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    Clinical Trial Results:
    A Randomized, Open Label, Multicenter Study of Cabazitaxel Versus an Androgen Receptor (AR)- targeted Agent (Abiraterone or Enzalutamide) in mCRPC Patients Previously Treated with Docetaxel and Who Rapidly Failed a Prior AR-targeted Agent (CARD)

    Summary
    EudraCT number
    		 2014-004676-29
    Trial protocol
    		 ES   BE   NL   IE   GR   FR   IS   AT   CZ   IT  
    Global end of trial date
    15 Mar 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Jan 2023
    First version publication date
    29 Mar 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updated safety optional field

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS14201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02485691
    WHO universal trial number (UTN)
    		 U1111-1166-5329
    Sponsors
    Sponsor organisation name
    Sanofi aventis Groupe (SAG)
    Sponsor organisation address
    54, rue La Boetie, Paris, France, 75008
    Public contact
    Sanofi aventis recherche & développement, Trial Transparency Team, Contact-US@sanofi.com
    Scientific contact
    Sanofi aventis recherche & développement, Trial Transparency Team, Contact-US@sanofi.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
    13 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the radiographic Progression-Free Survival (rPFS) [Using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for tumor lesions and Prostate Cancer Working Group 2 (PCWG2) criteria for bone scan lesions or death due to any cause] with chemotherapy (Cabazitaxel plus prednisone) (Arm A) versus Androgen Receptor (AR)-targeted therapy (enzalutamide or abiraterone acetate plus prednisone) (Arm B) in mCRPC subjects who had been treated with docetaxel and who had disease progression while receiving AR-targeted therapy within 12 months of AR treatment initiation (less than or equal to [<=] 12 months) (either before or after docetaxel).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 8
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Czechia: 19
    Country: Number of subjects enrolled
    France: 55
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Iceland: 9
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 29
    Worldwide total number of subjects
    255
    EEA total number of subjects
    248
    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)
    63
    From 65 to 84 years
    188
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 66 active centres in 13 countries. A total of 255 subjects were randomised between 09 November 2015 to 13 November 2018, out of which 250 subjects received treatment with the study drug.

    Pre-assignment
    Screening details
    		 Subjects were randomised to receive either cabazitaxel or AR targeted therapy (abiraterone or enzalutamide were assigned based on previous AR targeted treatment in which subjects previously treated with abiraterone were treated with enzalutamide and vice versa due to resistance).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cabazitaxel
    Arm description
    		 Subjects received cabazitaxel 25 milligrams per square metre (mg/m^2) intravenous (IV) infusion for over 1 hour on Day 1 of each 3-week treatment cycle in combination with Prednisone 10 mg orally once daily and primary prophylactic granulocyte-colony stimulating factor (G-CSF) as per investigator decision, until radiographic disease progression, unacceptable toxicity, or subject’s refusal of further study treatment (median duration = 22 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabazitaxel
    Investigational medicinal product code
    XRP6258
    Other name
    Jevtana
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cabazitaxel 25 mg/m^2 IV infusion for over 1 hour on Day 1 of each 3-week treatment cycle in combination with Prednisone 10 mg orally once daily and primary prophylactic G-CSF as per investigator decision.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 10mg given orally every 3 weeks.

    Arm title
    		 Abiraterone Acetate or Enzalutamide
    Arm description
    		 Subjects received either abiraterone acetate 1000 mg orally once daily from Day 1 to Day 21 of each 3-week treatment cycle in combination with prednisone 5 mg orally twice daily; or enzalutamide 160 mg orally once daily continuously from Day 1 to Day 21 of each 3-week treatment cycle, until radiographic disease progression, unacceptable toxicity, or subject’s refusal of further study treatment (median duration =12.5 weeks).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Abiraterone Acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Abiraterone acetate 1000 mg orally once daily along with oral prednisone 5 mg twice daily. Abiraterone was administered to subjects who had received enzalutamide prior to study entry.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Xtandi
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg orally once daily. Enzalutamide was administered to subjects who received prior abiraterone acetate.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 5 mg given orally twice daily.

    Number of subjects in period 1
    		Cabazitaxel Abiraterone Acetate or Enzalutamide
    Started
    129
    126
    Treated
    126
    124
    Completed
    0
    0
    Not completed
    129
    126
         Randomised and not treated
    3
    2
         Investigator's decision
    23
    5
         Disease progression
    57
    92
         Adverse events
    25
    11
         Other reason
    8
    9
         Poor compliance to protocol
    -
    1
         Subject's request
    13
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cabazitaxel
    Reporting group description
    		 Subjects received cabazitaxel 25 milligrams per square metre (mg/m^2) intravenous (IV) infusion for over 1 hour on Day 1 of each 3-week treatment cycle in combination with Prednisone 10 mg orally once daily and primary prophylactic granulocyte-colony stimulating factor (G-CSF) as per investigator decision, until radiographic disease progression, unacceptable toxicity, or subject’s refusal of further study treatment (median duration = 22 weeks).

