Effects of Endocrine Therapy with or without Trametinib or Dasatinib in Patients with Localized, Untreated Prostate Cancer Undergoing Surgery

Inclusion Criteria

• Willing and able to give informed consent
• Adenocarcinoma of the prostate with planned radical prostatectomy (RP) with curative intent as part of standard of care management plan
• Patient is a candidate for radical prostatectomy
• Tumor accessible to biopsy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Estimated life expectancy of >= 6 months
• Absolute neutrophil count > 1,500/µL
• Platelet count > 100,000/µL
• Hemoglobin > 5.6 mmol/L (9 g/dL) at the screening visit
• Total bilirubin within the normal range at the screening visit
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) within the normal range at the screening visit
• Creatinine < (1.5 mg/dL) at the screening visit
• International normalized ratio (INR) < 1.3 (or < 3 if on warfarin or other anticoagulants) at the screening visit
• Albumin > 30 g/L (3.0 g/dL) at the screening visit
• GROUP 2 (trametinib arm): Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
• Patients with clinically localized adenocarcinoma of the prostate who are scheduled to undergo radical prostatectomy (RP) with curative intent and have any the following clinico-pathologic features: (1) Gleason score sum >= 4+3 or any Gleason 5, (2) PSA > 20, and/or (3) clinical stage >= T3a (staging by magnetic resonance imaging [MRI] is allowed)
• Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• Willing to abstain from procreative sex or partake in appropriate form of contraception; for the purpose of this study, condom use or abstinence will be required

Exclusion Criteria

• Any prior treatment for prostate cancer
• Any non-adenocarcinoma histologic component
• Any evidence of lymphatic or hematogenous metastases
• Clinically significant cardiovascular disease including: * GROUP 2 (trametinib arm): LVEF < LLN * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months * Uncontrolled angina within 3 months * GROUP 1 and GROUP 3 (non-trametinib arms): 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 a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction that is >= 45% * GROUP 2 (trametinib arm): Any history of congestive heart failure of any NYHA class for patients assigned to Group 2 (trametinib arm) * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes) * Patients with intra-cardiac defibrillators or permanent pacemakers * Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mmHg) at the screening visit * Bradycardia as indicated by a heart rate of < 40 beats per minute on the screening electrocardiogram (ECG) * Treatment refractory hypertension defined as a blood pressure of systolic > 160 mmHG and/or diastolic > 95 mmHG which cannot be controlled by anti-hypertensive therapy * Corrected QT interval (QTC) >= 480 milliseconds * Known cardiac metastases
• Presence of a comorbid disease or medical condition that would impair the ability of the patient to receive or comply with the study protocol
• History of interstitial lung disease or pneumonitis
• GROUP 2 (trametinib arm): History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): * History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes). * Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as: ** Evidence of new optic disc cupping ** Evidence of new visual field defects ** Intraocular pressure > 21 mm Hg
• Evidence of a coagulopathy
• Patient receiving therapeutic anticoagulation
• Unwillingness to engage in adequate contraception
• Allergy/sensitivity to any study drug (degarelix, enzalutamide, trametinib, dasatinib), or drugs chemically related to study drug, or excipients or to dimethylsulfoxide
• Prior use of degarelix, enzalutamide, trametinib, or dasatinib in any context
• Known or suspected brain metastasis or active leptomeningeal disease or spinal cord compression
• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted)
• 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
• History of loss of consciousness or transient ischemic attack within past 12 months
• Prior use of androgen deprivation therapy or radiation therapy
• Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months)
• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 30 days of enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days of enrollment
• Hospitalization within 30 days of enrollment
• History of another malignancy within the previous 5 years other than curatively treated non-melanoma skin cancer
• Use of an investigational agent within 4 weeks of enrollment
• 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 10 mg of prednisone per day within 4 weeks of enrollment
• Use of any medications known to affect the serum androgen levels or the PSA
• 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