Enzalutamide/Leuprolide +/- Abiraterone/Pred in Prostate

Study Overview
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Brief Summary
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This study is comparing the effectiveness of enzalutamide with or without abiraterone acetate for men with high-risk, localized prostate cancer.

Detailed Description
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In this research study, the investigators are comparing the effectiveness of enzalutamide with or without abiraterone acetate for men with high-risk, localized prostate cancer. Abiraterone acetate with prednisone and enzalutamide are currently FDA-approved for use in the treatment of patients with metastatic castration-resistant prostate cancer, however they are investigational for the treatment of localized prostate cancer. Abiraterone acetate works by decreasing the production of male sex hormones, which cause prostate cancer growth. Enzalutamide works by blocking the effects of male sex hormones, which cause prostate cancer growth. The FDA (the U.S. Food and Drug Administration) has not approved the combination of enzalutamide and abiraterone acetate as neoadjuvant therapy for high risk prostate cancer undergoing prostatectomy but each drug has been approved for the treatment of more advanced prostate cancer. Participants will be randomized to one of two study arms. Randomization means that the participant is put into a group by chance. It is like flipping a coin. Neither participant nor the research doctor will choose what group participants are randomized to. The names of the study medications involved in this study are: Enzalutamide Abiraterone Acetate Prednisone Leuprolide Acetate

Official Title
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A Phase II Randomized Study of Enzalutamide+Leuprolide Versus Enzalutamide+Leuprolide+Abiraterone Acetate+Prednisone as Neoadjuvant Therapy for HIgh-Risk Prostate Cancer Undergoing Prostatectomy

