Prostate 101

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  • Dr. Gleason: Pathologist from Minnesota who pulblished a morphometric scale of PC grading
  • T1a incidental TURPT1c indicental PSAT2 palpableT3 ECE/SVIT4 Adjacent organs*Not everyone does LND*T score imperfect measure of dz: ie T1C Gleason 9 6 cores versus Gl 6 1 core
  • Enzyme liquifies semenInitially described in the forensic literatureMay have a role in local activation of GF at metastatic sitesPre and post DRE bx: change in value 0.04
  • • PSA density is used to help differentiate between cancer and BPH in men with moderately high PSA levels (4 to 10 ng/mL) and normal DRE results. Cancer causes a greater elevation in PSA per prostate volume than BPH -- which means PSA density should be higher in men with cancer. To find PSA density, doctors divide the PSA results by prostate volume (as estimated by transrectal ultrasound). This method is imperfect, but studies showing that PSA density levels over 0.15 indicate a high risk of cancer have led doctors to use PSA density tests for men with PSA levels between 4 and 10 ng/mL.• PSA velocity monitors changes in PSA over time. PSA levels rise more rapidly in men with prostate cancer than in other men. To be most effective, PSA should be measured at least three times over a two-year period to calculate PSA velocity. Research has found that about 70% of men with a PSA velocity of 0.75 ng/mL or greater have cancer when PSA is 4 to 10 ng/mL. But only about 50% of men with a PSA velocity below 0.75 ng/mL per year have cancer. The test is used primarily to determine the need for a repeat biopsy in those with PSA levels between 4 to 10 ng/mL and a prior negative biopsy.• Age-specific PSA levels have been suggested for younger men, because PSA levels usually rise with age. Thus, while 2 ng/mL may be normal in a 60-year old, this level is more likely to signify cancer in men between ages 40 and 49. Since research has yet to show that using age-specific PSA values will increase the detection of curable cancers, for now the standard cut-off of 4 ng/mL is still considered preferable for men between age 50 and 70.• Percent free PSA is the ratio of free (unbound) PSA to bound (attached to proteins) PSA in the blood. Men with prostate cancer have a lower percent free PSA than men without cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL.
  • 60-70% of all PC diagnosed >70 yoIn an aging population, the implications of detecting and diagnosing all prostate cancers is clear68 life expectancy 14.5-16.3 yrs; may die of other causes
  • The use of HT in PC was pioneered by Huggins et al in 1941 when they:he proved that administration of the female hormone estrogen slowed the growth of prostate cancer in males."the Huggins operation" -- castration -- for particularly advanced cases. Dr. Huggins, in collaboration with his students Clarence V. Hodges and William Wallace Scott, published three papers in 1941 that demonstrated the relationship between the endocrine system and the normal functioning of the prostate gland. The regression and the consequent relief of pain was often spectacular and occurred within days or sometimes even hours after treatment. Four of Dr. Huggins' original 21 hormone-therapy patients lived for more than 12 years after treatmentPalliation, relief of urinary symptoms, concomitant decline in acid phosphatase.
  • 9 % relative risk of death with intermittent therapyHowever upper limit of 95% CI was > 1.24 (more than the prespecified threshold of 1.2). SO OS with IT was NOT NON-INFERIOR to CONTINUOUSSurvival much better than 3 yrs expected so it took longer to observe the number of deaths required for the final analysis hence the longer duration
  • (1) AR is bound to the molecular chaparone HSP90 which prevents its degradation. HSP90 inhibitors, such as 17-AAG, cause AR degradation and decrease AR levels. (Dave Solit)(2) In men treated with GnRH agonists to shut down testicular androgen synthesis, residual serum androgens are synthesized by the adrenal glands. In additional, evidence suggests intratumoral androgen synthesis. Both can be inhibited by the nonspecific p450 inhibitor ketoconazole and the 17-lyase inhibitor abiraterone.(3) Testosterone is converted to the more potent dihydrotestosterone (DHT) by 5α-reductase, which is inhibited by finasteride and dutasteride. (Morris)(4) Ligands, such as DHT bind to AR and this is inhibited by antiandrogens such as bicalutamide and novel agents MDV-3100 and BMS641988. Mutation of AR as well as AR overexpression can convert endogenous steroids (e.g. progestins, estrogens, and corticosteroids) and some antiandrogens into agonists. MDV-3100 was designed to suppress AR function even when AR is overexpressed. (5) Activation of receptor tyrosine kinases, can lead to downstream AR activation. Two downstream kinases that directly phosphorylate AR on tyrosine are Ack1 and SRC. Other downstream pathways of receptor tyrosine kinases, including the AKT and MAP kinase pathways, are also implicated. Antibodies such as trastuzamab and pertuzumab and small molecular TKI inhibitors such as erlotinib and lapatinib target HER2. Dasatinib targets SRC. (6) Proper transcription mediated by AR requires the proper chromatin state. HDAC inhibitors inhibit transcription of AR target genes by the disruption of chromatin structure and inhibition of recruitment of coactivators and RNA polymerase II.
