Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer

Androgen deprivation has been the principal means of controlling advanced prostate cancer, but does not cure the disease and all patients ultimately progress if the 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 the 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.

Inclusion criteria

• Men 18 years or older with a histologic diagnosis of clinically localized prostate cancer prior to radical prostatectomy as defined by:

• Clinical stage T1-T2b
• Prostate specific Antigen (PSA) less than 20
• Gleason score 7-10
• Patient's tumor must be considered surgically resectable .
• Eastern Cooperative Group (ECOG) performance status of 0-1.
• Life expectancy greater than 2 years.
• Able to understand and give informed consent.
• Laboratory values must be within specified limits.

Exclusion criteria

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