    Reporting group title
    Abiraterone Acetate or Enzalutamide
    Reporting group description
    		 Subjects received either abiraterone acetate 1000 mg orally once daily from Day 1 to Day 21 of each 3-week treatment cycle in combination with prednisone 5 mg orally twice daily; or enzalutamide 160 mg orally once daily continuously from Day 1 to Day 21 of each 3-week treatment cycle, until radiographic disease progression, unacceptable toxicity, or subject’s refusal of further study treatment (median duration =12.5 weeks).

    Reporting group values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide Total
    Number of subjects
    		 129 126 255
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.7 ( 8.3 ) 69.7 ( 7.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 129 126 255

    End points

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    End points reporting groups
    Reporting group title
    Cabazitaxel
    Reporting group description
    		 Subjects received cabazitaxel 25 milligrams per square metre (mg/m^2) intravenous (IV) infusion for over 1 hour on Day 1 of each 3-week treatment cycle in combination with Prednisone 10 mg orally once daily and primary prophylactic granulocyte-colony stimulating factor (G-CSF) as per investigator decision, until radiographic disease progression, unacceptable toxicity, or subject’s refusal of further study treatment (median duration = 22 weeks).

    Reporting group title
    Abiraterone Acetate or Enzalutamide
    Reporting group description
    		 Subjects received either abiraterone acetate 1000 mg orally once daily from Day 1 to Day 21 of each 3-week treatment cycle in combination with prednisone 5 mg orally twice daily; or enzalutamide 160 mg orally once daily continuously from Day 1 to Day 21 of each 3-week treatment cycle, until radiographic disease progression, unacceptable toxicity, or subject’s refusal of further study treatment (median duration =12.5 weeks).

    Primary: Radiographic Progression-Free Survival (rPFS)

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    End point title
    		 Radiographic Progression-Free Survival (rPFS)
    End point description
    Radiographic progression-free survival: time (in months) from randomisation to occurrence of any one of following: radiological tumor progressions using response evaluation criteria in solid tumors (RECIST 1.1), progression of bone lesions using Prostate Cancer Working Group 2 (PCWG2) criteria or occurrence of death due to any cause. Progression as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Progression of bone lesions (PCWG2 criteria): first bone scan with greater than or equal to (>=) 2 new lesions compared to Baseline observed less than (<) 12 weeks from randomisation and confirmed by a second bone scan performed >=6 weeks; first bone scan with >=2 new lesions compared to Baseline observed >=12 weeks from randomisation. per protocol, data cut-off date for final analysis of this endpoint was date when 196 rPFS events had occurred. Analysed by Kaplan-Meier method. ITT population.
    End point type
    Primary
    End point timeframe
    From randomisation until tumor progression or bone lesion progression, death due to any cause, or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    129
    126
    Units: months
        median (confidence interval 95%)
    8.0 (5.7 to 9.2)
    3.7 (2.8 to 5.1)
    Statistical analysis title
    		 Cabazitaxel vs Abiraterone Acetate or Enzalutamide
    Statistical analysis description
    Hazard ratio was estimated using a Cox Proportional Hazards regression model. The Cox proportional hazard model was stratified by Eastern Cooperative Oncology Group performance status (ECOG) performance status, time from AR-targeted agent initiation progression, timing of AR targeted agent as specified at the time of randomisation.
    Comparison groups
    Cabazitaxel v Abiraterone Acetate or Enzalutamide
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.73
    Notes
    [1] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in an order the endpoints were reported and continued when previous endpoint was statistically significant at two-sided 0.05. Only the primary and the first 4 secondary endpoints were included in the procedure.
    [2] - P-value from 2-sided stratified log-rank test, stratified for ECOG performance status, time from AR- targeted agent initiation progression, timing of AR targeted agent as specified at the time of randomisation. Significance threshold was at 0.05.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival was defined as the time interval (in months) from the date of randomisation to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the last date subject was known to be alive or at the cut-off date whichever comes first. Analysis was performed by Kaplan-Meier method. Analysis was performed on ITT population that included any subject who had been allocated to a randomised treatment regardless of whether the treatment kit was used, analysed according to the treatment group allocated by randomisation.
    End point type
    Secondary
    End point timeframe
    From randomisation to death due to any cause, or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    129
    126
    Units: months
        median (confidence interval 95%)
    13.6 (11.5 to 17.5)
    11.0 (9.2 to 12.9)
    Statistical analysis title
    		 Cabazitaxel vs Abiraterone Acetate or Enzalutamide
    Statistical analysis description
    Hazard ratio was estimated using a Cox Proportional Hazards regression model. The Cox proportional hazard model was stratified by ECOG performance status, time from AR-targeted agent initiation progression, timing of AR targeted agent as specified at the time of randomisation.
    Comparison groups
    Cabazitaxel v Abiraterone Acetate or Enzalutamide
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0078 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.89
    Notes
    [3] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05. Only the primary and the first 4 secondary endpoints were included in the procedure.
    [4] - P-value from 2-sided stratified log-rank test, stratified for ECOG performance status, time from AR- targeted agent initiation progression, timing of AR-targeted agent as specified at the time of randomisation. Significance threshold was at 0.05.

