Primary Objective:

1. To define the tolerability of three different dose-levels of the angiogenesis inhibitor, sunitinib malate, in combination with hormone ablation and external beam radiation for high-risk and locally advanced prostate cancer.

Secondary Objectives:

1. Describe the qualitative and quantitative toxicity including serial quality of life changes.
2. Evaluate putative biomarkers of outcome at baseline, after sunitinib lead-in and at 12 and 24 months after completion of radiation therapy.

The Study Drugs:

Sunitinib malate is designed to block pathways that control important events such as the growth of blood vessels that are essential for the growth of cancer.

Luteinizing Hormone-Releasing Hormone (LHRH) Analogues like Lupron® (leuprolide) and Zoladex® (goserelin) are hormonal treatments used to help stop the body from making testosterone (male sex hormones) in the body. Prostate cancer cells need testosterone to survive.

Anti-Androgen drugs, like Casodex® (bicalutamide) also stop cell growth by blocking male hormones like testosterone.

Screening Tests:

Before you can start receiving sunitinib malate on this study, you will have "screening tests." These tests will help the study doctor decide if you are eligible to take part in this study.

Within 6 weeks before enrollment on this study, you will have the following tests and procedures performed.

• You will have a chest x-ray, bone scan, and computed tomography (CT) scans to check the status of the disease.
• You will have an electrocardiogram (ECG--a test to measure the electrical activity of the heart) and an echocardiogram or multiple gated acquisition (MUGA) scan (heart function tests).

Within 14 days before enrollment on this study, you will have the following tests.

• Your complete medical history will be recorded.
• You will have a physical exam, including measurements of your blood pressure and weight.
• You will be asked about any medications you are currently taking.
• You will complete a quality-of-life survey that will have questions about how you are feeling. They should take about 10 minutes to complete.

Within 7 days before enrollment on this study, you will have the following tests.

• Blood (about 3 teaspoons) and urine will be collected for routine tests. The blood testing will include measurement of prostate-specific antigen (PSA--a substance produced by the prostate) and testosterone levels.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will be assigned to a study group. Up to 3 groups of 6 participants each will be enrolled in this study. The group you are assigned to and dose of sunitinib malate you receive will depend on when you join this study. Three (3) dose levels of sunitinib malate will be tested. The first group of participants will receive the lowest dose of sunitinib malate. The next group enrolled will receive a higher dose of sunitinib malate, if no intolerable side effects were seen.

Before you begin taking sunitinib, you will begin receiving hormone therapy. You will receive leuprolide and bicalutamide or goserelin and bicalutamide. Leuprolide is given through a needle in your muscle, and goserelin is given through a needle under the skin in the abdomen. You will receive 1 of these injections every 3 months. Which hormonal drug you are given (leuprolide or goserelin) will be assigned by your doctor and/or will depend on your insurance coverage. You will take bicalutamide by mouth once a day for 2 weeks (with or without food).

After at least 4 weeks of hormone therapy have been given, you will begin taking sunitinib malate in combination with the hormone therapy. You will take sunitinib malate once a day (either with or without food) for 16 weeks in a row.

Radiation Therapy:

After 4 weeks of combined treatment with sunitinib and hormone therapy, you will begin radiation treatments. Radiation treatments will be given once a day, 5 days a week, for about 8 weeks. Each treatment will take 20-30 minutes. This procedure will be discussed with you in more detail. You will continue taking sunitinib and hormone therapy while you are on radiation treatments.

Study Visits:

On the day you start treatment with sunitinib, you will have the following tests and procedures performed:

• You will have a physical exam, including measurements of your blood pressure and weight.
• You will be asked about any side effects you may have had since your last visit.
• Blood (about 1 teaspoon) will be drawn for routine tests.

About Day 15 of treatment with sunitinib, and on the day you begin radiation therapy (before your first treatment), you will have the following tests and procedures performed:

• You will have a physical exam, including measurements of your blood pressure and weight.
• You will be asked about any side effects you may have had since your last visit.
• Blood (about 2 teaspoons) will be drawn for routine tests.

Every 2 weeks during radiation therapy, you will have the following tests and procedures performed:

• You will have a physical exam, including measurements of your blood pressure and weight (every 2 weeks)
• You will have blood drawn (about 2 teaspoons) for routine testing.
• You will be asked about any side effects you may have had since your last visit.

About 4 weeks after you stop radiation therapy, you will have the following test and procedures performed:

• You will have a physical exam, including measurements of your blood pressure and weight.
• Blood (about 2 teaspoons) and urine will be collected for routine tests. The blood testing will include measurement of PSA and testosterone levels.
• You will be asked about any side effects you have had since your last visit.

Length of Study:

You will continue taking sunitinib malate on this study for a total of 16 weeks. Radiation treatments will last for up to 8 weeks. Hormone injections will continue for a period of 2 years. You will be taken off this study if intolerable side effects occur or the disease gets worse.

Long-Term Follow-up:

You will be followed for up to 10 years once you have taken sunitinib malate for 20 weeks. You will have these tests every 12 weeks until 2 years after radiation, every 6 months until 5 years, and then yearly until 10 years. At these visits, you will be asked about any side effects you have experienced since your last visit. Blood (about 1 teaspoons) will be drawn for routine tests, including PSA and testosterone levels. At 12 and 24 months after radiation therapy, you will complete a quality-of-life survey that will have questions about how you are feeling. They should take about 10 minutes to complete.

This is an investigational study. Sunitinib malate is FDA approved and commercially available for the treatment of adults with kidney cancer. Sunitinib malate will be provided free of charge while you are on this study.

Bicalutamide, leuprolide, and goserelin are FDA approved and commercially available for use in prostate cancer.

Up to 18 patients will be enrolled in this multicenter trial. Up to 12 will be enrolled at M.D. Anderson.

• Drug: Leuprolide
• Drug: Goserelin
• Drug: Sunitinib Malate
• Drug: Casodex
• Radiation: Radiation Therapy (RT)

Inclusion Criteria:

1. Adenocarcinoma of the prostate with the following high-risk features are eligible: cT2c (palpable disease on digital rectal examination in both lobes) and Gleason Grade 7 (4+3) or higher with any PSA OR T3 or T4 disease of any Gleason Grade
2. Patients must have no evidence of metastatic disease by clinical and radiological staging including Chest X-ray, Bone scan and CT Scan of the Abdomen and Pelvis.
3. ECOG Performance Status 0-1
4. Calculated Creatinine clearance > 35cc/min, Absolute neutrophil count > 1,500/mm^3, Platelets >/= 100,000/mm^3, AST/ALT < 2.5 x UNL, Total bilirubin WNL.
5. No standard contraindications to radiation therapy including prior radiation therapy, inflammatory bowel disease and collagen vascular disease.
6. Patients must be at least 18 years of age

Exclusion Criteria:

1. Prior VEGFR/PDGFR inhibitor or other investigational therapy.
2. Inability to take oral medication
3. Uncontrolled hypertension (blood pressure > 140/90 mm Hg despite optimal medical therapy), Left Ventricular Ejection Fraction </= 40%, symptomatic congestive heart failure or symptomatic ischemic heart disease, deep venous thrombosis or pulmonary embolism in the last 12 months.
4. Known human immunodeficiency virus infection, alcoholism, chronic active hepatitis or liver cirrhosis