The goal of this clinical research study is learn if adding cabozantinib (also known as XL184) to hormonal therapy can help to control prostate cancer. The safety of this drug will also be studied.

Cabozantinib is designed to block certain proteins in your blood that cause cancer cells to grow. This may cause cancer cells to die.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take 1 capsule of cabozantinib by mouth 1 time every day while you are on study. You should not eat or drink anything other than water for 2 hours before and 1 hour after taking the study drug. You should take the capsule with at least 1 cup (8 ounces) of water. You will also be given separate directions about how to take the study drug.

You will also receive hormone therapy. The hormone drug you receive will be standard of care hormone therapy. The study doctor will decide what hormone therapy you will receive and will explain when and how you should take the hormone therapy, as well as its risks.

You will be given a drug diary where you will record when you take cabozantinib. You should return this diary to the study staff when you come into the clinic.

Study Visits:

At every visit, you will be asked about any side effects you may have had and any other drugs you may be taking.

If you are receiving Coumadin, every week for the first 3 weeks, you will have blood drawn (about 1 teaspoon) to test your blood clotting function.

Every 3 weeks for the first 12 weeks of the study, and then every 6 weeks after that:

• You will have a physical exam.
• Blood (about 3-4 teaspoons) will be drawn for routine tests.

Every 3 weeks for the first 12 weeks of the study, and then every 12 weeks after that, blood (about 1 teaspoon) will be drawn to check your thyroid and pancreatic function. The frequency of the testing may change if the study doctor thinks it is needed.

Every 6 weeks, you will have the following tests performed:

• Blood (about 2-3 teaspoons) will be drawn to measure your PSA levels and for biomarker testing.
• Urine will be collected for routine tests.
• You may have these test performed near your home if the study doctor thinks you are tolerating the treatment.

Every 12 weeks, you will have a bone scan and CT scans of the chest, abdomen, and pelvis to check the status of the disease.

Length of Study:

You may continue receiving the study drug for as long as the study doctor thinks it is in your best interest. You will be taken off study early if the disease gets worse, if you have intolerable side effects, or if your study doctor thinks it is in your best interest to stop.

Long-Term Follow-Up:

You will be contacted every 6 months after you stop taking the study drug to check on how you are feeling and the status of the disease. This will consist of a phone call, e-mail, or medical record review. If you are called, each call should last about 5 minutes.

This is an investigational study. Cabozantinib is FDA approved to treat patients with certain types of thyroid cancer. Its use in this study is investigational.

Up to 60 participants will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Histologic proof of prostate adenocarcinoma
2. Newly diagnosed Androgen-Dependent Prostate Cancer. Patients already on ADT are eligible as long as the time from initiation of LHRH analog or antagonist is not greater than 3 months.
3. Metastatic disease on bone scan and/or involvement of soft tissues (lymph nodes and/or viscera) by CT scan, PET/CT, or MRI
4. PSA > 1 ng/ml, unless anaplastic features are present (according to eligibility 10)
5. Life expectancy from a co-morbid illness > 3 years
6. Eastern Cooperative Oncology Group (ECOG) performance status </= 2
7. Patients must have adequate organ function as defined by: Absolute Neutrophil Count (ANC) >/= 1,500/ul (unless due to bone marrow infiltration by tumor in which case ANC >/=500/ml are allowed) Hemoglobin (Hgb) >/= 9 gm/dL (unless due to bone marrow infiltration by tumor in which case Hgb>8 gm/dL); Total bilirubin </= 1.5times the upper limit of normal (ULN). For patients with known Gilbert's disease, total bilirubin should be </= 3mg/dL; platelet count >/= 100,000/mm^3 (unless due to bone marrow infiltration by tumor in which case >/=50,000/ml are allowed); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 3.0 x ULN if no liver involvement, or </= 5 x ULN with liver involvement; Lipase < 2 x the upper limit of normal; Urine protein/creatinine ratio (UPCR) </= 1; Serum phosphorus >/= lower limits of normal (LLN); estimated creatinine clearance of >/=40 ml/min.
8. Prior ADT is allowed if it was an adjunct to definite local therapy, was given for </=1 year and was completed at least 12 months before initiating therapy for metastatic disease.
9. Prior therapy with other tyrosine kinase inhibitors (TKI) inhibitors or any other type of investigational agent is allowed if it was an adjunct to definitive local therapy, was given for </=6 months, and was completed at least 12 months before initiating therapy for metastatic disease.
10. Patients with "anaplastic" features are eligible for this trial as defined by at least one of the following: a) Any of the following metastatic presentations: exclusive visceral metastases, radiographically predominant lytic bone metastases identified by plain X-ray or CT scan, bulky (>5 cm in longest dimension) lymphadenopathy or high-grade (gleason >8) tumor mass in the prostate/pelvis.; b) Low PSA (</= 10 ng/ml) at initial presentation (prior to androgen ablation or at symptomatic progression in the castrate-setting) plus high volume (>/=20) bone metastases.; c) Elevated serum LDH (>/= 2 x ULN) or elevated serum CEA (>/= 2 x ULN) in the absence of other etiologies.; d) Short interval (</= 180 days) to castrate-resistant progression following initiation of hormonal therapy.
11. Sexually active fertile subjects, and their partners, must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study drug(s).