  • First time a hormone used post-chemo with a survival benefit. AR STILL RELEVANT.
  • The Kaplan Meier curve for the co-Primary endpoint of rPFS is shown here. The radiographic Progression Free Survival (rPFS), as assessed by independent radiologic review in the AA/Prednisone arm had not yet been reached and was 8.3 months in the Placebo/Prednisone arm, associated with a Hazard ratio of 0.43 (95% Confidence Interval 0.35-0.52) P<0.0001.
  • The Kaplan Meier plot for the Co-Primary endpoint of Overall Survival is shown here.the Median survival in the Prednisone control arm is 27.2 months while the median survival has not yet been reached in the Abiraterone arm., This conforms to a Hazard ratio of 0.75 and a p value of 0.0097 -A strong statistical trend in favor of AAThe prespecified p value for significance of OS at 43% of events is 0.0008 by the O’Brien-Fleming boundary (as implemented in the LanDemets alpha-spending method).
  • Taken in aggregate,AA proved favorable across a broad spectrum of clinical outcomes including: delay progression, improve survival, maintain QOLAs clinical oncologists charged with providing safe and effective treatment to our patients, these findings merit consideration of providing a new approach to a population in need of treatment with less toxicity.
  • Confocal microscopy
  • KETO: PRE 55/77 (71%) VS POST 23/63 (37%) This set the stage not just for using MDV3100 in CRPC post-chemo pts previously assumed tobe refractory, but also abiraterone.
  • >90% bone metsCurrently approved radiopharmaceuticalsdealy SRE but do not effect survivalAlkaline earth metals- taken up in bone
  • Sx= any analgesic or palliative RT within 12 weeks (even if rendered pain free)
  • Consistent across all subgroups: Doc, Bisphos,
  • Heme: Modest increase grade ¾ thrombocytopeniaExcretion: GI
  • Potent oral TKIInhibits MET and VEGFR2Randomized discontinuation trial of cabo inmCRPC
  • Majority tox grade 1 or 2
  • Prostate 101

    1. 1. Dana Rathkopf, MDGenitourinary Oncology ServiceMemorial Sloan Kettering Cancer CenterProstate Cancer 101The following material is intended for MSKCC internal medicine housestaff teaching purposes only. Theslides are courtesy of Dr. Dana Rathkopf and were updated for the LibGuide in 2012-2013.
