1. Castration-ResistantProstate Cancer (CRPC):AUA GuidelineMichael S. Cookson, MD, MMHCVice Chairman and Hart Professor of Urologic SurgeryVanderbilt University Medical CenterNashville, Tennessee

2. Header. Arial 48.Prostate cancer remains the 2nd leading cause of cancer deaths inAmerican menThis year alone, more than 28,000 men will die from prostate cancerHistorically, the median survival for men with mCRPC was less than2 yearsbut, we are beginning to impact on this and extend survivalThe recent surge of new treatment agents for men with mCRPC hasimproved survival, but unfortunately it remains an incurable diseaseScope of the ProblemSiegel R, et al: CA Cancer J Clin 2012; 62:10. 3. Header. Arial 48.Treatment Evolution2004:DocetaxelTannock et al.(TAX 327)2010:Cabazitaxelde Bono et al.(TROPIC)2010:Sipuleucel-TKantoff et al.(IMPACT)2011:Abirateronede Bono et al.(COU-AA-301)2012:EnzalutamideScher et al.(AFFIRM)2013:AbirateroneRyan et al.(COU-AA-302) Since the FDA approval of docetaxel, fouradditional agents with survival benefit have beenFDA approved based on RCTs While greater availability of effective agentsbenefits patients, multiple options andsequencing may complicate decision-making2003 2005 2007 2009 2011 2013 4. Header. Arial 48.Consistent with the AUA guideline methodology, acomprehensive systematic review of the publishedliterature on therapies for CRPC from January 1996through February 2013:5376 potential studies303 qualified included in the final analysisGuideline statements and a treatment algorithm wereformed based on this literature review.Systematic Review 5. Methodology: Rating of EvidenceStrength and QualityA Well conducted RCTs Exceptional observational studiesB RCTs and/or observationalstudies with some weaknessesC Observational studies that areinconsistent -difficult to interpret 6. Standard Benefits are >or< than the harms Level of evidence A or B Recommendation Benefits are >or< than the harms Level of evidence C Option Benefits = harms Level of evidence A, B, or CMethodology: Linking of Evidence toStatement Type 7. Header. Arial 48.To assist in clinical decision-making, six index patients weredeveloped representing the most common clinical scenarios thatare encountered in clinical practiceThese index patients were created based on the following:1. Presence or absence of metastatic disease2. Degree and severity of symptoms3. Patients performance status (ECOG scale)4. Prior docetaxel chemotherapyIndex Patients 8. Header. Arial 48.1. Asymptomatic non-metastatic CRPC and a rising PSA2. Asymptomatic or minimally symptomatic, metastatic (mCRPC)without prior docetaxel chemotherapy3. Symptomatic, mCRPC and no prior docetaxel chemotherapy withgood performance status4. Symptomatic, mCRPC and no prior docetaxel chemotherapy withpoor performance status5. Symptomatic, mCRPC and prior docetaxel chemotherapy withgood performance status6. Symptomatic, mCRPC and prior docetaxel chemotherapy withpoor performance statusIndex Patients 9. Header. Arial 48.Clinical AlgorithmStaging/ H&P/ImagingIndex Patient 1Index Patient 2Index Patient 3 Index Patient 4Index Patient 5Index Patient 6Non-metastatic CRPC and rising PSAMetastatic CRPCNo prior docetaxel Prior docetaxelAsymptomatic or mildlysymptomaticSymptomaticGood performance statusPoor performance statusGood performance statusPoor performance status 10. Header. Arial 48.Asymptomatic non-metastatic CRPCClinicians should recommend observation with continuedandrogen deprivation.(Recommendation; Evidence Level Grade C)Clinicians may offer treatment with first- generation anti-androgens (flutamide, bicalutamide and nilutamide) or first-generation androgen synthesis inhibitors (ketoconazole +steroid) to select patients who are unwilling to acceptobservation. (Option; Evidence Level Grade C)Index Patient 1 11. Header. Arial 48.Asymptomatic non-metastatic CRPCClinicians should NOT offer systemic chemotherapy orimmunotherapy to patients outside the context of a clinical trial.