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS:time duration (in months) from date of randomisation to date of first occurrence of any of following events: radiological tumor progression (RECIST 1.1); progression of bone lesions (PCWG2); symptomatic progression (developing urinary or bowel symptoms; need to change anti-cancer therapy), pain progression or death due to any cause. Tumor Progression(RECIST 1.1): at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Progression of bone lesion (PCWG2 criteria): first bone scan with >=2 new lesions compared to Baseline and confirmed by second bone scan performed >=6 weeks later; pain progression: increase by >=30% from Baseline in pain intensity score (calculated using scale ranged: 0=no pain to 5=extreme pain) or increase in analgesic usage score >=30% (calculated from analgesic use data, non-narcotic medications assigned value of 1 point and narcotic medications assigned 4 points). Analysed by Kaplan-Meier method. ITT.
    End point type
    Secondary
    End point timeframe
    From randomisation until tumor progression or bone lesion progression, pain progression, death due to any cause, or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    129
    126
    Units: months
        median (confidence interval 95%)
    4.4 (3.6 to 5.4)
    2.7 (2.3 to 2.8)
    Statistical analysis title
    		 Cabazitaxel vs Abiraterone Acetate or Enzalutamide
    Statistical analysis description
    Hazard ratio was estimated using a Cox Proportional Hazards regression model. The Cox proportional hazard model was stratified by ECOG performance status, time from AR-targeted agent initiation progression, timing of AR targeted agent as specified at the time of randomisation.
    Comparison groups
    Cabazitaxel v Abiraterone Acetate or Enzalutamide
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.68
    Notes
    [5] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05. Only the primary and the first 4 secondary endpoints were included in the procedure.
    [6] - P-value from 2-sided stratified log-rank test, stratified for ECOG performance status, time from AR- targeted agent initiation progression, timing of AR targeted agent as specified at the time of randomisation. Significance threshold was at 0.05.

    Secondary: Percentage of Subjects With Prostate Specific Antigen (PSA) Response

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    End point title
    		 Percentage of Subjects With Prostate Specific Antigen (PSA) Response
    End point description
    PSA response was defined as >= 50% decrease from Baseline in serum PSA levels, confirmed by a second PSA value at least 3 weeks later. Analysis was performed on subset of ITT population (any subject who had been allocated to a randomised treatment, analysed according to group allocated) with PSA level >2 nanograms per millilitre (ng/mL) at Baseline, and with at least two post-baseline assessments before any further anti-cancer therapy for specified endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to PSA response, death due to any cause or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    113
    105
    Units: percentage of subjects
        number (confidence interval 95%)
    36.3 (27.4 to 45.1)
    14.3 (7.6 to 21.0)
    Statistical analysis title
    		 Cabazitaxel vs Abiraterone Acetate or Enzalutamide
    Comparison groups
    Cabazitaxel v Abiraterone Acetate or Enzalutamide
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0003 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05. Only the primary and the first 4 secondary endpoints were included in the procedure.
    [8] - Cochran-Mantel-Haenszel test stratified by ECOG performance status, time from AR-targeted agent initiation to progression, timing of AR-targeted agent as specified at the time of randomisation. Significance threshold = 0.05.

    Secondary: Percentage of Subjects With Overall Objective Tumor Response

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    End point title
    		 Percentage of Subjects With Overall Objective Tumor Response
    End point description
    Overall objective tumor response was defined as having a partial response (PR) or complete response (CR) according to the RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and normalisation of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimetres (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. Analysis was performed on subset of ITT population (any subject who had been allocated to a randomised treatment, analysed according to group allocated) with measurable disease at Baseline and at least one post-baseline assessment before any further anti-cancer therapy for specified endpoint.
    End point type
    Secondary
    End point timeframe
    From randomisation until disease progression, death due to any cause or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    63
    52
    Units: percentage of subjects
        number (confidence interval 95%)
    36.5 (24.6 to 48.4)
    11.5 (2.9 to 20.2)
    Statistical analysis title
    		 Cabazitaxel vs Abiraterone Acetate or Enzalutamide
    Comparison groups
    Cabazitaxel v Abiraterone Acetate or Enzalutamide
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0004 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [9] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05. Only the primary and the first 4 secondary endpoints were included in the procedure.
    [10] - Cochran-Mantel-Haenszel test stratified by ECOG performance status, time from AR-targeted agent initiation to progression, timing of AR-targeted agent as specified at the time of randomisation. Significance threshold = 0.05.

