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

Alliance for Clinical Trials in Oncology

Status and phase: Completed; Phase 3

Conditions: Metastatic Cancer; Prostate Cancer

Treatments: Drug: androgen deprivation therapy; Dietary Supplement: Vitamin D; Drug: zoledronic acid; Drug: GnRH agonist; Other: placebo; Dietary Supplement: Calcium supplement

Study type: Interventional

Funder types: Other; NETWORK; Industry; NIH

Identifiers

NCT00079001

CAN-NCIC-PRC2

CALGB-90202

CDR0000353209 (Registry Identifier)

U10CA031946 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 645 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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645 participants in 2 patient groups

Zoledronic acid + androgen deprivation therapy

Experimental group

Description:

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).

Treatment:

Dietary Supplement: Vitamin D

Drug: androgen deprivation therapy

Drug: zoledronic acid

Dietary Supplement: Calcium supplement

Drug: GnRH agonist

Placebo + androgen deprivation therapy

Active Comparator group

Description:

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.

Treatment:

Dietary Supplement: Vitamin D

Drug: androgen deprivation therapy

Dietary Supplement: Calcium supplement

Other: placebo

Drug: GnRH agonist