    2. 2. Jemal, A. et al. CA Cancer J Clin 2010Estimated New Cancer Cases and Deaths, US, 2010
    3. 3. ANATOMY
    4. 4. Gleason Grading SystemCEA,Chromogranin APSAImage: Chris Pearson
    5. 5. Iyer Cancer 1999Simone Kaiser: Identification and Characterization of the Ion Channel TRPM8 in Prostate Cancer
    6. 6. Risk Factors for Prostate Cancer• Age– Less than 10% diagnosed in men <54 years– 64% diagnosed between 55-74 years• Ethnicity:– BM 68% higher incidence, 158% higher mortality• Dietary Fat:– Increased relative risk by a factor of 1.6 to 1.9• Family History:• 5-10% of all patients have family history• Relatives of patients younger than 55 years have greater risk• 1 relative = 2x lifetime risk, >= 2 relatives = 4x lifetime risk• At least 8 candidate susceptibility genes have been reported
    7. 7. Prostate Specific Antigen (PSA):An Imperfect Tool• Glycoprotein secreted by the prostate• ORGAN specific (not cancer-specific)• Sensitivity 70-80% and PPV 30% when PSA is‘normal’ (< 4)• Does not inform grade , and may lead to detection andtreatment of indolent disease• Influenced by biologic variations, age, prostate volume,inflammation, race/ethnicity• NOT influenced by DRE or ejaculation
    8. 8. Improving the use of PSA for Detection• PSA density: >0.15 suggestive of PCCA causes a greater elevation in PSA /volume than BPH• PSA velocity: >0.75 ng/ml/yr suggestive of PC• Percent free PSA: <25% suggestive of PCCA related PSA is bound to α-glycoprotein• Age specific PSA: <2.5 ng/ml 40-49 yo3.5 ng/ml 50-59 yo4.5 ng/ml 60-69 yo6.5 ng/ml 70-79 yo
    9. 9. Scardino and Kelman. Avery Press, 2005.• Average age at diagnosisis 68 years old• PSA screening advanceslead time by 5-10 years• Overdiagnosis?Implications of Early Detectionin an Aging Population
    10. 10. ERSPC Bottom Line: YESPSA-based screening reduced the rate ofdeath from prostate cancer by 20%; but wasassociated with a high risk of overdiagnosis.US PLCO Bottom Line: NOThe rate of death from prostate cancer wasvery low and did not differ significantlybetween the two study groups; but 40% ofusual care group had PSA testing.Prostate Cancer Screening:Results of 2 Randomized Controlled Studies
    11. 11. Prostate Cancer Screening GuidelinesPSA Screening(life expectancy >10 yrs)PSA Screening(+risk factors)American Cancer Societywww.cancer.orgOffer at age 50 Offer at age40-45American Urologic Associationwww.auanet.orgBaseline 40 years oldNational Comprehensive CancerNetworkwww.nccn.orgBaseline 40 years old:>1 ng/mL annual follow-up<1 ng/mL rescreen age 45US Preventive Services Task Forcehttp://www.uspreventiveservicestaskforce.orgNo screening for patients >75(No screening ever??)Baseline PSA at age 40 is a stronger independent predictor of PC riskthan ethnicity, family history, or DRE. (Loeb et al, AUA 2005)
    12. 12. Prostate Cancer Clinical StatesFDA-approved Agents for Prostate CancerRisingPSAClinicalMetastases:Castrate1st Line ChemoClinicalMetastases:CastratePre-ChemoClinicallyLocalizedDiseaseClinicalMetastases:Non-CastrateClinicalMetastases:CastratePost-ChemoNON-CASTRATEDiagnosis241, 740Androgen DeprivationTherapyCASTRATION -RESISTANTDeaths From Disease28, 170Docetaxel2004Sipuleucel -T2010Cabazitaxel2010Abiraterone2011Enzalutamide2012Abiraterone2012
    13. 13. Charles B. Huggins, MDNobel Prize in Physiology or Medicine, 1966Huggins C, Hodges CV. Studies on prostatic cancer I. The effect of castration, estrogen,and of androgen injection on serum phosphatases in metastatic carcinoma of theprostate. Cancer Res. 1941;1:293–297.William Wallace Scott, Charles B. Huggins, and Clarence V. Hodges
    14. 14. Hormones: Benefits70Before After
    15. 15. Hormonal Therapies• Anti-androgens:Casodex, Nilandron, FlutamideEnzalutamide• Adrenal ablationKetoconazole, Abiraterone
    16. 16. Antiandrogen Withdrawal Response-120-30 0 43 99 136164198 254357 387 417 437527Time (days)050100150200250PSA(ng/ml)FlutamidewithdrawalBicalutamide
    17. 17. Anti-Androgen WithdrawalKelly et al, 1997AuthorScherDupontHerradaSartorFiggSmallSmallOverall50% PSADecline16/57 (28%)32/40 (80%)11/39 (28%)14/29 (48%)7/21 (33%)12/82 (15%)4/8 (50%)96/276 (35%)Time toResponse(weeks)5.6NS<6<4<6NS<4Duration ofResponse(months)414.53.383.73.5NS
    18. 18. Hormones: Limitations• Hormones are NOT curative• Significant side effect profile:Diminished libido and potencyOsteoporosisWeight gainDiminished muscle massBreast enlargement and breast tendernessEmotional changesFatigueAnemia
    19. 19. Intermittent ADT Phase III TrialsTrial (Year) PatientPopulationNo. of ptsrandomizedPrimaryEndpointNCIC PR7 (2011) PSA relapse after RTNon-Metastatic1386 OSNo differenceEC 507 (2007) PSA relapse after RPNon-Metastatic167 TTPAP 17/95 (2007) Locally advanced/Metastatic (~40%)335 TTPSEUG (2009) Locally advanced/Metastatic (~30%)766 TTPFinnProstate (2012) Locally advanced/Metastatic (~50%)554 TTPTULP (2011) Metastatic 193 TTPSWOG 9346 (2012) Metastatic 1535 OSMODIFIED FROM SLIDES by William Oh, M.D.