    Secondary: Time to PSA Progression (TTPP)

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    End point title
    		 Time to PSA Progression (TTPP)
    End point description
    TTPP was defined as the time duration (in months) between the date of randomisation and the date of first documented PSA progression. PSA progression (as per PCWG 2) was defined as: 1) If decline from Baseline value: an increase of >=25% (at least 2 ng/mL) over the nadir value, confirmed by a second PSA value at least 3 weeks apart; 2) If no decline from Baseline value: an increase of >=25% (at least 2 ng/mL) over the Baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart. Analysis performed by Kaplan-Meier method. Analysis was performed on subset of ITT population (any subject who had been allocated to a randomised treatment, analysed according to group allocated) with PSA level > 2 ng/mL at Baseline, and with at least two post-baseline assessments before any further anti-cancer therapy for specified endpoint.
    End point type
    Secondary
    End point timeframe
    From time from randomisation until PSA progression, death due to any cause or data cut-off whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    113
    105
    Units: months
        median (confidence interval 95%)
    6.3 (4.2 to 8.3)
    2.1 (1.7 to 2.3)
    No statistical analyses for this end point

    Secondary: Duration of Tumor Response

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    End point title
    		 Duration of Tumor Response
    End point description
    Duration of tumor response was defined as time (in months) from date of first response (CR or PR) until date of first documentation of tumor progression or death, whichever occurs first. As per RECIST 1.1, CR: defined as disappearance of all target and non-target lesions and normalisation of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference Baseline sum diameters. Progression was defined as at least a 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysed by Kaplan-Meier method. Analysis was performed on subset of subjects with overall objective tumor response. Here, '99999' is used as a space filler and denotes that upper limit of confidence interval (CI) was not estimable due to less number of subjects with overall objective tumor response.
    End point type
    Secondary
    End point timeframe
    From the date of the first response to the date of first documented tumor progression, or death due to any cause or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    23
    6
    Units: months
        median (confidence interval 95%)
    6.5 (5.6 to 11.4)
    8.0 (1.1 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Pain Response Assessed Using Brief Pain Inventory-Short Form (BPI-SF) Pain Intensity Score

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    End point title
    		 Percentage of Subjects Achieving Pain Response Assessed Using Brief Pain Inventory-Short Form (BPI-SF) Pain Intensity Score
    End point description
    Pain response as per BPI-SF was defined as a decrease of at least 30% from Baseline in the average of BPI-SF pain intensity score observed at 2 consecutive evaluations >=3 weeks apart without increase in analgesic usage score (calculated from analgesic use data, with non-narcotic medications assigned value of 1 point and narcotic medications assigned 4 points). The BPI-SF is a self-administered questionnaire developed to assess the severity of pain on a 0-10 categorical scale where 0=no pain, 10=pain as bad as you can imagine. Higher scores indicated worst outcomes. Percentage of subjects achieving pain response assessed using BPI-SF pain intensity score were reported. Analysis was performed on subset of ITT population (any subject who had been allocated to a randomised treatment, analysed according to group allocated) with Baseline assessment and at least one post-baseline assessment before any further anti-cancer therapy for specified endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline until pain progression, first further anticancer therapy, or data cut-off whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    111
    109
    Units: percentage of subjects
        number (confidence interval 95%)
    45.9 (36.7 to 55.2)
    19.3 (11.9 to 26.7)
    No statistical analyses for this end point

    Secondary: Time to Pain Progression

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    End point title
    		 Time to Pain Progression
    End point description
    Time to pain progression: time duration (in months) between date of randomisation and date of 1st documented pain progression. Pain progression, in subjects with no pain or stable pain at Baseline: defined as increase of >=30% from baseline in BPI-SF pain intensity score observed at 2 consecutive evaluations >=3 weeks apart without decrease in analgesic usage score or increase in analgesic usage score (calculated from analgesic use data, with non-narcotic medications assigned value of 1 point and narcotic medications assigned 4 points) >=30%. BPI-SF: self-administered questionnaire assessed pain severity on 0-10 categorical scale where 0=no pain, 10=pain as bad as you can imagine. Higher scores: worst outcomes. Analysed by Kaplan-Meier method on subset of ITT population. '99999' is used as a space filler and denotes that median, lower and upper limit of CI was not estimable because the curve's upper CI bound had not crossed 50% survival threshold.
    End point type
    Secondary
    End point timeframe
    Baseline until pain progression or data cut-off whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    111
    109
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    8.5 (4.9 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Symptomatic Skeletal Events (SSE)

