Cabazitaxel Versus the Switch to Alternative AR Targeted Therapy Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Primary Resistant Patients to Abiraterone or Enzalutamide
Condition: Prostate Cancer Metastatic
MeSH terms: Prostatic Neoplasms
Intervention: Cabazitaxel XRP6258; Ezalutamide; Abiraterone acetate; Prednisone
Intervention MeSH terms: Prednisone; Abiraterone Acetate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Primary Objective:

      To demonstrate the superiority in term of radiographic Progression-Free Survival (rPFS) of
      cabazitaxel at at 25 milligram per meter square (mg/m^2) plus prednisone (Arm A) versus
      either enzalutamide at 160 milligram (mg) once daily or abiraterone acetate at 1000 mg once
      daily plus prednisone (Arm B) in chemotherapy-naïve participants with metastatic
      Castration-Resistant Prostate Cancer (mCRPC) who have disease progression while receiving
      androgen receptor (AR) targeted therapy (abiraterone plus prednisone or enzalutamide) within
      12 months of treatment initiation (≤12 months).

      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 in participants with measurable disease (RECIST 1.1)

        -  Pain response and time to pain progression.

        -  Symptomatic skeletal events (SSE) rate and time to occurrence of any SSE.

        -  To analyze messenger ribonucleic acids (mRNAs) including androgen-receptor splice
           variant 7 messenger RNA (AR-V7) as a biomarker in Circulating Tumor Cells (CTCs).

        -  To evaluate safety in the 2 treatment arms.
    

Eligibility criteria:

        Inclusion criteria:

          -  Diagnosis of histologically or cytologically confirmed prostate adenocarcinoma.

          -  Metastatic disease.

          -  Progressive disease (PD) while receiving AR targeted therapy with abiraterone acetate
             or enzalutamide within 12 months of treatment initiation (≤12 months) by at least one
             of the following:

          -  Progression in measurable disease Response Evaluation Criteria in Solid Tumors
             (RECIST) 1.1.

          -  Appearance of 2 or more new bone lesions according to Prostate Cancer Working Group 2
             (PCWG2).

          -  Rising PSA defined (PCWG2) as at least two consecutive rises in PSA to be documented
             over a reference value (measure 1) taken at least one week apart.

          -  A PSA value of at least 2 nanogram/milliliter (ng/mL) is required at study entry.

          -  Effective castration (serum testosterone levels ≤0.5 ng/mL).

          -  Prior AR targeted therapy (abiraterone acetate or enzalutamide) must be stopped at
             least 2 weeks before study treatment.

          -  Signed written informed consent.

        Exclusion criteria:

          -  Prior chemotherapy for prostate cancer, except estramustine and except
             adjuvant/neoadjuvant treatment completed >3 years ago. No further anti-cancer therapy
             after the previous AR targeted therapy and before inclusion. Prior docetaxel in
             hormone sensitive setting is allowed if completed >1 year before randomization. Prior
             immunotherapy is allowed.

          -  Less than 28 days elapsed from prior treatment with 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 for Adverse Events [NCI CTCAE] v4.0) at the time of
             randomization.

          -  Eastern Cooperative Oncology Group (ECOG) performance status >1.

          -  History of brain metastases, uncontrolled spinal cord compression, or carcinomatous
             meningitis, or new evidence of brain or leptomeningeal disease.

          -  Prior malignancy. Adequately treated basal cell or squamous cell skin or superficial
             (pTis, pTa, and pT1) bladder cancer are allowed, as well as any other cancer for which
             treatment has been completed ≥5 years ago and from which the patient 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.

          -  Any severe acute or chronic medical condition including uncontrolled diabetes
             mellitus, severe renal impairment, history of cardiovascular disease (uncontrolled
             hypertension, arterial thrombotic events in the past 6 months, congestive heart
             failure, severe or unstable angina pectoris, recent myocardial infraction within last
             6 months or uncontrolled cardiac arrhythmia), which could impair the ability of the
             patient to participate to the study or interfere with interpretation of study results,
             or patient unable to comply with the study procedures.

          -  Participants with reproductive potential who do not agree 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" will be based on the Investigator's judgment.

          -  Known allergies, hypersensitivity or intolerance to prednisone or excipients of
             abiraterone acetate or enzalutamide. History of hypersensitivity to docetaxel or
             polysorbate 80.

          -  Known history of mineralocorticoid excess or deficiency (not applicable to
             participants who have already been treated with abiraterone acetate in first line
             before inclusion).

          -  History of seizure, underlying brain injury with loss of consciousness, transient
             ischemic attack within the past 12 months, cerebral vascular accident, brain
             arteriovenous malformation or the use of concomitant medications that may lower the
             seizure threshold (not applicable to participants who have already been treated with
             enzalutamide in first line before inclusion).

          -  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 x 10^9/L.

          -  Platelet count <100 x 10^9/L.

          -  Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) >1.5 x Upper
             limit of normal (ULN).

          -  Total bilirubin >1.0 x ULN.

          -  Potassium <3.5 mmol/L.

          -  Serum albumin <3.0 g/dL.

          -  Child-Pugh Class B and C.

          -  Contraindications to the use of corticosteroid treatment.

          -  Symptomatic peripheral neuropathy grade ≥2 NCI CTCAE v4.0.

          -  Concomitant vaccination with yellow fever vaccine.

        The above information was not intended to contain all considerations relevant to a
        patient's potential participation in a clinical trial.