LHRH Analogue Therapy With Enzalutamide or Bicalutamide in Treating Patients With Hormone Sensitive Prostate Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies if enzalutamide added to standard luteinizing hormone-releasing hormone (LHRH) analogue therapy will improve effects against prostate cancer compared to the standard therapy of LHRH analogue and bicalutamide. Hormone therapies stop the body from producing or block the effect of male sex hormones (testosterone). Enzalutamide blocks the effect of male sex hormones which are responsible for the growth of prostate cancer. Hormonal therapies that lower the level of testosterone are among the most effective treatments for prostate cancer that have spread to other areas of the body (metastasized). It is not yet known whether LHRH analogue therapy with bicalutamide is more effective than LHRH analogue therapy with enzalutamide in treating prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the rates of achieving prostate-specific antigen (PSA) remission at month 7 with LHRH analogue therapy and enzalutamide (Arm A) with that achieved with LHRH analogue and bicalutamide (Arm B) in metastatic hormone sensitive prostate cancer. SECONDARY OBJECTIVES: I. To compare the primary endpoint by race. II. To compare the rates of each of 2 types of response by treatment arm: measurable disease response; and PSA response. III. To compare each of 7 time-to-event endpoints by treatment arm: duration of overall response (RD); duration of stable disease (SDD); time to treatment failure (TTF); time-to-progression (TTP); TTP in patients with bone metastases; progression-free survival (PFS); and overall survival (OS). IV. To compare the rates of each type of toxicity by treatment arm. V. To compare the incidence rate of skeletal related events (SRE), and the time until SRE, separately by treatment arm. VI. To compare the rates of circulating tumor cell (CTC) response by treatment arm. VIII. To explore the molecular mechanisms within the androgen receptor pathway by determining the levels of chemokine (C-X-C motif) receptor 4 (CXCR4) and transmembrane protease, serine 2 (TMPRSS2)-v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) expression, androgen metabolism enzymes; androgen receptor variants, and length of cytosine-adenine-guanine (CAG) repeats within the androgen receptor gene, and to associate them with the primary endpoint. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive enzalutamide orally (PO) once daily (QD) and undergo orchiectomy or receive LHRH analogue therapy (leuprolide acetate, goserelin acetate, or any other Food and Drug Administration [FDA] approved preparation). Treatment continues in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive bicalutamide PO QD and undergo orchiectomy or receive LHRH analogue therapy as in Arm A. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Official Title
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Randomized Phase II Screening Trial of Enzalutamide/MDV-3100 and LHRH Analogue vs Combined Androgen Deprivation (LHRH Analogue + Bicalutamide) in Metastatic Hormone Sensitive Prostate Cancer

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

Intervention / Treatment
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* Drug: enzalutamide
* Drug: bicalutamide
* Procedure: orchiectomy
* Drug: leuprolide acetate
* Drug: goserelin acetate
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed prostate adenocarcinoma with metastasis either starting or recently started on LHRH analogue therapy. [Late induction permitted within 3 months of starting LHRH analogue therapy or antiandrogen] All patients who have not initiated hormone therapy (Early induction patients) must have elevated PSA ≥ 4 ng/ml within 28 days prior to registration. For late induction registrations, PSA must be ≥ 4 ng/ml prior to start of androgen deprivation therapy; either antiandrogen or LHRH analogue or GNRH antagonist .If patients are on antiandrogen, this will need to be discontinued for at least 7 days prior to registration. Patients with a history of prior neoadjuvant or adjuvant hormone therapy are eligible provided they have received twenty four or less months of hormone treatment (single or combination treatment, excluding orchiectomy). Both therapies (neoadjuvant/adjuvant hormone therapy) must have been discontinued at least 6 months prior to registration. This is intended to exclude patients who might have been rendered indirectly androgen insensitive. There must be no plans to receive concomitant chemotherapy, biological response modifiers, radiation therapy or hormonal therapy. Concomitant radiation therapy is allowed for the palliation of severe pain/neuropathic compression. Prior or concomitant use of megestrol acetate for the treatment of hot flashes is allowed. Patients must have a performance status of 0 - 2 by Zubrod Criteria. Patients must have recovered from any major infections and/or surgical procedures and,in the opinion of the investigator, not have significant active medical illness precluding protocol treatment or survival. No prior malignancy is allowed except for adequately treated basal cell (or squamous cell) skin cancer, superficial or in situ cancer of the bladder. For an invasive cancer the patients should be disease free for at least 3 years prior to enrollment on study. For all patients a bone scan must be performed within 60 days prior to registration for tumor assessment. CT scans (abdomen and pelvis) and chest x-ray are optional, but must be repeated if used for disease assessment. For late induction registrations, tumor assessment imaging showing metastatic disease must be available prior to start of androgen deprivation therapy. Age 18 or older and willing and able to provide informed consent. Willingness to swallow pills and no medical condition that would interfere with this. 