Clinical trial NCT02485691: 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
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Prostate Cancer Metastatic
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2015-06-30
Enrollment: 255
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion criteria :

Histologically confirmed prostate adenocarcinoma.

* Metastatic disease.
* Effective castration with serum testosterone levels less than (\<)0.5 ng/mL. If the participant has been treated with Luteinizing hormone-releasing hormone agonist (LHRH) agonists or antagonist (i.e., without orchiectomy), then this therapy should be continued.
* Progressive disease defined by at least one of the following:
* Progression in measurable disease (RECIST 1.1 criteria).
* Appearance of 2 or more new bone lesions (PCWG2).
* Rising Prostate Specific Antigen (PSA) (PCWG2).
* Having received prior docetaxel for at least 3 cycles (before or after an AR-targeted therapy). Docetaxel administration in combination with androgen deprivation therapy (ADT) in metastatic hormone-sensitive disease was considered a prior exposure. Docetaxel rechallenge was allowed.
* Having progressive disease (PD) while receiving AR-targeted therapy with abiraterone acetate or enzalutamide within 12 months of AR treatment initiation (\<=12 months), even if treatment duration was longer than 12 months. Participants treated with Abiraterone Acetate + ADT in metastatic hormone-sensitive setting were eligible in the study if they have progressed within 12 months with the AR-targeted agent. Participants having PSA progression only (as per PCWG2) within 12 months were eligible.
* A PSA value of at least 2 ng/mL was required at study entry.
* Prior AR-targeted therapy (abiraterone acetate or enzalutamide) must be stopped at least 2 weeks before study treatment.
* Signed informed consent.

Exclusion criteria:

* Prior chemotherapy other than docetaxel for prostate cancer, except estramustine and except adjuvant/neoadjuvant treatment completed \>3 years ago.
* Less than 28 days elapsed from prior treatment with chemotherapy, immunotherapy, radiotherapy, or surgery to the time of randomization.
* Adverse events (excluding alopecia and those listed in the specific exclusion criteria) from any prior anticancer therapy of Grade \>1 (National Cancer Institute Common Terminology Criteria \[NCI CTCAE\] v4.0) at the time of randomization.
* Eastern Cooperative Oncology Group performance status (ECOG PS) \>2 (ECOG 2 must be related to prostate cancer, not to other comorbidities).
* Prior malignancy. Adequately treated basal cell or squamous cell skin or superficial (pTis, pTa, and pT1) bladder cancer were allowed, as well as any other cancer for which treatment has been completed \>=5 years ago and from which the participant has been disease-free for \>=5 years.
* Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to randomization.
* Acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease requiring antiretroviral treatment.
* Participants with reproductive potential who do 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 based on respective study treatment labelling and country-specific regulatory requirements, and were documented in the Informed Consent Form.
* Known allergies, hypersensitivity or intolerance to prednisone or excipients of abiraterone acetate, enzalutamide, docetaxel, or polysorbate 80.
* Known history of mineralocorticoid excess or deficiency.
* History of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain arteriovenous malformation, brain metastases, or the use of concomitant medications that may lower the seizure threshold.
* Unable to swallow a whole tablet or capsule.
* Inadequate organ and bone marrow function as evidenced by:
* Hemoglobin \<10.0 g/dL;
* Absolute neutrophil count \<1.5 \* 10\^9/L;
* Platelet count \<100 \* 10\^9/L;
* Aspartate aminotransferase/serum glutamic oxaloacetic transaminase and/or alanine aminotransferase/serum glutamic pyruvic transaminase \>1.5 \* the upper limit of normal (ULN);
* Total bilirubin \>1.0 \* ULN;
* Potassium \<3.5 mmol/L;
* Child-Pugh Class C.
* Contraindications to the use of corticosteroid treatment.
* Symptomatic peripheral neuropathy Grade \>=2 (NCI CTCAE v4.0).
* Uncontrolled severe illness or medical condition including uncontrolled diabetes mellitus, history of cardiovascular disease (uncontrolled hypertension, arterial thrombotic events in the past 6 months, congestive heart failure, severe or unstable angina pectoris, recent myocardial infarction within the last 6 months, or uncontrolled cardiac arrhythmia).