Conditions
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Prostate Adenocarcinoma, Prostate Cancer, High Risk Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Abiraterone Acetate
* Drug: Prednisone
* Drug: Leuprolide Acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male greater than or equal 18 years of age. Histologically confirmed adenocarcinoma of the prostate without histological variants (including overt neuroendocrine differentiation, small cell neuroendocrine carcinoma features, sarcomatoid features, pure ductal adenocarcinoma, squamous or transitional cell carcinoma). Must have tissue available from the pre-treatment diagnostic biopsy (tissue blocks if possible; if not possible, 10 unstained slides from each positive core sample for a total of 30 slides). Must have three core biopsies involved with cancer (a minimum of 6 core biopsies must be obtained). Prostate biopsy must be within three months from screening. Participants must have the following features: Intermediate-risk disease defined as Gleason 4+3=7 disease OR High-risk disease defined as Gleason 8-10 OR PSA > 20 ng/dL OR T3 disease (by prostate MRI) No evidence of metastatic or nodal disease as determined by radionuclide bone scans CT/MRI. Participants must be candidates for RP and considered surgically resectable by urologic evaluation. ECOG performance status 0 to 1 (Appendix A). Participants must have normal organ and marrow function as defined below: WBC ≥ 3,000/mcL ANC ≥ 1,500/mcL Platelets ≥ 100,000/mcL Serum potassium ≥ 3.5 mmol/L AST, ALT, and total bilirubin ≤ 1.5 x Institutional ULN Calculated creatinine clearance ≥ 60 mL/min PTT ≤ 60, INR ≤ 1.5 x Institutional ULN unless on warfarin therapy (investigator would need to determine if safe for participant to stop warfarin prior to biopsy and warfarin therapy) Controlled blood pressure defined as a systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg on no more than three anti-hypertensive agents. Drug formulations containing two or more anti-hypertensive agents will be counted based on the number of active agents in each formulation. Exclusion Criteria: Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens (including first-generation antiandrogens, enzalutamide, ARN-509 and others), CYP17 inhibitors (including abiraterone, TAK-700, galeterone, ketoconazole, and others), estrogens, LHRH agonist/antagonists. Prior therapy with 5α-reductace inhibitors is allowed. LHRH therapy allowed if begun within 4 weeks of day 1. Prior chemotherapy, radiation therapy, or immunotherapy for prostate cancer. Prior systemic treatment with an azole drug within four weeks of screening visit. Hypogonadism or severe androgen deficiency as defined by screening serum testosterone < 200 ng/dL. Clinically significant cardiovascular disease including: Acute coronary syndrome within 6 months of screening visit; Hypotension defined as a systolic blood pressure < 86 mmHg; Bradycardia defined as a heart rate of < 50 beats per minute, unless pharmaceutically induced and thus reversible (i.e. beta blockers); Uncontrolled angina (requiring escalating doses of nitrates) within 3 months of screening visit; Congestive heart failure NYHA Class III or IV or subjects with a history of congestive heart failure NYHA Class III or IV, unless screening ECHO results in left ventricular ejection fraction that ≥ 45%; History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes); Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening EKG > 470 msec; History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place; History of seizure or any condition or concurrent medication that may predispose to seizure. Thromboembolism within 6 months of screening visit. Severe hepatic impairment (Child-Pugh Class C). Active or symptomatic viral hepatitis or chronic liver disease. History of pituitary or adrenal dysfunction. GI disorders which may interfere with the absorption of the study drug. Pre-existing condition that warrants long-term corticosteroid use. Concomitant use of medications that may alter pharmacokinetics of abiraterone or enzalutamide. Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: non-muscle invasive bladder cancer, basal cell or squamous cell carcinoma of the skin. Major surgery or radiation therapy within 30 days of screening.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM 1<br>Participants will be randomized in a 2:1 ratio to neoadjuvant treatment (ARM 1) or (ARM 2). Participants will receive the assigned study treatment per cycle Enzalutamide- Once daily at prespecified dose, orally Abiraterone Acetate- Once daily at prespecified dose, orally Prednisone-Once daily at prespecified dose, orally Leuprolide Acetate-Intermuscular injection at prespecified dose and duration | Drug: Enzalutamide<br>* 160 mg (four 40 mg capsules), oral, once daily, 28 days (4 weeks) 6 cycles maximum. Can be taken with or without food.<br>* Other names: XTANDI;Drug: Abiraterone Acetate<br>* 1000 mg (four 250 mg tablets), oral, once daily, 28 days (4 weeks) 6 cycles maximum. No food should be consumed for at least two hours before the dose and for at least one hour after the dose.<br>* Other names: Zytiga;Drug: Prednisone<br>* 5 mg, oral, once daily, 28 days (4 weeks) 6 cycles maximum.Take with food, preferred to be taken in the morning .<br>Drug: Leuprolide Acetate<br>* Either 7.5 mg monthly or 22.5 mg every three months, Intramuscular, monthly or every three months.<br>* Other names: - Viadur;|
| Experimental: ARM 2<br>Participants will be randomized in a 2:1 ratio to neoadjuvant treatment (ARM 1) or (ARM 2). Participants will receive the assigned study treatment per cycle. Enzalutamide- once daily at prespecified dose, orally Leuprolide Acetate- Intermuscular injection at prespecified dose and duration | Drug: Enzalutamide<br>* 160 mg (four 40 mg capsules), oral, once daily, 28 days (4 weeks) 6 cycles maximum. Can be taken with or without food.<br>* Other names: XTANDI;Drug: Leuprolide Acetate<br>* Either 7.5 mg monthly or 22.5 mg every three months, Intramuscular, monthly or every three months.<br>* Other names: - Viadur;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pathologic Complete Response (pCR) or Minimal Residual Disease (MRD) | pCR is defined as the absence of morphologically identifiable carcinoma in the radical prostatectomy (RP) specimen. MRD is defined as the largest cross-sectional dimension of residual tumor measuring </= 0.5 cm. If the tumor is multifocal, the size of the largest focus will be used to determine the size of the residual tumor. | after RP approximately 24 weeks from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Pathologic Complete Response (pCR) | pCR is defined as the absence of morphologically identifiable carcinoma in the radical prostatectomy (RP) specimen. | after RP approximately 24 weeks from study entry | 
| Residual Cancer Burden (RCB) | RCB was analyzed using radical prostatectomy (RP) tissue. The largest area of tumor was measured by ruler and the longest tumor dimension in this area was used as the dimension for calculation. | after RP approximately 24 weeks from study entry | 
| Positive Surgical Margin Status | Participants were classified by presence or absence of positive surgical margins defined as margins, which are the edges of the removed tumor, that show some cancer cells. | after RP approximately 24 weeks from study entry | 
| Median Prostate Specific Antigen (PSA) Nadir | PSA nadir is the lowest PSA level recorded during neoadjuvant therapy. | PSA was assessed at baseline and every cycle during neoadjuvant therapy (up to 24 weeks). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate adenocarcinoma, advanced prostate cancer, high risk prostate cancer