Hormone Therapy Compared With Combination Chemotherapy in Treating Patients With Prostate Cancer

A Phase III Randomized Trial for Evaluating Second Line Hormonal Therapy (Ketoconazole/Hydrocortisone) Versus Paclitaxel/Estramustine Combination Chemotherapy on Progression Free Survival in Asymptomatic Patients With a Rising PSA After Hormonal Therapy for Prostate Cancer

RATIONALE: Androgens can stimulate the growth of prostate cancer cells. Drugs such as ketoconazole may stop the production of androgens. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether hormone therapy is more effective than combination chemotherapy in treating prostate cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of hormone therapy with that of combination chemotherapy in treating patients who have prostate cancer that has been previously treated with androgen suppression.

OBJECTIVES:

• Compare time to objective progression in patients with prostate cancer and a rising prostate-specific antigen (PSA) after androgen suppression when treated with second-line hormonal therapy (ketoconazole and hydrocortisone) vs combination chemotherapy (docetaxel and estramustine).
• Compare time to PSA progression and correlate this with time to objective progression in patients treated with these regimens.
• Compare the quality of life in patients treated with these regimens.
• Compare overall survival of patients treated with these regimens.
• Compare the natural history of progression in patients treated with these regimens.
• Identify prognostic indicators of clinical outcome by immunohistochemical evaluation of apoptopic biomarkers in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior treatment with bisphosphonates (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral ketoconazole three times daily and oral hydrocortisone twice daily. Treatment continues in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral estramustine three times daily on days 1-5 and docetaxel IV over 1 hour on day 2. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, on day 1 of week 9, at 6 months and 1 year, and then annually for up to 10 years or until beginning of first non-protocol therapy.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 590 patients (295 per treatment arm) will be accrued for this study within 4 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate that was continuously treated with androgen suppression

• Rising prostate-specific antigen (PSA), defined as PSA > 5 ng/mL, rising on 2 consecutive measurements at least 4 weeks apart

• Gleason score 7 or higher and/or seminal vesicle involvement at diagnosis

• Patients previously treated with antiandrogen or glucocorticoid therapy must meet the following criteria:

  • Must show a continued rise in PSA after stopping antiandrogen (flutamide, bicalutamide, or nilutamide) or glucocorticoid (dexamethasone or prednisone)

    • At least 4 weeks continued rise in PSA after flutamide or nilutamide (6 weeks for bicalutamide)

• Testosterone less than 50 ng/dL

  • Patients who have not undergone surgical castration must continue primary androgen suppression to maintain castrate levels of testosterone

• No progressive or measurable local or metastatic disease (including bone metastases)

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Granulocyte count at least 2,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• SGOT no greater than 2 times upper limit of normal
• Bilirubin no greater than 1.5 mg/dL

Renal:

• Creatinine no greater than 1.7 mg/dL

Cardiovascular:

• No American Heart Association class III or IV heart disease
• No uncontrolled congestive heart failure
• No life-threatening cardiac arrhythmias

Other:

• Fertile patients must use effective contraception
• No other prior malignancy unless curatively treated and disease-free for appropriate time period for specific cancer
• No preexisting peripheral neuropathy greater than grade 1
• No known hypersensitivity to polysorbate 80

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• At least 5 years since prior systemic chemotherapy

Endocrine therapy:

• See Disease Characteristics
• At least 4 weeks since prior hydrocortisone
• No prior ketoconazole

Radiotherapy:

• At least 28 days since prior radiotherapy to primary site
• No prior palliative radiotherapy
• No concurrent radiotherapy

Surgery:

• See Disease Characteristics

Other:

• Recovered form prior therapy
• At least 7 days since prior parenteral antibiotics for active infection
• No concurrent digitalis
• No concurrent H_2 blockers or proton pump inhibitors (arm I only)
• Concurrent bisphosphonates allowed provided they were initiated prior to study therapy