NCT00079001 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2020-05-12

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.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Time to First Skeletal Related Event

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outcome · POSTED

Overall Survival

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outcome · POSTED

Progression-free Survival

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility 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)
healthy Volunteers: false
minimum Age: 18 Years
sex: MALE
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

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).
intervention Names
Drug: zoledronic acid
Drug: androgen deprivation therapy
Drug: GnRH agonist
Dietary Supplement: Calcium supplement
Dietary Supplement: Vitamin D
label
Zoledronic acid + androgen deprivation therapy
type
EXPERIMENTAL
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.
intervention Names
Other: placebo
Drug: androgen deprivation therapy
Drug: GnRH agonist
Dietary Supplement: Calcium supplement
Dietary Supplement: Vitamin D
label
Placebo + androgen deprivation therapy
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
Zoledronic acid + androgen deprivation therapy
description
Given IV
name
zoledronic acid
type
DRUG
arm Group Labels
Placebo + androgen deprivation therapy
description
Given IV
name
placebo
type
OTHER
arm Group Labels
Placebo + androgen deprivation therapy
Zoledronic acid + androgen deprivation therapy
description
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.
name
androgen deprivation therapy
type
DRUG
arm Group Labels
Placebo + androgen deprivation therapy
Zoledronic acid + androgen deprivation therapy
description
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.
name
GnRH agonist
type
DRUG
arm Group Labels
Placebo + androgen deprivation therapy
Zoledronic acid + androgen deprivation therapy
description
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.
name
Calcium supplement
type
DIETARY_SUPPLEMENT
arm Group Labels
Placebo + androgen deprivation therapy
Zoledronic acid + androgen deprivation therapy
description
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.
name
Vitamin D
type
DIETARY_SUPPLEMENT

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: QUADRUPLE
who Masked: PARTICIPANT
CARE_PROVIDER
INVESTIGATOR
OUTCOMES_ASSESSOR

primary Purpose

TREATMENT

Enrollment

count: 645
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
Time to First Skeletal Related Event
time Frame
Up to 10 years

secondary Outcomes

description
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.
measure
Overall Survival
time Frame
Up to 10 years
description
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.
measure
Progression-free Survival
time Frame
Up to 10 years

Full study description

brief Summary: 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: 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.

Source references

references

citation
Smith MR, Halabi S, Ryan CJ, Hussain A, Vogelzang N, Stadler W, Hauke RJ, Monk JP, Saylor P, Bhoopalam N, Saad F, Sanford B, Kelly WK, Morris M, Small EJ. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol. 2014 Apr 10;32(11):1143-50. doi: 10.1200/JCO.2013.51.6500. Epub 2014 Mar 3.
pmid
24590644
type
RESULT
citation
Jakob T, Tesfamariam YM, Macherey S, Kuhr K, Adams A, Monsef I, Heidenreich A, Skoetz N. Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: a network meta-analysis. Cochrane Database Syst Rev. 2020 Dec 3;12(12):CD013020. doi: 10.1002/14651858.CD013020.pub2.
pmid
33270906
type
DERIVED