Abiraterone Acetate and Antiandrogen Therapy With or Without Cabazitaxel and Prednisone in Treating Patients With Metastatic, Castration-Resistant Prostate Cancer Previously Treated With Docetaxel

Study Overview
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Brief Summary
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This randomized phase II trial studies how well abiraterone acetate and antiandrogen therapy, with or without cabazitaxel and prednisone, work in treating patients with castration-resistant prostate cancer previously treated with docetaxel that has spread to other parts of the body. Androgens can cause the growth of prostate cancer cells. Hormone therapy using abiraterone acetate and antiandrogen therapy may fight prostate cancer by lowering and/or blocking the use of androgens by the tumor cells. Drugs used in chemotherapy, such as cabazitaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving abiraterone acetate and antiandrogen therapy with or without cabazitaxel and prednisone may help kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess whether the addition of 6 cycles of cabazitaxel to abiraterone acetate in patients with castration-resistant prostate cancer (CRPC) that have previously received docetaxel and androgen deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) can improve progression-free survival (PFS) compared to abiraterone acetate alone. SECONDARY OBJECTIVES: I. To assess whether the addition of 6 cycles of cabazitaxel to abiraterone acetate in patients with CRPC that have previously received docetaxel and ADT for HSPC can increase the percentage of change in prostate-specific antigen (PSA) from baseline to week 12 of treatment as well as the maximum decline in PSA that occurs at any point after treatment compared to abiraterone acetate alone. II. To assess whether the addition of 6 cycles of cabazitaxel to abiraterone acetate in patients with CRPC that have previously received docetaxel for HSPC can prolong time to PSA progression compared to abiraterone acetate alone. III. To assess whether the addition of 6 cycles of cabazitaxel to abiraterone acetate in patients with CRPC that have previously received docetaxel for HSPC can improve radiographic response (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) compared to abiraterone acetate alone. IV. To assess whether the addition of 6 cycles of cabazitaxel to abiraterone acetate in patients with CRPC that have previously received docetaxel and ADT for HSPC can prolong the overall survival (OS) compared to abiraterone acetate alone. V. To assess safety and tolerability of the combination of 6 cycles of cabazitaxel and abiraterone acetate. TERTIARY OBJECTIVES: I. To examine whether patients with circulating tumor cells (CTCs) positive for AR-V7 at baseline have a longer radiographic or clinical PFS to the combination of cabazitaxel and abiraterone acetate vs. abiraterone acetate alone. II. To examine whether the addition of cabazitaxel to abiraterone acetate can change the AR-V7 status of patients who are positive at study entry. III. To examine whether the addition of cabazitaxel to abiraterone acetate has any impact on future development of AR-V7 positivity at the time of disease progression. IV. To assess if the changes in total tumor burden from baseline to week 12 as assessed with sodium fluoride (NaF) positron emission tomography (PET)/computed tomography (CT) will differ between two arms. V. To correlate total tumor burden at the baseline as assessed with NaF PET/CT with the PFS. VI. To correlate heterogeneity of response from baseline to week 12 as assessed with NaF PET/CT with the PFS. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive abiraterone acetate orally (PO) once daily (QD) on days 1-21, prednisone PO twice daily (BID) on days 1-21. Courses of abiraterone acetate and prednisone repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients receive cabazitaxel intravenously (IV) over 1 hour on day 1, and treatment with cabazitaxel repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care antiandrogen therapy with either luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, or surgical castration with bilateral orchiectomy. ARM B: Patients receive abiraterone acetate and prednisone as in Arm A. Patients also receive standard of care antiandrogen therapy with either LHRH agonist or antagonist, or surgical castration with bilateral orchiectomy. After completion of study treatment, patients are followed up every 3 or 6 months and then annually for up to 5 years.

