Inclusion Criteria

1. Patients must have documented histological or cytological evidence of adenocarcinoma of the prostate.
2. Patients must have received enzalutamide or abiraterone for CRPC.
   1. Patients who have received combination enzalutamide/abiraterone or combination ARN509/abiraterone as part of ongoing clinical trials are allowed and will be included in "Prior Abiraterone" arm of this study.
   2. Prior treatment with sequential enzalutamide-abiraterone or abiraterone-enzalutamide will not be allowed.
   3. Prior treatment with first-generation AR antagonists (i.e., bicalutamide, nilutamide, flutamide) before abiraterone or enzalutamide is allowed. 
   4. Prior use of other 2nd generation CYP17 inhibitors and androgen receptor antagonists are allowed in addition to abiraterone or enzalutamide.
3. Patients must have demonstrated disease progression while on enzalutamide and/or abiraterone. Progressive disease is defined by one or more of the following:
   • A rise in PSA on two successive determinations at least one week apart and PSA level ≥2ng/ml.
   • Soft-tissue progression defined by RECIST 1.1
   • Bone disease progression defined by PCWG2 with two or more new lesions on bone scan
4. Patients must have a minimum serum PSA level of ≥2 ng/ml that is rising based on the PCWG2 criteria.
5. Patients must be ≥18 years of age.
6. Patients must have castrate levels of testosterone (<50 ng/dl [1.74 nmol/l]).
7. Patients must have undergone orchiectomy, or have been on LHRH agonists or antagonists, for at least 3 months prior to drug initiation. Patients on LHRH agonists/antagonists must remain on these agents for the duration of the study.
8. Patients must have an ECOG Performance Score of 0-1.
9. Patients must have adequate hematopoietic function as evidenced by:
   • WBC ≥3,000/µl
   • ANC ≥1,500/µl
   • Platelet count ≥100,000/µl
   • HGB ≥10 g/dl
10. Patients must have adequate hepatic function as evidenced by AST/ALT levels <3X the ULN and bilirubin levels of <2.0 mg/dl.
11. Patients must have adequate renal function as evidenced by a serum creatinine of <2.0 mg/dl.
12. Patients must have K+ >3.5 mEq/l.
13. Patients or their legal representatives must be able to provide written informed consent.
14. Patients must have discontinued enzalutamide or abiraterone/prednisolone ≥4 weeks prior to study drug initiation. 
    1. Patients who are on replacement doses of corticosteroids when coming onto study may continue those steroids while on study.
15. Patients who have partners of child-bearing potential must be willing to use at least two forms of effective birth control (one form must be a barrier method) during the treatment period and for 90 days after last dose of VT-464. Patients must also agree to not donate sperm through 90 days following the last dose of VT-464.

Exclusion Criteria

1. Patients who have received prior cytotoxic chemotherapy for castration-resistant prostate cancer. Prior docetaxel for castration-sensitive disease is permitted.
2. Patients who have received TAK-700 (Orteronel®), TOK-001 (Galeterone®), ARN-509 or any other therapeutic investigational product directed towards the androgen receptor (AR) or androgen biosynthesis. Patients who receive ARN-509 in combination with abiraterone as part of a clinical trial are allowed.
3. Patients who have received ketoconazole, aminoglutethimide, or high-dose estrogen for CRPC.
4. Patients who have completed sipuleucel-T (Provenge ®) treatment within 30 days of study drug initiation.
5. Patients on 5 alpha reductase inhibitors such as finasteride (PROSCAR®, PROPECIA®), or dutasteride (AVODART®) within 3 months from study drug initiation.
6. Patients who have received systemic corticosteroids within 30 days of study drug initiation; use of replacement doses, topical, inhaled or ophthalmic steroids is permitted.
7. Patients who have received any therapeutic investigational agent within 2 weeks of study drug initiation.
8. Patients who have received palliative radiotherapy within 4 weeks of study drug initiation.
9. Patients who have received herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity (e.g., saw palmetto, PC-SPES, PC-HOPE, St. John's wort, selenium supplements, grape seed extract, etc.) within 4 weeks of study drug initiation or plans to initiate treatment with these products/alternative therapies during the entire duration of the study.
10. Patients with active CNS metastases from prostate cancer. Patients with treated epidural disease are eligible to enroll. Patients with treated brain metastases can be included as long as >4 weeks have elapsed since last treatment (radiotherapy or surgery) for brain metastases, the patient is neurologically and radiographically stable, and is not receiving corticosteroids for brain metastases. Patients with untreated brain metastases are excluded. Brain imaging (CT or MRI) is not required at baseline if brain metastases are not clinically suspected.
11. Patients with a history of adrenal insufficiency. Patients who have received systemic corticosteroids for >2 weeks within 6 months of study drug initiation (including those receiving prednisolone with abiraterone) must have adrenal insufficiency ruled out by a morning plasma cortisol concentration ≥500 nmol/l or a plasma cortisol response to an ACTH stimulation test that is deemed clinically normal.
12. Patients with a history within the last 3 years of another invasive malignancy (excluding non-melanoma skin cancer).
13. Patients with a QTcF interval of >470 msec; if the Screening ECG QTcF interval is >470 msec, it may be repeated, and if repeat ≤470 msec, the patient may be enrolled.
14. Patients with a history of clinically significant cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes and second degree or third degree atrioventricular heart block without a permanent pacemaker in place. Patients with resolved or rate-controlled atrial fibrillation/atrial flutter are allowed.
15. Patients with NYHA Class III or IV congestive heart failure, unstable angina, myocardial infarction/acute coronary syndrome within the preceding 6 months.
16. Patients with diabetes mellitus who have had more than 2 episodes of diabetic ketoacidosis in the preceding 12 months.
17. Inadequately controlled hypertension (defined as blood pressure >150mmHg systolic and/or >100 mmHg diastolic despite antihypertensive medication) or any history of hypertensive crisis or hypertensive encephalopathy.
18. Patients with a history of seizure within the past 2 years or those who require prophylactic anti-seizure medications are excluded.
19. History of loss of consciousness or transient ischemic attack within 12 months before study drug initiation.
20. Patients who have known active HIV, Hepatitis B, or Hepatitis C infections.
21. Patients with any other medical, psychiatric, or social condition, including substance abuse, which in the opinion of the Investigator would preclude safe participation in the study.