Exclusion Criteria:

1. Biological agents (antibodies, immune modulators, cytokines, or vaccines) or radionuclide treatment within 6 weeks of the first dose of study treatment.
2. Radiation therapy within 2 weeks prior to initiation of study treatment.
3. Symptomatic or uncontrolled brain metastasis or epidural disease requiring current treatment including steroids and anti-convulsant.
4. The subject has had another diagnosis of malignancy requiring systemic treatment within the last two years, unless non-melanoma skin cancer, or superficial bladder cancer.
5. The subject has uncontrolled or significant intercurrent illness including, but not limited to, the following conditions: Chronically uncontrolled hypertension, defined conventionally as consistent and repeated systolic pressures above 140 mmHg or diastolic pressures above 90 mmHg despite anti-hypertensive therapy. This may be better established with home BP readings than with clinic visit results. There is no criterion related to a specific BP result required for eligibility, nor are acute BP elevations that are related to iatrogenic causes, acute pain, or other transient reversible causes considered to be an exclusion criteria. The intent is to exclude patients with chronically uncontrolled hypertension that might be further exacerbated by Cabozantinib.
6. Continued from # 5) Other cardiovascular disorders such as symptomatic congestive heart failure (CHF), unstable angina pectoris, clinically-significant cardiac arrhythmias, history of stroke (including transient ischemic attack [TIA], or other ischemic event) within 6 months of study treatment, myocardial infarction within 6 months of study treatment, history of thromboembolic event requiring therapeutic anticoagulation within 6 months of study treatment or main portal vein or vena cava thrombosis or occlusion. ;Gastrointestinal (GI) disorders particularly those associated with a high risk of perforation or fistula formation including: Any of the following at the time of screening; a) intra-abdominal tumor/metastases invading GI mucosa b) active peptic ulcer disease, c) inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
7. Continued from # 6) Any of the following within 6 months before the first dose of study treatment: a) history of abdominal fistula b) gastrointestinal perforation c) bowel obstruction or gastric outlet obstruction; d) intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 6 months ago. GI surgery (particularly when associated with delayed or incomplete healing) within 28 days. Note: Complete healing following abdominal surgery must be confirmed prior to initiating treatment with cabozantinib even if surgery occurred more that 28 days ago. Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus.
8. The subject is unable to swallow capsules tablets
9. The subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulation.
10. Oral corticosteroids >/= 7.5mg/day prednisone (or prednisone equivalents).
11. Prior treatment with cabozantinib.
12. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before randomization.

From the first dose through 30 days after the last day of treatment, up to 80 months