Enzalutamide Versus Standard Androgen Deprivation Therapy for the Treatment Hormone Sensitive Prostate Cancer

Study Overview
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Brief Summary
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This randomized phase II trial compares enzalutamide with standard androgen deprivation therapy in reducing incidence of metabolic syndrome in patients with prostate cancer that has spread to other places in the body. Metabolic syndrome is defined as changes in cholesterol, blood pressure, circulating sugar levels, and body weight. Previous studies have shown that patients with prostate cancer, who have been treated with standard medical therapy that lowers testosterone levels, have an increased risk of these changes. Hormone therapy using enzalutamide may fight prostate cancer by blocking the use of testosterone by the tumor cells instead of lowering testosterone levels. It is not yet known whether prostate cancer patients who receive enzalutamide will have reduced incidence of metabolic syndrome than patients who receive standard androgen deprivation therapy.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the incidence of metabolic syndrome within 12 months, as defined by the Adult Treatment Panel III, in patients treated with enzalutamide compared to standard androgen deprivation therapy. SECONDARY OBJECTIVES: I. To determine the incidence of metabolic syndrome within 6 months, as defined by the Adult Treatment Panel III, in patients treated with enzalutamide compared to standard androgen deprivation therapy. II. To assess bone health, as measured by a dual-energy x-ray absorptiometry (DXA) scanner. III. To assess body composition (sarcopenic obesity), as measured by a DXA scanner. IV. To assess quality of life (QOL), as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Sexual Health Inventory in Men (SHIM). V. To assess time to prostate-specific antigen (PSA) progression and time to radiographic progression. VI. To assess the incidence of developing individual risk factors, or components, which comprise metabolic syndrome. VII. To assess the change in high-sensitivity C-reactive protein (hs-CRP) as a marker of inflammation. VIII. To assess the safety and tolerance of enzalutamide or androgen deprivation therapy (ADT). IX. To assess the change in physical function as measured by the Short Physical Performance Battery (SPPB). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive enzalutamide orally (PO) once daily (QD) for 12 months in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive standard of care ADT comprising one of the following at the discretion of the treating physician: leuprolide acetate, goserelin acetate, histrelin acetate, triptorelin, or degarelix subcutaneously (SC) or intramuscularly (IM) for 12 months in the absence of disease progression or unacceptable toxicity. Patients may also choose to undergo surgical castration as an alternative form of ADT. After completion of study treatment, patients are followed up at 30 days.

Official Title
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An Open Label, Randomized, Phase II Trial of Metabolic Complications in Patients Treated With Enzalutamide vs Standard ADT for the Treatment of Hormone Sensitive Prostate Cancer

Conditions
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Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage III Prostate Cancer, Stage IV Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: leuprolide acetate
* Drug: goserelin acetate
* Drug: histrelin acetate
* Drug: triptorelin
* Drug: degarelix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven adenocarcinoma of the prostate; if pathology is unavailable, the principal investigator (PI) may also make a determination of prostate cancer based on unequivocal clinic data Patients with advanced prostate cancer suitable for systemic treatment defined as: having metastatic disease, a biochemical relapse after primary therapy, or patients in whom primary therapy is not appropriate or feasible; patients without metastatic disease will need evaluation for local therapy and deemed inappropriate or have refused this treatment option Eastern Cooperative Oncology Group (ECOG) 0-2 Age > 18 years Must use a condom if having sex with a pregnant woman A male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration Life expectancy estimated at > 12 months Ability to understand and willingness to provide written informed consent document Exclusion Criteria: A history of androgen deprivation therapy; patients receiving hormonal therapy in the adjuvant and/or neoadjuvant setting must have discontinued therapy at least 6 months prior to day 1 of treatment AND have a serum testosterone level >= 50 ng/dL