    Started
    515
    515
    Treated
    514
    514
    Completed
    0
    0
    Not completed
    515
    515
         Consent withdrawn by subject
    10
    8
         Physician decision
    3
    1
         Death
    336
    326
         Withdrawal by Parent/Guardian
    1
    1
         Sponsor decision
    165
    178
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab + Docetaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly received dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.

    Reporting group title
    Placebo + Docetaxel
    Reporting group description
    		 Participants received placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly received dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.

    Reporting group values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel Total
    Number of subjects
    		 515 515 1030
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 120 105 225
        From 65-84 years
    		 386 407 793
        85 years and over
    		 9 3 12
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 69.9 ( 7.9 ) 70.4 ( 7.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 0 0 0
        Male
    		 515 515 1030
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 6 8 14
        Asian
    		 78 76 154
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 13 13 26
        White
    		 401 399 800
        More than one race
    		 15 18 33
        Unknown or Not Reported
    		 1 1 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 79 77 156
        Not Hispanic or Latino
    		 402 393 795
        Unknown or Not Reported
    		 34 45 79
    Prior Treatment with a Next Generation Hormonal Agent (NHA): Abiraterone Acetate
    Participants were stratified according to prior treatment with abiraterone acetate. Participants were eligible for the study if they had received prior treatment with a NHA (abiraterone acetate) for metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (CRPC) and either progressed after treatment or became intolerant of the drug.
    Units: Subjects
        Yes: Prior Treatment with NHA
    		 278 277 555
        No: Prior Treatment with NHA
    		 237 238 475
    Type of Metastases at Baseline
    Participants were stratified by the type of metastases present at baseline determined by blinded independent central review. If the metastases were only in the bone the participants were categorized as bone only. If the metastases were not in the bone, but in the liver, participants were categorized as liver. All other participants were categorized as other.
    Units: Subjects
        Bone only
    		 268 239 507
        Liver
    		 34 33 67
        Other
    		 213 243 456
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    Participants were classified by ECOG PS defined as: ECOG=0: Fully active, able to carry out all pre-disease performance with no restriction; ECOG=1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; ECOG=2: Ambulatory and capable of all self-care but unable to carry out work activities, up and about >50% of waking hours; ECOG=3: Capable of only limited self-care, confined to bed or chair >50% of waking hours; ECOG=4: Completely disabled, cannot carry out self-care, totally confined to bed or chair; ECOG=5: Dead
    Units: Subjects
        ECOG = 0
    		 298 286 584
        ECOG = 1
    		 212 227 439
        ECOG = 2
    		 0 0 0
        ECOG = 3
    		 0 0 0
        ECOG = 4
    		 1 0 1
        ECOG = 5
    		 0 0 0
        Missing
    		 4 2 6

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab + Docetaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly received dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.

    Reporting group title
    Placebo + Docetaxel
    Reporting group description
    		 Participants received placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly received dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.

    Primary: 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 was calculated using the product-limit Kaplan-Meier (K-M) method for censored data. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. This was analyzed in all randomized participants in the intent to treat (ITT) population who had data available.
    End point type
    Primary
    End point timeframe
    Up to 36.5 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    515
    515
    Units: Months
        median (confidence interval 95%)
    19.6 (18.2 to 20.9)
    19.0 (17.9 to 20.9)
    Statistical analysis title
    		 OS
    Comparison groups
    Pembrolizumab + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1030
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.1677 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.09
    Notes
    [1] - HR based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior treatment with a NHA (abiraterone acetate) and type of metastases at baseline.
    [2] - One-sided p-value based on log-rank test stratified by prior treatment with a NHA (abiraterone acetate) and type of metastases at baseline.

    Primary: Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
    End point description
    rPFS was defined as the time from randomization to occurrence of: radiological tumor progression using RECIST 1.1 as assessed by BICR; progression of bone lesions using PCWG criteria; or death due to any cause. Radiological progression as per RECIST 1.1 was ≥20% increase in sum of diameters of target lesions and progression of existing non-target lesions. Progression of bone lesions by PCWG criteria was the appearance of ≥2 new bone lesions on bone scan, that have been confirmed to not represent tumor flare, and was persistent for ≥6 weeks. The rPFS was calculated using the product-limit K-M method for censored data. Participants without a rPFS event were censored at the date of last disease assessment. This was analyzed in all randomized participants in the ITT population who had data available.
    End point type
    Primary
    End point timeframe
    Up to approximately 28 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    515
    515
    Units: Months
        median (confidence interval 95%)
    8.6 (8.3 to 10.2)
    8.3 (8.2 to 8.5)
    Statistical analysis title
    		 rPFS
    Comparison groups
    Pembrolizumab + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1030
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0335 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.01
    Notes
    [3] - HR based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.
    [4] - One-sided p-value based on log-rank test stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.