    20. 20. [TITLE]Overall survival with Intermittent Hormonal Therapy isNOT “NONINFERIOR” to Continuous Therapy(Translation: it is POTENTIALLY inferior)Modified Slide
    21. 21. ConclusionsIntermittent is NOT Non-Inferior to Continuous ADT• Continuous ADT remains the standard of care forhormone sensitive metastatic PC• Neither this nor any randomized trial has EVER shown asuperior cancer outcome with intermittent ADT• Will more potent reduction of intratumoral androgen(abiraterone) or inhibition of AR signaling (enzalutamide)lead to better outcomes with initial ADT?
    22. 22. UntreatedPrimaryMetastatic CastrationResistantScher et al.Endocrine-RelatedCancer 11:2004;459The Androgen Receptor is Often Overexpressed inCastration Resistant Tumors and is a Target for TherapyIncreased AR proteinAR mRNA overexpressionIncreased AR DNAcopy numberoPost-AndrogenDepletion
    23. 23. ARHSP90AR degradedAR PAR PARPTranscription ofTMPRSS-ETS, etcfor growth and survivalSRCAndrogenprecursorsAndrogensAdrenal synthesisTumor synthesisDHTAR ARCell surfaceligand/receptorAKTARPmutARARARARAmpAR+antiandrogens,progestinsglucocorticoidsModified from Chen et al.Curr Opin Pharm, 2008Therapeutic Targets of the AR Signaling PathwayAGONIST CONVERSIONALTERNATIVE LIGANDSADRENAL/INTRATUMORALANDROGENSLIGAND INDEPENDENT ARPHOSPHORYLATION
    24. 24. FDA Approved Agentswith an Overall Survival Benefit in CRPCAgent YearApprovedMechanism MedianOverall SurvivalHazardRatioDocetaxel1vs Mitoxantrone2004 Anti-microtubule 2.518.9 vs 16.50.76Sipuleucel-T2vs Placebo2010 Immunomodulatory 4.125.8 vs 21.70.78Cabazitaxel3vs Mitoxantrone2010 Anti-microtubule 2.415.1 vs 12.70.70Abiraterone4vs PlaceboPOST-DOCETAXEL*2011 Androgen synthesisinhibitor3.714.8 vs 10.90.65MDV31005vs PlaceboPOST-DOCETAXEL*2012 AR antagonist 4.818.4 vs 13.60.631Tannock et al., NEJM 2004; 2Kantoff et al., NEJM 2010; 3DeBono et al., NEJM 2010; 4DeBono et al., NEJM 2011;5Medivation Interim Analysis of the AFFIRM Trial in CRPC post-Docetaxel 11/3/11*CTC biomarker analysis at MSKCC embedded in the phase 3 trials as a surrogate for survival
    25. 25. Adapted from J E Ang, et al, British Journal of Cancer, 2009Secondary Mineralicorticoid Syndrome*Low dose steroids minimizes toxicity*Suppression of the Renin-Angiotensin Pathway4 fold increase due to elevatedACTH partially reverses17-hydroxylase activityAbiraterone AcetateSelective and Irreversible Inhibition of CYP17
    26. 26. POST-DOCETAXEL ABIRATERONE (Zytiga)FDA APPROVED April 28, 2011Proof of principle that AR IS STILL RELEVANT IN CRPC!!!
    27. 27. POST-DOCETAXEL: ABIRATERONEMS 15.8m versus 11.2mHR 0.740 (0.63-0.85)De Bono et al., Journ Clin Oncol , 2011.
