Androgen Receptor Abnormal, DNA, Prostate Cancer
Conditions
Keywords
Prostate Cancer, Androgen Receptor Genomics, Enzalutamide, Prostatectomy, Neoadjuvant androgen ablation
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.
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. 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
Interventions
DRUGEnzalutamide
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.
Sponsors
Astellas Pharma Inc
The Netherlands Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men over 18 years of age. 2. clinically non-metastasized prostate cancer, tumor that can be imaged (TRUS or MRI) in order to allow for accurate preoperative biopsies. 3. Gleason score 7-10 4. written informed consent 5. WHO performance 0-1
Exclusion criteria
1. A history of seizures. 2. Clinically nodal metastases. 3. Prostatitis or urinary tract infection. 4. Androgen ablative therapy within 6 weeks of inclusion (including 5 alpha-reductase inhibitors). 5. Tumor of the prostate that can not be visualized by TRUS or MRI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
Outcome results
None listed