Cabazitaxel Versus the Switch to Alternative AR-targeted Agent (Enzalutamide or Abiraterone) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients Previously Treated With Docetaxel and Who Rapidly Failed a Prior AR-targeted Agent
- Conditions
- Prostate Cancer Metastatic
- Interventions
- Registration Number
- NCT02485691
- Lead Sponsor
- Sanofi
- Brief Summary
Primary Objective:
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 participants who have 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).
Secondary Objective:
* To compare efficacy for:
* Prostate-specific antigen (PSA) response rate and time to PSA progression (TTPP).
* Progression-free survival (PFS).
* Overall survival (OS).
* Tumor response rate and duration of tumor response.
* Pain response and time to pain progression.
* Symptomatic skeletal event (SSE) rate and time to occurrence of any SSE.
* Health status and Health-related Quality of Life (HRQOL).
* To evaluate the correlation of a signature of resistance to AR-targeted agents with clinical outcome via the analysis of circulating tumor cell (CTC) phenotypes as well as expression and localization of proteins including AR isoforms in CTCs.
* To evaluate safety in the 2 treatment arms.
- Detailed Description
The duration of the study per participant was approximately 2 years. Each participant was treated until radiographic disease progression, unacceptable toxicity, or participant's refusal of further study treatment, and each participant was followed after completion of study treatment until death, study cut-off date, or withdrawal of participant consent.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 255
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cabazitaxel cabazitaxel XRP6258 Participants received Cabazitaxel 25 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 participant's refusal of further study treatment (median duration = 22 weeks). Cabazitaxel prednisone Participants received Cabazitaxel 25 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 participant's refusal of further study treatment (median duration = 22 weeks). Abiraterone acetate or enzalutamide enzalutamide Participants 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 participant's refusal of further study treatment (median duration = 12.5 weeks). Abiraterone acetate or enzalutamide abiraterone acetate Participants 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 participant's refusal of further study treatment (median duration = 12.5 weeks). Abiraterone acetate or enzalutamide prednisone Participants 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 participant's refusal of further study treatment (median duration = 12.5 weeks).
- Primary Outcome Measures
Name Time Method Radiographic Progression-Free Survival (rPFS) From randomization 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) Radiographic progression-free survival: time (in months) from randomization 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 \>= 2 new lesions compared to Baseline observed less than (\<) 12 weeks from randomization and confirmed by a second bone scan performed \>=6 weeks; first bone scan with \>=2 new lesions compared to Baseline observed \>=12 weeks from randomization. In accordance with protocol, data cut-off date for final analysis of this endpoint was the date when 196 rPFS events had occurred. Analysis done by Kaplan-Meier method.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) From randomization to death due to any cause, or data cut-off date whichever comes first (maximum duration: up to 141 weeks) Overall survival was defined as the time interval (in months) from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the last date participant was known to be alive, or at the cut-off date whichever comes first. Analysis was performed by Kaplan-Meier method.
Progression Free Survival (PFS) From randomization 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) PFS:time duration (in months) from date of randomization 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 from 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). Analyzed by Kaplan-Meier method.
Percentage of Participants With Prostate Specific Antigen (PSA) Response Baseline up to PSA response, death due to any cause or data cut-off date whichever comes first (maximum duration: up to 141 weeks) PSA response was defined as \>= 50% decrease from baseline in serum PSA levels, confirmed by a second PSA value at least 3 weeks later.
Percentage of Participants With Overall Objective Tumor Response From randomization until disease progression, death due to any cause or data cut-off date whichever comes first (maximum duration: up to 141 weeks) 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 normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 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.
Time to PSA Progression (TTPP) From time from randomization until PSA progression, death due to any cause or data cut-off whichever comes first (maximum duration: up to 141 weeks) TTPP was defined as the time duration (in months) between the date of randomization 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.
Duration of Tumor Response 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) Duration of tumor response was defined as the 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 was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 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. Progression was defined as at least a 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method.
Percentage of Participants Achieving Pain Response Assessed Using Brief Pain Inventory-Short Form (BPI-SF) Pain Intensity Score Baseline until pain progression, first further anticancer therapy, or data cut-off whichever comes first (maximum duration: up to 141 weeks) 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 Participants Achieving Pain Response assessed using BPI-SF Pain Intensity Score were reported.
Time to Pain Progression Baseline until pain progression or data cut-off whichever comes first (maximum duration: up to 141 weeks) Time to pain progression was defined as the time duration (in months) between the date of randomization and the date of first documented pain progression. Pain progression, in participants with no pain or stable pain at Baseline was defined as increase of \>=30% from baseline in the 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%. 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. Analysis was performed by Kaplan-Meier method.
Number of Symptomatic Skeletal Events (SSE) Baseline until occurrence of first SSE or data cut-off, whichever comes first (maximum duration: up to 141 weeks) 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.
Time to Symptomatic Skeletal Event From date of randomization until first SSE, or data cut-off whichever comes first (maximum duration: up to 141 weeks) Time to SSE was defined as the time duration (in months) between the date of randomization and the date of occurrence of the first SSE. Analysis was performed by Kaplan-Meier method.
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 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) Health-related quality of life (HRQOL) evaluation was performed using the FACT-P questionnaire (Version 4). FACT-P was a 39-item participant rated questionnaire that measures the concerns of participants with prostate cancer. It consisted of 5 sub-scales assessing physical well-being (7 items), social/family well-being (7 items), emotional well-being (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.
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 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) EQ-5D was a standardized HRQOL questionnaire consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression measured on 3 levels (no problem, some problems \& severe problems) within a particular EQ-5D dimension. 5 dimensional 3-level system was converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state. EQ-5D VAS was used to record a participant's rating for his/her current health-related quality of life state and captured on a vertical VAS scale ranging from 0-100, where 0=worst imaginable health state and 100=best imaginable health state, where higher states indicated better outcomes. Baseline corresponded to last evaluable assessment before treatment administration.
