Enzalutamide With or Without Abiraterone and Prednisone in Treating Patients With Castration-Resistant Metastatic Prostate Cancer

• ClinicalTrials.gov Identifier: NCT01949337
• Recruitment Status: Active, not recruiting
• First Posted: September 24, 2013
• Results First Posted: June 1, 2020
• Last Update Posted: September 28, 2023
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); Astellas Pharma US, Inc.; Medivation, Inc.; Biologics, Inc.
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: September 20, 2013
• First Posted Date: September 24, 2013
• Results First Submitted Date: May 14, 2020
• Results First Posted Date: June 1, 2020
• Last Update Posted Date: September 28, 2023
• Actual Study Start Date: January 22, 2014
• Actual Primary Completion Date: November 2, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 14, 2020)

Overall Survival (OS) [ Time Frame: Up to 5 years post treatment ]

Overall survival is defined as the time from study registration to death due to any cause.

• Original Primary Outcome Measures (submitted: September 20, 2013): Overall survival (OS) [ Time Frame: Up to 5 years post-registration ]

Current Secondary Outcome Measures (submitted: May 14, 2020)

• Number of Participants Who Has Experienced at Least One Toxicity (Defined as a Grade 3 or Higher Adverse Event Deemed at Least Possibly Related to Treatment) [ Time Frame: Up to 5 years post treatment ]
  The number of participants who has experienced at least one toxicity (defined as a grade 3 or higher adverse event deemed at least possibly related to treatment)
• Decline in Prostate Specific Antigen (PSA) [ Time Frame: Up to 5 years post treatment ]
• Progression Free Survival (PFS) [ Time Frame: Up to 5 years post treatment ]
• Objective Response Rate [ Time Frame: Up to 5 years post treatment ]
• Radiographic Progression Free Survival (rPFS) [ Time Frame: Up to 5 years post treatment ]
• Tumor Burden and Bone Activity [ Time Frame: Up to 5 years post treatment ]

Original Secondary Outcome Measures (submitted: September 20, 2013)

• Grade 3 or higher toxicity profile using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years post-registration ]
• Decline in Prostate Specific Antigen (PSA) [ Time Frame: Up to 5 years post-registration ]
• Progression Free Survival (PFS) [ Time Frame: Up to 5 years post-registration ]
• Objective response rate [ Time Frame: Up to 5 years post-registration ]
• Radiographic Progression Free Survival (rPFS) [ Time Frame: Up to 5 years post-registration ]
• Tumor burden and bone activity [ Time Frame: Up to 5 years post-registration ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Enzalutamide With or Without Abiraterone and Prednisone in Treating Patients With Castration-Resistant Metastatic Prostate Cancer
• Official Title: Phase III Trial of Enzalutamide (NSC# 766085) Versus Enzalutamide, Abiraterone and Prednisone for Castration Resistant Metastatic Prostate Cancer
• Brief Summary: This randomized phase III trial studies enzalutamide to see how well it works compared to enzalutamide, abiraterone, and prednisone in treating patients with castration-resistant metastatic prostate cancer. Androgens can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, abiraterone acetate, and prednisone, may lessen the amount of androgens made by the body.

Detailed Description

Patients are randomized to one of two treatment groups: enzalutamide or enzalutamide, abiraterone and prednisone. Treatment will continue until disease progression or unacceptable toxicity. Patients are followed for clinical outcomes for a maximum of 5 years post study treatment. The primary and secondary objectives are described below.

1. Primary Objective:

   To compare the overall survival of patients with progressive metastatic castration-resistant prostate cancer (CRPC) treated with either enzalutamide only or enzalutamide with abiraterone and prednisone

2. Secondary Objectives:

   • To assess the grade 3 or higher toxicity profile and compare safety by treatment arm.
   • To assess and compare post-treatment prostate-specific antigen (PSA) declines by treatment arm.
   • To compare radiographic progression free survival defined by Prostate Cancer Working Group 2 (PCWG2), and objective response rate, by treatment arm.
   • To test for radiographic progression free survival (rPFS) treatment interaction in predicting overall survival.
   • To assess pre- and post-treatment measures of tumor burden and bone activity using sodium fluoride (NaF) positron emission tomography (PET)/computed tomography (CT) and technetium (Tc) methylene diphosphonate (MDP) bone scintigraphy and correlate these measures with overall survival.
   • To develop and validate prognostic and predictive models of overall survival that include baseline clinical and molecular markers.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Adenocarcinoma of the Prostate
• Hormone-resistant Prostate Cancer
• Recurrent Prostate Cancer
• Stage IV Prostate Cancer

Intervention

• Drug: enzalutamide
  Enzalutamide 160 mg daily, orally
• Drug: abiraterone
  abiraterone 1000 mg daily, orally
• Drug: prednisone
  prednisone 5 mg twice daily, orally

Study Arms

• Experimental: Arm A: (enzalutamide)
  Patients receive enzalutamide 160 mg PO QD. Treatment will continue until confirmed disease progression or unacceptable toxicity.
  Intervention: Drug: enzalutamide
• Experimental: Arm B: (enzalutamide, abiraterone, prednisone)
  Patients receive enzalutamide 160 mg PO QD, abiraterone 1000 mg PO QD, and prednisone 5 mg PO BID. Treatment will continue until confirmed disease progression or unacceptable toxicity.
  Interventions:

  • Drug: enzalutamide
  • Drug: abiraterone
  • Drug: prednisone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 28, 2016): 1311
• Original Estimated Enrollment (submitted: September 20, 2013): 1224
• Estimated Study Completion Date: August 31, 2024
• Actual Primary Completion Date: November 2, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Eligibility Criteria:

1. Documentation of Disease - Progressive castration-resistant metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features

2. Patients must have measurable or non-measurable disease:

   1. Measurable Disease - For visceral or extra nodal lesions to be considered measurable, they must be ≥ 10 mm in one dimension, using spiral CT. For lymph nodes to be considered measurable (ie, target or evaluable lesions), they must be ≥ 20 mm in at least one dimension, using spiral CT.
   2. Non-Measurable Disease - All other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions. Lesions that are considered non-measurable include bone lesions (only).
   3. Patients with node only disease (ie, no presence of visceral, extra nodal lesions or bone lesions) must have node(s) that measure ≥ 15 mm in short axis.