    28. 28. Overall Study Design of COU-AA-302CHEMONAIVE CRPC• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151sites in 12 countries• Stratification by ECOG performance status 0 vs 1• No prior novel anti-androgens (MDV3100), ketoconazole or chemotherapyCo-Primary Endpoints:• rPFS by central review• OSSecondary:• Time to opiate use (cancer-related pain)• Time to initiation ofchemotherapy• Time to ECOG-PSdeterioration• TTPPAA 1000 mg dailyPrednisone 5 mg BID(Actual n = 546)Efficacy end pointsPlacebo dailyPrednisone 5 mg BID(Actual n = 542)RANDOMIZED1:1• Progressive chemo-naïve mCRPC patients(Planned N = 1088)• Asymptomatic ormildly symptomaticPatients
    29. 29. Landmarks of Disease Progression in mCRPCPlanned Interim Analysis at 43% of Events31BaselinePSAProgressionTumor/BoneProgressionPainDeathAdapted from Halabi S. et al, J Clin Oncol. 2009;27:2766-2771.ChemotherapyECOG PS DeclineSecondary EndpointsECOG PS= Eastern Cooperative Oncology GroupPerformance Status24-48 monthsp < 0.0001 p < 0.0001 p = 0.001 p = 0.0053rPFSp < 0.0001OSp = 0.0097
    30. 30. Safety Profile Consistent Despite LongerDuration of ExposureMost Prevalent AEAA + P(n = 542)%Placebo + P(n = 540)%All Grades Grades 3/4 All Grades Grades 3/4Fatigue 39 2.2 34 1.7Fluid retention 28 0.7 24 1.7Hypokalemia 17 2 13 2Hypertension 22 4 13 3Cardiac disorders 19 6 16 3ALT increased 12 5.4 5 0.8AST increased 11 3.0 5 0.932• Most of the ALT and AST increases occurred during the first 3 months of treatment
    31. 31. Statistically Significant Improvement in rPFSPrimary End PointNR, not reached; PL, placebo.1008060402000ProgressionFree(%)3 6 9 15 1812AA + P (median, mos): NRPL + P (median, mos): 8.3HR (95% CI): 0.43 (0.35-0.52)P value: < 0.00015465424894003402041649012300AAPlacebo4630Time to Progression or Death (Months)AAPlacebo
    32. 32. Strong Trend in OS Primary End Point*†*O’Brien-Fleming boundary used; †Data cut off 12/20/2011; ‡Nominal significance level 0.0008.546542538534482465452437272500524509503493021201062582374123871008060402000Survival(%)3 12 15 27Time to Death (Months)33AAPlacebo6 9 30242118AAPlaceboAA + P (median, mos): NRPL + P (median, mos): 27.2HR (95% CI): 0.75 (0.61-0.93)P value: 0.0097‡
    33. 33. Summary: New Standard of Care?AA and Prednisone for Pre-chemo mCRPC• Delays disease progression• Increases survival* (but not by pre-specified amount)• Extends time with minimal or no symptoms• No new important safety signals* 55% Interim Analysis due at ASCO 2013
    34. 34. Compared to bicalutamide… 20-fold higher affinity for the AR6/19/06Rathkopf et al, Clin Cancer Res, 2011-100%-75%-50%-25%0%25%50%75%100%1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55Dosedecline post BMS Therapy BY DOSE5 mg 10 mg 20 mg 40 mg 60 mg 100 mg
    35. 35. WISH LISTSecond Generation AR AntagonistBicalutamide BMS641988 2nd Gen AAEffective in cellswith high ARexpressionXOvercomesagonistactivityX XNovelmechanismof actionX X
    36. 36. Ligand1. AR Binding Affinity• DHT ~ 5nM• Bicalutamide ~160 nM• MDV3100 ~35 nM2. Nuclear Import• DHT: ++++• Bicalutamide: ++++• MDV3100: ++3. DNA Binding• DHT: ++++• Bicalutamide: ++• MDV3100: -4. Coactivator recruitment:No agonist effects.• DHT: ++++• Bicalutamide: ++• MDV3100: -MDV3100: A Novel AR Antagonist1234DNAPOL IIHSP90LBDHDDBDNTDChen et al. Lancet Oncol 10:981, 2009Tran et al., Science 324:787, 2010.
