Metastatic Cancer, Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, recurrent prostate cancer, stage IV prostate cancer, bone metastases
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.
Interventions
DRUGzoledronic acid
Given IV
OTHERplacebo
Given IV
DRUGandrogen deprivation therapy
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.
DRUGGnRH agonist
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.
DIETARY_SUPPLEMENTCalcium supplement
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.
DIETARY_SUPPLEMENTVitamin D
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.
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Eastern Cooperative Oncology Group
NCIC Clinical Trials Group
Novartis Pharmaceuticals
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Skeletal Related Event | Up to 10 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 10 years | 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. |
| Progression-free Survival | Up to 10 years | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
Between January 2004 and May 2012, 645 participants were registered and randomized.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid + Androgen Deprivation Therapy 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). | 323 |
| Placebo + Androgen Deprivation Therapy 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. | 322 |
| Total | 645 |
Baseline characteristics
| Characteristic | Zoledronic Acid + Androgen Deprivation Therapy | Total | Placebo + Androgen Deprivation Therapy |
|---|---|---|---|
| Age, Continuous | 66.1 years | 66.3 years | 66.7 years |
| ECOG Performance Status 0 | 205 participants | 410 participants | 205 participants |
| ECOG Performance Status 1 | 105 participants | 210 participants | 105 participants |
| ECOG Performance Status 2 | 13 participants | 25 participants | 12 participants |
| Prior Skeletal Related Event No | 281 participants | 563 participants | 282 participants |
| Prior Skeletal Related Event Yes | 42 participants | 82 participants | 40 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 11 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 42 Participants | 92 Participants | 50 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 19 Participants | 9 Participants |
| Race (NIH/OMB) White | 261 Participants | 517 Participants | 256 Participants |
| Region of Enrollment Canada | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 323 participants | 644 participants | 321 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 323 Participants | 645 Participants | 322 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 269 / 310 | 266 / 308 |
| serious Total, serious adverse events | 60 / 310 | 61 / 308 |
Outcome results
Primary
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.
Time frame: Up to 10 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid + Androgen Deprivation Therapy | Time to First Skeletal Related Event | 31.9 months |
| Placebo + Androgen Deprivation Therapy | Time to First Skeletal Related Event | 28.8 months |
Comparison: The null hypothesis was that the hazard ratio is greater than or equal to 1.0 versus the alternative hypothesis that the hazard ratio is less than 0.77. With a target of 470 SREs, log-rank statistic had 88% power to detect a 23% decrease in hazard of SRE (equivalent to an increase in median time to SRE from 30 months to 39 months), assuming a one-sided type I error rate of .05.p-value: 0.38595% CI: [0, 1.174]Log Rank
Secondary
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.
Time frame: Up to 10 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid + Androgen Deprivation Therapy | Overall Survival | 37.9 months |
| Placebo + Androgen Deprivation Therapy | Overall Survival | 36.0 months |
p-value: 0.2995% CI: [0.7, 1.12]Log Rank
Secondary
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.
Time frame: Up to 10 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid + Androgen Deprivation Therapy | Progression-free Survival | 10.6 months |
| Placebo + Androgen Deprivation Therapy | Progression-free Survival | 9.2 months |
p-value: 0.2295% CI: [0.74, 1.07]Log Rank