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 abitererone, 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 adn 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