AND cannot have received more than 18 months of previous ADT A history of orchiectomy Previous androgen blockade (e.g. antiandrogens) in the last 3 months Patients already meeting the criteria for metabolic syndrome as defined by the Adult Treatment Panel III Criteria which requires 3/5 parameters encompassing glucose control, blood pressure, lipids and waist circumference; patients with 2 of the parameters at baseline will be allowed enrollment provided that one of those risk factors is hypertension (>= 130/>= 85 mm Hg) Baseline hypogonadism as defined as a testosterone < 50 ng/dL PSA < 0.5 ng/dL Serum vitamin D 25, hydroxy (OH) < 12 ng/mL Active hepatitis C virus Use of corticosteroids as defined by a daily dose of prednisone (or equivalent) of 5 mg or greater for more than 1 month continuously within 3 months of screening Corrected calcium > 10.6 mg/dL Absolute neutrophil count < 1500/uL Platelet count < 100,000/uL Hemoglobin < 9 g/dL Total bilirubin >= 1.5 x upper limit of normal (ULN) (unless documented Gilbert's) Alanine aminotransferase or aspartate aminotransferase >= 2.5 x ULN Creatinine > 2 mg/dL Clinically significant cardiovascular disease as evidenced by: myocardial infarction within 6 months of screening; uncontrolled angina within 3 months of screening; New York Heart Association (NYHA) class 3 or 4 congestive heart failure; clinically significant ventricular arrhythmia; Mobitz II/2nd degree/or 3rd degree heart block without a pacemaker in place; uncontrolled hypertension (HTN) (systolic > 180 mmHg or diastolic > 105 mmHg at screening) Previous exposure to enzalutamide Use of an investigational therapeutic within 30 days History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agent Known or suspected brain metastasis or active leptomeningeal disease History of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma) at any time in the past; also, history of loss of consciousness or transient ischemic attack within 12 months of day 1 visit Have any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements

Ages Eligible for Study
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Minimum Age: 19 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: Arm I (enzalutamide)<br>Patients receive enzalutamide PO QD for 12 months in the absence of disease progression or unacceptable toxicity. | Drug: Enzalutamide<br>* Given PO<br>* Other names: XTANDI;|
| Active Comparator: Arm II (ADT)<br>Patients receive standard of care ADT comprising one of the following at the discretion of the treating physician: leuprolide acetate, goserelin acetate, histrelin acetate, triptorelin, or degarelix SC or IM for 12 months in the absence of disease progression or unacceptable toxicity. Patients may also choose to undergo surgical castration as an alternative form of ADT. | Drug: leuprolide acetate<br>* Given SC or IM<br>* Other names: Lupron Depot;Drug: goserelin acetate<br>* Given SC or IM<br>* Other names: Zoladex;Drug: histrelin acetate<br>* Given SC or IM<br>* Other names: Vantas;Drug: triptorelin<br>* Given SC or IM<br>* Other names: TRIP;Drug: degarelix<br>* Given SC or IM<br>* Other names: Firmagon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic Syndrome Incidence, Summarized by the Number of Patients With at Least 3 of the 5 Pre-specified Criteria | Metabolic syndrome will be assessed at the beginning of each course and defined by the presence of 3 of the following five traits: abdominal obesity, defined as a waist circumference > 102 cm (> 40 in); serum triglycerides >= 150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides; serum high density lipoprotein (HDL) cholesterol < 40 mg/dL (1 mmol/L) or drug treatment for low HDL; blood pressure >= 130/>= 85 mmHg or drug treatment for elevated blood pressure; and fasting plasma glucose (FPG) >= 100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose. | Within the first 12 months of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic Syndrome Incidence, Summarized by the Proportion of Patients With at Least 3 of the 5 Pre-specified Criteria | Metabolic syndrome will be assessed at the beginning of each course and defined by the presence of 3 of the following five traits: abdominal obesity, defined as a waist circumference > 102 cm (> 40 in); serum triglycerides >= 150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides; serum HDL cholesterol < 40 mg/dL (1 mmol/L) or drug treatment for low HDL; blood pressure >= 130/>= 85 mmHg or drug treatment for elevated blood pressure; and FPG >= 100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose. | Within the first 6 months of therapy | 
