This is a prospective, open-label, randomized, cross-over, pilot study of reprogramming therapy in patients with recurrent PCa based on rising PSA only. The primary objectives are to compare the disease progression-free rate at the end of 12 weeks of treatment between 5-AZA+ATRA and no therapy and to assess safety of the 5-AZA and ATRA combination. All study enrollees will receive Lupron. After one month, they will be assigned in a 1:1 randomization to either the '5-AZA+ATRA' group or the 'no therapy' group. Patients in the '5-AZA + ATRA' group will receive treatment on a 28-day cycle, in the absence of prohibitive toxicities, for 3 cycles. In the 'no therapy' group, patients will initially be observed for 3 cycles and then receive treatment for 3 cycles, in the absence of prohibitive toxicities. After the treatment period, all patients will be followed for up to 24 months from the start of the study or until the events leading to discontinuation are observed.

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate
• Rising PSA
• PSADT ≤ 10 months prior to initiation of ADT
• No evidence of regional or active distant metastases, except for regional metastasis where salvage radiation therapy is not an option
• Indication for ADT after receiving definitive local therapy
• Males ≥ 18 years.
• ECOG performance status of ≤ 2
• Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 90 days after completion of therapy
• Ability to understand and the willingness to sign a written informed consent
• Ability to adhere to the study visit schedule and requirements of the protocol

Exclusion Criteria:

• Patients who have received ADT and/or other chemotherapy within 3 months prior to entering the study.
• Patients who have had radiotherapy or surgery within 4 weeks prior to entering the study. Minimally-invasive procedures for the purpose of diagnosis or staging of the disease are permitted.
• Patients may not be receiving any other investigational agents.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-AZA and ATRA.
• 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.
• Significant active cardiac disease within the previous 6 months
• Inadequate organ and marrow function as defined below:
• leukocytes ≤ 3,000/mcL
• absolute neutrophil count ≤ 1,500/mcL
• platelets ≤ 100,000/mcl
• total bilirubin above normal institutional limits
• AST(SGOT)/ALT(SPGT) ≥ 2.5 X institutional upper limit of normal
• creatinine above normal institutional limits

Data collected during the course of this clinical trial will primarily be shared with other investigators and health system staff, the IRB, FDA, and other reporting agencies, and/or transferred to other collaborators. Prior to transfer, the data collected must comply with, and must be limited by, the MSH's guidelines for Protecting the Rights and Privacy of Human Subjects.

24 months

At the end of study completion. It will be available for 5 years.

24 months