    Secondary: Time to Initiation of the First Subsequent Anti-cancer Therapy (TFST)

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    End point title
    		 Time to Initiation of the First Subsequent Anti-cancer Therapy (TFST)
    End point description
    TFST was defined as the time from randomization to initiation of the first subsequent anti-cancer therapy or death; whichever occurred first. The TFST was calculated using the product-limit K-M method for censored data. Any participant not known to have further subsequent therapy or death was censored at the last known time that no subsequent new anti-cancer therapy was received. This was analyzed in all randomized participants in the ITT population who had data available.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    515
    515
    Units: Months
        median (confidence interval 95%)
    10.7 (10.4 to 11.1)
    10.4 (9.7 to 11.1)
    Statistical analysis title
    		 TFST
    Comparison groups
    Pembrolizumab + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1030
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0331 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.01
    Notes
    [5] - HR based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.
    [6] - One-sided p-value based on log-rank test stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.

    Secondary: Prostate-specific Antigen (PSA) Response Rate

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    End point title
    		 Prostate-specific Antigen (PSA) Response Rate
    End point description
    The Prostate-specific Antigen (PSA) response rate was the percentage of participants who had PSA response defined as a reduction in the PSA level from baseline by ≥50%. The reduction in PSA level was confirmed by an additional PSA evaluation performed ≥3 weeks from the original response. The analysis was performed on participants who had baseline PSA measurements. This was analyzed in all randomized participants in the ITT population, who had a PSA measurement at baseline, and had data available.
    End point type
    Secondary
    End point timeframe
    Up to 36.5 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    474
    486
    Units: Percentage of participants
        number (confidence interval 95%)
    44.5 (40.0 to 49.1)
    45.7 (41.2 to 50.2)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Objective Response Rate (ORR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
    End point description
    ORR was defined as the percentage of participants with complete response (CR: disappearance of all target lesions per RECIST 1.1; and no evidence of disease (NED) on bone scan per PCWG) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1; and non-progressive disease, non-evaluable [NE], or NED on bone scan or CR with non-progressive disease or NE bone scan per PCWG). This was analyzed in all randomized participants in the ITT population, with measurable disease at baseline, who had data available.
    End point type
    Secondary
    End point timeframe
    Up to 36.5 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    203
    221
    Units: Percentage of participants
        number (confidence interval 95%)
    33.5 (27.0 to 40.4)
    35.3 (29.0 to 42.0)
    Statistical analysis title
    		 ORR
    Comparison groups
    Pembrolizumab + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6545 [7]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Percent Difference
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.7
         upper limit
    		 7.1
    Notes
    [7] - Based on Miettinen & Nurminen method stratified by prior treatment with a NHA (abiraterone acetate) and type of metastases at baseline.

    Secondary: Duration of Response (DOR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Duration of Response (DOR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
    End point description
    DOR was the time from first evidence of complete response (CR: disappearance of all target lesions per RECIST 1.1; and no evidence of disease [NED] on bone scan per PCWG) or partial response (PR: ≥30% decrease in the sum of diameters of target lesions per RECIST 1.1; and non-progressive disease, non-evaluable [NE], or NED on bone scan or CR with non-progressive disease or NE bone scan per PCWG) until progressive disease (PD) or death. PD was ≥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. PD per PCWG was the appearance of ≥2 new bone lesions on bone scan that don’t represent tumor flare and persisted for ≥6 weeks. The DOR was calculated using the product-limit K-M method. Participants who did not progress were censored at the date of last assessment. This was analyzed in all randomized participants in the ITT population, who had CR or PR, and data available.
    End point type
    Secondary
    End point timeframe
    Up to 36.5 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    68
    78
    Units: Months
        median (confidence interval 95%)
    6.3 (6.1 to 7.8)
    6.2 (6.2 to 6.4)
    No statistical analyses for this end point

