Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib (KHAD-L) in Prostate Cancer

Inclusion Criteria: * Patients with CRPC with metastatic bone disease. At least one site of metastatic disease must be amenable to a needle biopsy. Bone sites include lumbar vertebrae, pelvic bones and long bones. Excluded sites are thoracic, cervical vertebrae, skull and rib lesions * Patients may have had a number of previous hormonal therapies including ketoconazole and abiraterone, provided these were discontinued \>3 months before starting the trial * Patients may have had any number of previous cytotoxic therapies * Castrate resistant disease as defined by PSA working group. Patients must have a rise in PSA on two successive determinations at least one week apart and PSA levels 5ng/ml or greater and testosterone levels \<50 * Adequate renal, hepatic and bone marrow function as outlined in protocol * PTT\< 60, INR \<1.5NL unless on warfarin therapy * \> 6 month life expectancy * At least a 4 week interval from previous treatment other than LHRH analog and bisphosphonates. Patients on bicalutamide must have discontinued this medication for at least 6 weeks to be eligible * Patients receiving bisphosphonate can be maintained on this therapy * No major surgery or radiation therapy within 4 weeks * No strontium-89 or samarium-153 therapy within 4 weeks * ECG showing normal QT interval * No thromboembolism in past 6 months * Age \> 18 years * Investigator must check current patient medications against the list of CYP3A4 inhibitors and inducers prior to registration * Echocardiogram or MUGA demonstrating ejection fraction within institutional normal limits Exclusion Criteria: * No previous therapy with lapatinib * No previous therapy with ketoconazole within 3 months of starting trial * The use of complementary therapy directed at prostate cancer treatment excluding the following: green tea, commercial multivitamin preparations. Vitamin B complex, C, D, E and multivitamins are permitted if these are being taken at less than 3 times the RDA * The concomitant use of drugs known to be narrow therapeutic index CYP3A4 substrates are excluded * Drugs that are sensitive to CYP3A4 substrates are excluded * Patients taking drugs that may further prolong QT intervals and present a known risk for Torsades de Pointes are excluded. * Patients who have alcohol or drug dependence currently or in the last 6 months are excluded from this study * Any other events, other than those defined above, in the opinion of the investigator, may make the patient ineligible for this trial * No contraindication to biopsy such as bleeding disorders. Patients on anticoagulants such as warfarin must be able to safely stop the drug for a three-day period. Patients may not go on heparin during this time * No active malignancy other than skin cancer or superficial bladder cancer * Cardiac disease: congestive heart failure \> class II NYHA. Patients must no have unstable angina or new onset angina or myocardial infarction within the past 6 months. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Patients must have an ejection fraction within normal limits at the enrolling institution based on an echocardiogram * Uncontrolled hypertension defined as sustained BP \> 160 and diastolic \> 100 despite optimal medical management * Known HIV or chronic Hep B or C * Thrombolic or embolic events such as CVA within the last 6 months * Pulmonary hemorrhage or any bleeding event CTCAE Grade 2 or greater within 6 months of first dose of study drug of KHAD * Serious non-healing wound, ulcer, or bone fracture * Evidence of history of bleeding diathesis or coagulopathy * Major surgery or significant traumatic injury within 4 weeks of first study drug of KHAD