(Recommendation; Evidence Level Grade C)Index Patient 1 12. Header. Arial 48.Asymptomatic or minimally symptomatic,mCRPC without prior docetaxel chemotherapyClinicians should offer abiraterone + prednisone, docetaxel orsipuleucel-T to patients with good performance status. [Standard;Evidence Level Grade A (abiraterone) / B (docetaxel) /B (sipuleucel-T)]Clinical Principle: As there are no direct studies comparing the agentsto inform optimal sequencing, it is preferable to give the least toxicagent first and other considerations including ease of administrationIndex Patient 2 13. Header. Arial 48.Asymptomatic or minimally symptomatic,mCRPC without prior docetaxel chemotherapyClinicians may offer first-generation anti-androgen therapy,ketoconazole + steroid or observation to patients with goodperformance status and no prior docetaxel chemotherapy who donot want or cannot have one of the standard therapies.(Option; Evidence Level Grade C)Index Patient 2 14. Header. Arial 48.Symptomatic, mCRPC with good performancestatus and no prior docetaxel chemotherapyClinicians should offer docetaxel to patients with symptomatic,mCRPC with good performance status and no prior docetaxelchemotherapy. (Standard; Evidence Level Grade B)Clinicians may offer abiraterone + prednisone to patients withsymptomatic, mCRPC with good performance status and no priordocetaxel chemotherapy.(Recommendation; Evidence Level Grade C)Index Patient 3 15. Header. Arial 48.Symptomatic, mCRPC with good performancestatus and no prior docetaxel chemotherapyClinicians may offer ketoconazole + steroid, mitoxantrone orradionuclide therapy to patients who do not want or cannot have oneof the standard therapies. [Option; Evidence Level Grade C(ketoconazole) /B (mitoxantrone) / C (radionuclide therapy)]Clinicians should NOT offer treatment with either estramustine orsipuleucel-T. (Recommendation; Evidence Level Grade C)Index Patient 3 16. Header. Arial 48.Symptomatic, mCRPC with poor performancestatus and no prior docetaxel chemotherapyClinicians may offer treatment with abiraterone + prednisone topatients with symptomatic, mCRPC with poor performance status andno prior docetaxel chemotherapy. (Option; Evidence Level Grade C)Clinicians may offer treatment with ketoconazole + steroid orradionuclide therapy who are unable or unwilling to receiveabiraterone + prednisone. (Option; Evidence Level Grade C)Index Patient 4 17. Header. Arial 48.Symptomatic, mCRPC with poor performancestatus and no prior docetaxel chemotherapyClinicians may offer docetaxel or mitoxantrone chemotherapy topatients in select cases, specifically when the performancestatus is directly related to the cancer. (Expert Opinion)Clinicians should NOT offer sipuleucel-T to patients withsymptomatic mCRPC with poor performance status and no priordocetaxel. (Recommendation; Evidence Level Grade C)Index Patient 4 18. Header. Arial 48.Symptomatic, mCRPC with good performancestatus and prior docetaxel chemotherapyClinicians should offer treatment with abiraterone + prednisone,cabazitaxel or enzalutamide. If the patient received abiraterone +prednisone prior to docetaxel chemotherapy, he should beoffered cabazitaxel or enzalutamide. [Standard; Evidence LevelGrade A (abiraterone) /B (cabazitaxel) /A (enzalutamide)]Index Patient 5 19. Header. Arial 48.Symptomatic, mCRPC with good performancestatus and prior docetaxel chemotherapyClinicians may offer ketoconazole + steroid if abiraterone +prednisone, cabazitaxel or enzalutamide is unavailable.(Option; Evidence Level Grade C)Clinicians may offer retreatment with docetaxel to patients withmCRPC with good performance status who were benefitting at thetime of discontinuation (due to reversible side effects) ofdocetaxel chemotherapy. (Option; Evidence Level Grade C)Index Patient 5 20. Header. Arial 48.Symptomatic, mCRPC with poor performancestatus and prior docetaxel chemotherapyClinicians should offer palliative care to patients with mCRPC withpoor performance status who received prior docetaxel chemotherapy.Alternatively, for selected patients, clinicians may offertreatment with abiraterone + prednisone, enzalutamide,ketoconazole + steroid or radionuclide therapy.(Expert Opinion)Index Patient 6 21. Header. Arial 48.The following statements apply to all indexpatients:Clinicians should offer preventative treatment (e.g., supplementalcalcium, Vitamin D) for fractures and skeletal related events to CRPCpatients. (Recommendation; Evidence Level Grade C)Clinicians may choose either denosumab or zoledronic acid whenselecting a preventative treatment for skeletal related events formCRPC patients with bony metastases.(Option; Evidence Level Grade C)Bone Health 22. Staging/ H&P/ImagingIndex Patient 1Index Patient 2Index Patient 3 Index Patient 4Index Patient 5Index Patient 6 Clinicians should recommendobservation with continuedandrogen deprivation Clinicians may offer treatmentwith first- generation anti-androgens (flutamide,bicalutamide and nilutamide) orfirst-generation androgensynthesis inhibitors(ketoconazole+steroid) to selectpatients unwilling to acceptobservation Clinicians should NOT offersystemic chemotherapy orimmunotherapy outside thecontext of a clinical trialNon-metastatic CRPCMetastatic CRPCNo prior docetaxel Prior docetaxel Clinicians should offerabiraterone + prednisone,docetaxel systemicchemotherapy or sipuleucel-Timmunotherapy Clinicians may offer first-generation anti-androgentherapy, ketoconazole + steroidor observation to patients whodo not want or cannot have oneof the previously listed standardtreatments.Asymptomatic or mildlysymptomaticSymptomaticGood performance status Clinicians should offerpalliative care Clinicians may offertreatment withabiraterone + prednisone,enzalutamide,ketoconazole + steroid orradionuclide therapy Clinicians should NOT offersystemic chemotherapy orimmunotherapyGood performance statusPoor performance status Clinicians should offer docetaxel Clinicians may offer abiraterone+ prednisone Clinicians may offerketoconazole + steroid,mitoxantrone or radionuclidetherapy to patients who do notwant or cannot have one of thepreviously listed treatments Clinicians should NOT offertreatment with eitherestramustine or sipuleucel-T Clinicians may offer treatment withabiraterone + prednisone Clinicians may offer treatment withketoconazole + steroid orradionuclide therapy to patientswho are unable or unwilling toreceive abiraterone + prednisone Clinicians may offer docetaxel ormitoxantrone chemotherapy inselect cases, specifically whenperformance status is directlyrelated to the cancer Clinicians should NOT offersipuleucel-T Clinicians should offertreatment with abiraterone+ prednisone, cabazitaxel orenzalutamide; if the patientreceived abiraterone +prednisone prior todocetaxel chemotherapy,cabazitaxel or enzalutamideshould be offered Clinicians may offerketoconazole + steroid ifone of the previously listedstandard treatments isunavailable Clinicians may offerretreatment with docetaxelto patients who werebenefitting at the time ofdiscontinuation (due toreversible side effects) ofdocetaxel treatmentGuideline Statements on Bone Health for all Index Patients Clinicians should offer preventative treatment (e.g. supplemental calcium, VitaminD) for fractures and skeletal related events to CRPC patients Clinicians may choose either denosumab or zoledronic acid when selecting apreventative treatment for skeletal related events for CRPC patients with bonymetastasesPoor performance status 23. AcknowledgementsCRPC PanelMichael S. Cookson, MD (Chair)Adam S. Kibel, MD (Vice Chair)Philipp Dahm, MD, MHScChristine Engstrom, PhD, CRNP, AOCNStephen J. Freedland, MDMaha Hussain, MD, FACPDaniel W. Lin, MDWilliam T. Lowrance, MDWilliam K. Oh, MDDavid F. Penson, MDBruce J. Roth, MDMethodologyHassan Murad, MD, MPHOsama Altayar, MDMohammed Nabhan, MDAUA Guidelines Staff.AcknowledgementsFOR MORE INFORMATION, PLEASE ATTEND:Detection of Prostate Cancer & Castration-Resistant Prostate Cancer CourseMay 6, Noon-130pm San Diego Convention Center 6C