DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate

• Progressive disease after androgen deprivation therapy, defined by 1 of the following:

  • Measurable progressive disease

  • No measurable disease AND meets 1 of the following criteria:

    • Elevated PSA with PSA level ≥ 2 ng/mL, rising on ≥ 2 consecutive occasions measured ≥ 2 weeks apart (if the third confirmatory PSA value is < the second value, then a fourth PSA value is required to document progression)
    • Positive bone scan with or without elevated PSA

• Demonstrates disease progression after antiandrogen withdrawal, as defined by 1 of the following:

  • Documented osseous or soft tissue progression
  • Two consecutive rising PSA values (obtained ≥ 2 weeks apart)

• Testosterone < 50 ng/dL

  • Must continue concurrent primary androgen deprivation with a luteinizing hormone releasing hormone analogue if no prior orchiectomy
• No large pleural or pericardial effusions
• No CNS (brain or leptomeningeal) metastases

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• Fertile patients must use effective contraception during and for 4 weeks after completion of study therapy (even if patient has undergone a prior successful vasectomy)
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8 g/dL
• ALT and AST normal
• Creatinine ≤ 1.5 times upper limit of normal
• Bilirubin normal
• PT/INR and PTT normal (unless on anticoagulants)
• Calcium normal
• No other malignancies within the past 5 years except curatively treated basal cell or squamous cell skin cancer, stage Ta transitional cell carcinoma of the bladder, or carcinoma in situ of the breast
• No serious, concurrent infection or nonmalignant medical illness, including uncontrolled autoimmune disorders
• No known contraindication to ketoconazole or lenalidomide
• No known hypersensitivity to thalidomide or its analogues
• No known positivity for HIV or infectious hepatitis type A, B, or C
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 4 weeks since prior cancer therapy, including radiotherapy and surgery
• At least 4 weeks since prior megestrol acetate, finasteride, any herbal product known to decrease PSA levels (e.g., saw palmetto or PC-SPES), or any systemic corticosteroids
• At least 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium) and recovered
• At least 6 weeks since prior bicalutamide or nilutamide
• At least 4 weeks since prior flutamide

• No prior systemic chemotherapy for prostate cancer

  • All other systemic chemotherapy must have been completed ≥ 5 years prior to study entry
• No prior ketoconazole, aminoglutethimide, or corticosteroids for treatment of progressive prostate cancer
• No prior immunotherapy including, but not limited to, vaccines, sargramostim (GM-CSF), thalidomide, and/or lenalidomide-like agents
• No prior lenalidomide
• At least 7 days since prior and no concurrent statin drugs (e.g., fluvastatin, atorvastatin, lovastatin, and simvastatin)
• At least 7 days since prior and no concurrent astemizole, terfenadine, cisapride, rifampin, or isoniazid
• More than 28 days since prior experimental drug or therapy

• No concurrent supplements or complementary medicines/botanicals, except for any combination of the following:

  • Conventional multivitamin supplements
  • Selenium
  • Lycopene
  • Soy supplements

• Concurrent bisphosphonates allowed provided the following criteria are met:

  • Patient is on a stable dose that shows tumor progression
  • No bisphosphonate therapy is initiated within 4 weeks of study entry

• Concurrent acetylsalicylic acid or warfarin allowed for deep vein thrombosis (DVT) prophylaxis provided the following criteria are met:

  • Daily acetylsalicylic acid is initiated on day 1 of study therapy
  • Patients with a history of DVT are on a stable-dose of warfarin
• No concurrent GM-CSF or other anticancer therapies, including radiotherapy, thalidomide, chemotherapy, immunotherapy, or other investigational agents

• No concurrent use of the following drugs:

  • Alprazolam
  • Diazepam
  • Temazepam
  • Triazolam
  • Midazolam
  • Ergot alkaloids
  • Pimozide