* Concomitant vaccination with yellow fever vaccine.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Radiographic Progression-Free Survival (rPFS)
timeFrame: 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)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization to death due to any cause, or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
measure: Progression Free Survival (PFS)
timeFrame: 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)
measure: Percentage of Participants With Prostate Specific Antigen (PSA) Response
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)
measure: Percentage of Participants With Overall Objective Tumor Response
timeFrame: From randomization until disease progression, death due to any cause or data cut-off date whichever comes first (maximum duration: up to 141 weeks)
measure: Time to PSA Progression (TTPP)
timeFrame: 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)
measure: Duration of Tumor Response
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)
measure: Percentage of Participants Achieving Pain Response Assessed Using Brief Pain Inventory-Short Form (BPI-SF) Pain Intensity Score
timeFrame: Baseline until pain progression, first further anticancer therapy, or data cut-off whichever comes first (maximum duration: up to 141 weeks)
measure: Time to Pain Progression
timeFrame: Baseline until pain progression or data cut-off whichever comes first (maximum duration: up to 141 weeks)
measure: Number of Symptomatic Skeletal Events (SSE)
timeFrame: Baseline until occurrence of first SSE or data cut-off, whichever comes first (maximum duration: up to 141 weeks)
measure: Time to Symptomatic Skeletal Event
timeFrame: From date of randomization until first SSE, or data cut-off whichever comes first (maximum duration: up to 141 weeks)
measure: 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
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)
measure: 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
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)
measure: Radiographic Progression-Free Survival (rPFS) in Participants With Presence and Absence of Biomarker
timeFrame: 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)
Other outcomes:
Locations:
city: Linz
country: Austria
facility: Investigational Site Number 040002
city: Wien
country: Austria
facility: Investigational Site Number 040003
city: Wien
country: Austria
facility: Investigational Site Number 040004
city: Brugge
country: Belgium
facility: Investigational Site Number 056013
city: Brussels
country: Belgium
facility: Investigational Site Number 056007
city: Bruxelles
country: Belgium
facility: Investigational Site Number 056003
city: Charleroi
country: Belgium
facility: Investigational Site Number 056006
city: Gent
country: Belgium
facility: Investigational Site Number 056001
city: Leuven
country: Belgium
facility: Investigational Site Number 056005
city: Brno
country: Czechia
facility: Investigational Site Number 203005
city: Olomouc
country: Czechia
facility: Investigational Site Number 203001
city: Plzen
country: Czechia
facility: Investigational Site Number 203002
city: Praha 4
country: Czechia
facility: Investigational Site Number 203003
city: Clermont Ferrand
country: France
facility: Investigational Site Number 250010
city: Lyon Cedex 8
country: France
facility: Investigational Site Number 250006
city: Marseille
country: France
facility: Investigational Site Number 250004
city: Montpellier
country: France
facility: Investigational Site Number 250011
city: Paris Cedex 15
country: France
facility: Investigational Site Number 250002
city: Paris
country: France
facility: Investigational Site Number 250013
city: Paris
country: France
facility: Investigational Site Number 250007
city: Plerin
country: France
facility: Investigational Site Number 250014
city: Reims
country: France
facility: Investigational Site Number 250016
city: Saint-Mandé
country: France
facility: Investigational Site Number 250018
city: Strasbourg
country: France
facility: Investigational Site Number 250009
city: Suresnes
country: France
facility: Investigational Site Number 250005
city: Tours
country: France
facility: Investigational Site Number 250008
city: Villejuif
country: France
facility: Investigational Site Number 250001
city: Aschaffenburg
country: Germany
facility: Investigational Site Number 276028
city: Berlin
country: Germany
facility: Investigational Site Number 276008