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    End point title
    		 Number of Symptomatic Skeletal Events (SSE)
    End point description
    SSE was defined as occurrence of a new symptomatic pathological fracture, use of external beam radiation to relieve bone pain, occurrence of spinal cord compression or tumor- related orthopedic surgical intervention. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline until occurrence of first SSE or data cut-off, whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    129
    126
    Units: events
    24
    35
    No statistical analyses for this end point

    Secondary: Time to Symptomatic Skeletal Event

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    End point title
    		 Time to Symptomatic Skeletal Event
    End point description
    Time to SSE was defined as the time duration (in months) between the date of randomisation and the date of occurrence of the first SSE. Analysis was performed by Kaplan-Meier method on ITT population. Here, '99999' is used as a space filler and denotes that median and upper limit of CI were not estimable because of low number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From date of randomisation until first SSE, or data cut-off whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    129
    126
    Units: months
        median (confidence interval 95%)
    99999 (20.0 to 99999)
    16.7 (10.8 to 99999)
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQOL): Change From Baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) Total Score at Cycle 2, 3, 4, 5, 6, 7, 8 and End of Treatment

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    End point title
    		 Health-Related Quality of Life (HRQOL): Change From Baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) Total Score at Cycle 2, 3, 4, 5, 6, 7, 8 and End of Treatment
    End point description
    Health-related quality of life (HRQOL) evaluation was performed using the FACT-P questionnaire (Version 4). FACTP was a 39-item subject rated questionnaire that measures the concerns of subjects with prostate cancer. It consisted of 5 sub-scales assessing physical well-being (7 items), social/family well-being (7 items), emotional wellbeing (6 items), functional well-being (7 items), and prostate-specific concerns (12 items). FACT-P total score was the sum of all 5 subscale scores. It ranged from 0 to156 with higher score indicated better quality of life with fewer symptoms. Baseline corresponded to last evaluable assessment before treatment administration. Analysis was performed on HRQOL population which included subjects who received at least one dose of the study drug and with an evaluable FACT-P questionnaire at Baseline and at least one post-baseline evaluable FACT-P. Here 'n' = subjects in each treatment group with available data for each cycle.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8 and at End of Treatment (any time up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    108
    114
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 (n=104,106)
    2.6 ( 12.3 )
    -0.0 ( 12.4 )
        Cycle 3 (n=99,94)
    2.7 ( 16.1 )
    -1.0 ( 16.8 )
        Cycle 4 (n=93,77)
    2.8 ( 14.8 )
    -0.7 ( 16.8 )
        Cycle 5 (n=79,56)
    2.1 ( 17.9 )
    -1.0 ( 16.1 )
        Cycle 6 (n=64,39)
    -3.7 ( 18.0 )
    0.4 ( 18.6 )
        Cycle 7 (n=58,33)
    -2.2 ( 19.3 )
    2.7 ( 19.9 )
        Cycle 8 (n=47,25)
    -4.8 ( 20.4 )
    0.8 ( 23.0 )
        End of treatment (n=51,31)
    -6.3 ( 16.1 )
    -7.5 ( 15.7 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Utility Single Index and Visual Analogue Scale (VAS) Scores at Cycle 2, 3, 4, 5, 6, 7, 8 and End of Treatment

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    End point title
    		 Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Utility Single Index and Visual Analogue Scale (VAS) Scores at Cycle 2, 3, 4, 5, 6, 7, 8 and End of Treatment
    End point description
    EQ-5D: HRQOL questionnaire with EQ-5D descriptive system & Visual Analogue Scale (VAS). EQ-5D descriptive system had 5 dimensions: mobility, self-care, usual activities, pain/discomfort & anxiety/depression measured on 3 levels (no problem, some problems & severe problems) within particular EQ-5D dimension. 5 dimensional 3-level system converted into single index utility score. Possible values for single index utility score ranged -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 = best health state. EQ-5D VAS recorded subject's rating for his/her current HRQOL state, captured on a vertical VAS scale ranging 0-100, where 0=worst health state & 100=best health state, where higher states: better outcomes. Baseline: last evaluable assessment before treatment administration. Health status population: had at least 1 dose of study drug and Baseline evaluable EQ-5D-5L with at least 1 post-baseline evaluable EQ-5D-5L. 'n' = subjects with data.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8 and at End of Treatment (any time up to: 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    115
    115
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2: VAS (n=108,109)
    3.6 ( 14.4 )
    0.9 ( 14.6 )
        Cycle 3: VAS (n=104,94)
    4.5 ( 15.0 )
    1.5 ( 13.4 )
        Cycle 4: VAS (n=100,77)
    4.6 ( 16.5 )
    -1.1 ( 18.2 )
        Cycle 5: VAS (n=84,57)
    0.6 ( 17.1 )
    3.2 ( 17.0 )
        Cycle 6: VAS (n=68,39)
    -1.3 ( 22.8 )
    -1.5 ( 23.1 )
        Cycle 7: VAS (n=60,32)
    2.9 ( 18.1 )
    -0.2 ( 20.1 )
        Cycle 8: VAS (n=49,23)
    2.8 ( 18.0 )
    1.2 ( 19.6 )
        End of treatment: VAS (n=56,33)
    -3.3 ( 19.3 )
    -5.9 ( 23.1 )
        Cycle 2: Utility Index Score (n=108,109)
    0.026 ( 0.179 )
    -0.010 ( 0.178 )
        Cycle 3: Utility Index Score (n=103,94)
    0.041 ( 0.183 )
    -0.011 ( 0.182 )
        Cycle 4: Utility Index Score (n=99,79)
    0.051 ( 0.176 )
    -0.002 ( 0.188 )
        Cycle 5: Utility Index Score (n=79,59)
    0.027 ( 0.209 )
    -0.035 ( 0.185 )
        Cycle 6: Utility Index Score (n=67,42)
    0.015 ( 0.191 )
    -0.000 ( 0.176 )
        Cycle 7: Utility Index Score (n=60,34)
    0.029 ( 0.182 )
    0.024 ( 0.153 )
        Cycle 8: Utility Index Score (n=47,24)
    0.008 ( 0.213 )
    -0.014 ( 0.138 )
        End of treatment: Utility Index Score (n=56,35)
    -0.048 ( 0.188 )
    -0.079 ( 0.200 )
    No statistical analyses for this end point