Official Title
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Cabazitaxel With Abiraterone Versus Abiraterone Alone Randomized Trial for Extensive Disease Following Docetaxel: The CHAARTED2 Trial

Conditions
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Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma in the Soft Tissue, Prostate Carcinoma Metastatic in the Bone, Stage IV Prostate Adenocarcinoma AJCC v7

Intervention / Treatment
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* Drug: Abiraterone Acetate
* Drug: Antiandrogen Therapy
* Drug: Cabazitaxel
* Other: Laboratory Biomarker Analysis
* Procedure: Orchiectomy
* Other: Pharmacological Study
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate) Previous chemotherapy with at least 3 cycles of docetaxel for hormone-sensitive metastatic prostate cancer Metastatic disease as evidenced by the presence of soft tissue and/or bone metastases on imaging studies (CT/magnetic resonance imaging [MRI] of abdomen/pelvis, bone scintigraphy or NaF PET/CT) Ability to swallow abiraterone acetate tablets as a whole All patients must be receiving standard of care androgen deprivation treatment (surgical castration versus LHRH agonist or antagonist treatment); subjects receiving LHRH agonist or antagonist must continue treatment throughout the time on this study Patients must have castrate serum level of testosterone of < 50 ng/dL (< 1.73 nmol/L) Patients must have progressive disease while receiving androgen deprivation therapy defined by any one of the following as per the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria for PSA, measurable disease or non-measurable (bone) disease during treatment with ADT: PSA: At least two consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, with the final value >= 2.0 ng/mL Measurable disease (by RECIST 1.1): > 20% increase in the sum of the longest diameters of all measurable lesions or the development of new measurable lesions; the short axis of a target lymph node must be more that 15 mm to be assessed for change in size Non-measurable (bone) disease: The appearance of two or more new areas of uptake on bone scan (or NaF PET/CT) consistent with metastatic disease compared to previous imaging during castration therapy; the increased uptake of pre-existing lesions on bone scan will not be taken to constitute progression, and ambiguous results must be confirmed by other imaging modalities (e.g. X-ray, CT or MRI) Patients may or may not have been treated previously with a nonsteroidal antiandrogen, such as flutamide, bicalutamide or nilutamide; for patients previously treated with an antiandrogen, they must be off treatment for at least 4 weeks (for flutamide) or 6 weeks (for bicalutamide or nilutamide) prior to registration and must have shown PSA progression after discontinuing the anti-androgen Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Absolute neutrophil count (ANC) >= 1500/mm^3 Hemoglobin (HgB) >= 9.0 gr/dL Platelets >= 100,000/mm^3 Creatinine < 2.0 mg/dL Patients must be informed of the experimental nature of the study and its potential risks, and must sign an Institutional Review Board (IRB)-approved written informed consent form indicating such an understanding Patients with resected or irradiated brain metastases or those treated with stereotactic radiation therapy are eligible to enroll, provided that they do not require treatment with steroids that exceeds 10 mg of prednisone daily or equivalent Sexually active males must use an accepted and effective method of double barrier contraception or abstain from sexual intercourse for the duration of their participation in the study and for 26 weeks after the last dose of study drug NaF PET/CT OPTIONAL SUB-STUDY ELIGIBILITY CRITERIA Ability to lie still for imaging Weight =< 300 lbs (pounds) Exclusion Criteria: Any prior chemotherapy or androgen receptor (AR)-directed therapy for CRPC, (e.g. docetaxel, cabazitaxel, mitoxantrone, abiraterone acetate, ketoconazole, or enzalutamide); previous treatment with radium-223 or sipuleucel-T is allowed Pure small cell or other variant (non-adenocarcinoma) prostate cancer histology for which treatment with abiraterone would not be considered appropriate Patients may not be receiving other therapeutic investigational agents or be receiving concurrent anticancer therapy other than standard androgen deprivation therapy; concurrent treatment with agents to prevent skeletal-related events (such as zoledronic acid or denosumab) will be allowed as long as it was initiated prior to study entry Any medical condition for which prednisone (corticosteroid) is contraindicated If total