Androgen Receptor Antagonist ARN-509 With or Without Abiraterone Acetate, Gonadotropin-Releasing Hormone Analog, and Prednisone in Treating Patients With High-Risk Prostate Cancer Undergoing Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well androgen receptor antagonist ARN-509 works with or without abiraterone acetate, gonadotropin-releasing hormone agonist, and prednisone in treating patients with high-risk prostate cancer undergoing surgery. Androgen can cause the growth of prostate cancer cells. Hormone therapy using androgen receptor antagonist ARN-509, abiraterone acetate, and gonadotropin-releasing hormone analog (GnRH agonist) may fight prostate cancer by lowering the levels of androgen the body makes. Prednisone may either kill the tumor cells or stop them from dividing. Giving androgen receptor agonist ARN-509 with or without abiraterone acetate, GnRH agonist and prednisone may work better in treating patients with prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the effect of neoadjuvant androgen receptor antagonist ARN-509 (apalutamide) with or without abiraterone acetate, GnRH agonist, and prednisone on the feasibility of performing nerve-sparing radical prostatectomy (RP) in men with high-risk prostate cancer (PCa). OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive androgen receptor antagonist ARN-509 orally (PO) daily for 3 months. Patients then undergo radical prostatectomy. ARM II: Patients receive GnRH agonist subcutaneously (SC) on day 1, androgen receptor antagonist ARN-509 PO daily PO for 4 times, abiraterone acetate PO daily for 4 times, and prednisone PO daily for 3 months. Patients then undergo radical prostatectomy. ARM III: Patients undergo radical prostatectomy. After completion of study treatment, patients are followed up for 2 years.

Official Title
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Randomized Three-Arm Trial to Evaluate the Effect of Neoadjuvant Apalutamide Alone or in Combination With Abiraterone Acetate and GnRH Agonist on Enhancing Surgical Outcome of Nerve-Sparing Radical Prostatectomy in Men With High-Risk Prostate Cancer

Conditions
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Stage II Prostate Adenocarcinoma, Stage III Prostate Adenocarcinoma

Intervention / Treatment
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* Drug: Abiraterone Acetate
* Drug: Androgen Receptor Antagonist ARN-509
* Biological: Gonadotropin-releasing Hormone Analog
* Drug: Prednisone
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Procedure: Radical Prostatectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven adenocarcinoma of the prostate and: Gleason > 8 OR prostatic specific antigen (PSA) > 20 and more than 1 positive core Patients with Eastern Cooperative Oncology Group performance scale (ECOG PS) 0 or 1 Clinical stage T3 or less as demonstrated by abdominal/pelvic computed tomography (CT) or magnetic resonance imaging (MRI) will be selected as the prostate is resectable Hemoglobin >= 9.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization Platelet count >= 100,000 x 10^9/uL independent of transfusion and/or growth factors within 3 months prior to randomization Serum albumin >= 3.0 g/dL Glomerular filtration rate (GFR) >= 45 mL/min Serum potassium >= 3.5 mmol/L Serum total bilirubin =< 1.5 × upper limit of normal (ULN) (Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 × ULN, subject may be eligible) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 × ULN Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug; must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug Exclusion Criteria: Clinical stage T4 (invasion into rectum or ureters) significantly increases the morbidity of the surgery Patients with rectal or ureteral invasion will be considered to have unresectable disease History of any of the following: Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1year to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign central nervous system [CNS] or meningeal disease which may require treatment with surgery or radiation therapy) Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial within 6 months prior to randomization Venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks) within 6 months prior to randomization Clinically significant ventricular arrhythmias within 6 months prior to randomization Metastatic prostate cancer Baseline moderate or severe hepatic impairment (Child-Pugh class B or C)
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 I (androgen receptor ARN-509, radical prostatectomy)<br>Patients receive androgen receptor antagonist ARN-509 PO daily for 3 months. Patients then undergo radical prostatectomy. | Drug: Androgen Receptor Antagonist ARN-509<br>* Given PO<br>* Other names: ARN-509;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Radical Prostatectomy<br>* Undergo radical prostatectomy<br>* Other names: Prostatovesiculectomy;|
| Active Comparator: Arm II (ARN-509, abiraterone acetate, GnRH, prednisone, RP)<br>Patients receive GnRH agonist SC on day 1, androgen receptor antagonist ARN-509 PO daily PO for 4 times, abiraterone acetate PO daily for 4 times, and prednisone PO daily for 3 months. Patients then undergo radical prostatectomy. | Drug: Abiraterone Acetate<br>* Given PO<br>* Other names: Zytiga;Drug: Androgen Receptor Antagonist ARN-509<br>* Given PO<br>* Other names: ARN-509;Biological: Gonadotropin-releasing Hormone Analog<br>* Given SC<br>* Other names: Luteinizing Hormone-Releasing Hormone Analog;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Radical Prostatectomy<br>* Undergo radical prostatectomy<br>* Other names: Prostatovesiculectomy;|
| Active Comparator: Arm III (radical prostatectomy)<br>Patients undergo radical prostatectomy. | Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Radical Prostatectomy<br>* Undergo radical prostatectomy<br>* Other names: Prostatovesiculectomy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-surgical potency rate defined as proportion of patients with International Index of Erectile Function score >= 17 | Each of the experimental arms will be compared to the surgery-only arm, so each test will be a 2.5% level one-sided test to control for the fact that there are two comparisons. | At 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in tumor volume on pelvic MRI after neoadjuvant therapy | Will be correlated with clinical outcomes before and after androgen receptor antagonist ARN-509 or androgen receptor antagonist ARN-509, GnRH agonist, prednisone plus abiraterone acetate. | Baseline to week 13 | 
| Number of patients with biochemical recurrence defined using the Prostate Cancer Clinical Trials Working Group 2 definition |  | Up to 5 years | 
| Number of patients with pathological T0 |  | Up to 5 years | 
| Number of patients with positive surgical margins |  | Up to 5 years | 
| Postoperative continence rate as determined by the American Urological Association Symptom Score (AUAss) |  | Up to 24 months after surgery | 
| Postoperative continence rate as determined by the Sexual Health Inventory for Men |  | Up to 24 months after surgery | 
| Postoperative continence rate as determined by the Expanded Prostate Cancer Index Composite (EPIC) |  | Up to 24 months after surgery | 
| Quality of life as assessed by the AUAss questionnaires |  | Up to 24 months after surgery | 
| Quality of life as assessed by the EPIC questionnaires |  | Up to 24 months after surgery |