S0421, Docetaxel and Prednisone With or Without Atrasentan in Treating Patients With Stage IV Prostate Cancer and Bone Metastases That Did Not Respond to Previous Hormone Therapy

OBJECTIVES:

Primary

• Compare the survival and progression-free survival of patients with hormone-refractory stage IV prostate cancer and bone metastases treated with docetaxel and prednisone combined with either atrasentan vs placebo.

Secondary

• Compare pain progression of patients treated with these regimens.
• Compare the qualitative and quantitative toxicity of these regimens in these patients.
• Compare the quality of life, in terms of palliation of metastatic bone pain and improvement in functional status, of patients treated with these regimens.
• Compare prostate-specific antigen (PSA) response rates in patients treated with these regimens.
• Compare objective response in patients with measurable disease treated with these regimens.
• Determine whether a 30% reduction in PSA and the slope of PSA from baseline to 3 months is a surrogate marker for survival in patients treated with these regimens.
• Correlate PSA progression with clinical progression and death in patients treated with these regimens.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to disease progression (measurable or non-measurable disease progression vs prostate-specific antigen progression only), use of bisphosphonates at study entry (yes vs no), worst pain, measured by the Brief Pain Inventory "pain" scale (< grade 4 vs ≥ grade 4), and extraskeletal metastases (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive docetaxel IV over 1 hour on day 1. Patients also receive oral atrasentan and oral prednisone once daily on days 1-21. Treatment repeats every 21 days for up to 12 courses. Patients with stable or responding disease after course 12 may register for continued oral atrasentan treatment for up to 52 weeks in the absence of disease progression* or unacceptable toxicity.
• Arm II: Patients receive docetaxel and prednisone as in arm I. Patients also receive oral placebo once daily on days 1-21. Treatment repeat every 21 days for up to 12 courses. Patients with stable or responding disease after course 12 may register for continued oral placebo treatment for up to 52 weeks in the absence of disease progression* or unacceptable toxicity.

NOTE: *Patients with PSA progression alone will be allowed to continue treatment

Quality of life is assessed at baseline, before courses 4, 7, and 10, and then after completion of study treatment.

After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months for up to 3 years from study entry.

PROJECTED ACCRUAL: A total of 930 patients will be accrued for this study within 4 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate

• Stage IV disease (any T, any N, M1b)

• Evidence of bone metastases by bone scan or MRI
• Measurable or nonmeasurable disease

• Soft tissue disease that has been irradiated within the past 2 months is not assessable as measurable disease
• Hormone-refractory disease despite androgen deprivation and antiandrogen withdrawal, as defined by 1 of the following criteria:

• Prostate-specific antigen (PSA) progression, defined as 3 consecutive rising PSA levels* taken ≥ 1 week apart

• PSA ≥ 5 ng/mL NOTE: *If the third confirmatory PSA level is < the second level, the patient is considered eligible provided a fourth PSA level is > the second level
• Progression of measurable disease
• Progression of nonmeasurable disease by bone scan
• Must have undergone surgical or medical (e.g., luteinizing hormone-releasing hormone [LHRH] agonist [e.g., leuprolide or goserelin] or LHRH antagonist therapy) castration

• Patients who have undergone medical castration must continue LHRH agonist or antagonist therapy during study treatment
• Must have completed 12 courses of blinding protocol treatment (atrasentan/placebo) AND stopped docetaxel for any reason (including completion of 12 courses) other than progressive disease
• No symptomatic pleural effusion
• No third space fluid accumulation (e.g., ascites)
• No prior or concurrent brain metastases

• Patients with clinical evidence of brain metastases must have a negative brain CT scan or MRI within the past 8 weeks

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-3* NOTE: For a performance status of 3, the cause must be due to pain secondary to bone metastases

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Other

• Fertile patients must use effective contraception
• Able to take oral medication without crushing, dissolving, or chewing tablets
• No major infection
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or stage I or II cancer in complete remission
• No symptomatic sensory neuropathy ≥ grade 2
• No history of hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80
• No other significant, active medical illness that would preclude study treatment or survival

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No more than 1 prior systemic vaccine or biologic therapy

• At least 4 weeks since prior vaccine or biologic therapy and recovered
• No concurrent biological response modifiers
• No concurrent prophylactic colony-stimulating factors

Chemotherapy

• More than 2 years since prior adjuvant therapy with a single non-taxane-containing cytotoxic regimen
• No prior cytotoxic chemotherapy for metastatic prostate cancer
• No other concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics
• At least 6 weeks since prior bicalutamide or nilutamide AND has subsequent disease progression
• At least 4 weeks since prior flutamide or ketoconazole AND has subsequent disease progression
• Prior or concurrent megestrol for treatment of hot flashes allowed
• No other concurrent corticosteroid or hormonal therapy unless continuing luteinizing hormone-releasing hormone treatment and/or bisphosphonate therapy

Radiotherapy

• See Disease Characteristics
• Prior samarium allowed
• At least 3 weeks since prior radiotherapy and recovered
• No prior radiotherapy to ≥ 30% of the bone marrow
• No prior strontium
• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• At least 3 weeks since prior surgery and recovered

Other

• More than 4 weeks since prior investigational drugs
• Concurrent bisphosphonates allowed provided therapy is started prior to study entry, dose is maintained during the first 12 weeks of study treatment, and patient meets criteria for disease progression

• No initiation of bisphosphonates during the first 12 weeks of study treatment
• No concurrent herbal medications or food supplements (e.g., PC-SPES, saw palmetto, Hypericum perforatum [St. John's wort])

• Concurrent daily vitamins and calcium supplements allowed
• At least 14 days since prior and no concurrent administration of any of the following:

• Antibiotics (e.g., clarithromycin, erythromycin, troleandomycin, rifampin, rifabutin, and rifapentine)
• Antifungals (e.g., itraconazole, ketoconazole, fluconazole [doses > 200 mg/day], and voriconazole)
• Antidepressants (e.g., nefazodone and fluvoxamine)
• Calcium channel blockers (e.g., verapamil, diltiazem)
• Miscellaneous (e.g., amiodarone [no use within 6 months prior to study entry], grapefruit juice, bitter orange, or modafinil)
• Anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital, and oxcarbazepine)
• Antibiotics (e.g., rifampin, rifabutin, and rifapentine)