bilirubin is > upper limit of normal (ULN) (NOTE: in subjects with Gilbert?s syndrome, if total bilirubin is > ULN, measure direct and indirect bilirubin and if direct bilirubin is within normal range, subject may be eligible) or Alanine (ALT) or aspartate (AST) aminotransferase > 1.5 x ULN Active infection requiring treatment with antibiotics History of adrenal insufficiency or hypoaldosteronism Myocardial infarction or arterial thrombotic event within 6 months, heart failure of New York Heart Association class II or higher, uncontrolled angina, severe uncontrolled ventricular arrhythmia External beam radiation therapy within 4 weeks of registration Prior history of allergic reactions to G-CSF Prior history of allergic reactions to docetaxel and/or to medications formulated with polysorbate 80 History of active malignancy; patients with a history of cancer that has been adequately treated and are free of disease recurrence for 3 years or more are allowed to participate; patients with non-melanoma skin cancers or carcinoma in situ of the bladder that have been adequately excised are eligible to participate Life expectancy of < 12 months at screening Grade >= 2 neuropathy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (abiraterone acetate, prednisone, cabazitaxel)<br>Patients receive abiraterone acetate PO QD on days 1-21, prednisone PO BID on days 1-21. Courses of abiraterone acetate and prednisone repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients receive cabazitaxel IV over 1 hour on day 1, and treatment with cabazitaxel repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care antiandrogen therapy with either LHRH agonist or antagonist, or surgical castration with bilateral orchiectomy. | Drug: Abiraterone Acetate<br>* Given PO<br>* Other names: Zytiga;Drug: Antiandrogen Therapy<br>* Receive standard of care antiandrogen therapy with either LHRH agonist or antagonist<br>* Other names: Hormone-Deprivation Therapy;Drug: Cabazitaxel<br>* Given IV<br>* Other names: XRP-6258;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Orchiectomy<br>* Undergo standard of care surgical castration with bilateral orchiectomy<br>* Other names: orchidectomy;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;|
| Active Comparator: Arm B (abiraterone acetate, prednisone)<br>Patients receive abiraterone acetate and prednisone as in Arm A. Patients also receive standard of care antiandrogen therapy with either LHRH agonist or antagonist, or surgical castration with bilateral orchiectomy. | Drug: Abiraterone Acetate<br>* Given PO<br>* Other names: Zytiga;Drug: Antiandrogen Therapy<br>* Receive standard of care antiandrogen therapy with either LHRH agonist or antagonist<br>* Other names: Hormone-Deprivation Therapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Orchiectomy<br>* Undergo standard of care surgical castration with bilateral orchiectomy<br>* Other names: orchidectomy;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Will be compared between the two arms. Patients who are alive without progression will be censored at the date of last disease assessment. | From randomization to radiographic progression, symptomatic deterioration or death, whichever occurs first, assessed for up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in PSA in serum | Will be compared between the two arms using Wilcoxon rank sum test. | Baseline to 12 weeks | 
| Maximum decline in PSA while on treatment | Will be compared between the two arms using Wilcoxon rank sum test. | Baseline up to 30 days from last treatment on study | 
| Time to PSA progression | Will be estimated using the Kaplan-Meier method. Stratified log rank test will be used to compare between the two arms. | Time from randomization to PSA progression, assessed for up to 30 days from last treatment on study | 
| Overall survival (OS) | Will be estimated for each arm using the Kaplan-Meier method and the stratified logrank test will be used to compare this endpoint across treatments. | Time from randomization to time of death or date last known alive, assessed for up to 5 years | 
| Radiographic response (complete and partial response) assessed per Response Evaluation Criteria in Solid Tumors 1.1 | Fisher's exact test will be used to compare rates between the two arms. Patients with radiographic response unknown or unevaluable will be considered as non-responders in this analysis. | Up to 5 years | 
| Incidence of adverse events assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | Will be evaluated for toxicity and the percent of patients with various toxicities will be tabulated. | Up to 30 days from last treatment on study |