| Change in Bone Turnover Markers, as Measured by Bone-specific Alkaline Phosphatase | Will be assessed for each treatment group. Measurements will be taken at day 1 of each course. A paired t-test will test within an arm as to whether the change from baseline to 12 months is significantly different from zero. | Baseline and month 12 | 
| Change in Bone Density | We will measure bone density via a DXA scanner, Left Femur and Right femur T scores will be added to a composite score. A paired t-test will test within an arm as to whether the change from baseline to twelve months is significantly different from zero. The T-score is the standard deviation of how much bone density differs from the bone mass of an average healthy 30 year old. A score of 0 indicates no deviation from average. The following ranges are used: T-score of -1.0 or above = normal bone density T-score between -1.0 and -2.5 = low bone density, or osteopenia T-score of -2.5 or lower = osteoporosis | Baseline to 12 months | 
| Change in Free Fat Mass, as Measured by a DXA Scanner | A paired t-test will test within an arm as to whether the change from baseline to each time point is significantly different from zero. These data are not able to be reported as the DXA did not measure free fat mass and thus we will be using cross sectional CT analysis. | Baseline to up to 12 months | 
| Change in Fat Mass, as Measured by a DXA Scanner | A paired t-test will test within an arm as to whether the change from baseline to each time point is significantly different from zero. | Baseline to up to 12 months | 
| Change in Quality of Life (QOL) Scores, as Measured by the Functional Assessment of Cancer Therapy - Prostate (FACT-P) and Sexual Health in Men (SHIM) | The FACT-P is the Functional Assessment of Cancer Therapy - Prostate and measures physical/emotional quality of life in prostate cancer patients. NUMBER OF ITEMS:39 PATIENT POPULATION:Prostate cancer patients 18 years and older RECALL PERIOD:Past 7 days RESPONSE SCALE:5 point Likert-type scale SUBSCALE DOMAINS: Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB), Functional Well-Being (FWB), Prostate Cancer Subscale (PCS) SCORING: Scores range from 0-158. In general, the higher the score, the better the quality of life. Sexual Health in Men (SHIM). 5 item measure of erectile function. Total score is 1-25 with a higher score indicating better sexual health. Scores: no ED (SHIM total score, 22-25), mild (17-21), mild to moderate (12-16), moderate (8-11), and severe ED (1-7). | Baseline to up to 7 months | 
| Number of Patients With PSA Progression | PSA progression as defined by an increase in >= 50% from nadir and an absolute increase of at least 2 ng/mL above the nadir, occurring at least 12 weeks after start of therapy that is confirmed by two consecutive increases taken at least 2 weeks apart. Log rank test will be used to compare the distributions of above variables between the group treated with enzalutamide to the group on standard ADT. | Time from randomization to the earliest objective evidence of PSA progression as defined per protocol, assessed up to 30 days after the last dose of study drug | 
| Time to Radiographic Progression | Log rank test will be used to compare the distributions of above variables between the group treated with enzalutamide to the group on standard ADT. | Time from randomization to the earliest objective evidence of radiographic progression as defined per protocol, assessed up to 30 days after the last dose of study drug | 
| Change in Markers of Inflammation, as Measured by Circulating Hs-CRP | Mean change in available samples from baseline to 12 months, presented in mg/dL | Difference between baseline and 12 months. | 
| Incidence of Adverse Events, Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.1 | The incidence of adverse events has been reported in the adverse events log for clinicaltrials.gov | Up to 30 days after the last dose of study drug | 
| Change in Physical Function, as Measured by Short Physical Performance Battery (SPPB). | The Short SPPB incorporates 3 validated portions to assess a patient's balance and mobility. SPPB scores range from zero to 12 possible points. SPPB score of 3-9 points in persons with no mobility disability indicates frailty; SPPB score of 10 or greater for persons with no sarcopenia and no mobility disability indicates robustness. The higher the score, the better the physical function. Will be measured as a continuous outcome. | Difference between baseline and 12 months. | 
| Change in Bone Turnover Markers as Measured by N-telopeptide | Will be assessed for each treatment group. Measurements will be taken at day 1 of each course. A paired t-test within an arm as to whether the change from baseline to 12 months is significantly different from zero. N-Telopeptide units - nM Bone Collagen Equivalent (BCE). | Baseline and 12 months |