This study will test how effective the drug, Carfilzomib, reduces progression of prostate cancer in patients who have previously received chemotherapy and androgen inhibitors. Carfilzomib is approved for multiple myeloma but is not approved for prostate cancer. Therefore, it is considered investigational. Other approved methods of treatment for metastatic prostate cancer have demonstrated only modest benefits. Novel and tolerable agents are necessary to make further gains and extend overall survival.

First-line chemotherapy for metastatic castration-resistant prostate cancer (CRPC) combined with androgen inhibitors modestly extends overall survival. Carfilzomib is anticipated to enhance progression-free survival (PFS) as well as reduce pain and toxicities.

Proteasome inhibitors are promising agents used in the therapy of prostate cancer. Carfilzomib is a more potent and irreversible proteasome inhibitor than the frequently used proteasome inhibitor, Bortezomib. In Phase I trials Carfilzomib demonstrated substantial antitumor activity while exhibiting tolerable side effects.

Carfilzomib has been approved by the FDA for patients with multiple myeloma. The drug, however, is not approved for the use with CRPC patients. This trial will evaluate the tolerance and effectiveness of Carfilzomib in men with metastatic progressive CRPC following chemotherapy and androgen inhibitors.

Inclusion Criteria:

• Histologically proven adenocarcinoma of the prostate
• Metastatic disease
• Progressive disease (PSA, radiologic, symptomatic) following abiraterone acetate and/or Enzalutamide (prior sipuleucel-T and chemotherapy are allowed); PSA progression is defined as baseline increase followed by any PSA increase ≥1 week apart.
• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to one of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse if female partner of childbearing age.
• An elevated PSA level of >2ng/mL for patients progressing by PSA criteria is required (last confirmatory sample must be >2ng/mL)
• Currently on androgen ablation hormone therapy (a luteinizing hormone- releasing hormone (LHRH) agonist/antagonist or orchiectomy) with testosterone level <50ng/dL)
• Has an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 - 2
• Left ventricular ejection fraction (LVEF) ≥40% on 2-D transthoracic echocardiogram (ECHO); Multi-gated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
• ≥19 years of age
• Resolution of all acute toxic effects of prior chemotherapy or surgical procedures to NCI CTCAE Version 4.03 Grade <1, in the opinion of the treating physician.
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patient has a platelet count of <100,000/mm3, or absolute neutrophil count of <1500/mm3 or Hemoglobin <8.0gm/dL
• Patient has a calculated or measured creatinine clearance of <30 milliliters (mL)/minute
• Patient has total bilirubin >2 x upper limit of normal (ULN), or aspartate aminotransferase (AST), alanine aminotransferase (ALT) >3.5 x ULN
• Patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrollment
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Before study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant.
• Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the breast; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas.
• Known HIV, hepatitis B and hepatitis C infection
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization
• Prior treatment with bortezomib
• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize Carfilzomib)
• Has received prior radiation to >50% of the bone marrow
• Has had significant bleeding/thrombosis in previous 4 weeks
• Has received treatment with radiation therapy, surgery, chemotherapy, or an investigational agent within 4 weeks prior to registration, (6 weeks for radiation therapy, radionuclides, nitrosoureas, or Mitomycin C) or who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Has evidence of uncontrolled Central Nervous System (CNS) involvement (previous radiation and off steroids is acceptable)
• Patients may not be receiving any other investigational agents
• Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious infection
• Is unable to comply with study requirements
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.