Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer

Summary

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 than 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). The investigators 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. The investigators will assay serum and intraprostatic androgen levels, while assessing relative levels of apoptosis of normal and malignant tissue.

Conditions

• Cancer
• Prostate Neoplasms

Interventions

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 200 mg tid (with hydrocortisone 30 mg).

Sponsors & Collaborators

• GlaxoSmithKline

  collaborator INDUSTRY

• AstraZeneca

  collaborator INDUSTRY

• University of Washington

  lead OTHER

Principal Investigators

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

• Peter S. Nelson, MD · Fred Hutchinson Cancer Research Center; Seattle Cancer Care Alliance

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

100 Years

Sex

MALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2006-07-31

Primary Completion

2010-06-30

Completion

2014-01-31

Countries

• United States

Study Locations