    Secondary: Radiographic Progression-Free Survival (rPFS) in Subjects With Presence and Absence of Biomarker

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    End point title
    		 Radiographic Progression-Free Survival (rPFS) in Subjects With Presence and Absence of Biomarker
    End point description
    Circulating tumor cell (CTC) counts: biomarker in liquid biopsy. rPFS in subjects with presence and absence of CTC biomarker subtypes i.e. chromosomal instability (CIN) and neuroendocrine (NE) is reported. rPFS: time (in months) from randomisation to 1st occurrence of any 1 of following: radiological tumor progressions (RECIST1.1), progression of bone lesions (PCWG2 criteria) or death due to any cause. Analysis performed on subset of subjects analyzed per the treatment group allocated by randomisation with evaluable samples. Here, 'n' = subjects in each treatment group with data for each specified category.
    End point type
    Secondary
    End point timeframe
    From randomisation until tumor progression or bone lesion progression, death due to any cause, or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
    End point values
    		 Cabazitaxel Abiraterone Acetate or Enzalutamide
    Number of subjects analysed
    109
    106
    Units: month
    median (full range (min-max))
        Presence of CIN (n=27,27)
    4.2 (2.1 to 11.2)
    4.2 (0.03 to 21.0)
        Absence of CIN (n=82,79)
    8.5 (0.03 to 33.1)
    3.4 (0.03 to 28.0)
        Presence of NE (n=7,14)
    3.0 (2.6 to 11.2)
    3.9 (0.03 to 21.0)
        Absence of NE (n=102,92)
    8.2 (0.03 to 33.1)
    3.5 (0.03 to 28.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AE) data were collected from Baseline up to 30 days after the last treatment administration (up to 197 weeks), deaths were collected from Baseline up to end of study (up to 197 weeks).
    Adverse event reporting additional description
    Reported AEs were TEAEs i.e., AEs that developed/worsened during the ‘on-treatment period’ (time from first dose of study drug until 30 days after last administration of study drug), and all deaths for the safety population (i.e., all subjects who received at least one dose of study drugs, analysed according to treatment actually received).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Enzalutamide or Abiraterone
    Reporting group description
    		 Subjects received either abiraterone acetate 1000 mg orally once daily from Day 1 to Day 21 of each 3-week treatment cycle in combination with prednisone 5 mg orally twice daily; or enzalutamide 160 mg orally once daily continuously from Day 1 to Day 21 of each 3-week treatment cycle, until radiographic disease progression, unacceptable toxicity, or subject’s refusal of further study treatment (median duration =12.5 weeks).

    Reporting group title
    Cabazitaxel
    Reporting group description
    		 Subjects received cabazitaxel 25 mg/m^2 IV infusion for over 1 hour on Day 1 of each 3-week treatment cycle in combination with Prednisone 10 mg orally once daily and primary prophylactic G-CSF as per investigator decision, until radiographic disease progression, unacceptable toxicity, or subject’s refusal of further study treatment (median duration = 22 weeks).