Radiographic Progression-Free Survival (rPFS) in Participants With Presence and Absence of Biomarker From randomization 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) Circulating tumor cell (CTC) counts were considered as biomarker in a liquid biopsy. rPFS in participants with presence and absence of subtypes of CTC biomarker i.e. chromosomal instability (CIN) and neuroendocrine (NE) was reported in this outcome measure. rPFS was defined as: time (in months) from randomization to the first occurrence of any one of following: radiological tumor progressions (RECIST1.1), progression of bone lesions (PCWG2 criteria) or death due to any cause. Progression (RECIST1.1): at least a 20% 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 \>= 2 new lesions compared to Baseline observed \<12 weeks from randomization and confirmed by a second bone scan performed \>=6 weeks later; first bone scan with \>=2 new lesions compared to Baseline observed \>=12 weeks from randomization and new lesions were verified on next bone scan \>= 6 weeks later.
Trial Locations
- Locations (65)
Investigational Site Number 056007
🇧🇪Brussels, Belgium
Investigational Site Number 056005
🇧🇪Leuven, Belgium
Investigational Site Number 250010
🇫🇷Clermont Ferrand, France
Investigational Site Number 056003
🇧🇪Bruxelles, Belgium
Investigational Site Number 056006
🇧🇪Charleroi, Belgium
Investigational Site Number 250018
🇫🇷Saint-Mandé, France
Investigational Site Number 203002
🇨🇿Plzen, Czechia
Investigational Site Number 276023
🇩🇪Essen, Germany
Investigational Site Number 056013
🇧🇪Brugge, Belgium
Investigational Site Number 724002
🇪🇸Madrid, Spain
Investigational Site Number 250002
🇫🇷Paris Cedex 15, France
Investigational Site Number 250009
🇫🇷Strasbourg, France
Investigational Site Number 276028
🇩🇪Aschaffenburg, Germany
Investigational Site Number 250007
🇫🇷Paris, France
Investigational Site Number 056001
🇧🇪Gent, Belgium
Investigational Site Number 250004
🇫🇷Marseille, France
Investigational Site Number 276022
🇩🇪Duisburg, Germany
Investigational Site Number 276004
🇩🇪Magdeburg, Germany
Investigational Site Number 276018
🇩🇪Mannheim, Germany
Investigational Site Number 250014
🇫🇷Plerin, France
Investigational Site Number 276007
🇩🇪Göttingen, Germany
Investigational Site Number 380006
🇮🇹Napoli, Italy
Investigational Site Number 380002
🇮🇹Pisa, Italy
Investigational Site Number 276026
🇩🇪Jena, Germany
Investigational Site Number 276010
🇩🇪Rostock, Germany
Investigational Site Number 826001
🇬🇧Sutton, United Kingdom
Investigational Site Number 276008
🇩🇪Berlin, Germany
Investigational Site Number 724004
🇪🇸Madrid, Spain
Investigational Site Number 380008
🇮🇹Verona, Italy
Investigational Site Number 276006
🇩🇪Münster, Germany
Investigational Site Number 380009
🇮🇹Meldola, Italy
Investigational Site Number 352001
🇮🇸Reykjavik, Iceland
Investigational Site Number 300001
🇬🇷Athens, Greece
Investigational Site Number 724003
🇪🇸Sevilla, Spain
Investigational Site Number 276002
🇩🇪Frankfurt Am Main, Germany
Investigational Site Number 380001
🇮🇹Roma, Italy
Investigational Site Number 300005
🇬🇷Marousi, Athens, Greece
Investigational Site Number 300004
🇬🇷Thessaloniki, Greece
Investigational Site Number 528002
🇳🇱Breda, Netherlands
Investigational Site Number 528003
🇳🇱Nijmegen, Netherlands
Investigational Site Number 528005
🇳🇱Rotterdam, Netherlands
Investigational Site Number 528004
🇳🇱Sittard-Geleen, Netherlands
Investigational Site Number 578001
🇳🇴Grålum, Norway
Investigational Site Number 040004
🇦🇹Wien, Austria
Investigational Site Number 372003
🇮🇪Dublin 7, Ireland
Investigational Site Number 250013
🇫🇷Paris, France
Investigational Site Number 250008
🇫🇷Tours, France
Investigational Site Number 250001
🇫🇷Villejuif, France
Investigational Site Number 203003
🇨🇿Praha 4, Czechia
Investigational Site Number 040003
🇦🇹Wien, Austria
Investigational Site Number 040002
🇦🇹Linz, Austria
Investigational Site Number 250016
🇫🇷Reims, France
Investigational Site Number 203005
🇨🇿Brno, Czechia
Investigational Site Number 250011
🇫🇷Montpellier, France
Investigational Site Number 203001
🇨🇿Olomouc, Czechia
Investigational Site Number 250006
🇫🇷Lyon Cedex 8, France
Investigational Site Number 250005
🇫🇷Suresnes, France
Investigational Site Number 276025
🇩🇪Lübeck, Germany
Investigational Site Number 380004
🇮🇹Brescia, Italy
Investigational Site Number 372001
🇮🇪Dublin 24, Ireland
Investigational Site Number 276003
🇩🇪Nürtingen, Germany
Investigational Site Number 276011
🇩🇪Tübingen, Germany
Investigational Site Number 380005
🇮🇹Candiolo, Italy
Investigational Site Number 578002
🇳🇴Trondheim, Norway
Investigational Site Number 724001
🇪🇸Barcelona, Spain