Matching Biology to Therapy Along the Path to AR Signaling in CRPC

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Matching Biology to Therapy Along the Path to AR Signaling in CRPC

Matching Biology to Therapy Alongthe Path to AR Signaling in CRPCCharles J. Ryan, MDUniversity of California, San FranciscoUC 1 SFUCSF


Matching Rx to BiologyPro-androgenic microenvironment …Intracrine androgen production …Androgen receptor (AR) amplification …Calls for “Anti-Androgen” therapy!


Presentation OutlineBiological EventTherapeutic InterventionDrugsAndrogenProductionSCC InhibitorsCYP 17 InhibitorsKetoconazole: genericAbiraterone: phase IIITak-700: phase ITok-001: phase IAndrogen Transport& CirculationBlock TransportHE-3235Conversion to DHT5-α Reductase InhibitorsSulfatase InhibitorsDutasteride / CombinationsBN-83495: sulfataseAR BindingNovel AR InhibitorsMDV-3100ARN-509Tok-001UC SF


Matching Biology to Therapy Along thePath to AR SignalingBiological EventTherapeutic InterventionAndrogenProductionSCC InhibitorsCYP 17 InhibitorsAndrogen Transport& CirculationConversion to DHTAR BindingUC SF


PituitaryAdrenal Androgen SynthesisACTHCholesterolKetoconazoleAdrenal CortexAbirateronedesmolasePregnenolone3-BHSD-IProgesterone DOC Corticosterone18OH-CorticosteroneAldosterone21-hydroxylase 11 -hydroxylase 18-hydroxylase 18-oxidase17 -hydroxylase17OH-pregnenolone17OH-progesterone 11-DOC Cortisol3-BHSD-IPeripheral TissuesC17-20 lyaseDHEA3-BHSD-IAndrostenedione Testosterone DHT17-keto-reductase5 -reductase


Both Ketoconazole and Abiraterone(CB7630) Inhibit CYP17Haidar S, et al. J Ster Biochem Molec Biol. 2003;84:555-562.


Abiraterone Acetate (AA) Phase II TrialsAttard G, et al, J Clin Oncol.2009;27:3742-3748.Pre-chemoRyan C, et al. J Clin Oncol.2010;28(15s). Abstract 4671.30% PSA decline – 90.0%50% PSA decline – 87.9%90% PSA decline – 48.5%Danila DC, et al. J Clin Oncol.2010;28:1496-1501.Post-chemoReid AH, et al. J Clin Oncol.2010;28:1489-1495.30% PSA decline - 68.1%50% PSA decline - 51.1%90% PSA decline - 14.9%7


PSA Response to AA in Patients WithPrior Ketoconazole50% PSA decline – 54.8%50% PSA decline – 45.2%Danila DC, et al. J Clin Oncol.2010;28:1496-1501.Ryan C, et al. J Clin Oncol.2010;28:1481-1488.


Androgen Levels at Time of ProgressionKetoconazoleAndrogens RiseAbirateroneAndrogens PlateauDHEADHEAAndrostenedioneTestosteroneAdapted fromSmall EJ, et al. J Clin Oncol. 2004;22:1025-1033. Ryan C, et al. J Clin Oncol. 2010;28:1481-1488.


AA 301 TrialPhase III DesignPatients• Progressive,metastatic CRPC• Failed 1 or2 chemotherapyregimens, one ofwhich containeddocetaxelRandomize 2:1Abiraterone1000 mg dailyPrednisone 5 mg BIDn = 797Placebo dailyPrednisone 5 mg BIDn = 398Efficacy endpoints (ITT)Primary endpoint:• OS (25% improvement;HR 0.8)Secondary endpoints:• PSA• Time to PSA progression• Radiographic progressionfreesurvival• Phase III trial at 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 PSAprogression)de Bono JS, et al. Ann Oncol. 2010;21(suppl 8). Abstract LBA5.Clinicaltrials.gov identifier: NCT00638690


Survival (%)AA 301 TrialOverall Survival10080HR = 0.646 (0.54-0.77) P < 0.0001Abiraterone acetate:14.8 months (95% CI: 14.1, 15.4)604020Placebo:10.9 months (95% CI: 10.2, 12.0)00 100 200 300 400 500 600 700Days From RandomizationAA 797 728 631 475 204 25 0Placebo 398 352 296 180 69 8 1