    37. 37. MDV3100 is active in AR expressing tumor models andinhibits AR nuclear translocationTran et al., Science 324:787, 2009LnCAP-AR Cell LinesRD162 is the precursor of the clinical candidate MDV3100
    38. 38. Chemo naïve; N=65 Chemo exposed; N=75MDV3100: Maximum PSA decrease from baselineModified from Scher et al., Lancet, 201062%40/65>50% PSAdecline51%38/75>50% PSAdecline-100%-75%-50%-25%0%25%147101316192225283134374043464952555861646770737679828588919497100103106109112115118121124127130133136139
    39. 39. Pre- and Post-Treatment FDHT PET ImagingOn-Target Effect of AR inhibition with MDV310018-Fluorodihydrotestosterone (F-DHT) PETPre -TreatmentPost -TreatmentScher HI et al., Lancet, 2010Dosage
    40. 40. AFFIRM Trial DesignEnrollment between September 2009 and November 2010156 centers from 15 countries and 5 continents.RANDOMIZED2:1PrimaryEndpoint:Overall SurvivalEnzalutamide160 mg dailyn = 800Placebon = 399Patient Population:1199 patients withprogressive CRPC* Failed docetaxelchemotherapy
    41. 41. Enzalutamide Prolonged Survival, ReducingRisk of DeathHR = 0.631 (0.529, 0.752) P <0.000137% reduction in risk of deathEnzalutamide: 18.4 months(95% CI: 17.3, NYR)Placebo: 13.6 months(95% CI: 11.3, 15.8)Enzalutamide 800 775 701 627 400 211 72 7 0Placebo 399 376 317 263 167 81 33 3 0
    42. 42. AFFIRM: Clinical OutcomesVariable Enzalutamide(800 pts.)Placebo(399 pts.)Hazard Ratio P -valueOS(months)18.4 13.6 0.631 <0.0001PSA progression(months)8.3 3.0 0.218 <0.0001rPFS(months)8.3 2.9 0.404 <0.00011st SRE(months)16.7 13.3 0.621 <0.0001CR + PR 28.9% 3.8% - <0.0001FACT-P 43.3% 17.8% - <0.0001Slide modified from presentation by Kevin Kelly, DO
    43. 43. Favorable Adverse Risk ProfileAll Grades Grades >3*Enzalutamide(n = 800)Placebo(n = 399)Enzalutamide(n = 800)Placebo(n = 399)AEs 98.1% 97.7% 45.3% 53.1%Serious AEs 33.5% 38.6% 28.4% 33.6%Discontinuations dueto AEs7.6% 9.8% 4.6% 7.0%AEs leading to death 2.9% 3.5% 2.9% 3.5%All Grades Grade ≥ 3 EventsEnzalutamide(n = 800)Placebo(n = 399)Enzalutamide(n = 800)Placebo(n = 399)Seizure 0.6% 0.0% 0.6% 0.0%Slide modified from presentation by Kevin Kelly, DO and Johann De Bono, MD
    44. 44. • AR antagonist drug class causes convulsions in laboratory animals athigh doses by an off-target mechanism• AR antagonist seizure risk increases with brain drug concentrations• AR antagonist drug class inhibits the GABA-A current1• Seizures have been observed in clinical testing of the next generationAR antagonists BMS-641988 and MDV3100Seizure potential is an important considerationin the development of AR antagonists**Slide adapted from discussion by Dr. WK Kelly at 2012 ASCO Annual Meeting1Foster WR et al. Prostate . 2011
    45. 45. ARN-509 Produces SuperiorAntitumor Responses thanBicalutamide in CastrationResistant LNCaP/AR-Luc Xenografts.Clegg N et al., Cancer Res 2012ARN-509: A Novel Anti-Androgen for Prostate Cancer TreatmentExhibits Characteristics Predicting a Higher Therapeutic Index than Current AR Antagonists
    46. 46. Phase II Study of the Novel AR Antagonist ARN-509 in CRPCActivity across the spectrum of CRPC including post-abirateroneNon-Metastatic CRPC Metastatic CRPC Post-Abiraterone CRPCBaseline PSA(ng/mL, range)9.7(0.5, 201.7)14.7(1.1, 2552.1)64.1(12.0, 1315.2)12-Week PSAResponse* 91% 88% 29%%ChangeinPSAfrombaselineIndividual Patients* Per PCWG2, the % of patients that reach ≥ 50% decline from baseline at week 12 (3 months) on studyn=45 n=25 n=14Rathkopf et al. Poster Presentation, 2012 Prostate Cancer Foundation Annual Meeting-100-75-50-250255075100
    47. 47. Beyond Hormones:ChemotherapyHistorically regarded as inactive forprostate cancer: new trial designs and newdrugs have changed this view.
