• Overall survival [ Designated as safety issue: No ]
• Progression-free survival [ Designated as safety issue: No ]
• Toxicity [ Designated as safety issue: Yes ]

• Overall survival
• Progression-free survival
• Toxicity

RATIONALE: Zoledronate may prevent or decrease skeletal (bone)-related events (such as pain or fractures) caused by bone metastases and androgen deprivation therapy. It is not yet known whether treatment with zoledronate is effective in preventing bone-related events in patients who have prostate cancer and bone metastases.

PURPOSE: This randomized phase III trial is studying how well zoledronate works in preventing bone-related events in patients who are receiving androgen deprivation therapy for prostate cancer and bone metastases.

OBJECTIVES:

Primary

• Compare the time to first skeletal-related events in patients with prostate cancer and bone metastases undergoing androgen deprivation therapy when treated with zoledronate vs placebo.

Secondary

• Compare the overall and progression-free survival of patients treated with these regimens.
• Compare the toxic effects in patients treated with these regimens.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study followed by an open-label study. Patients are stratified according to ECOG performance status (0-1 vs 2), prior skeletal-related event (no vs yes), and serum alkaline phosphatase (< upper limit of normal [ULN] vs ≥ ULN).

Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive zoledronate IV over 15 minutes on day 1.
• Arm II: Patients receive placebo IV over 15 minutes on day 1. In both arms, courses repeat every 4 weeks in the absence of disease progression or a skeletal-related event. All patients receive concurrent androgen deprivation therapy. Patients also receive oral calcium and cholecalciferol (vitamin D) supplements daily.

Patients progressing to androgen-independent prostate cancer proceed to open-label therapy comprising zoledronate IV over 15 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or a skeletal-related event.

Patients are followed periodically for approximately 10 years after randomization.

PROJECTED ACCRUAL: A total of 680 patients (340 per treatment arm) will be accrued for this study within 4 years.

• Metastatic Cancer
• Prostate Cancer

• Drug: zoledronic acid
• Other: placebo

• Experimental: Patients receive zoledronate IV over 15 minutes on day 1. Courses repeat every 4 weeks in the absence of disease progression or a skeletal-related event.
• Placebo Comparator: Patients receive placebo IV over 15 minutes on day 1. Courses repeat every 4 weeks in the absence of disease progression or a skeletal-related event.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate
• No small cell, neuroendocrine, or transitional cell carcinomas

• At least 1 bone metastasis by bone scan, MRI, CT scan, or plain radiographs

  • Indeterminate lesions should be confirmed by a second imaging method
  • At least 1 bone metastasis with no prior irradiation

• Concurrent androgen deprivation therapy required, defined as any of the following:

  • Bilateral orchiectomy
  • Gonadotropin-releasing hormone (GnRH) agonist with or without an antiandrogen

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Creatinine clearance ≥ 30 mL/min
• Corrected calcium ≥ 8.0 mg/dL and < 11.6 mg/dL

Other

• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Concurrent standard biologic response modifiers allowed during open-label therapy only

Chemotherapy

• Concurrent standard cytotoxic chemotherapy allowed during open-label therapy only

Endocrine therapy

• See Disease Characteristics
• Prior neoadjuvant and/or adjuvant hormonal therapy allowed provided duration of therapy was no more than 6 months AND therapy was discontinued more than 6 months before study entry

• No more than 6 months since initiation of any of the following hormonal therapies:

  • Orchiectomy
  • GnRH agonist (e.g., leuprolide, goserelin, or triptorelin)
  • Estrogen therapy
  • Antiandrogens (e.g., bicalutamide, flutamide, or nilutamide)
  • Any other therapy known to lower testosterone levels or inhibit testosterone effect
• No intermittent androgen deprivation therapy except for patients concurrently enrolled on SWOG-9346
• Concurrent palliative corticosteroids allowed during open-label therapy only
• Concurrent standard hormonal agents allowed during open-label therapy only

Radiotherapy

• See Disease Characteristics
• No prior radiopharmaceuticals
• At least 4 weeks since prior radiotherapy
• Concurrent standard radiotherapy to extraskeletal and/or skeletal tumor sites allowed during open-label therapy only

Surgery

• See Disease Characteristics

Other

• No prior bisphosphonates
• No other concurrent agents expected to alter osteoclast activity (e.g., calcitonin, mithramycin, gallium nitrate, or any other bisphosphonate)
• Concurrent daily supplemental elemental calcium (500 mg) and a multivitamin containing cholecalciferol (Vitamin D) (400 IU) OR a combination tablet containing both recommended
• Concurrent standard marketed antineoplastic therapies allowed during open-label therapy only

• National Cancer Institute (NCI)
• Southwest Oncology Group
• Eastern Cooperative Oncology Group
• National Cancer Institute of Canada