DARANA: Dynamics of Androgen Receptor Genomics and Transcriptomics After Neoadjuvant Androgen Ablation

Sponsor

The Netherlands Cancer Institute (Other)

Overall Status

Completed

CT.gov ID

NCT03297385

Collaborator

Astellas Pharma Inc (Industry)

Enrollment

Arm

31.1

Actual Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer DNA Androgen Receptor Abnormal	Drug: Enzalutamide	Phase 2

Detailed Description

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.

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

Study Design

Study Type:

Interventional

Actual Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention 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.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)

Primary Purpose:

Treatment

Official Title:

Dynamics of Androgen Receptor Genomics and Transcriptomics After Neoadjuvant Androgen Ablation

Actual Study Start Date :

Aug 28, 2014

Actual Primary Completion Date :

Apr 1, 2017

Actual Study Completion Date :

Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prostatectomy after enzalutamide 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 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. Other Names: Xtandi

Arm

Intervention/Treatment

Experimental: Prostatectomy after enzalutamide

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

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.

Other Names:

Xtandi

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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.