    Secondary: Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24 Hours") and Opiate Analgesic Use Assessed by the Analgesic Quantification Algorithm (AQA) Score

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    End point title
    		 Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24 Hours") and Opiate Analgesic Use Assessed by the Analgesic Quantification Algorithm (AQA) Score
    End point description
    TTPP was the time from randomization to pain progression (PP) per BPI-SF Item 3 and AQA score. For BPI-SF item 3, participant responses to “Please rate your worst pain in the last 24 hours” are scored from 0 (no pain) to 10 (worst pain). A higher score means greater pain. AQA captures analgesic use, scored from 0 (no analgesic) to 7 (strong use). A higher score means higher intensity of use. Asymptomatic at baseline (BL): PP is ≥2-point change from BL (CBL) in item 3 score OR opioid use initiation. Symptomatic at BL: PP is ≥2-point CBL in Item 3 score, a score of ≥4 and no decrease in average opioid use OR increase in use. Participants with >2 consecutive unevaluable visits were censored at the last assessment. This was analyzed by K-M method in all participants in the patient-reported outcomes (PRO) full analysis set (FAS) who got ≥1 dose of study drug and had PRO data available. 9999: value not reached at time of data cutoff due to insufficient number of participants with an event.
    End point type
    Secondary
    End point timeframe
    Up to 36.5 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    507
    502
    Units: Months
        median (confidence interval 95%)
    21.1 (13.7 to 9999)
    9999 (13.8 to 9999)
    Statistical analysis title
    		 TTPP
    Comparison groups
    Pembrolizumab + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1009
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.6178 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.43
    Notes
    [8] - HR based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.
    [9] - One-sided p-value based on log-rank test stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.

    Secondary: Time to First Symptomatic Skeletal-related Event (SSRE)

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    End point title
    		 Time to First Symptomatic Skeletal-related Event (SSRE)
    End point description
    SSRE was the time from randomization to the first symptomatic skeletal-related event defined as: 1. Use of external-beam radiation therapy (EBRT) to prevent or relieve skeletal symptoms 2. Occurrence of new symptomatic pathologic bone fracture (vertebral or non-vertebral) 3. Occurrence of spinal cord compression 4. Tumor-related orthopedic surgical intervention, whichever occurs first. The SSRE was calculated using the product-limit K-M method for censored data. Participants without symptomatic skeletal-related events were censored at the last evaluable assessment. This was analyzed in all randomized participants in the ITT population who had data available. 9999: Value not reached at time of data cutoff due to insufficient number of participants with an event.
    End point type
    Secondary
    End point timeframe
    Up to 36.5 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    515
    515
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 SSRE
    Comparison groups
    Pembrolizumab + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1030
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.9788 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.33
    Notes
    [10] - HR based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.
    [11] - One-sided p-value based on log-rank test stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.

    Secondary: Time to Prostate-specific Antigen (PSA) Progression

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    End point title
    		 Time to Prostate-specific Antigen (PSA) Progression
    End point description
    The time to PSA progression was the time from randomization to PSA progression. The PSA progression date was defined as the date of: 1. ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second value ≥3 weeks later if there was PSA decline from baseline; OR 2. ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there was no PSA decline from baseline Time to PSA progression was calculated using the product-limit K-M method for censored data. Participants without PSA progression were censored at the last evaluable assessment. This was analyzed in all randomized participants in the ITT population, who had a PSA measurement at baseline, and had data available.
    End point type
    Secondary
    End point timeframe
    Up to 36.5 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    515
    515
    Units: Months
        median (confidence interval 95%)
    6.9 (6.2 to 7.6)
    7.0 (6.3 to 7.6)
    Statistical analysis title
    		 Time to PSA Progression
    Comparison groups
    Pembrolizumab + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1030
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.297 [13]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.12
    Notes
    [12] - HR based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.
    [13] - One-sided p-value based on log-rank test stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.

