Zoledronate in Preventing Skeletal (Bone)-Related Events in Men Who Are Receiving Androgen Deprivation Therapy For Prostate Cancer and Bone Metastases

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Double-Blind, Placebo-Controlled Phase III Study of Early Versus Standard Zoledronic Acid to Prevent Skeletal Related Events in Men With Prostate Cancer Metastatic to Bone

Conditions
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Metastatic Cancer, Prostate Cancer

Intervention / Treatment
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* Drug: zoledronic acid
* Other: placebo
* Drug: androgen deprivation therapy
* Drug: GnRH agonist
* Dietary Supplement: Calcium supplement
* Dietary Supplement: Vitamin D


Participation Criteria
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Eligibility Criteria
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Histologic Documentation: Histologic documentation of prostate adenocarcinoma. Patients with small cell, neuroendocrine, or transitional cell carcinomas are not eligible. 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. 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. 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. ECOG (CTC) performance status 0-2 Age: ≥ 18 years 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zoledronic acid + androgen deprivation therapy<br>4mg by IV over 15 minutes every 4 weeks in the absence of disease progression or the first skeletal-related event. Participants who progression on blinded treatment before having a skeletal event may continue on open label Zoledronic acid (4 mg by IV over 15 minutes every 3 weeks). | Drug: zoledronic acid<br>* Given IV<br>Drug: androgen deprivation therapy<br>* Patients concurrently enrolled on the Phase III study of intermittent androgen deprivation in patients with stage D2 prostate cancer will receive androgen deprivation therapy per SWOG-9346. All other patients will receive androgen deprivation therapy at a standard dose and schedule throughout the study.<br>Drug: GnRH agonist<br>* Patients concurrently enrolled on the Phase III study of intermittent androgen deprivation in patients with stage D2 prostate cancer will receive the GnRH agonist per SWOG-9346. All other patients will receive GnRH agonist at a standard dose and schedule throughout the study.<br>Dietary Supplement: Calcium supplement<br>* Patients will receive 500 mg by mouth daily of a calcium supplement or a combination tablet containing approximately 500 mg elemental calcium and 400-500 IU vitamin D by mouth daily.<br>Dietary Supplement: Vitamin D<br>* Patients will receive a multivitamin tablet containing 400-500 IU vitamin D by mouth daily or a combination tablet containing approximately 500 mg elemental calcium and 400-500 IU vitamin D by mouth daily.<br>|
| Active Comparator: Placebo + androgen deprivation therapy<br>Placebo bu IV over 15 minutes for 4 weeks in the absence of disease progression or the first skeletal-related event. Participants who progress on blinded treatment before having a skeletal event may continue on open label Zoledronic acid. | Other: placebo<br>* Given IV<br>Drug: androgen deprivation therapy<br>* Patients concurrently enrolled on the Phase III study of intermittent androgen deprivation in patients with stage D2 prostate cancer will receive androgen deprivation therapy per SWOG-9346. All other patients will receive androgen deprivation therapy at a standard dose and schedule throughout the study.<br>Drug: GnRH agonist<br>* Patients concurrently enrolled on the Phase III study of intermittent androgen deprivation in patients with stage D2 prostate cancer will receive the GnRH agonist per SWOG-9346. All other patients will receive GnRH agonist at a standard dose and schedule throughout the study.<br>Dietary Supplement: Calcium supplement<br>* Patients will receive 500 mg by mouth daily of a calcium supplement or a combination tablet containing approximately 500 mg elemental calcium and 400-500 IU vitamin D by mouth daily.<br>Dietary Supplement: Vitamin D<br>* Patients will receive a multivitamin tablet containing 400-500 IU vitamin D by mouth daily or a combination tablet containing approximately 500 mg elemental calcium and 400-500 IU vitamin D by mouth daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Skeletal Related Event | Time to first skeletal related event (SRE) was defined as the time from randomization to first skeletal event. Skeletal events are defined as radiation to bone, clinical fracture, surgery to bone and spinal cord compression and death due to prostate cancer. The median with 95% CI was estimated using the Kaplan Meier method. | Up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) was defined as the time from randomization to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method. | Up to 10 years | 
| Progression-free Survival | Progression Free Survival (PFS) was defined as the time from registration until disease progression or death, whichever occurs first. The median PFS with 95% CI was estimated using the Kaplan-Meier method. Progression is defined as one or more of the following: new bone metastases, biochemical progression of PSA, treatment with radiation therapy while on treatment. | Up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bone metastases, adenocarcinoma of the prostate, recurrent prostate cancer, stage IV prostate cancer