    Serious adverse events
    		 Enzalutamide or Abiraterone Cabazitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    50 / 124 (40.32%)
    49 / 126 (38.89%)
         number of deaths (all causes)
    102
    96
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain
         subjects affected / exposed
    2 / 124 (1.61%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine Carcinoma Of The Skin
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oncologic Complication
         subjects affected / exposed
    1 / 124 (0.81%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour Pain
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (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
    Asthenia
         subjects affected / exposed
    1 / 124 (0.81%)
    3 / 126 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    8 / 124 (6.45%)
    4 / 126 (3.17%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    General Physical Health Deterioration
         subjects affected / exposed
    2 / 124 (1.61%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Inflammation
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Product issues
    Device Dislocation
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         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
    Femoral Neck Fracture
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity To Various Agents
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 124 (0.00%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Carotid Artery Stenosis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cognitive Disorder
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    3 / 124 (2.42%)
    4 / 126 (3.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 124 (0.81%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    0 / 124 (0.00%)
    4 / 126 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperfibrinolysis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 124 (0.00%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea Haemorrhagic
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus Paralytic
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 124 (2.42%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (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 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 124 (1.61%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    4 / 124 (3.23%)
    3 / 126 (2.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haematuria
         subjects affected / exposed
    3 / 124 (2.42%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 124 (0.81%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelocaliectasis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    3 / 124 (2.42%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 124 (0.81%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Obstruction
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    4 / 124 (3.23%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    1 / 124 (0.81%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Pain
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device Related Sepsis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter Sepsis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Infection
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal Cellulitis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 124 (0.81%)
    4 / 126 (3.17%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Sepsis
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 124 (0.00%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Tooth Infection
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (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
    3 / 124 (2.42%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary Tract Infection Bacterial
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Enzalutamide or Abiraterone Cabazitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 124 (83.87%)
    114 / 126 (90.48%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain
         subjects affected / exposed
    9 / 124 (7.26%)
    9 / 126 (7.14%)
         occurrences all number
    10
    15
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 124 (6.45%)
    5 / 126 (3.97%)
         occurrences all number
    8
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 124 (16.94%)
    36 / 126 (28.57%)
         occurrences all number
    27
    65
    Asthenia
         subjects affected / exposed
    26 / 124 (20.97%)
    33 / 126 (26.19%)
         occurrences all number
    37
    69
    Oedema Peripheral
         subjects affected / exposed
    11 / 124 (8.87%)
    10 / 126 (7.94%)
         occurrences all number
    12
    13
    Pain
         subjects affected / exposed
    6 / 124 (4.84%)
    8 / 126 (6.35%)
         occurrences all number
    7
    8
    Pyrexia
         subjects affected / exposed
    7 / 124 (5.65%)
    7 / 126 (5.56%)
         occurrences all number
    7
    10
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 124 (2.42%)
    7 / 126 (5.56%)
         occurrences all number
    5
    8
    Investigations
    Weight Decreased
         subjects affected / exposed
    7 / 124 (5.65%)
    5 / 126 (3.97%)
         occurrences all number
    7
    6
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    5 / 124 (4.03%)
    15 / 126 (11.90%)
         occurrences all number
    7
    18
    Neuropathy Peripheral
         subjects affected / exposed
    3 / 124 (2.42%)
    8 / 126 (6.35%)
         occurrences all number
    3
    11
    Polyneuropathy
         subjects affected / exposed
    0 / 124 (0.00%)
    8 / 126 (6.35%)
         occurrences all number
    0
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 124 (11.29%)
    38 / 126 (30.16%)
         occurrences all number
    24
    75
    Leukopenia
         subjects affected / exposed
    1 / 124 (0.81%)
    8 / 126 (6.35%)
         occurrences all number
    3
    12
    Neutropenia
         subjects affected / exposed
    1 / 124 (0.81%)
    28 / 126 (22.22%)
         occurrences all number
    3
    35
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    3 / 124 (2.42%)
    10 / 126 (7.94%)
         occurrences all number
    3
    12
    Constipation
         subjects affected / exposed
    13 / 124 (10.48%)
    19 / 126 (15.08%)
         occurrences all number
    18
    27
    Diarrhoea
         subjects affected / exposed
    8 / 124 (6.45%)
    50 / 126 (39.68%)
         occurrences all number
    8
    88
    Nausea
         subjects affected / exposed
    26 / 124 (20.97%)
    29 / 126 (23.02%)
         occurrences all number
    31