    Secondary: Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

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    End point title
    		 Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
    End point description
    The time to radiographic soft tissue progression was defined as the time from randomization to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1 as assessed by BICR. Progression 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 have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered progression. Time to radiographic soft tissue progression was calculated using the product-limit K-M method for censored data. Participants without radiographic soft tissue progression were censored at the last evaluable assessment. This was analyzed in all randomized participants in the ITT population who had data available.
    End point type
    Secondary
    End point timeframe
    Up to 36.5 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    515
    515
    Units: Months
        median (confidence interval 95%)
    12.4 (10.7 to 14.9)
    11.2 (10.4 to 12.5)
    Statistical analysis title
    		 Time to Radiographic Soft Tissue Progression
    Comparison groups
    Pembrolizumab + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1030
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.2876 [15]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.15
    Notes
    [14] - HR based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.
    [15] - One-sided p-value based on log-rank test stratified by prior treatment with NHA (abiraterone acetate) and type of metastases at baseline.

    Secondary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE)
    End point description
    An AE was 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. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. This was analyzed in all participants who received ≥1 dose of study treatment. The number of participants who experienced an AE is presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    514
    514
    Units: Participants
    508
    505
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE)
    End point description
    An AE was 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. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. This was analyzed in all participants who received ≥1 dose of study treatment. The number of participants who discontinued study treatment due to an AE is presented.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months
    End point values
    		 Pembrolizumab + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    514
    514
    Units: Participants
    150
    115
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 48 months
    Adverse event reporting additional description
    All-cause mortality: All randomized participants; AEs: all participants who got ≥1 dose of study drug. Per protocol, disease progression of cancer was not considered an AE unless considered related to study drug. Thus, MedDRA preferred terms "Neoplasm progression" (NP), "Malignant NP" and "Disease progression" unrelated to study drug are excluded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Placebo + Docetaxel
    Reporting group description
    		 Participants received placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly received dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.

    Reporting group title
    Pembrolizumab + Docetaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly received dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.

