Official Title: “Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer”

Prostate cancer (CaP) is the most commonly diagnosed cancer among males in the U.S. and the second leading cause of cancer-related mortality. More than 230,000 men will be diagnosed with prostate cancer in the USA this year and more that 30,000 will die of this disease.

Androgen deprivation, the elimination of testosterone and its active metabolites, remains the single most effective intervention available for the treatment of advanced prostate carcinoma. This is usually achieved by surgical removal of the testes (orchiectomy), by suppressing production of testosterone (LHRH agonists) and/or by blocking the androgens at receptor sites (antiandrogens). Unfortunately, androgen suppression does not cure the disease. Most patients progress within 0-5 years, and all patients ultimately progress if the cancer is not eliminated during initial therapy (usually prostatectomy or radiation).

Hormone suppression treatment eliminates the detectable levels of testosterone in the blood.

However, the testosterone levels in tissue remain high enough to stimulate androgen receptors. Overexpression of androgen receptors is present in all cell lines which demonstrate "androgen independence," i.e., are resistant to androgen-suppressive therapy.

Approximately 95% of testosterone is supplied by the testes, with the remaining 5% supplied by the adrenal glands. The presumption that standard androgen deprivation achieves the optimal level of androgen suppression for patients is based on the levels of androgen which result from orchiectomy. However, because adrenal androgen levels are unaffected by standard modes of androgen deprivation, 5% of the body's testosterone remains despite hormone therapy.

The hypothesis of this study is that more effective suppression of the androgen axis through elimination of adrenal androgens and more effective suppression of testosterone metabolites will lower intraprostatic androgen levels, minimizing activation of the androgen receptor and augmenting natural cell death (apoptosis). We propose to test this hypothesis by administering neoadjuvant (pre-surgery) androgen deprivation therapy of different types before prostatectomy for patients with clinically localized prostate cancer. We will assay serum and intraprostatic androgen levels, while assessing relative levels of apoptosis of normal and malignant tissue.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Single Group Assignment

Study Primary Completion Date: February 2011

Androgen deprivation has been the principal means of controlling advanced prostate cancer, but does not cure the disease and all patients ultimately progress if tumor is not eliminated with definitive local therapy. It has been demonstrated that despite androgen deprivation with LHRH agonists or orchiectomy, prostate tissue and prostate cancer maintain levels of androgens which are more than adequate to stimulate the androgen receptor. These levels of androgen may continue to stimulate the receptor and allow both survival of tumor cells and induction of resistance by overexpression of receptor. The presumption that standard androgen deprivation achieves the optimal level of androgen suppression for patients is based on the levels of androgen achieved with castration, which achieves relatively short term control of cancer in the majority of patients. The hypothesis of this study is that more effective suppression of the androgen axis through elimination of adrenal androgens and more effective suppression of conversion to dihydrotestosterone will lower intraprostatic androgen levels, minimizing activation of the androgen receptor and augmenting apoptosis. We propose to test this hypothesis in a prospective, randomized trial, administering neoadjuvant androgen deprivation therapy of different types prior to radical prostatectomy for patients with clinically localized prostate cancer for 3 months.

Plan of therapy

Patients with clinically localized (cT1-T2) prostate cancer, at intermediate-high risk for relapse who are candidates for radical prostatectomy will be treated with one of three regimens: - Goserelin with dutasteride - Goserelin with bicalutamide and dutasteride - Goserelin with bicalutamide and dutasteride and ketoconazole

Patients will undergo radical prostatectomy 3 months after initiation of treatment.

Preoperative and intraoperative biopsies of the prostate gland will be utilized for analysis of prostatic hormones, gene expression and apoptosis.

Intervention(s) in this Clinical Trial

• Drug: goserelin with dutasteride
  • Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd; continue bicalutamide for one more week.
• Drug: goserelin with bicalutamide and dutasteride
  • Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.
• Drug: goserelin with bicalutamide and dutasteride and ketoconazole
  • Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot), begin dutasteride 3.5 mg qd and ketoconazole 200mg tid (with hydrocortisone 30 mg).

