Zoledronate in Preventing Skeletal (Bone)-Related Events in Men Who Are Receiving Androgen Deprivation Therapy For Prostate Cancer and Bone Metastases
Zoledronate in Preventing Skeletal (Bone)-Related Events in Men Who Are Receiving Androgen Deprivation Therapy For Prostate Cancer and Bone Metastases
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.
Zoledronic acid decreases the risk of skeletal related events in men with prostate cancer
 metastatic to bone and disease progression after primary hormonal therapy.

 This study is designed to evaluate whether earlier treatment with zoledronic acid will
 further decrease the risk of skeletal related events. 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).

 The primary objective of the study is to determine whether treatment with zoledronic acid at
 the time of initiation of androgen deprivation therapy for metastatic prostate cancer will
 delay the time to first skeletal related event. The secondary objective of the study is to
 compare the effect of treatment with zoledronic acid to placebo on overall survival (OS),
 progression-free survival (PFS) and toxicity in men receiving androgen deprivation therapy
 for metastatic prostate cancer.

 Patients are randomized to 1 of 2 treatment arms. Treatment continues in the absence of
 disease progression or a skeletal-related event. All patients receive concurrent androgen
 deprivation therapy with a GnRH agonist. Patients also receive oral calcium and (vitamin D)
 supplements daily. Patients progressing to androgen-independent prostate cancer proceed to
 the open-label therapy with zoledronic acid IV. Treatment continues for 3 weeks in the
 absence of disease progression or the first skeletal-related event.

 Patients are followed periodically for approximately 10 years after entry on the study.
1. Histologic Documentation: Histologic documentation of prostate adenocarcinoma.
 Patients with small cell, neuroendocrine, or transitional cell carcinomas are not
 eligible.

 2. Staging: At least one bone metastasis by radiographic imaging (bone scan, magnetic
 resonance imaging, computed tomography, or plain radiographs). Indeterminate lesions
 should be confirmed by a second imaging method. Imaging to document bone metastases is
 to be completed either within 12 weeks before registration or within 12 weeks before
 initiating androgen deprivation therapy for bone metastases.

 3. Hormone Therapy

 -  While on this study, patients must receive androgen deprivation therapy (ADT) for
 treatment of prostate cancer. Androgen deprivation therapy may have begun prior
 to enrollment on this study; however patients must have initiated ADT ≤ 6 months
 prior to enrollment.

 -  Androgen deprivation therapy is defined as bilateral orchiectomy or gonadotropin-
 releasing hormone (GnRH) agonist with or without an antiandrogen.

 -  Patients treated with intermittent androgen deprivation therapy are not eligible
 except for patients concurrently enrolled in SWOG-9346/INT-0162/CALGB 9594, Phase
 III Study of Intermittent Androgen Deprivation in Patients with Stage D2 Prostate
 Cancer.

 4. Prior Treatment:

 -  Hormone therapy at any point prior to 6 months before enrollment is prohibited.
 This includes any of the following treatments:

 -  orchiectomy,

 -  GnRH agonist (e. g., leuprolide, goserelin, triptorelin),

 -  estrogen therapy,

 -  antiandrogen (e. g., bicalutamide, flutamide, nilutamide), or

 -  any other therapy known to lower testosterone level or inhibit testosterone
 effect.

 -  Prior neoadjuvant and/or adjuvant hormone therapy is allowed provided that the
 duration of hormone therapy was six months or less and the hormone therapy was
 discontinued more than 6 months prior to study entry.

 -  No prior treatment with a bisphosphonate

 -  No prior treatment with denosumab

 -  No prior treatment with radiopharmaceuticals

 -  ≥ 4 weeks since completion of prior radiation therapy with at least one bone
 metastasis present that has NOT been radiated.

 5. ECOG (CTC) performance status 0-2

 6. Age: ≥ 18 years

 7. Required Initial Laboratory Data:

 -  Calculated Creatinine Clearance ≥ 30 mL/min

 -  Corrected serum calcium ≥ 8.0 mg/dL (2.00 mmol/L) and <11.6 mg/dL (2.90 mmol/L)