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. Patients are also required to use a condom if having sex with a pregnant woman. Patient should agree to a tumor tissue biopsy prior to protocol enrollment. Post therapy biopsy is optional. Patients who are being treated with a GNRH antagonist should be willing to switch to a LHRH analogue after registration. Patients must have one of the following a) Low volume disease (defined as no visceral metastases and < 4 bone metastases) or b) are not candidates for docetaxel based chemotherapy or 3) refused docetaxel chemotherapy Exclusion Criteria: 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; Known or suspected brain metastasis or active leptomeningeal disease; Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment; Absolute neutrophil count < 1,000/μL, or platelet count < 50,000/μL, or hemoglobin<8 g/dL) at the Screening visit. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal Creatinine > 177 μmol/L (2 mg/dL) Clinically significant cardiovascular disease including: Myocardial infarction within 6 months; Uncontrolled angina within 3 months; Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure (NYHA) class 3 or 4 in the past, unless screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction that is greater or equal to 45%; History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes); History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place; Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mmHg) at the Screening visit; Bradycardia as indicated by a heart rate of < 50 beats per minute on the Screening ECG; Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months); Treatment with concurrent 5-α reductase inhibitors (finasteride, dutasteride), estrogens, and/or cyproterone Treatment with systemic biologic therapy for prostate cancer (other than approved bone targeted agents and GnRH-analogue therapy) or other agents with anti-tumor activity within 4 weeks of enrollment (Day 1 visit); History of prostate cancer progression on ketoconazole; Prior use, or participation in a clinical trial, of an investigational agent that blocks androgen synthesis (e.g., abiraterone acetate, TAK-700, TAK-683, TAK-448) or agents that block the androgen receptor (e.g.,ARN-509) Previous enzalutamide therapy; Use of an investigational agent within 2 weeks of enrollment (Day 1 visit); Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of replacement steroids or > equivalent of 10 mg of prednisone per day within 4 weeks of enrollment (Day 1 visit); Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data. Prior chemotherapy for metastatic disease. >30 days of antiandrogen therapy monotherapy without androgen deprivation therapy. Life expectancy of 6 months or less.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (enzalutamide and LHRH analogue therapy)<br>Patients receive enzalutamide orally PO QD and undergo orchiectomy or receive LHRH analogue therapy (leuprolide acetate, goserelin acetate, or any other FDA approved preparation). Treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: enzalutamide<br>* Given PO<br>* Other names: XTANDI;Procedure: orchiectomy<br>* Undergo orchiectomy or receive LHRH analogue therapy<br>Drug: leuprolide acetate<br>* Undergo orchiectomy or receive LHRH analogue therapy<br>* Other names: Lupron Depot;Drug: goserelin acetate<br>* Undergo orchiectomy or receive LHRH analogue therapy<br>* Other names: Zoladex;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Active Comparator: Arm B (bicalutamide and LHRH analogue therapy)<br>Patients receive bicalutamide PO QD and undergo orchiectomy or receive LHRH analogue therapy as in Arm A. Treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: bicalutamide<br>* Given PO<br>* Other names: CDX;Procedure: orchiectomy<br>* Undergo orchiectomy or receive LHRH analogue therapy<br>Drug: leuprolide acetate<br>* Undergo orchiectomy or receive LHRH analogue therapy<br>* Other names: Lupron Depot;Drug: goserelin acetate<br>* Undergo orchiectomy or receive LHRH analogue therapy<br>* Other names: Zoladex;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With PSA Remission Assessed Using the Prostate Cancer Clinical Trials Working Group (PCWG2) Criteria | Number of Participants with PSA Remission Assessed Using the Prostate Cancer Clinical Trials Working Group (PCWG2) Criteria specifically at the 7 month time point. The binary endpoint (yes/no) will be summarized with its point estimate (an occurrence rate), and 2-sided Wilson type 95% confidence interval (CI). PSA response rates will be compared by treatment arm in a stratified logistic regression model. | Month 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of Measurable Disease Response | The number of participants with Measurable disease response per RECIST v1.1. | Up to 2 years | 
| Achievement of PSA Response Assessed Using PCWG2 Criteria | Will be summarized with point estimates (occurrence rates), and 2-sided Wilson type 95% CIs. | Up to 2 years | 
| The Percentage of Patients Responding | Point estimates will be calculated and CI estimates will be derived from the Wilcoxon method using STATA software. | 6 months | 
| Time to Treatment Failure | Time to Treatment Failure from date of first treatment to date off treatment or date patient is taken off study for any reason. TTF will be estimated with standard K-M methodology. Point and CI estimates of the median and various time point-specific rates will be derived from the K-M life table. | Assessed up to 6 years. | 
| Percentage of Patients Progression Free at One Year | Percentage of patients progression free at one year using the Kaplan-Meier method. | assessed at 1 year | 
| Percentage of Patients With Bone Metastases Progression Free at Six Months | Percentage of patients with bone metastases Progression free at six months using the Kaplan-Meier method. | assessed at six months | 
| Percentage of Patients Progression-free at 6 Months | Will be estimated with standard K-M methodology. Point and CI estimates of the six-month rate will be derived from the K-M life table. | From registration to PSA progression defined by PCWG II criteria or measurable disease by RECIST 1.1, assessed at 6 months | 
| Overall Survival at 2 Years | Overall Survival will be measured from date of registration to death or last follow up. OS will be estimated with standard K-M methodology. Point and CI estimates of the 2-year rate will derived from the K-M life table. | Assessed at 2 years | 
| The Number of Participants With a CTC Response | Will be summarized with point estimates (occurrence rates). A CTC response is defined as any level of CTC < 5 that is maintained or any level of CTC that is reduced from baseline. | Up to month 1 |