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Group 1
  • Goserelin + dutasteride
• Active Comparator: Group 2
  • Bicalutamide for one week, begin goserelin plus dutasteride, continue bicalutamide for the full 12 weeks.
• Active Comparator: Group 3
  • Begin bicalutamide for one week, goserelin injection; begin dutasteride, ketoconazole (and replacement hydrocortisone), continue bicalutamide for the full 12 weeks

Primary Measures

• The primary endpoint of the study is to evaluate the effect of different combinations of anti-androgen medicines on androgen levels in the prostate tissue.
  • Time Frame: pre- and post-treatment
    Safety Issue?: No

Secondary Measures

• To determine the effects of different modes of androgen deprivation on intraprostatic DHT, T, DHEA and androstenedione
  • Time Frame: pre- and post-treatment
    Safety Issue?: No
• To determine the effects of different modes of androgen deprivation on serum DHT, T, DHEA and androstenedione
  • Time Frame: pre- and post-treatment
    Safety Issue?: No
• To determine the effects of different modes of androgen deprivation on apoptosis and androgen regulated gene expression as assessed by cDNA array, RT-PCR and immunohistochemistry.
  • Time Frame: pre- and post-treatment
    Safety Issue?: No

Inclusion Criteria:

• 1. Men 18 years or older with a histologic diagnosis of clinically localized prostate cancer prior to radical prostatectomy as defined by:
• 1. Clinical stage T1-T2b
• 2. PSA less than 20
• 3. Gleason score 7-10
• 2. Patient's tumor must be considered surgically resectable
• 3. ECOG performance status of 0-1
• 4. Life expectancy greater than 2 years
• 5. Able to understand and give informed consent
• 6. Laboratory values must be within specified limits

Exclusion Criteria:

• 1. Patients with locally advanced or high risk disease not meeting the criteria defined above.
• 2. Patients who have a total testosterone less than 280 ng/dL.
• 3. Patients who are receiving any other investigational therapy.
• 4. Patients with an active serious infection or other serious underlying medical condition.
• 5. Dementia or significantly altered mental status that would prohibit the understanding and/or giving of informed consent.
• 6. Histologic evidence of small cell carcinoma of the prostate.
• 7. Patients who are currently receiving active therapy for other neoplastic disorders.
• 8. Patients who are receiving any androgens, estrogens or progestational agents.
• 9. Patients who are taking drugs or herbal supplements which affect androgen metabolism (e.g. spironolactone, aprepitant, bexarotene, clarithromycin, itraconazole, ketoconazole, St. John's wort).
• 10. Patients who have chronic active hepatitis
• 11. Patients taking any of the following medications who cannot discontinue these medications for three months during administration of ketoconazole; statin cholesterol medications, cyclosporine, isoniazid, rifampin, terfenadine, triazolam or astemizole.
• 12. Patients who have history of cerebrovascular accident, deep venous thrombosis, pulmonary emboli, unstable angina or clinical congestive heart failure.
• 13. Medical conditions, which, in the opinion of the investigators would jeopardize either the patient or the integrity of the data obtained.
• 14. Patients unwilling to use contraceptives while on study.
• 15. Patients with a risk of nodal involvement of greater than 10% as defined by the Partin tables should have received a bone scan and CT of the pelvis prior to screening for the study as part of standard of care.

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Washington

Overall Clinical Trial Officials and Contacts

R. Bruce Montgomery, MD Principal Investigator University of Washington; Seattle Cancer Care Alliance; VA Puget Sound HCS  

Overall Contact: Sara Teller 206-598-0854 saratell@u.washington.edu

Information obtained from ClinicalTrials.gov on August 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00298155

Study ID Number: 05-8538-V 01

ClinicalTrials.gov Identifier: NCT00298155

Health Authority: United States: Institutional Review Board

University of Washington website: Research Studies Seeking Volunteers