    Serious adverse events
    		 Placebo + Docetaxel Pembrolizumab + Docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    197 / 514 (38.33%)
    212 / 514 (41.25%)
         number of deaths (all causes)
    329
    343
         number of deaths resulting from adverse events
    28
    29
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell carcinoma
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour compression
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 514 (0.39%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery aneurysm
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 514 (0.19%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 514 (0.39%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    General physical health deterioration
         subjects affected / exposed
    2 / 514 (0.39%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 514 (0.78%)
    6 / 514 (1.17%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Oedema genital
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 514 (0.78%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 514 (0.00%)
    5 / 514 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Obstructive airways disorder
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    6 / 514 (1.17%)
    15 / 514 (2.92%)
         occurrences causally related to treatment / all
    5 / 6
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    8 / 514 (1.56%)
    6 / 514 (1.17%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 514 (0.19%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Lung disorder
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 514 (0.19%)
    4 / 514 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood calcium increased
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cystitis radiation
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 514 (0.19%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Patella fracture
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion related complication
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sternal fracture
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    3 / 514 (0.58%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary radiation injury
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 514 (0.78%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 514 (0.19%)
    3 / 514 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subendocardial ischaemia
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 514 (0.00%)
    6 / 514 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Nervous system disorders
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    5 / 514 (0.97%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 514 (0.19%)
    3 / 514 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebellar haematoma
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 514 (0.97%)
    5 / 514 (0.97%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    22 / 514 (4.28%)
    28 / 514 (5.45%)
         occurrences causally related to treatment / all
    22 / 23
    33 / 34
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    7 / 514 (1.36%)
    6 / 514 (1.17%)
         occurrences causally related to treatment / all
    7 / 8
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotic lymphadenopathy
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anal fissure
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 514 (0.00%)
    4 / 514 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 514 (0.00%)
    3 / 514 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    9 / 514 (1.75%)
    13 / 514 (2.53%)
         occurrences causally related to treatment / all
    7 / 10
    10 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ulcer
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oroantral fistula
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    4 / 514 (0.78%)
    8 / 514 (1.56%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    3 / 514 (0.58%)
    6 / 514 (1.17%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    3 / 514 (0.58%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crowned dens syndrome
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    4 / 514 (0.78%)
    4 / 514 (0.78%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    6 / 514 (1.17%)
    5 / 514 (0.97%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    3 / 514 (0.58%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 514 (0.19%)
    6 / 514 (1.17%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    6 / 514 (1.17%)
    3 / 514 (0.58%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    COVID-19 pneumonia
         subjects affected / exposed
    6 / 514 (1.17%)
    5 / 514 (0.97%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Catheter site cellulitis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 514 (0.58%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial sepsis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related bacteraemia
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster meningomyelitis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis meningococcal
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal candidiasis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 514 (0.00%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 514 (2.33%)
    14 / 514 (2.72%)
         occurrences causally related to treatment / all
    10 / 14
    7 / 14
         deaths causally related to treatment / all
    1 / 2
    0 / 3
    Pneumonia bacterial
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    2 / 514 (0.39%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 514 (0.39%)
    3 / 514 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    3 / 514 (0.58%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 514 (0.58%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 514 (0.39%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    4 / 514 (0.78%)
    2 / 514 (0.39%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Urinary tract infection staphylococcal
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 514 (1.36%)
    8 / 514 (1.56%)
         occurrences causally related to treatment / all
    0 / 8
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 514 (0.39%)
    3 / 514 (0.58%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 514 (0.19%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 514 (0.19%)
    0 / 514 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 514 (0.00%)
    1 / 514 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 514 (0.19%)
    3 / 514 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 514 (0.19%)
    3 / 514 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Docetaxel Pembrolizumab + Docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    488 / 514 (94.94%)
    496 / 514 (96.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    29 / 514 (5.64%)
    28 / 514 (5.45%)
         occurrences all number
    32
    31
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    42 / 514 (8.17%)
    58 / 514 (11.28%)
         occurrences all number
    52
    69
    Oedema peripheral
         subjects affected / exposed
    106 / 514 (20.62%)
    95 / 514 (18.48%)
         occurrences all number
    120
    105
    Mucosal inflammation
         subjects affected / exposed
    31 / 514 (6.03%)
    26 / 514 (5.06%)
         occurrences all number
    34
    31
    Fatigue
         subjects affected / exposed