    48. 48. Chemotherapy for CRPCBackground• 1985: No evidence for palliative benefit from chemotherapy.Chemotherapy recommended only for clinical trials.• 1996: Mitoxantrone + prednisone vs prednisone aloneestablishes a palliative benefit for mitoxantrone in 30%of symptomatic patients. Studies are too small to detect a survivalbenefit. FDA approval.• 2004: The larger TAX327 and SWOG 99-16 trials show a 3month improvement in survival (1619 months) for Docetaxelcompared to Mitoxantrone. FDA approval.
    49. 49. Relief of Pain (Palliation):Mitoxantrone, the gold standardTannock et al: J Clin Oncol. 1996ResponseMito. +Pred.(n = 80)Pred.(n = 81) P-ValuePrimary Endpoint(decreased pain)23 (29%) 10 (12%) .011Secondary Endpoint(decreased analgesics)7 7Total PalliativeResponse30 (38%) 17 (21%) .025
    50. 50. TAX 327 Established Docetaxel as the First-Line Standardof Care for Castration-Resistant Prostate Cancer:Benefit Was Restricted to Every 3 Week DosingMonthsMediansurvival Hazard(mos) ratio P-valueDocetaxel every 3 weeks: 18.9 0.76 0.009Docetaxel weekly: 17.3 0.91 0.3Mitoxantrone 16.4 – –ProbabilityofSurviving0 6 12 18 24 300.00.10.20.30.40.50.60.70.80.91.0Docetaxel 3 wklyDocetaxel wklyMitoxantroneTannock et al., NEJM, 351:1502, 2004
    51. 51. 53Cabazitaxel Primary Endpoint:Overall Survival—Updated ITT Analysis*28% reduction in risk of deathTime (months)ProportionofOS(%)3773782993211952419413731609191008060402000 6 12 18 24 30MP CBZPMedian OS (months) 12.7 15.1Hazard ratio 0.7295% CI 0.61–0.84P-value <.0001Numberat RiskMPCBZPCensoredMPCBZPCombined medianfollow-up: 13.7 months* Data cut-off 3/10/2010
    52. 52. Why do we need clinical trials?• Hormones and chemotherapy are not curative• Durability of effects is limited• Despite the proven benefits, both have significant sideeffects• There are patients who will not respond to standardtreatments
    53. 53. RADIUM-223T1/2 Range in tissueAverageparticleenergyper decayBone surfaceto red bonemarrow doseratioStrontium 89 50.5 d 2.4 mm 0.58 MeV 1.6Samarium153-EDTMP1.9 d 0.55 mm 0.22 MeV 4.4Radium 223 11.4 d < 0.1 mm 27.4 MeV 10.3Adapted from Bruland et al, Clin Cancer Res, 2006
    54. 54. Radium-223 Targets Bone Metastases• Radium-223 actsas a calcium mimic• Naturally targetsnew bone growthin and aroundbone metastases• Radium-223 isexcreted by thesmall intestineRaCa
    55. 55. ALSYMPCA (ALpharadin in SYMptomatic ProstateCAncer) Phase III Study DesignTREATMENT6 injections at4-week intervalsRadium-223 (50 kBq/kg) +Best standard of care(IV q 4 weeks up to 6 treatments)Placebo (saline)+ Best standard of careRANDOMISED2:1N = 921PATIENTS• ConfirmedsymptomaticCRPC• ≥ 2 bonemetastases• No knownvisceralmetastases• Post-docetaxelor unfit fordocetaxelPrimary Endpoint: Overall Survival• Total ALP:< 220 U/L vs ≥ 220 U/L• Bisphosphonate use:Yes vs No• Prior docetaxel:Yes vs NoSTRATIFICATIONClinicaltrials.gov identifier: NCT00699751
    56. 56. ALSYMPCA Updated AnalysisOverall SurvivalRadium-223, n = 614Median OS: 14.9 monthsPlacebo, n = 307Median OS: 11.3 monthsHR = 0.69595% CI, 0.581, 0.832P = 0.00007Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 00102030405060708090100%