3. Progressive Disease - Patients must have progressive disease at study entry defined as one or more of the following three criteria that occurred while the patient was on androgen deprivation therapy. For patients enrolling on the basis of soft tissue or bone progression, the baseline scan must show progression relative to a comparison scan. If the comparison scan is not available, the baseline scan report must reference the previous scan to document progression.

   1. PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination. Patients who received an anti-androgen must have progression documented by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination such that at least the second of these rises is ≥ 4 weeks since last flutamide, bicalutamide or nilutamide.

      The PSA value at the screening should be ≥ 2 µg/L (2 ng/mL) .

   2. Soft tissue disease progression defined by the protocol
   3. Bone disease progression defined by the Prostate Cancer Working Group 2 (PCWG2) with two or more new lesions on bone scan

4. Prior Treatment

   1. No treatment with prior taxane-based chemotherapy for metastatic disease

      • Patients who received prior taxane-based chemotherapy as neoadjuvant or adjuvant therapy for local disease, or who received taxane-based therapy in the PSA clinical (non-metastatic) state is allowable provided that the total duration of exposure was six cycles or less and chemotherapy was completed more than 6 months prior to registration
      • Taxane-based chemotherapy that was aborted due to allergic reactions or intolerance to chemotherapy and therefore received one cycle of prior therapy is allowable
   2. No prior enzalutamide, abiraterone or other novel antiandrogen or androgen synthesis inhibitor

   3. No treatment with any of the following for prostate cancer within 4 weeks prior to enrollment:

      • Hormonal therapy (e.g., androgen receptor [AR] antagonists, 5 alpha reductase inhibitors, estrogens) Note: Treatment with bicalutamide and nilutamide within 4 weeks prior to enrollment is not allowed. Treatment with flutamide within 4 weeks prior to enrollment is not allowed. Treatment with all other gonadotropin- releasing hormone (GnRH) analogues or antagonists is allowed.
      • Chemotherapy
      • Biologic therapy
      • Investigational therapy
      • Immunotherapy
   4. No use of herbal products that may decrease PSA levels within 4 weeks prior to enrollment
   5. No use of systemic steroids greater than the equivalent of 10 mg of prednisone/prednisolone per day within 4 weeks prior to enrollment
   6. No prior use of ketoconazole for greater than 7 days
   7. No prior radiation therapy or radionuclide therapy for the treatment of metastasis within four weeks prior to enrollment
   8. Patients receiving bisphosphonate therapy or denosumab must have been on a stable dose for at least 4 weeks prior to enrollment
   9. Patients must maintain ongoing androgen deprivation therapy with a GnRH analogue, antagonist, or bilateral orchiectomy (i.e., surgical or medical castration)

5. Patient History

   1. No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)
   2. No planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
   3. No structurally unstable bone lesions suggesting impending fracture
   4. No history of seizure or any condition that may increase the patient's seizure risk (e.g., prior cortical stroke, significant brain trauma). No history of transient ischemic attack (TIA) within 12 months of enrollment

   5. No clinically significant cardiovascular disease including:

      • Myocardial infarction (MI) within 6 months
      • Uncontrolled angina within 3 months
      • Congestive heart failure (CHF) with New York Heart Association (NYHA) class 3 or 4, or patients with NYHA class 3 or 4 in the past, unless a screening echocardiogram (echo) or multigated acquisition scan (MUGA) performed within three months demonstrates an ejection fraction (EF) > 45%
      • History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
      • History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
      • Hypotension (systolic blood pressure [BP] < 86 mmHg) or bradycardia (< 50 bpm) at screening
      • Uncontrolled hypertension (systolic BP > 170 mmHg or diastolic BP > 105 mmHg at screening)
   6. No gastrointestinal (GI) disorder that negatively affects absorption
   7. No major surgery within 4 weeks prior to enrollment

6. Age and performance status

   1. Age ≥ 18 years of age
   2. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
   3. Asymptomatic or mildly symptomatic from prostate cancer

7. Required Initial Laboratory Values

   1. Granulocytes ≥ 1,500/µL
   2. Platelet count ≥ 100,000/µL
   3. Hemoglobin ≥ 9 g/dL
   4. Creatinine ≤ 2 x upper limits of normal (ULN)
   5. Bilirubin ≤ 1.5 x ULN
   6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2 x ULN
   7. Albumin ≥ 3 g/dl
   8. Total testosterone ≤ 50 ng/dL (1.7 nmol/L)

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Puerto Rico, United States

Administrative Information

• NCT Number: NCT01949337
• Other Study ID Numbers: A031201; U10CA031946 ( U.S. NIH Grant/Contract ); NCI-2013-01737 ( Registry Identifier: Clinical Trial Reporting Program )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute (NCI)
• Astellas Pharma US, Inc.
• Medivation, Inc.
• Biologics, Inc.

Investigators

• Study Chair: Michael Morris, M.D.; Memorial Sloan Kettering Cancer Center

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: September 2023