AA 301 TrialSubgroup Analysis of Overall SurvivalVariable Subgroup N HR 95% CIAll subjects All 1195 0.66 0.56-0.79Baseline ECOG 0-1 1068 0.64 0.53-0.782 127 0.81 0.53-1.24Baseline BPI < 4 659 0.64 0.50-0.824 536 0.68 0.53-0.85No. prior chemo regimens 1 833 0.63 0.51-0.782 362 0.74 0.55-0.99Type of progression PSA only 363 0.59 0.42-0.82Radiographic 832 0.69 0.56-0.84Baseline PSA above median YES 591 0.65 0.52-0.81Visceral disease at entry YES 709 0.60 0.48-0.74Baseline LDH above median YES 581 0.71 0.58-0.88Baseline ALK-P abovemedianYES 587 0.60 0.48-0.74Region North America 652 0.64 0.51-0.80Other 543 0.69 0.54-0.90BPI = Brief Pain Inventory.ALK-P, = alkaline phosphatase.FavorsAAde Bono JS, et al. Ann Oncol. 2010;21(suppl 8). Abstract LBA5.0.5 0.75 1 1.5FavorsplaceboClinicaltrials.gov identifier: NCT0063869012


AA 301 TrialSecondary EndpointsAA(n = 797)Placebo(n = 398)HR(95% CI)P ValueTTPP (months; 95% CI) 10.2 6.6 0.58(0.46, 0.73)< 0.0001rPFS (months; 95% CI) 5.6 3.6 0.67(0.59, 0.78)< 0.0001PSA response rateTotal 38.0% 10.1% < 0.0001Confirmed 29.1% 5.5% < 0.0001de Bono JS, et al. Ann Oncol. 2010;21(suppl 8). Abstract LBA5.Clinicaltrials.gov identifier: NCT0063869013


AA 301 TrialAdverse Event (AE) SummaryAA(n = 791)Placebo(n = 394)All treatment-emergent AEs 98.9% 99.0%Grade 3/4 54.5% 58.4%Serious AEs 37.5% 41.4%Grade 3/4 32.1% 35.3%AEs leading to discontinuation 18.7% 22.8%AEs leading to death 11.6% 14.7%All deaths within 30 days of last dose 10.5% 13.2%Underlying disease 7.5% 9.9%Other specified cause 2.9% 3.3%de Bono JS, et al. Ann Oncol. 2010;21(suppl 8). Abstract LBA5.Clinicaltrials.gov identifier: NCT00638690


TTTTAA 301 TrialWhy Prednisone?CholesterolLow-dose steroid replacement reducesmineralocorticoid-related toxicityNo PrednisonePrednisonePregnenolone Progesterone DOC CorticosteroneAldosteroneSALTMineralocorticoidsCYP1717α-hydroxylaseAbirateroneHTNLow K+17α-OHpregnenolone17α –OHprogesterone11-DeoxycortisolCortisolSUGARGlucocorticoidsCYP17C17,20-lyaseAbirateroneDHEA Androstenedione TestosteroneDHTSEXAndrogensEstradiolAttard G, et al. J Clin Oncol. 2008;26:4563-4571; Ryan C, et al. J Clin Oncol. 2010;28:1481-1488.


AA 301 TrialAEs of Special Interest (All Grades)AA(n = 791)Placebo(n = 394)Fluid retention 30.5% 22.3%Hypokalaemia 17.1% 8.4%LFT abnormalities 10.4% 8.1%Hypertension 9.7% 7.9%Cardiac disorders 13.3% 10.4%• Grade 3/4 hypokalemia: 3.8% of the AA group vs 0.8% of the placebo group• Grade 3/4 hypertension: 1.3% of the AA vs 0.3% of the placebo groupde Bono JS, et al. Ann Oncol. 2010;21(suppl 8). Abstract LBA5.LFT = liver function test.16


AA 302 TrialPhase III DesignProgressive metastatic,castrate-resistant prostatecancerWITHOUT prior docetaxelbasedchemotherapySymptomatic or mildlysymptomaticRANDOMIZEArm AAbiraterone plusPrednisoneArm BPlacebo plusPrednisoneEndpoints – PFS, Overall SurvivalClinicaltrials.gov identifier: NCT00887198


Additional Research Directions WithInhibitors of Androgen Production• What are the mechanisms of resistance?• Effect on intracrine androgen production?• Continue beyond progression (like other forms of ADT?)• Earlier disease stages?• Metastasis prevention• Initial ADT