    49
    Stomatitis
         subjects affected / exposed
    2 / 124 (1.61%)
    10 / 126 (7.94%)
         occurrences all number
    3
    13
    Vomiting
         subjects affected / exposed
    14 / 124 (11.29%)
    16 / 126 (12.70%)
         occurrences all number
    18
    21
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 124 (0.00%)
    7 / 126 (5.56%)
         occurrences all number
    0
    7
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    5 / 124 (4.03%)
    18 / 126 (14.29%)
         occurrences all number
    6
    27
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 124 (16.13%)
    10 / 126 (7.94%)
         occurrences all number
    35
    14
    Back Pain
         subjects affected / exposed
    27 / 124 (21.77%)
    20 / 126 (15.87%)
         occurrences all number
    41
    22
    Bone Pain
         subjects affected / exposed
    7 / 124 (5.65%)
    4 / 126 (3.17%)
         occurrences all number
    7
    4
    Pain In Extremity
         subjects affected / exposed
    13 / 124 (10.48%)
    6 / 126 (4.76%)
         occurrences all number
    18
    7
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    4 / 124 (3.23%)
    10 / 126 (7.94%)
         occurrences all number
    4
    10
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    19 / 124 (15.32%)
    16 / 126 (12.70%)
         occurrences all number
    21
    21
    Hypokalaemia
         subjects affected / exposed
    7 / 124 (5.65%)
    5 / 126 (3.97%)
         occurrences all number
    14
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2015
    Changed secondary objectives: FACT-P questionnaire was added. Changed exploratory objectives: New biomarkers to study was identified. For scientifically interpretable data, collection of germline DNA derived from saliva at Baseline was found necessary. Changed inclusion criteria: Minimum dose exposure to docetaxel was specified. At least 3 cycles were needed to consider prior treatment with docetaxel. Specified docetaxel administration in combination with ADT in metastatic hormone-sensitive disease was considered prior exposure. Per ESMO guidelines, ADT+docetaxel: recommended as first-line treatment of metastatic hormone-naive disease in men fit enough for chemotherapy. Time to progression with first AR-targeted agent was extended from 6-12 months (with stratification [0;6 months] versus[6;12 months]) to evaluate optimal management of such subjects. Published retrospective data suggested that subjects with acquired resistance to AR-targeted agents poorly respond to another targeted agent. Unpublished retrospective data suggested that subjects having disease progression within 6-12 months with first AR-targeted agent in post-docetaxel setting may poorly respond to another AR-targeted agent. In pre-docetaxel setting, subjects having disease progression within 6-12 months with abiraterone or enzalutamide were considered ‘rapid progressors’ and could also poorly respond to another AR-targeted agent. Changed exclusion criteria. Clarified immunotherapy, previous immunotherapy was allowed. Modified as per NoMA request to give more details on contraception. Creatinine clearance <50 mL/min was removed per last SmPC update. Cabazitaxel is minimally excreted through kidney. No dose adjustment was necessary in subjects with renal impairment, not requiring hemodialysis. Per SmPC clarified exclusion of subjects with symptomatic peripheral neuropathy Grade 2 as well as subjects with Grade >2 and concomitant vaccination with yellow fever vaccine was added (also per NoMA request).
    11 May 2018
    Introduced name and address of: Coordinating Investigator and Sponsor in cover page. Clarified definition of rPFS in the Primary Objective and Primary Endpoint sections. Clarified definition of PFS. Clarified & adapted the Inclusion criteria based on recent guidelines updates: As per ESMO guidelines, prostate cancer diagnosis was to be confirmed by histology, (cytology is not mentioned). Per ESMO guidelines on management of metastatic CRPC, the sentence: “If the subject has been treated with LHRH agonists or antagonist (i.e., without orchiectomy), then this therapy should be continued” was added. LHRH agonists or antagonists were already allowed in section concomitant treatments, but to avoid any ambiguity and add clarity. Abiraterone acetate + androgen deprivation therapy (ADT) was now indicated in Europe for the treatment of metastatic hormone-sensitive prostate cancer. Such subjects were thus eligible in CARD if they have progressed within 12 months with this regimen. It has also been clarified that subjects having PSA progression only (as per PCWG 2) within 12 months, were eligible, even if total treatment duration with the AR-targeted agent was more than 12 months. Revised statistical power and accrual rates assumptions, and as a consequence reduced the sample size. Introduced the 500mg dosage of the Investigational Medicinal Product(s)– abiraterone acetate (Zytiga) and adapt dose modification and dose delay accordingly and to align dose adaptation rules with revised abiraterone acetate European labelling. Introduced time window of + or - 1 week for tumor assessment during treatment and in follow up if applicable, as well as all follow up visit to increase compliance and flexibility for subjects. Clarified change to procedure and consequence for subject withdrawal from study. Corrected inconsistencies throughout the protocol with regards to general guidelines for reporting AEs.
    08 Nov 2018
    This amendment had introduced mainly a new format of Abiraterone acetate 500 mg tablets (available in two formats (wallets 60 or 56 tablets, previously only 60 tablets), with no changes concerning the immediate packaging or daily dose), and introduced the new address of coordinating investigator.
    01 Mar 2019
    Inclusion criteria was updated and harmonised for the three arms of treatment, based on the approved label (for abiraterone and enzalutamide) and cabazitaxel IB. Subjects with reproductive potential who did not agree, in conjunction with their partner, to use accepted and effective method of contraception during the study treatment period and up to 6 months after the last administered dose. The definition of “effective method of contraception” described hereafter: oral contraceptives, combined hormonal intravaginal, transdermal, intra uterine device or condoms was be based on respective study treatment labelling and country-specific regulatory requirements, and were documented in the Informed Consent Form.

    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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