    184 / 514 (35.80%)
    183 / 514 (35.60%)
         occurrences all number
    224
    255
    Asthenia
         subjects affected / exposed
    128 / 514 (24.90%)
    132 / 514 (25.68%)
         occurrences all number
    201
    180
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    59 / 514 (11.48%)
    61 / 514 (11.87%)
         occurrences all number
    63
    66
    Cough
         subjects affected / exposed
    36 / 514 (7.00%)
    47 / 514 (9.14%)
         occurrences all number
    39
    53
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    46 / 514 (8.95%)
    43 / 514 (8.37%)
         occurrences all number
    46
    51
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    49 / 514 (9.53%)
    47 / 514 (9.14%)
         occurrences all number
    112
    107
    Blood alkaline phosphatase increased
         subjects affected / exposed
    25 / 514 (4.86%)
    28 / 514 (5.45%)
         occurrences all number
    26
    28
    Aspartate aminotransferase increased
         subjects affected / exposed
    24 / 514 (4.67%)
    29 / 514 (5.64%)
         occurrences all number
    27
    32
    Alanine aminotransferase increased
         subjects affected / exposed
    28 / 514 (5.45%)
    27 / 514 (5.25%)
         occurrences all number
    30
    38
    White blood cell count decreased
         subjects affected / exposed
    27 / 514 (5.25%)
    32 / 514 (6.23%)
         occurrences all number
    54
    60
    Weight decreased
         subjects affected / exposed
    29 / 514 (5.64%)
    42 / 514 (8.17%)
         occurrences all number
    29
    45
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    100 / 514 (19.46%)
    132 / 514 (25.68%)
         occurrences all number
    108
    143
    Neuropathy peripheral
         subjects affected / exposed
    27 / 514 (5.25%)
    27 / 514 (5.25%)
         occurrences all number
    30
    28
    Headache
         subjects affected / exposed
    34 / 514 (6.61%)
    38 / 514 (7.39%)
         occurrences all number
    39
    49
    Dysgeusia
         subjects affected / exposed
    79 / 514 (15.37%)
    73 / 514 (14.20%)
         occurrences all number
    85
    88
    Dizziness
         subjects affected / exposed
    41 / 514 (7.98%)
    38 / 514 (7.39%)
         occurrences all number
    49
    42
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    37 / 514 (7.20%)
    41 / 514 (7.98%)
         occurrences all number
    47
    52
    Anaemia
         subjects affected / exposed
    126 / 514 (24.51%)
    147 / 514 (28.60%)
         occurrences all number
    168
    177
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    38 / 514 (7.39%)
    33 / 514 (6.42%)
         occurrences all number
    38
    35
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    28 / 514 (5.45%)
    26 / 514 (5.06%)
         occurrences all number
    32
    30
    Constipation
         subjects affected / exposed
    85 / 514 (16.54%)
    110 / 514 (21.40%)
         occurrences all number
    99
    152
    Vomiting
         subjects affected / exposed
    70 / 514 (13.62%)
    50 / 514 (9.73%)
         occurrences all number
    90
    70
    Stomatitis
         subjects affected / exposed
    29 / 514 (5.64%)
    34 / 514 (6.61%)
         occurrences all number
    30
    43
    Nausea
         subjects affected / exposed
    135 / 514 (26.26%)
    124 / 514 (24.12%)
         occurrences all number
    194
    178
    Diarrhoea
         subjects affected / exposed
    184 / 514 (35.80%)
    209 / 514 (40.66%)
         occurrences all number
    289
    356
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    29 / 514 (5.64%)
    23 / 514 (4.47%)
         occurrences all number
    32
    24
    Nail discolouration
         subjects affected / exposed
    27 / 514 (5.25%)
    25 / 514 (4.86%)
         occurrences all number
    28
    26
    Nail disorder
         subjects affected / exposed
    30 / 514 (5.84%)
    30 / 514 (5.84%)
         occurrences all number
    30
    30
    Pruritus
         subjects affected / exposed
    26 / 514 (5.06%)
    46 / 514 (8.95%)
         occurrences all number
    31
    53
    Rash
         subjects affected / exposed
    54 / 514 (10.51%)
    57 / 514 (11.09%)
         occurrences all number
    62
    70
    Alopecia
         subjects affected / exposed
    193 / 514 (37.55%)
    182 / 514 (35.41%)
         occurrences all number
    198
    185
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    28 / 514 (5.45%)
    23 / 514 (4.47%)
         occurrences all number
    32
    25
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    16 / 514 (3.11%)
    35 / 514 (6.81%)
         occurrences all number
    17
    37
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    46 / 514 (8.95%)
    40 / 514 (7.78%)
         occurrences all number
    57
    47
    Myalgia
         subjects affected / exposed
    42 / 514 (8.17%)
    49 / 514 (9.53%)
         occurrences all number
    50
    55
    Bone pain
         subjects affected / exposed
    45 / 514 (8.75%)
    44 / 514 (8.56%)
         occurrences all number
    51
    47
    Back pain
         subjects affected / exposed
    101 / 514 (19.65%)
    91 / 514 (17.70%)
         occurrences all number
    117
    105
    Arthralgia
         subjects affected / exposed
    99 / 514 (19.26%)
    86 / 514 (16.73%)
         occurrences all number
    122
    125
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    33 / 514 (6.42%)
    36 / 514 (7.00%)
         occurrences all number
    38
    48
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    15 / 514 (2.92%)
    27 / 514 (5.25%)
         occurrences all number
    20
    37
    Hyperglycaemia
         subjects affected / exposed
    54 / 514 (10.51%)
    47 / 514 (9.14%)
         occurrences all number
    67
    54
    Decreased appetite
         subjects affected / exposed
    98 / 514 (19.07%)
    107 / 514 (20.82%)
         occurrences all number
    126
    145

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2019
    Amendment 1 included corrections to the Schedule of Activities, Objectives, and Appendices, and minor edits throughout.
    10 Feb 2020
    Amendment 2 included changes to eligibility criteria to align with latest standard of care (SOC) (NHAs given prior to mCRPC), and updates to stratification criteria to reflect this change.
    17 Sep 2020
    Amendment 3 included addition of an extension portion in China to allow for the required exposure and number of events to investigate efficacy and safety in participants enrolled in China.
    21 Jul 2021
    Amendment 4 included an update to the dose modification and toxicity management guidelines for irAEs.
    14 Jan 2022
    Amendment 5 included addition of the TEA survey to document the investigator’s choice to recruit participants for the MK-3475-921 study rather than using other available treatment options.
    08 Nov 2022
    Amendment 6 included information on the study having achieved its prespecified scientific objective to evaluate the combination of pembrolizumab and docetaxel in this setting, and the study being closed as a result of having completed its final analysis. It also included language to state that upon study completion, participants are discontinued from the study and may be enrolled in a pembrolizumab extension study, if available.

    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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