Zoledronate in Preventing Skeletal (Bone)-Related Events in Men 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)