Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer
Condition: Cancer; Prostate Neoplasms
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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.
    

Intervention name(s): goserelin with dutasteride; goserelin with bicalutamide and dutasteride; goserelin with bicalutamide and dutasteride and ketoconazole
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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.; Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.; 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).
Intervention MeSH terms: Ketoconazole; Goserelin; Bicalutamide; Dutasteride
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment