Androgen Deprivation Therapy on Bone Mineral Density Change in Prostate Cancer Patients

Study Overview
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Brief Summary
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Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment to improve overall survival for intermediate- and high-risk localized disease as well as metastatic disease. While ADT improves survival, it can cause significant morbidity and a decrement in quality of life. In particular, ADT is associated with decrease in bone mineral density (BMD) and increased risk of fracture. Although current guidelines recommend continuous androgen deprivation therapy (CAD) as standard therapy for high-risk disease, there has been increasing recognition of adverse effects from CAD. Since 1986, intermittent androgen deprivation therapy (IAD) as alternative therapeutic strategy for prostate cancer has been proposed to delay development of castration resistance and to reduce the side effects of ADT. While both CAD and IAD are commonly used in real clinical practice, no prior study examined BMD change after CAD or IAD, and assessed whether bone loss would recover during off-treatment of IAD. The investigators therefore determine the rate of change in BMD induced by ADT (CAD versus IAD) in men with prostate cancer.

Detailed Description
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Objective: To determine the rate of bone mass loss induced by two therapeutic strategies of ADT (CAD versus IAD) in men with prostate cancer. Design, setting, and participants: the investigators will perform randomized, open label clinical trial. Men aged over 50 yrs old with prostate cancer (localized, locally advanced, metastatic prostate cancer) who are treated with primary ADT for newly diagnosed prostate cancer or salvage ADT at biochemical recurrence following radical prostatectomy will be included. Participants will be randomly assigned to one of the following treatment arms: Arm 1 (CAD): ADT without any discontinuation during study period (12 months). Arm 2 (IAD): ADT for the first 6 months of study period, if the prostate-specific antigen (PSA) reaches its nadir (< 4 ng/dL) and serum testosterone reaches castration level (< 50 ng/dL). Outcomes: Primary outcome: change of L-spine total BMD. Secondary outcomes: change of femur neck BMD, incidence rate of osteoporosis, risk of 10 year major osteoporotic fracture, quality of life based on Expanded Prostate Cancer Index (EPIC) questionnaire. Timing of outcome measurement: at baseline and up to 12 months after randomization. Statistical analyses: student's t test for continuous outcomes and Fisher's exact or chi-square test for dichotomous outcomes.

Official Title
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The Impact of Continuous Versus Intermittent Androgen Deprivation Therapy on Bone Mineral Density Change in Prostate Cancer Patients: A Multicenter, Randomized Clinical Trial

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Leuprorelin
* Drug: Goserelin
* Drug: Triptorelin
* Drug: Degarelix
* Drug: Bicalutamide
* Drug: Flutamide
* Drug: Maximum androgen blockade


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged over 50 yrs old with histologically diagnosed prostate cancer (localized, locally advanced, metastatic prostate cancer) who are treated with primary ADT for newly diagnosed prostate cancer or salvage ADT at biochemical recurrence following radical prostatectomy. . Exclusion Criteria: men with double primary malignancies, men who have been treated with ADT or other drug therapy such as denosumab, bisphosphonate or steroid, men with osteoporosis at baseline (T-score ≤ -2.5), men with a known bone disease, men with poor performance status (i.e. Eastern Cooperative Oncology Group performance status 4), men with life expectancy < 12 months, men with increased serum PSA levels (≥ 4 ng/dL) or testosterone levels (≥ 50 ng/dL) even after 6 month ADT, men who are not able to understand trial information or informed consent,

Ages Eligible for Study
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Minimum Age: 50 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermittent Androgen Deprivation<br>ADT including luteinizing hormone-releasing hormone (LHRH) agonist and antagonist, antiandrogen, or maximum androgen blockade (MAB) should be withdrawn after 6 months of ADT, if the prostate-specific antigen (PSA) reaches its nadir (< 4 ng/dL) and serum testosterone reaches castration level (< 50 ng/dL). | Drug: Leuprorelin<br>* LHRH agonist<br>* Other names: Leuprorelin acetate;Drug: Goserelin<br>* LHRH agonist<br>* Other names: Goserelin acetate;Drug: Triptorelin<br>* LHRH agonist<br>* Other names: Triptorelin acetate;Drug: Degarelix<br>* LHRH antagonist<br>* Other names: Degarelix acetate;Drug: Bicalutamide<br>* Antiandrogen<br>* Other names: Casodex;Drug: Flutamide<br>* Antiandrogen<br>* Other names: Niftolide;Drug: Maximum androgen blockade<br>* Combination therapy with LHRH agonist and antiandrogen<br>* Other names: LHRN agonist and antiandrogen;|
| Active Comparator: Continuous Androgen Deprivation<br>ADT including LHRH agonist and antagonist, antiandrogen, or MAB without any discontinuation during study period. | Drug: Leuprorelin<br>* LHRH agonist<br>* Other names: Leuprorelin acetate;Drug: Goserelin<br>* LHRH agonist<br>* Other names: Goserelin acetate;Drug: Triptorelin<br>* LHRH agonist<br>* Other names: Triptorelin acetate;Drug: Degarelix<br>* LHRH antagonist<br>* Other names: Degarelix acetate;Drug: Bicalutamide<br>* Antiandrogen<br>* Other names: Casodex;Drug: Flutamide<br>* Antiandrogen<br>* Other names: Niftolide;Drug: Maximum androgen blockade<br>* Combination therapy with LHRH agonist and antiandrogen<br>* Other names: LHRN agonist and antiandrogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of L-spine total BMD | Measured by bone densitometry | At baseline and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of femur neck BMD | Measured by bone densitometry | At baseline and 12 months | 
| Osteoporosis | Defined as newly diagnosed osteoporosis based on T-score (≤ -2.5) | At 12 months | 
| Risk of 10 year major osteoporotic fracture | Estimated by Fracture Risk Assessment Tool (FRAX®, available at www.sheffield.ac.uk/FRAX) | At 12 months | 
| Quality of life after treatment | Measured by EPIC questionnaire | At baseline and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Androgen Antagonists, Bone Density, Prostatic Neoplasms