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 (CARD)

Sanofi

Status and phase: Completed; Phase 4

Conditions: Prostate Cancer Metastatic

Treatments: Drug: abiraterone acetate; Drug: enzalutamide; Drug: cabazitaxel XRP6258; Drug: prednisone

Study type: Interventional

Funder types: Industry

Identifiers

NCT02485691

2014-004676-29 (EudraCT Number)

LPS14201

U1111-1166-5329 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 255 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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255 participants in 2 patient groups

Cabazitaxel

Experimental group

Description:

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).

Treatment:

Drug: prednisone

Drug: cabazitaxel XRP6258

Abiraterone acetate or enzalutamide

Experimental group

Description:

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).

Treatment:

Drug: prednisone

Drug: enzalutamide

Drug: abiraterone acetate