city: Duisburg
country: Germany
facility: Investigational Site Number 276022
city: Essen
country: Germany
facility: Investigational Site Number 276023
city: Frankfurt Am Main
country: Germany
facility: Investigational Site Number 276002
city: Göttingen
country: Germany
facility: Investigational Site Number 276007
city: Jena
country: Germany
facility: Investigational Site Number 276026
city: Lübeck
country: Germany
facility: Investigational Site Number 276025
city: Magdeburg
country: Germany
facility: Investigational Site Number 276004
city: Mannheim
country: Germany
facility: Investigational Site Number 276018
city: Münster
country: Germany
facility: Investigational Site Number 276006
city: Nürtingen
country: Germany
facility: Investigational Site Number 276003
city: Rostock
country: Germany
facility: Investigational Site Number 276010
city: Tübingen
country: Germany
facility: Investigational Site Number 276011
city: Athens
country: Greece
facility: Investigational Site Number 300001
city: Marousi, Athens
country: Greece
facility: Investigational Site Number 300005
city: Thessaloniki
country: Greece
facility: Investigational Site Number 300004
city: Reykjavik
country: Iceland
facility: Investigational Site Number 352001
city: Dublin 24
country: Ireland
facility: Investigational Site Number 372001
city: Dublin 7
country: Ireland
facility: Investigational Site Number 372003
city: Brescia
country: Italy
facility: Investigational Site Number 380004
city: Candiolo
country: Italy
facility: Investigational Site Number 380005
city: Meldola
country: Italy
facility: Investigational Site Number 380009
city: Napoli
country: Italy
facility: Investigational Site Number 380006
city: Pisa
country: Italy
facility: Investigational Site Number 380002
city: Roma
country: Italy
facility: Investigational Site Number 380001
city: Verona
country: Italy
facility: Investigational Site Number 380008
city: Breda
country: Netherlands
facility: Investigational Site Number 528002
city: Nijmegen
country: Netherlands
facility: Investigational Site Number 528003
city: Rotterdam
country: Netherlands
facility: Investigational Site Number 528005
city: Sittard-Geleen
country: Netherlands
facility: Investigational Site Number 528004
city: Grålum
country: Norway
facility: Investigational Site Number 578001
city: Trondheim
country: Norway
facility: Investigational Site Number 578002
city: Barcelona
country: Spain
facility: Investigational Site Number 724001
city: Madrid
country: Spain
facility: Investigational Site Number 724004
city: Madrid
country: Spain
facility: Investigational Site Number 724002
city: Sevilla
country: Spain
facility: Investigational Site Number 724003
city: Sutton
country: United Kingdom
facility: Investigational Site Number 826001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: de Wit R, Wulfing C, Castellano D, Kramer G, Eymard JC, Sternberg CN, Fizazi K, Tombal B, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdottir A, Theodore C, Feyerabend S, Helissey C, Foster MC, Ozatilgan A, Geffriaud-Ricouard C, de Bono J. Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study. ESMO Open. 2021 Oct;6(5):100241. doi: 10.1016/j.esmoop.2021.100241. Epub 2021 Aug 24.
citation: Sternberg CN, Castellano D, de Bono J, Fizazi K, Tombal B, Wulfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdottir A, Theodore C, Feyerabend S, Helissey C, Poole EM, Ozatilgan A, Geffriaud-Ricouard C, de Wit R. Efficacy and Safety of Cabazitaxel Versus Abiraterone or Enzalutamide in Older Patients with Metastatic Castration-resistant Prostate Cancer in the CARD Study. Eur Urol. 2021 Oct;80(4):497-506. doi: 10.1016/j.eururo.2021.06.021. Epub 2021 Jul 15.
citation: Fizazi K, Kramer G, Eymard JC, Sternberg CN, de Bono J, Castellano D, Tombal B, Wulfing C, Liontos M, Carles J, Iacovelli R, Melichar B, Sverrisdottir A, Theodore C, Feyerabend S, Helissey C, Oudard S, Facchini G, Poole EM, Ozatilgan A, Geffriaud-Ricouard C, Bensfia S, de Wit R. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study. Lancet Oncol. 2020 Nov;21(11):1513-1525. doi: 10.1016/S1470-2045(20)30449-6. Epub 2020 Sep 11.
citation: de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wulfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdottir A, Theodore C, Feyerabend S, Helissey C, Ozatilgan A, Geffriaud-Ricouard C, Castellano D; CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518. doi: 10.1056/NEJMoa1911206. Epub 2019 Sep 30.