This phase II trial studies how well giving oxaliplatin and pemetrexed disodium together works in treating patients with refractory hormone-resistant prostate cancer. Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving oxaliplatin together with pemetrexed disodium may kill more tumor cells.

PRIMARY OBJECTIVES: I. To determine the response rate by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, prostate-specific antigen (PSA) response by the PSA Working Group criteria, and overall clinical benefit defined by summation of RECIST complete responses (CR) plus RECIST partial responses (PR) plus PSA PRs. SECONDARY OBJECTIVES: I. To determine time to progression in patients with hormone-refractory prostate cancer (HRPC) receiving oxaliplatin and pemetrexed. II. To describe the safety profile of this treatment. III. Pain response will be evaluated in an exploratory manner. IV. Undertake a pilot analysis of excision repair cross-complementing 1 (ERCC1) expression levels and polymorphisms, looking at their ability to predict response to platinum therapy. OUTLINE: Patients receive oxaliplatin intravenously (IV) over 2 hours and pemetrexed disodium IV on day 1. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.

Inclusion Criteria:

• Histologically confirmed prostate cancer
• Measurable disease on computed tomography (CT) or evaluable disease on bone scan with an elevated PSA
• For patients who did not initially present with metastatic disease, definitive treatment with either radical prostatectomy or external beam radiation is permitted
• Documented progression on (a) two prior hormone treatments AND (b) one or two chemotherapy regimens
• Documented progression on two prior hormone therapies is defined as orchiectomy followed by anti-adrenal medication upon progression OR gonadotropin-releasing hormone (GnRH) analog +/- androgen receptor blocker with addition or subtraction upon progression; castrate level of testosterone must be documented at study entry
• Documented progression on taxane-based chemotherapy; in addition, patients may have failed a second prior chemotherapy regimen
• Palliative radiation therapy for metastatic disease is allowed only if less than 25% of total body bone marrow was irradiated; 28 days must have elapsed since completion of radiation therapy (RT) with bone marrow recovery; soft tissue disease irradiated in the prior 2 months may not be designated as measurable disease
• ECOG performance score of 0-2
• Absolute neutrophil count (ANC) >= 1500/uL
• Platelet count >= 100,000/uL
• Creatinine clearance >= 45 mL/min
• Serum total bilirubin =<1.5 mg/dL
• Alkaline phosphatase =< 3x the upper limit of normal (ULN) for the reference lab (=< 5x the ULN for patients with known hepatic metastases) and no upper limit for patients with known bone metastases
• Serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT) =< 3x the ULN for the reference lab (=< 5x the ULN for patients with known hepatic metastases)
• Patients must be recovered from both acute and late effects of any prior surgery, radiotherapy or other antineoplastic therapy
• Patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial
• Men of childbearing potential must consent to use barrier contraception while on treatment and for 90 days thereafter
• Patients with pleural or peritoneal effusions are eligible
• Willingness and ability to take vitamin supplementation and steroid premedication as specified in protocol
• Patients with superficial bladder cancer or skin cancer who have second malignancy within 5 years which was removed with curative intent

Exclusion Criteria:

• Active infection or with a fever >= 38.5 degrees Celsius (C) within 3 days of the first scheduled protocol treatment
• Patients with brain metastases
• Prior malignancy within the past 5 years, except for curatively treated basal cell or squamous cell carcinoma of the skin or superficial bladder cancer
• Known hypersensitivity to any of the components of oxaliplatin or pemetrexed
• Received radiotherapy to more than 25% of their bone marrow, or patients who received any radiotherapy within 4 weeks of entry
• Received treatment with strontium
• Receiving concurrent investigational therapy or who have received investigational therapy within 30 days of the first scheduled day of protocol treatment
• Life expectancy < 6 months
• Peripheral neuropathy >= Grade 2
• Any other medical condition, including mental illness or substance abuse
• History of allogeneic transplant
• Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated, or both)
• Inability to stop nonsteroidal anti-inflammatory drugs (NSAIDS) for a period of 2 days before, the day of, and 2 days following administration of Alimta; 5 days before, the day of, and 2 days following administration of Alimta for long-acting NSAIDS