Inclusion Criteria:

• Males ≥18 years;
• Written informed consent/authorization;
• Histological or cytological confirmation of metastatic prostate cancer with documented progression on hormonal therapy (objective progressive disease [PD], new bone lesions, or stable soft tissue or bone lesions with PSA increase);
• Patients must have either measurable disease or bone metastasis. Patients with measurable disease are preferred;
• Rising PSA, with a minimum study entry PSA of ≥5 ng/mL;
• Karnofsky performance status of ≥80%;
• Life expectancy of >12 weeks;
• For patients treated with anti-androgens, elevation of PSA must be demonstrated after cessation of anti-androgen treatment;
• Three lines of hormonal therapy are permitted prior to study entry (anti-androgen withdrawal is not considered as a second hormonal treatment);
• Serum testosterone level of <50 ng/mL in patients without surgical castration;
• Patients must have serum potassium levels >4.0 mEq/L and serum magnesium levels >2.0 mg/dL.

Exclusion Criteria:

• Concomitant use of any anti-cancer therapy, except for continued use of luteinizing hormone-releasing hormone (LHRH) agonists or antiandrogens, or bisphosphonates or steroids initiated at least 4 weeks prior to study entry;
• Concomitant use of any investigational agent, including PC-SPES;
• Use of any investigational agent within 4 weeks of study entry;
• Concomitant use of warfarin (due to a potential drug-to-drug interaction with depsipeptide);
• Major surgery within 2 weeks of study entry;
• Prior treatment with chemotherapy;
• Patients with known cardiac abnormalities such as:
• Congenital long QT syndrome;
• QTc interval > 480 milliseconds;
• Patients who have had a myocardial infarction within 12 months of study entry;
• Patients who have a history of coronary artery disease (CAD) e.g., angina Canadian Class II IV (see Appendix K). In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
• Patients with an ECG recorded at screening showing evidence of cardiac ischemia (ST depression of ≥2 mm). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
• Patients with congestive heart failure that meets NYHA Class II to IV (see Appendix J) definitions and/or ejection fraction <40% by MUGA scan or <50% by echocardiogram and/or magnetic resonance imaging (MRI);
• Patients with a history of sustained VT, VF, Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
• Patients with hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes (in doubt, see ejection fraction criteria above);
• Patients with uncontrolled hypertension i.e., ≥160/95;
• Patients with any cardiac arrhythmia requiring anti-arrhythmic medication;
• Concomitant use of medications which may cause a prolongation of QT/QTc (see Appendix D) interval;
• Concomitant use of medications that are inhibitors of the cytochrome P-450 isoenzyme CYP 3A4 (see Appendix E);
• Clinically significant active infection;
• Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C;
• Previous extensive radiotherapy involving 30% of bone marrow (e.g., whole of pelvis, half of spine);
• Clinical or radiological imaging evidence of brain metastasis (computed tomography [CT] or MRI scans are required only if brain metastasis is suspected clinically);

• Inadequate bone marrow or other organ function, as evidenced by:

  • hemoglobin <9.0 g/dL (transfusions and/or erythropoietin are permitted);
  • absolute neutrophil count (ANC) ≤1.5 x 109 cells/L;
  • platelet count <100 x 109 cells/L;
  • total bilirubin >1.25 x upper limit of normal (ULN) for institution or >2.0 x ULN in the presence of demonstrable liver metastases;
  • aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) >2.0 x ULN or >5.0 x ULN in the presence of demonstrable liver metastases;
  • serum creatinine >2 mg/dL;
• Serum potassium levels < 4.0 mEq/L and serum magnesium levels <2.0 mg/dL;
• Coexistent second malignancy or history of prior malignancy within previous 5 years (excluding basal or squamous cell carcinoma of the skin that has been treated curatively); or
• Any significant medical or psychiatric condition that might prevent the patient from complying with all study procedures.