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
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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
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Results information
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Results version number |
v1 |
This version publication date |
29 Mar 2022
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First version publication date |
29 Mar 2022
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
LPS14201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02485691 | ||
WHO universal trial number (UTN) |
U1111-1166-5329 | ||
Sponsors
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Sponsor organisation name |
Sanofi aventis Groupe (SAG)
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Sponsor organisation address |
54, rue La Boetie, Paris, France, 75008
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Public contact |
Sanofi aventis recherche & développement, Trial Transparency Team, Contact-US@sanofi.com
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Scientific contact |
Sanofi aventis recherche & développement, Trial Transparency Team, Contact-US@sanofi.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Apr 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Mar 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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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).
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Nov 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 15
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Country: Number of subjects enrolled |
Norway: 8
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Country: Number of subjects enrolled |
Spain: 31
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Country: Number of subjects enrolled |
United Kingdom: 7
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Country: Number of subjects enrolled |
Austria: 15
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Country: Number of subjects enrolled |
Belgium: 19
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Country: Number of subjects enrolled |
Czechia: 19
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Country: Number of subjects enrolled |
France: 55
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Country: Number of subjects enrolled |
Germany: 31
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Country: Number of subjects enrolled |
Greece: 15
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Country: Number of subjects enrolled |
Iceland: 9
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Country: Number of subjects enrolled |
Ireland: 2
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Country: Number of subjects enrolled |
Italy: 29
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Worldwide total number of subjects |
255
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EEA total number of subjects |
248
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
63
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From 65 to 84 years |
188
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85 years and over |
4
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Recruitment
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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
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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
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
XRP6258
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Other name |
Jevtana
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Investigational medicinal product name |
Prednisone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Prednisone 10mg given orally every 3 weeks.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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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.
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Investigational medicinal product name |
Enzalutamide
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Investigational medicinal product code |
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Other name |
Xtandi
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Enzalutamide 160 mg orally once daily. Enzalutamide was administered to subjects who received prior abiraterone acetate.
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Investigational medicinal product name |
Prednisone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Prednisone 5 mg given orally twice daily.
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Baseline characteristics reporting groups
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Reporting group title |
Cabazitaxel
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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
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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). | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cabazitaxel
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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
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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). |
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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.
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End point type |
Primary
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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)
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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.
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Comparison groups |
Cabazitaxel v Abiraterone Acetate or Enzalutamide
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Number of subjects included in analysis |
255
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.54
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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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. |
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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.
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End point type |
Secondary
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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)
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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.
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Comparison groups |
Cabazitaxel v Abiraterone Acetate or Enzalutamide
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Number of subjects included in analysis |
255
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.0078 [4] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.64
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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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. |
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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.
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End point type |
Secondary
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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)
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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.
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Comparison groups |
Cabazitaxel v Abiraterone Acetate or Enzalutamide
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Number of subjects included in analysis |
255
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | ||||||||||||
P-value |
< 0.0001 [6] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.52
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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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. |
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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.
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End point type |
Secondary
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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)
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Statistical analysis title |
Cabazitaxel vs Abiraterone Acetate or Enzalutamide | ||||||||||||
Comparison groups |
Cabazitaxel v Abiraterone Acetate or Enzalutamide
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Number of subjects included in analysis |
218
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | ||||||||||||
P-value |
= 0.0003 [8] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
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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. |
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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.
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End point type |
Secondary
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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)
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Statistical analysis title |
Cabazitaxel vs Abiraterone Acetate or Enzalutamide | ||||||||||||
Comparison groups |
Cabazitaxel v Abiraterone Acetate or Enzalutamide
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Number of subjects included in analysis |
115
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Analysis specification |
Pre-specified
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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. |
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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.
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End point type |
Secondary
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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)
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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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)
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline until pain progression, first further anticancer therapy, or data cut-off whichever comes first (maximum duration: up to 141 weeks)
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline until pain progression or data cut-off whichever comes first (maximum duration: up to 141 weeks)
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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End point timeframe |
Baseline until occurrence of first SSE or data cut-off, whichever comes first (maximum duration: up to 141 weeks)
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
|
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End point timeframe |
From date of randomisation until first SSE, or data cut-off whichever comes first (maximum duration: up to 141 weeks)
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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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)
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No statistical analyses for this end point |
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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.
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End point type |
Secondary
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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)
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No statistical analyses for this end point |
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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.
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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)
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No statistical analyses for this end point |
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Adverse events information
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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).
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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).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
Cabazitaxel
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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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Enzalutamide or Abiraterone
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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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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). |
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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. |
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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. |
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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. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |