Treatment of Advanced Prostate Cancer: The Changing LandscapeWm. Kevin Kelly, DOProfessor, Medical Oncology and UrologyDirector, Division of Solid Tumor OncologyThomas Jefferson University

DisclosuresSanofi Aventis: Research support

Outline Evolving Biology of CRPCNovel Agents for the treatment of CRPCAndrogen Biosynthesis Inhibitors (ABIs)/novel anti-androgensAbiraterone, Enzalutamide (MDV-3100)Cytotoxics CabazitaxelImmunotherapiesSipuleucel-TBone\micro-environment directed therapiesAlpharadinPicking the right treatment for the right patients at the right time

Prostate Cancer: Growth Rate and ProgressionLife ExpectancyCancer ProgressionOnset ofCancerEarlyDetectionLocalizedDiseaseMetastaticDisease

Prostate Cancer DeathNaturalDeath

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Castration resistant:deaths from diseaseWith detectable metastases:deaths from cancer exceed that from other causes28,660186,320Non-CastrateAndrogen depletion / blockade (bicalutamide)Prostate Cancer Clinical States: A Framework for ClinicalPractice, Drug Development, and Biomarker Qualification

Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4. Docetaxel CRPCOverall SurvivalTAX 327

What to do when first line Docetaxel treatment fails?VS.Three years ago the choices were limitedPalliative Chemotherapy Phase I studyBeach

Understanding the Biology of CRPCDriver Pathways of Dependency of PCTomlins, S. A. Eur Urol 2009Taylor, B et al, Cancer Cell 2010Kong D. Cancer Sci 2008Jenkins, R. B. Cancer Res 1997Khor, L. Y. Clin Cancer Res 2007

Intratumoral Androgen Levels Are Increased Due ToOverexpression of The Androgen Synthetic EnzymesSteroid contentGerald et al, Amer J Pathol 164:217, 2004Montgomery et al. Cancer Res 68:4447, 2008Squaline Monoxygenase

Prostate Cancer: Adapting to castrate environmentPenning & Knudsen2010

Targeting the Androgen PathwayAndrogen Biosynthesis Inhibitors*Abiraterone AcetateTAK 700VN/124-1 (TOK-001)Novel Anti-Androgens*MDV3100RD 162EPI-001 (AR N-Terminal)SNARE-1 (selective nuclear receptor exporter-1)* FDA approved

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Hormonal Impact of AbirateroneLow-dose steroid replacement minimizes mineralocorticoid-related toxicity

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60Testosterone (by LC-MS/MS)01123456ng/dL1020Start of TreatmentAt Progression70DaysLower Limit of SensitivityDHEAStart of Treatment2856At ProgressionDays02.55.07.510.012.5Nmol/L0210.072856At ProgressionDaysStart of TreatmentAndrostenedionenmol/LEstradiol102030405060Days Post Treatment2.55.07.510.012.50mol/LAbiraterone Suppresses Steroids Downstream of C17,20-lyase: Proof-of-Concept Phase I TrialConfidential. For Internal Use Only. Do not distribute.

Phase II Trials of Abiraterone Acetate in Castration Resistant Prostate Cancer1Ryan et al. J Clin Oncol 2009; 27(suppl):245s (abstract 5046)2Reid et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5047)3Danila et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5048)

Patient populationNPSA decline 50%Tumor response(RECIST)ECOG PS Improvement(at least one level)CRPC: Chemotherapy nave13324 (73%)PR: 9 (27%)SD: 19 (58%)8 (61.5%)CRPC: Prior docetaxel24724 (51%)PR: 6 (13%)SD: 25 (53%)11 (35%)CRPC: Prior docetaxel3No prior ketoconazolePrior ketoconazole312716 (52%)8 (30%)(n = 18)PR: 3 (17%)SD: 11 (61%)16 (48%)

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COU-AA-301 Study DesignPhase III, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada)Stratification according to ECOG performance status (0-1 vs 2)Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present]) Prior chemotherapy (1 vs 2)Type of progression (PSA only vs radiographic progression with or without PSA progression)Abiraterone 1000 mg dailyPrednisone 5 mg BIDn=797Primary end pointOS (25% improvement; HR 0.8)Secondary endpoints (ITT)TTPPPFSPSA responseEfficacy endpoints (ITT)

Placebo dailyPrednisone 5 mg BIDn=398

R A N D O M I Z E D 2:11195 patients with progressive mCRPCFailed 1 or 2chemotherapy regimens, one of which contained docetaxelPatientsAbbreviations: ; BPI=Brief Pain Inventory; TTPP=time to PSA progression; ITT=intent to treat; mCRPC=metastatic castrate-resistant prostate cancer.Source: Clinicaltrials.gov identifier: NCT00638690.deBono N Engl J Med. 2011 May 26;364(21):1995-2005

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COU-AA-301: Abiraterone Acetate Improves OS in mCRPCHR=0.646 (0.54-0.77) P

Overall Study Design of COU-AA-302Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, CanadaStratification by ECOG performance status 0 vs 1

AA 1000 mg dailyPrednisone 5 mg BID(Actual n = 546)Co-Primary:rPFS by central reviewOSSecondary:Time to opiate use (cancer-related pain)Time to initiation of chemotherapyTime to ECOG-PS deteriorationTTPPEfficacy end points

Placebo dailyPrednisone 5 mg BID(Actual n = 542)

R A N D O M I Z E D

1:1Progressive chemo-nave mCRPC patients (Planned N = 1088)Asymptomatic or mildly symptomaticPatientsRyan et al. ASCO 2012

Statistically Significant Improvement in rPFS Primary End PointNR, not reached; PL, placebo.Data cutoff 12/20/2010.1008060402000Progression-Free (%)3691518125465424894003402041649012300AAPL4630Time to Progression or Death (Months)AA + PPL + PRyan et al. ASCO 2012

AA + P (median, mos): NRPL + P (median, mos): 8.3HR (95% CI): 0.43 (0.35-0.52)P value: < 0.0001

Strong Trend in OS Primary End Point546542538534482465452437272500524509503493021201062582374123871008060402000Survival (%)3121527Time to Death (Months)33AA + PPL + P6930242118AAPLUpdated GU ASCO 2013: Rathkopf et al. Abstract # 5-r PFS16.5 vs. 8.3 mo. HR 0.53 (0.45-0.62) p =

No New Safety Concerns Identified with Longer AA Treatment than in 301 StudyMost ALT and AST increases occurred during the first 3 months of treatmentRyan et al. ASCO 2012

AA + P(n = 542)%Placebo + P(n = 540)%All GradesGrades 3/4All GradesGrades 3/4Fatigue392342Fluid retention280.7241.7Hypokalemia172132Hypertension224133Cardiac disorders 196163 Atrial fibrillation41.350.9ALT increased125.450.8AST increased113.050.9

Subsequent Therapy Was Commonand Still a Survival Trend Observed*Prior to unblinding (e.g. not per protocol)Ryan et al. ASCO 2012

AA + P(n = 546) n (%)Placebo + P(n = 542) n (%) No. with selected subsequent therapy for mCRPC242 (44.3)327 (60.3)Docetaxel207 (37.9)287 (53.0)Cabazitaxel45 (8.2)52 (9.6)Ketoconazole39 (7.1)63 (11.6)Sipuleucel-T27 (4.9)24 (4.4)Abiraterone acetate*26 (4.8)54 (10.0)

TAK-700 (Ortoronel) in mCRPC: PSA Response and Safetyinhibit the enzyme 17,20-lyase 53% with PSA decreases 50% at 12 wksSerious AEs in 25 patients (26%): hypokalemia (n = 3), acute renal failure (n = 3), pneumonia (n = 2), urinary tract infection (n = 2), hypotension (n = 2), neutropenia (n = 2), fatigue (n = 2)Efficacy and tolerability demonstrated with TAK-700 administered with or without prednisone, suggesting feasibility of a steroid-free regimenX Previous ketoconazole therapyAgus DB, et al. ASCO 2011. Abstract 4531.27525022520017515012510025-25-7575500-50-100-125PSA Change at 12 Wks (%)xxxxX x xxxxxxxxX x xx x x x x x300 mg BID (n = 23)600 mg BID + prednisone (n = 26)400 mg BID + prednisone (n = 24)600 mg QDAM (n = 24)Treatment

Enzalutamide (MDV3100)Novel anti-androgensDevelopment of EnzalutamideBuilt of the scaffolding of the non-steroidal agonist RU59063Screened ~ 200 derivatives Derivatives were optimized RD162 and MDV3100Tran et al. Science 324:787-790, 2009

MDV3100 (Enzalutamide) Was Designed to Overcome Deficiencies of Available Anti-Androgens and Has Several Unique Mechanisms of Action and No Agonist EffectsEnzalutamide3TTCell nucleusInhibits Binding of Androgens to ARInhibits Nuclear Translocation of ARInhibits AssociationOf AR with DNAMDV3100 is an oral investigational drug rationally designed as a new hormonal agent to target androgen receptor (AR) signaling, a key driver of prostate cancer growth.

MDV3100 is the first in a new class of Androgen Receptor Signaling Inhibitors that affects multiple steps in the androgen receptor signaling pathway.

Cell cytoplasmTran et al. Science 2009;324:78790.

Bicalutamide vs. EnzalutamideEnzalutamide has a 5-8 fold increased affinity to AR than bicalutamide Enzalutamide does not have agonists effects in castrate resistant settingEnzalutamide suppressed growth and induced apoptosis in cells lines with AR gene amplicationsTran et al. Science 324:787-790, 2009

Anti-tumor activity if MDV3100 in castration-resistant prostate cancer: a phase 1-2 study Pre-chemotherapyN=65 Post-chemotherapyN=75Scher et al. Lancet 375:1437-1446, 2010

Grade 3-4 adverse events in >2 patients N (%)Adverse eventAll doses(n = 140) 240mg/day (n = 87)Fatigue16 (11%)5 (17%)Anemia 4 (3%)3 (3%)Arthralgia3(2%)2(2%)Seizure3 (2%)0

AFFIRM: Phase 3 Trial of Enzalutamide vs Placebo in Post-Chemotherapy Castration-Resistant Prostate Cancer (CRPC)*Glucocorticoids were not required but allowedASCO June 2012Tran et al. Science 2009;324:78790.

AFFIRM: Clinical OutcomesDe Bono et al. ASCO 2012

VariableEnzalutamide(800 pts.)Placebo(399 pts.)Hazard RatioP -valueOS(months)18.4 13.60.631

Favorable Adverse Risk Profile De Bono et al. ASCO 2012

All GradesGrades >3* Enzalutamide(n = 800)Placebo(n = 399)Enzalutamide(n = 800)Placebo(n = 399)AEs98.1%97.7%45.3%53.1%Serious AEs33.5%38.6%28.4%33.6%Discontinuations due to AEs7.6%9.8%4.6%7.0%AEs leading to death2.9%3.5%2.9%3.5%

All GradesGrade 3 EventsEnzalutamide(n = 800)Placebo(n = 399)Enzalutamide(n = 800)Placebo(n = 399)Seizure0.6%0.0%0.6%0.0%

rPFS PSA Association of PSA progression and rPFSde Bono JS et al. N Engl J Med 2011;364:1995-2005De Bono et al. ASCO 2012AFFIRMCOU-AA-301

Novel Agents Targeting the Androgen Pathway

AgentFunctionPhaseAbiraterone AcetateCYP 17 -hydroxylase\12,20-lyase inhibitorFDA approvedTAK-700CYP 17,20 lyase inhibitor-Phase IIIEnzalutamide (MDV3100)Anti-androgen\androgen receptor signaling inhibitor-Completed Phase III-Ongoing Phase III in non-castrate diseaseARN-509 Anti-androgen-Phase IIIAZD3514AR down-regulator\anti-androgen-Phase ITOK-001Anti-androgen\CYP 17 inhibitor-Phase I-IIEPI-001Anti-androgen\N-terminal Domain-pending clinical trials

CabazitaxelMicrotubule stabilizerDeveloped in docetaxel-resistant prostate cancer cell linesa favorable pharmacokinetic and safety profile decreased propensity for P-glycoprotein (Pgp)-mediated drug resistance. inhibited cell growth in a wide range of human cancer cell lines, including tumor models expressing Pgp.

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TROPIC Cabazitaxel vs Mitoxantrone

CRPCPD during or after docetaxelRANDOMIZECabazitaxel 25 mg/m2 Q 21 dPrednisone 10 mg dailyN=755MitoxantronePrednisone 10 mg daily146 Sites / 26 CountriesAbbreviation: PD=progressive disease.Source: deBono et al. Lancet. 2010;376:1147-1154.

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TROPIC Primary Endpoint OS (ITT Analysis)Number at RiskAbbreviation: ITT=intent-to-treat.Source: deBono et al. Lancet. 2010;376:1147-1154.Proportion of OS (%)

MP37730018867111 CBZP37832123190284

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Most Frequent Grade 3 Treatment-Emergent AEs**Sorted by decreasing frequency of events grade 3 in the CBZP arm.deBono et al. Lancet. 2010;376:1147-1154

MP (n=371)CBZP (n=371)All Grades (%)Grade 3 (%)All Grades (%)Grade 3 (%)Any AE88.439.495.757.4Febrile neutropenia1.31.37.57.5Diarrhea10.50.346.66.2Fatigue27.5336.74.9Asthenia12.42.420.54.6Back pain12.1316.23.8Nausea22.90.334.21.9Vomiting10.2022.61.9Hematuria3.80.516.71.9Abdominal pain3.5011.61.9

Immunotherapy Approaches in PCActive immunotherapytumor associated antigen is directly targeted by loading in that antigen in APC or into vaccine vector at protein or DNA levelAntigen specific immunotherapySipuleucel-TPoxvirus-based vectorsDNA based vaccines Passive immunotherapyAntibodies to specific receptors/antigensProstate Specific Membrane Antigen (PSMA)Immune Checkpoint InhibitorsStrategies to maintain activated tumor specific T-cells by neutralizing co-inhibitory receptors Anti-cytotoxic T lymphocyte protein 4 (CTLA 4) Ipilumimab, tremelimumabAnti- program death 1 (PD-1)MDX-1106

Patients white blood cells harvested Short-term culture with protein cassetteShippingGM-CSFProstatic acid phosphatase Active Cellular Immunotherapy(Sipuleucel-T)

Sipuleucel-T in Prostate CancerCheever and Higano., Clin Cancer Res 2011;17:3520-3526

Overall SurvivalStudy D9902BStudy D9902AStudyD9901Sip-TPlaceboSip-TPlaceboSip-TPlaceboMedian, Months

(95% CI)25.8

(22.8, 27.7)21.7

17.7, 23.8)19

(13.6, 31.9)15.7

(12.8, 25.4)25.9

(20.0, 32.4)21.4

(12.3, 25.8)Hazard Ratio

(95% CI)0.775

(0614,0.979)0.786

(0.484, 1.278)0.568

(0.388, 0.884)P0.0320.0100.331

CD54 is a surrogate marker of antigen presenting cell activationSerum cytokines or humoral responses by ELISA have limited utility

Second Generation Anti-PSMA Abs: J5912nd generation mAbsBind extracellular domainBind viable PSMA+ cellsRapidly internalizedMay be conjugated

Liu H et al. Cancer Res 1997; 57: 3629Liu H et al. Cancer Res 1998; 58: 4055Capromab binding siteJ591binding site

90% decline177Lu-J591 Rx: Excellent Targeting & PSA Response6 months99mTc-MDP bone scan 177Lu-J591 mAbPSADT=3.9 mo Ant Post Ant PostLog scaleArithmetic scale30/32 (94%) with accurate targeting of known sites of diseaseTagawa et al, ASCO 2008

Defining the Future:Ongoing Immumotherapy Trials

StudyPhaseStudyPopulationTreatmentOutcomePROTECTP-11IIINon-metastatic ADPC3 mo. ADT + Sip-T vs. controlPSADT,Distant Failure,OSNeoACTP07-1IILocalized PCSip-T x 3 prior to RPPost-op Boost vs. no BoostImmune response, SafetyProACTP07-2IIAsymptomatic or minimally symptomatic CRPC3 different dose levels of PA2024CD54 upreg.,Immune response,QOL, CTC, OSCornell 177Lu-J591IIHigh risk non-metastatic CRPCKetoconazole + hydrocortisone active 177Lu-J591PFS, OS, PSA, RECISTBMS CA 184043Ipi\ProstateIIICRPC post docetaxelXRT + Ipi vs. XRT + placeboOS, PFS, Pain, Safety

Radioisotopes Targets Bone MetastasesNaturally targets new bone growth in and around bone metastasesMost acts as a calcium mimic Strontium-89Samrarium-153Radium-223

Radium-223 (AlpharadinTM )Based on alpha emitter Radium-223ideal half-life of 11.4 daysExcreted via small bowelSafe and easy to produce, deliver and handleRange of alpha-particleRadium-223Encouraging Phase II results

AlphaBetaRelative particle mass70001Initial energy (MeV)3-80.01-2.5Range in tissue (m)40-9050-5000LET (KeV/m)60-2300.015-0.4Charge+2-1Ion pairs/m2000-70005-20DNA hits to kill cell1-5100-1000

TREATMENT 6 injections at 4-week intervalsRadium-223 (50 kBq/kg) + Best standard of carePlacebo (saline) + Best standard of careN = 922PATIENTSALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study DesignClinicaltrials.gov identifier: NCT00699751. Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs NoSTRATIFICATION

Planned follow-up is 3 years

ALSYMPCA Overall Survival0102030405060708090100 %Radium-223, n = 541Median OS: 14.0 monthsPlacebo, n = 268Median OS: 11.2 monthsHR 0.695; 95% CI, 0.552-0.875 P = 0.00185EORTC 2011

Month0369121518212427Radium- 22354145033021312072301530Placebo26821814789492815730

*In patients who had elevated total ALP at baseline.ALSYMPCA Secondary Endpoints: ALP and PSAEORTC 2011

Radium-223 n (%) Placebo n (%) P-value Total ALP response (30% reduction) 165 (43) 4 (3) < 0.001 Total ALP normalisation* 83 (33) 1 (1) < 0.001

Hazard ratio 95% CI P-valueTime to Total ALP progression0.163 (0.121 0.221) < 0.00001 Time to PSA progression 0.671 (0.546 0.826) 0.00015

ALSYMPCA Adverse EventsEORTC 2011

All GradesGrades 3 or 4Radium-223(n = 509) n (%)Placebo(n = 253) n (%)Radium-223(n = 509) n (%)Placebo(n = 253)n (%)Haematologic Anaemia136 (27)69 (27)54 (11)29 (12) Neutropenia20 (4)2 (1)9 (2)2 (1) Thrombocytopenia42 (8)14 (6)22 (4)4 (2)

Non-Haematologic Bone pain217 (43)147 (58)89 (18)59 (23) Diarrhoea112 (22)34 (13)6 (1)3 (1) Nausea174 (34)80 (32)8 (2)4 (2) Vomiting88 (17)32 (13)10 (2)6 (2) Constipation89 (18)46 (18)6 (1)2 (1)

Targeting the micro-environment

Bevacizumab (monoclonal VEGF)Sunitinib (TKI VEGF 1,2,3)Aflibercept (VEGF 1 and 2 domains fused to Fc portion IgG1VENICE Trial-completedLenalidomide (Immunomodulatory derivative of thalidomide)MAINSAIL TrialTasquinimod (quinolone-3-carboxamide)Cabozantinib (VEGFR2/MET inhibitor)Dasatanib (SRC inhibitor)

Cabozantinib, Dual MET/VEGFR TKI, vs Placebo in mCRPC*At progression, patients on placebo could cross-over to cabozantinib (n = 14).Lead-in StageCabozantinib100 mg/day PO(n = 171)Patients with mCRPC and measurabledisease; rising PSA only, not eligibleSD(n = 31)12 wksCabozantinib100 mg/day PO(n = 14)Placebo daily(n = 17)Until PD*RandomizationPR or CR(n = 79)Open-Label ExtensionCabozantinib100 mg/day POPD(n = 61)Discontinue cabozantinibHussain M, et al. ASCO 2011. Abstract 4516.

Cabozantinib vs Placebo in mCRPC: Efficacy and SafetyAuthors concluded that cabozantinib has substantial antitumor activity in progressive mCRPCDisease control at Wk 12: 68%Measurable disease regression: 74%Evidence of improvement on bone scan: 76%Pain improvement: 67%Moderate but manageable toxicity profile; similar to other TKIsHussain M, et al. ASCO 2011. Abstract 4516.-120102030405060PFS per mRECIST, Postrandomization (Wks)12-Wk Lead-in StageProportion Progression Free1.000.750.500.25Cabozantinib (n = 14) Placebo (n = 17)(HR 0.13; log-rank P = .0007)Median PFS, Wks 21 6

Phase III Trials for CRPC (First line chemotherapy trials)*Closed to accrual*Closed to accrualNo improvement of Survival

SponsorTreatment*NovaceaDocetaxel DN101*SWOGDocetaxel atrasentan*CALGBDocetaxel bevacizumab*Sanofi-AventisDocetaxel afliberceptNCIDocetaxel or KAVE Doxorubicin Strontium-89*Cell GenesysDocetaxel vs. GVAX*Cell GenesysDocetaxel GVAX*ZenecaDocetaxel zibotentan*BristolDocetaxel dasatinibOncGeneXDocetaxel Custirsen

OS Benefit in Recent CRPC Trials* Only 60% of these patients were post-docetaxel patients Would suggest the post-chemotherapy population remains heterogonous De Bono et al. ASCO 2012

Trial/Agent/ Date ApprovedMechanismComparatorSurvival(months)Hazard RatioP-valueAFFIRMEnzalutamide2012 Androgen Receptor Signaling InhibitorPlacebo18.4 vs. 13.60.631

Who is the right patient for which novel therapy?What is the optimal sequencing of these agents? Does it matter?How long do I give these agents?Why are patients still relapsing?

Multivariate Model: Higher Baseline Androgens Associate With Improved OS:Treatment effect: RobustLaboratory parameters: All significant (LDH, Hgb, ALP, PSA)

*Including 1 androgen at a time (dichotomized) and other lab parameters (dichotomized). Ryan et al Proc AACR 2012Baseline Serum Adrenal Androgens Are Prognostic and Predictive of Overall Survival in Patients With mCRPC: Results from the COU-AA-301 Phase 3 Randomized Trial

HRp ValueTestosterone0.667< 0.0001

HRp ValueAndrostenedione0.679< 0.0001

HRp ValueDHEA0.691< 0.0001

androgen\enzyme tissue levels(A) Pretreatment intense nuclear androgen receptor (AR) expression in combination with CYP17 expression in the bone marrowinfiltrating tumor of a patient with treatment duration more than 4 months.Efstathiou E et al. JCO 2012;30:637-643Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in BoneSerum Androgen Levels

Molecular characterization of CTCs in CRPC(N= 89 patients treated with Abiraterone)Attard, G. et al. Cancer Res 2009;69:2912-2918CTC collected by Immunicon system57% had CTC 4 (40% chemo nave; 82% Docetaxel treated)ERG rearrangement was associated with magnitude of PSA decline on abirateroneConcordance in ERG gene status of CRPC tumor biopsy and CTCs Heterogeneity in AR copy number and PTEN loss noted

The RB loss signature should be developed as a metric to direct therapeutic intervention for CRPCFeb 2011:Gene Chip to readout for RB function & other key prostate-specific markers generated & validatedSharma et al, J. Clin Investigation

A phase II multicenter trial combining Cabazitaxel and Abiraterone Acetate in treatment of metastatic Castration Resistant Prostate Cancer (Knudsen\Kelly) RB Prostate SignatureAndrogen ProfilesTestosteroneAndrostenedioneDHEAConducted in PCCTC

The Changing Landscape in Prostate Cancer Therapies with a Clinical BenefitNeed for biomarker driven trials to direct patient treatment

17 hydrolase/17, 20 lyase inhibitor Abiraterone, TAK 700Anti-angiogenic/immunomodulatoryCC-4047,Lenalidomide, ABR-215050, cediranib, AS1404Anti-CTLA4\PD-1 antibodyIpilimumab, MLN2704Anti-CCL2CNTO 888Anti-FGFR3TKI 258Anti-Il-6 antibodyCNTO 95Anti-insulin-like GFR antibodyIMC-A12Anti-integrin anti-bodyCNTO 95Anti-PSMA immunoconjugateMLN2704, 177 Lu-J591Anti-prostate stem cell antibodyAGS-PSCAAnti-VEGFBevacizumab, AlfiberceptCytotoxic agentABT-751, abraxane, E7389, SB-715992, carbazitaxelIrofulven, Paclitaxel poliglumex, TPI 287, E7389Clusterin inhibitorOGX-11EGFR antibodies\TKIPertuzumab, Cetuximab, Erlotinib, Gefitnib, Faranesyl protein transferase inhibitorR115777GMP phospodiesterase inhibitorExisulindHSP-90 inhibitor17-AAG, IPI-504HDACiLBH589, Vorinostat, Belinostat, SB939HGF inhibitorAMG 102Hypoxia activated pro-drugTH 302IGF inhibotorsCitutumumab, figitumumab, octreotide, pasireotideIntegrin receptor antagonistCilengitideIl-11 inhibitorBMTP-11JAK inhibitorINCB-18424M-TOR inhibitorTemsirolimus Multi-targeted TKISunitinib, Sorafenib, CEP 701, vatalinib, DMXAAMMP-9 inhibitorPCK 3145Pro-apoptotic agentAT-101Proteosome InhibitorBortezomibRANKL inhibitorDenosumabSRC kinase inhibitorKX2-391Signal Transduction inhibitorPCK-3145Survivin suppressantYM155

Novel Agents in CRPC

Phase I Trial of Weekly Cabazitaxel with Concurrent Intensity Modulated Radiation Therapy and Androgen Deprivation Therapy for the Treatment of Locally Advanced High Risk Adenocarcinoma of the Prostate.- LinA Phase II Study of Cabazitaxel in Patients with Urothelial Carcinoma Who Have Disease Progression Following Platinum-Based Chemotherapy. -HoffmanPhase I Trial of High Dose Rate Brachytherapy Combined with Stereotactic Body Radiation Therapy for Intermediate Risk Prostate Cancer Patients.-DenA Pilot Phase II Study of Digoxin in Patients with Recurrent Prostate Cancer as Evident by a Rising PSA.-LinA Multi-Institutional Translational Clinical Trial of Disulfiram in Men with Recurrent Prostate Cancer as Evident by a Rising PSA.-LinA Phase I/II multicenter trial combining Cabazitaxel and Abiraterone Acetate in Treatment of Metastatic Castration Resistant Prostate Cancer. -Kelly A Phase I/II Study of MLN8237 in combination with Abiraterone for patients with castration- resistant prostate cancer after progression on Abiraterone.-LinGU-Investigator Initiated Trails at KCC

Genitourinary Oncology TeamMedical OncologyJean Hoffman-Censits, MDJianqing Lin, MDGwen Slakind, RNDiane Woodford, APRNRadiation OncologyAdam Dicker, PhD, MDRobert Den, MDMark Hurwitz, MDUrologyLenny Gomella, MDEdouard Trabulsi, MDCostas Lallas, MDPathologyPeter McCue, MDRuth BirbieClinical Trials Office\Data CollectionMonica ByrnesChristine HubertsBrooke KennedyDeborah Kilpatrick, RNZachary FoerstBasic ScienceAllessandro Fatalis, MDKaren Knudsen, PhDLucia Languino, PhDMarja Nevalainen, PhDEric Wickstrom, PhDAdministrative SupportTeresa BryantBeth Schade

Thank You

****07/12/09*Driver mechanisms refer to cancer genes that undergo statistically significant mutation frequencies in large scale sequencing analysis and confer a and tumors become dependent on this alteration for survival and proliferation

Genetic Dependency of PC Progression is a more broad term that does not require Driver mutation in an oncogene but have deletions or and/or loss of expression of TSG such as PTEN which causes dependency of tumors on the PI3Kinase activation which is equivalent to oncogene activation. In this case the AR could serve such function.

Many driver events are not present at high frequency or are recurrent.

It is unclear which fraction of driver mechanisms are operant in any given tumor are the due to structural gene alterations as opposed to epigenetic or other regulatory mechanisms and therefore while driver mechanisms, i.e. mutations of a given genes may be low, when considered at the family or molecular pathway level the frequency may be much higher (AR??).*******This was a Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study conducted at 147 sites in the United States/Europe/Australia/Canada comparing the efficacy and safety of abiraterone acetate plus prednisone with placebo plus prednisone in men with metastatic CRPC who had failed 1 or 2 chemotherapy regimens, one of which contained docetaxel. Subjects were randomized in a 2:1 ratio to receive abiraterone acetate plus prednisone or placebo plus prednisone, respectively, and were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2), worst pain over the past 24 hours on The Brief Pain Inventory (BPI)-Short Form (0-3 [absent] vs. 4-10 [present]), prior chemotherapy regimens (1 vs. 2), and type of progression (PSA only vs. radiographic progression with or without PSA progression). Subjects could receive treatment until documented disease progression (of all 3 types including 1) PSA progression, 2) radiographic progression and 3) symptomatic or clinical progression) or unacceptable toxicity.Efficacy analysis set: ITT (intent-to-treat). Primary efficacy endpoint: Overall survival (OS).Secondary efficacy endpoints: prostatespecific antigen (PSA) response rate, time to PSA progression, and radiographic progression-free survival (R_PFS).*

*****I want to move now to look at TAK-700 or orteronel, which is the second in a line of development of androgen biosynthesis inhibitors. This drug is interesting because it may have the potential for administration without corticosteroids and in the data presented here you can see that the PSA responses at 12weeks are impressive: 53% of patients achieved a 50% reduction in PSA by that time. There was a range of adverse events, but the schematic and waterfall plots show the sequence of responses based on PSA change at 12weeks for different doses. So, the first one, in blue, shows TAK-700 300mg twice a day with no prednisone; the second one shows 400mg twice a day with prednisone; in the orange, 600mg twice a day with prednisone and then in the yellow 600mg daily in the absence of prednisone. And so from that perspective it appears that the drug can be dosed, at least with a PSA effect, without the addition of prednisone and that may provide an advantage over and above abiraterone, which does appear in the majority of cases to require steroid.The other point here is that responses were seen in patients that had had prior ketoconazole and whether thats consistently the case will require further follow-up.

AE, adverse event; CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen*Consider revision bullet 2 to remove new class****TROPIC slide deck. Slide21*TROPIC slide deck. Slide34*The next schematic demonstrates the sipuleucel-T active cellular immunotherapy process in which patients have a leukapheresis and have their white cells harvested. Theyre then sent to a processing plant for short-term culture with a protein cassette that incorporates prostatic acid phosphatase and GM-CSF. Once stringency standards are met and theres a cellular activation that indicates an immune response the product is then shipped back to the infusion center where its given to the patient over about an hour.

GM-CSF, granulocyte macrophage colony stimulating factor; IV, intravenous**Added Kantoff NEJM referenceDefine controlAdded NEJM reference*Sensitivity analyses were performed in a number of patient subgroups to test the robustness of the survival results in the pivotal trialThe results of these analyses show that the positive effect of PROVENGE on survival was consistent across multiple subgroups of patientsHazard ratios to the left of 1 favor the PROVENGE group vs control groupThe horizontal line represents the 95% confidence intervalThe differences in treatment effect for many of these subgroups are not statistically significant

ReferenceKantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castrationresistant prostate cancer. N Engl J Med. 2010;363:411-422.

***Earlier I mentioned cabozantinib, also called XL-184. This is a dual Met VEGF receptor pathway tyrosine kinase inhibitor and this drug was evaluated in a large phaseII experience led by Drs.DavidSmith and MahaHussain at the University of Michigan. The design of this study was to evaluate response to the drug and then to select a group of patients who had stable disease for a randomized discontinuation design. In this study, 171patients were accrued. They had to have castrate-resistant disease that was in some way measurable or assessable with either CT or a bone scan. They could not go onto the study if they had only PSA rising disease. Seventy-nine patients achieved a partial or complete response. Thirty-one of the patients had stable disease at the end of the initial 12-week run-in period and these were randomized to receive either ongoing cabozantinib or placebo until progression; 61 of the 171patients had progressive disease.

*The patients that continued on cabozantinib in the randomized discontinuation design had a much better control of disease with a median progression-free survival of 21weeks compared to those that went on to placebo with a median progression-free survival of 6 weeks. There were other markers of significant activity seen in this study. Most particularly, the disease control rate at Week12 was 68% and measurable disease regression was seen in 74%, with improvement in bone scans in three quarters of the patients and two thirds of the patients reported improved pain. Just to focus on the bone scans which are shown in this schematic, theres a series of bone scans here from patients that have either had docetaxel previously or not and each of these scans showed major responses, in fact normalization in a number of cases of what was originally a very abnormal bone scan. Importantly, this normalization was characterized by marked improvement in pain and so is not likely to be simply an epiphenomenon where the bone scan is turned off to no clinical benefit and this will be pursued in subsequent planned phaseIII studies. There is moderate to manageable toxicity. Some patients experienced diarrhea and severe lethargy similar to other tyrosine kinase inhibitors and the majority of our experience in this area comes from renal cell cancer where we routinely use tyrosine kinase inhibitors and have to manage the side effects. Whether cabozantinib will have unique side effects and whether therell be unique side effects in this population is something that we have to determine.

*(A) Pretreatment intense nuclear androgen receptor (AR) expression in combination with CYP17 expression in the bone marrowinfiltrating tumor of a patient with treatment duration more than 4 months. (B) Pretreatment CYP17 expression in tumor is correlated with increased bone marrow aspirate (BMA) plasma testosterone (T) concentration in 19 cases with paired samples. MS, mass spectrometry.**