Matching Biology to Therapy Along thePath to AR SignalingBiological EventTherapeutic InterventionDrugsAndrogenProductionSCC InhibitorsCYP 17 InhibitorsKetoconazole: genericAbiraterone: phase IIITak-700: phase ITok-001: phase IAndrogen Transport& CirculationBlock TransportHE-3235Conversion to DHT5-α Reductase InhibitorsSulfatase InhibitorsDutasteride / CombinationsBN-83495: sulfataseAR BindingUC SF


5-Alpha Reductase in RecurrentProstate Cancer• 5-alpha reductaseconverts– T to DHT in tumor– Androstenedione toandrostanedione• Result– Type 1 5-alphareductase increasesrelative to Type 2 inrecurrent prostatecancerN = 23N = 23N = 22Titus, et al. Clin Canc Res. 2005;11:4365-4371.20


Dutasteride as a Therapeutic?• Dual inhibitor of Type 1and Type 1 5 alphareductase (finasterideonly Type 2)• DFCI studies• KHAD – keto +dutasteride (0.5mg): Rxduration 8 months• Late addition of 0.5reduces PSA in pts withketo refractory disease• Approved drug for BPH at0.5 mg• Being tested in CRPC at3.5 mg• Multiple combination studiesunderway• Testosterone• Estrogen• “Off phase” of intermittent ADTTaplin ME, et al. Clin Canc Res. 2009;15:7099-7105; Sartor O, Clin Genitorurin Cancer. 2009;7:E90-E92.21


AR Overexpression is Frequent in Castrate-Resistant Tumors and is a Target for TherapyoPrimaryTumorsCastrationResistantScher HI, et al.Endocr RelatCancer. 2004;11:459-476.


The Amplified AR as a Drug TargetMDV-3100 andARN-509Both developed inmodel of ARamplificationMDV-3100: phase IIIARN-509: phase Ipending


AR Amplification is Common in LateStage CRPCGenome Topography> 90% of CRPC samplesshow AR amplificationLiu W, et al. Nat Med. 2009;15:559-565.At autopsy – 73% of15 samples exhibit ARamplificationFriedlander T, et al. 2010 Genitourinary CancersSymposium. Abstract 62.


MDV-3100A Second-Generation Antiandrogen• Engineered for activity in prostate cancer cellsthat overexpress the androgen receptor (AR)• Binds the AR more potently than bicalutamide• Unlike bicalutamide, MDV-3100 inhibitsnuclear translocation of the AR and its bindingto DNA• Induces apoptosis in prostate cancer cells


AR Antagonism With MDV-3100ToxicitiesScher HI, et al. Lancet. 2010:375:1437-1466.?? Class effect of drug??


MDV-3100 – PSA DeclinesScher HI, et al. Lancet. 2010:375:1437-1466.27


MDV-3100 Durability of ResponsesTime to progression based on:PSA rise > 25% from nadirProgression of PSArise > 25% frombaselineRadiologicprogressionScher HI, et al. Lancet. 2010:375:1437-1466.28


Decreased DHT Avidity WithMDV-3100 … AR Blocked?Cmin ss by DosePET withFluoro-dihydrotestosterone (FDHT)Percent Change inFDHT SUV max by Dose29Scher HI, et al. Lancet. 2010:375:1437-1466.


MDV-3100 Schematic of Phase III Trial DesignArm A• Progressive prostatecancer after docetaxelbasedchemotherapy• No prior abiraterone orketoconazoleRANDOMIZEMDV-3100Arm BPlacebo2:1 RandomizationPrimary Endpoint – Overall survivalSecondary aims – PFS and Pain controlClinicalTrials.gov Identifier NCT00974311


Directions for Next GenerationAR Inhibitors• Combinations with abiraterone?• Continue post-progression?• Replace castration?31


Non-Overlap IN MOA Suggests CombinationTherapy Could OccurAR Amplification andPersistenceCRPCIntratumor AndrogenProduction / conversionAnti-AndrogensMDV-3100ARN-509Persistent SerumAndrogens (eg,adrenals)AndrogenBiosynthesisInhibitorsAbirateroneTak-70032


Matching Biology to Therapy Along thePath to AR SignalingBiological EventTherapeutic InterventionDrugsAndrogenProductionSCC InhibitorsCYP 17 InhibitorsKetoconazole: genericAbiraterone: phase IIITak-700: phase ITok-001: phase IAndrogen Transport& CirculationBlock TransportHE-3235Conversion to DHT5-α Reductase InhibitorsSulfatase InhibitorsDutasteride / CombinationsBN-83495: sulfataseAR BindingNovel AR InhibitorsMDV-3100ARN-509Tok-001UC SF

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