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