Dynamics of Androgen Receptor Genomics and Transcriptomics After Neoadjuvant Androgen Ablation

Study Overview
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Brief Summary
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Rationale: Understanding the mechanisms of enzalutamide as an androgen receptor inhibitor in early prostate cancer could lead to improved patient selection for treatment. Objective: To study the effects of enzalutamide on surgical margin status and AR / DNA interaction and gene expression. Intervention : Men with localized prostate cancer will undergo an additional set of targeted tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The prostatectomy specimen will be additionally sampled, ex vivo.

Detailed Description
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Rationale: Understanding the mechanisms of enzalutamide as an androgen receptor inhibitor in early prostate cancer could lead to improved patient selection for treatment. Objective: To study the effects of enzalutamide on surgical margin status and AR / DNA interaction and gene expression. Study design: A phase II prospective single-arm analysis. With a power of 80% to detect an expected reduction in positive surgical margin rate from 34% to 17% the investigators will have to included 55 men. For the AR/DNA interaction patients will serve as there own control since biopsies will be taken before and after enzalutamide treatment. Study population: Patients over 18 years of age with localized prostate cancer that are planned for prostatectomy. Intervention : Men with localized prostate cancer will undergo an additional set of targeted tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The prostatectomy specimen will be additionally sampled, ex vivo. Main study parameters/endpoints: 1. The effects of neoadjuvant androgen ablation on tumor downstaging. 2. The genetic and transcriptional changes caused by neoadjuvant androgen ablation by enzalutamide. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Burden and risks: Patients will be submitted to an additional set of 4 tumor targeted biopsies under local anesthesia and antibiotic prophylaxis. This comprises a 5 minute intervention with an elevated (2%) risk of postbiopsy urinary tract infection. Additionally oral enzalutamide treatment for a period of 3 months will result in temporary signs of androgen ablation such as: hot flushes (20%), headache (12%), diarrhea (1%), and seizures (0.9%). Benefits: neoadjuvant enzalutamide treatment has been shown to result in tumor and prostate downsizing. Earlier neoadjuvant androgen ablation studies with other agents have shown a reduced positive surgical margin rate and reduced intraoperative blood loss

Official Title
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Dynamics of Androgen Receptor Genomics and Transcriptomics After Neoadjuvant Androgen Ablation

Conditions
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DNA, Prostate Cancer, Androgen Receptor Abnormal

Intervention / Treatment
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* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men over 18 years of age. clinically non-metastasized prostate cancer, tumor that can be imaged (TRUS or MRI) in order to allow for accurate preoperative biopsies. Gleason score 7-10 written informed consent WHO performance 0-1 Exclusion Criteria: A history of seizures. Clinically nodal metastases. Prostatitis or urinary tract infection. Androgen ablative therapy within 6 weeks of inclusion (including 5 alpha-reductase inhibitors). Tumor of the prostate that can not be visualized by TRUS or MRI.

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
Intervention Model: Single Group Assignment
Interventional Model Description: A phase II prospective single-arm analysis. With a power of 80% to detect an expected reduction in positive surgical margin rate from 34% to 17% we will have to included 55 men. For the AR/DNA interaction patients will serve as there own control since biopsies will be taken before and after enzalutamide treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prostatectomy after enzalutamide<br>This is a single-arm study. Patients will have biopsies, after which they will receive enzalutamide for 3 months. After 3 months they will have a prostatectomy. | Drug: Enzalutamide<br>* Men with localized prostate cancer will undergo an additional set of targeted tumor biopsies and will be subsequently treated with 3 months of enzalutamide. The prostatectomy specimen will be additionally sampled, ex vivo.<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of enzalutamide on tumor downstaging | To study the effects of enzalutamide on surgical margin status and AR / DNA interaction and gene expression. | From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months). | 
| Genetic and transcriptional changes caused by enzalutamide | The genetic and transcriptional changes caused by neoadjuvant androgen ablation by enzalutamide. | From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical down-staging of enzalutamide pretreatment | To assess the effects of 3 months enzalutamide pretreatment on clinical down-staging | From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months). | 
| AR-chromatin binding alterations and Ki-67 expression | Study the correlation between AR-chromatin binding alterations and Ki-67 expression. | From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months). | 
| AR-dependant genes such as PSA, human kallikrein and PSMA | Compare the AR-chromatin binding with expression alterations of known AR-dependent genes such as PSA, human kallikrein and PSMA. | From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months). | 
| Gleason grading | Compare AR-chromatin binding patterns with Gleason grading. | From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months). | 
| Find associated genes in prostate tissue, using tissue microarray (TMA). | Find associated genes on TMA derived from prostatectomy specimens. | From baseline (prior to treatment), until disease progression or as long as treatment is tolerated or until study completion (60 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Androgen Receptor Genomics, Enzalutamide, Prostatectomy, Neoadjuvant androgen ablation