    57. 57. ALYSMPCA Updated Analysis Conclusions• Significantly improved OS (3.6m), SRE (5.5m)• Favorable safety profile• Has activity and safety profile compatible for use withpatients who are not good candidates for docetaxelRadium-223, a novel alpha-pharmaceutical, may provide a newstandard of care for the treatment of CRPC patients with bonemetastases
    58. 58. Cabozantinib (XL184)in Chemotherapy-pretreated Metastatic CastrationResistant Prostate Cancer (mCRPC): Results from a Phase2 Nonrandomized Expansion Cohort(abstract #4513)M.R. Smith, C. Sweeney, D. Rathkopf, H.I. Scher, C. Logothetis, D.J.George, C.S. Higano, E.Y. Yu, A.L. Harzstark, E.J. Small, O.A. Sartor, M.S.Gordon, N.J. Vogelzang, D.C. Smith, M. Hussain,J.S. de Bono, N.B. Haas, C. Scheffold, Y. Lee, P.G. CornMassachusetts General Hospital Cancer Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Sidney Kimmel Center for Prostate andUrologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; The University of Texas MD Anderson Cancer Center, Houston, TX;Duke University Medical Center, Durham, NC; Fred Hutchinson Cancer Research Center, Seattle, WA; University of California, San Francisco,San Francisco, CA; Tulane Cancer Center, New Orleans, LA; Pinnacle Oncology Hematology, Scottsdale, AZ; US Oncology Research/Comprehensive Cancer Centers NV, Las Vegas, NV; University of Michigan, Ann Arbor, MI; Royal Marsden Hospital & Institute of CancerResearch, Sutton, United Kingdom; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Exelixis, South San Francisco, CA;University of Texas M. D. Anderson Cancer Center, Houston, TX
    59. 59. Cabozantinib (XL-184)Oral TKI that Inhibits MET and VEGFR• Randomized discontinuation trial in CRPC– High rates of bone scan improvement– Reduction in bone markers– Regression of soft tissue disease– PFS improvement– Pain improvement and narcotics reduction– PSA changes discordant with othermeasures of antitumor activityM. Hussain et al. ASCO 2011 (Abstract #4516)Bone scanBaseline Follow-up
    60. 60. Subject 1316-2127 (Taxotere-pretreated)Partial Response; Bone Scan and Pain Improvement; ↓PSA; ↓tALPScreening Week 12CT scan: confirmed PR with 41% tumor decrease at Week 12-2 0 2 4 6 8 10 12 140100200300400500600700800900tALPPSA0100200300400500ScreeningWeeks On StudytALPPSABaseline Week 6Target lesions:-33%Week 12Target lesions:-41%
    61. 61. Most Frequently Reported Adverse Events (N = 93)Adverse Event All Grades, n (%) Grade 3, n (%) Grade 4, n (%)Fatigue 77 (83) 24 (26) 2 ( 2)Decreased appetite 68 (73) 6 ( 6) -Diarrhea 65 (70) 10 (11) -Nausea 62 (67) 9 (10) -Vomiting 35 (38) 4 (4) -Dysgeusia 35 (38) - -Weight decreased 34 (37) 3 (3) -Dysphonia 33 (35) - -Back pain 32 (34) 5 (5) 2 (2)Dyspnea 30 (32) 4 (4) 1 (1)Hypothyroidism 29 (31) - -Adverse Events of InterestHand-foot syndrome 23 (25) 5 (5) -Hypertension 22 (24) 8 (9) -Thrombosis venous 12 (13) 1(1) 5 (5)One patient with extensive liver disease experienced a related Grade 3 portal vein thrombosis with Grade 5 liver failure84% of patients experienced at least one dose reduction due to AE
    62. 62. SUMMARYExciting Time in Treatment for CRPC• The Androgen Receptor remains a relevant target.• New technology to evaluate response and progression:circulating tumor cells, FDHT PET.• Collaborative efforts to increase accrual and share conceptsand ideas.• 4 new drugs approved …More to come!!!

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