Toremifene Followed by Radical Prostatectomy in Treating Patients With Stage I or Stage II Prostate Cancer

A Phase II Randomized Controlled Clinical Trial Of The Antiestrogen GTx-006 In Subjects With Prostate Cancer

RATIONALE: Androgens can stimulate the growth of prostate cancer cells. Hormone therapy using toremifene may fight prostate cancer by reducing the production of androgens.

PURPOSE: Randomized phase II trial to study the effectiveness of toremifene followed by radical prostatectomy in treating patients who have stage I or stage II prostate cancer.

OBJECTIVES:

• Compare the percent of high-grade prostatic intraepithelial neoplasia (HGPIN) present in the radical prostatectomy tissue (excluding the luminal area) of patients with stage I or II adenocarcinoma of the prostate treated with toremifene vs observation alone followed by radical prostatectomy.
• Compare the absolute and relative changes in HGPIN in patients treated with toremifene vs observation alone.
• Compare biomarkers (including DNA ploidy and nuclear morphology; Ki67 and MIB-1 expression; bcl-2 expression; frequency of cells expressing apoptotic bodies; microvessel density; and intraprostatic testosterone, dihydrotestosterone (DHT), and estradiol) in the radical prostatectomy tissue of patients treated with toremifene vs observation alone.
• Compare changes from baseline in serum biomarkers, particularly PSA and hormone profiles (testosterone, DHT, androstenedione, dehydroepiandrosterone, androstanediol-glucuronide, estradiol, and sex hormone binding globulin), in patients treated with toremifene vs observation alone.
• Compare the safety of toremifene in these patients.
• Determine the relationships among pairs of biomarkers, biomarker changes, and outcome measures, including toxicity of toremifene and posttreatment HGPIN in these patients.
• Determine the relationship between HGPIN or biomarker responses and antiandrogen germline CAG repeat length polymorphism in patients treated with toremifene.
• Compare the tumor volume, margin status, and pT stage in patients treated with toremifene vs observation alone.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center and baseline high-grade prostatic intraepithelial neoplasia (none vs more than 0% up to 10% vs more than 10%). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral toremifene daily for 3-6 weeks in the absence of unacceptable toxicity.
• Arm II: Patients undergo observation alone. Patients in both arms then undergo radical prostatectomy.

PROJECTED ACCRUAL: A total of 78 patients (52 for arm I, 26 for arm II) will be accrued for this study at a rate of 6-7 patients per month.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate

  • Organ-confined (cT1-2) disease (stage I or II)
  • Must be schedule to undergo radical prostatectomy
  • Prior sextant biopsy required

PATIENT CHARACTERISTICS:

Age:

• Over 18

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Neutrophil count greater than 1,500/mm^3
• Platelet count greater than 100,000/mm^3

Hepatic:

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• ALT and AST less than 2 times ULN
• Alkaline phosphatase less than 2 times ULN
• No chronic hepatitis or cirrhosis

Renal:

• Creatinine less than 1.5 times ULN

Other:

• No severe mental or physical illness that would preclude radical prostatectomy
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Not specified

Endocrine therapy:

• At least 5 years since prior antiestrogen, antiandrogen, LHRH agonist, estrogen, or progestational agent

Radiotherapy:

• Not specified

Surgery:

• See Disease Characteristics