ZOMETA® (Zoledronic Acid) for Prevention of Bone Metastases

• To assess the effects of i.v. Zometa® (zoledronic acid) 4 mg, with respect to the following efficacy parameters as well as safety and tolerability:
• Effects on pain and analgesic drug consumption, assessed by the composite pain score from BPI (Brief Pain Inventory) for pain and by analgesic score
• Time to first event of bone pain
• Time to first occurrence of Skeletal Related Events (SREs), defined as pathologic bone fractures, spinal cord compression, surgery to bone, radiation therapy to bone (including the use of radioisotopes)
• Proportion of patients in each arm having SRE
• Serum PSA
• Overall safety

To determine if therapy with Zometa® (zoledronic acid) 4mg will be effective in preventing the occurrence of bone metastases in prostate cancer patients at high risk of developing them. In addition, pain and analgesic scores and overall safety are to be evaluated throughout the study.

This is a prospective, randomized, stratified open-label (Zometa + hormonal ablation versus hormonal ablation alone) multicenter clinical study evaluating the efficacy of Zometa 4mg given every 3 month as an adjunct to hormonal or surgical castration for prevention of bone metastases in locally advanced, high risk prostate cancer patients, who are hormone-naiv at time of randomization. the primary efficacy variable is the time to occurrence of first bone metastases.

Zometa® (zoledronic acid) provided as 4mg lyophilised powder Supplementation 500mg Calcium +400-500IU Vitamin D p.o. qd

Arm A:

Zometa® (zoledronic acid) in 100ml of calcium free solution i.v. as a 15 minute infusion every 3 months

Arm B:

no reference therapy

• Experimental: zoledronic acid
  Zometa® (zoledronic acid) in 100ml of calcium free solution i.v. as a 15 minute infusion every 3 months
  Intervention: Drug: Zometa
• No Intervention: no intervention
  no reference therapy

Inclusion Criteria:

• Signed informed consent
• Age > 18 years
• Histologically confirmed diagnosis of carcinoma of the prostate
• ECOG performance status of 0, 1, or 2
• No radiological evident bone metastasis (negative bone scan or verification of suspected foci as benign lesions by additional radiological examination)
• T3-4 AND highest pre-study PSA >20 ng/ml AND Gleason score = 8 (or Gleason grade = 4)
• Patients with prior prostatectomy or prior local radiotherapy are eligible for this study
• Patients are destined to receive medical (LHRH analogue) or surgical (orchiectomy) castration and Zometa® treatment will start not later than 6 weeks after surgery
• Patients should be fully recovered from prior interventions where applicable

Exclusion Criteria:

• Patients with a serum creatinine determination >265 µmol/L (3.0 mg/dL)
• Patients that received prior medical (LHRH analogue) castration
• Current (or previous) evidence of metastatic disease to the bone
• History of any other neoplasm within the past five years except for nonmelanomatous skin cancer.
• Previous hormonal therapy with LHRH agonists or other forms of hormonal ablation
• WBC<3.0x109, ANC < 1500/mm3, Hgb<8.0 g/dL, platelets < 75 x 109/L
• Liver function tests >2.5 ULN
• Prior treatment with Zometa® (zoledronic acid) or other bisphosphonates
• Treatment with calcitonin, mithramycin, or gallium nitrate within 2 weeks prior to the date of randomization (Visit 2)
• Use of other investigational drugs (drugs not marketed for any indication) within 30 days prior to the date of randomization (Visit 2)
• Patients with evidence in the six months prior to randomization of severe cardiovascular disease (defined as uncontrolled congestive heart failure), hypertension refractory to treatment, or symptomatic coronary artery disease uncontrolled by treatment
• History of noncompliance to medical regimens and patients who are considered potentially unreliable or incapable of giving informed consent as judged by the investigator.