Prostate Cancer Standard of Practice in 2018 and future directions. Eleni Efstathiou MD PhD

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2 Prostate Cancer Standard of Practice in 2018 and future directions Eleni Efstathiou MD PhD

3 Disclosures Eleni Efstathiou Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Janssen-Cilag, Sanofi-Aventis, Astellas/Medivation NA Janssen-Cilag, Sanofi-Aventis, Astellas/Medivation. Oric NA NA Janssen-Cilag, Sanofi-Aventis Janssen-Cilag, Sanofi-Aventis, MSD, Viamet, Takeda, Tokai, Bayer Presentation includes discussion of the off-label use of a drug or drugs (depending on country of origin)

4 Discovery is our Business Charles Huggins ( ) Nobel Prize in Medicine 1966

5 A Medical Oncologist should be the coordinator 1.Local disease treatment 2.Biochemical Recurrence 3. Metastatic Disease hormone naive (HNPC) castrate resistant (CRPC) We care for the Man not the cancer : keeping him healthy against the odds of ADT and other treatments Providing coaching for diet exercise well being Information Clarity are paramount.

6 Prostate Cancer Heterogeneity has not been addressed Graphical representation of seven prostate cancer genomes M F. Berger et al. Nature 470, (2011) doi: /nature09744

7 Pathology dictated by Morphology Gleason Grade and Score (STILL!!) Tips to remember: Gleason Scoring differs Between biopsy and Prostatectomy specimen Gleason Scoring does not apply when Androgen Deprivation is used Cribriform / intraductal spread Associated with more aggressive Disease

8 Hormone Naïve Prostate Cancer Chemotherapy Tumor volume & activity 1.De Novo Metastatic 2. Biochemical Recurrence 3. Recurrent Metastatic Hormone Sensitive

9 Intermittent ADT (IAD) is non inferior to Continuous (CAD) in Biochemical Recurrence Crook et al NEJM 2012

10 Causes of Death More PCa related deaths in IAD arm Crook et al NEJM 2012

11 Overall conclusion: in mhnpc IAD is NOT non inferior compared to CAD Hussain et al NEJM 2014 Hussain M et al. Oral presentation, ASCO, Chicago, 3 June 2012

12 Progress Report Three practice changing years in Hormone Naive Prostate Cancer 1. The reemergence of Chemotherapy (2 positive / 1 negative trial) 2. Moving Androgen Biosynthesis Inhibition earlier in the disease spectrum (2 positive trials) To date the biggest impact in survival exhibited

13 Upfront Use of Chemo in Hormone Sensitive Metastatic Disease Failed Attempt 1 : GETUG 15 GETUG15 The first trial in HSPC testing Docetaxel A negative Trial GETUG 15 ADT-docetaxel: 60.9 m ADT alone: 46.5 m p = 0.44 Gravis, et al. Lancet Oncology

14 Successful Attempt 2 :CHAARTED Phase 3, multicenter, open label study (N = 790) Patient Characteristics Diagnosis of prostate cancer with metastatic disease ECOG PS 0-2 Prior adjuvant ADT was allowed if the duration o 24 months and progression >12 months after completion Patients receiving ADT for metastatic disease were eligible if no evidence of progression and treatment commenced 120 days before randomization R A N D O M I Z E D 1 : 1 ARM A ADT + Docetaxel 75 mg/m 2 21 days for maximum 6 cycles ARM B ADT (androgen deprivation therapy alone) Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks Evaluate every 12 weeks Follow up for time to progression and overall survival Chemotherapy at investigator s discretion at progression Stratification Extent of metastasis: high volume vs low volume* Age: 70 vs <70 years ECOG: 0-1 vs 2 CAB > 30 days: yes vs no SRE prevention: yes vs no Prior adjuvant ADT: 12 vs >12 months ADT allowed up to 120 days prior to randomization Intermittent ADT dosing was not allowed Standard dexamethasone premedication but no daily prednisone *At study start only pts with high volume disease were to be enrolled. Study was amended to also include patients with low-volume disease. Sweeney C J et al. Clin Oncol 32:5s, 2014 (suppl; abstr LBA2) Sweeney C J et al. N Engl J Med. 2015;373(8):

15 CHAARTED Overall Survival All Patients High Volume: >=4 bone mets at least 1 Outside axial skeleton Or /and visceral mets p= HR=0.60 ( ) Median OS: ADT + D: 49.2 months ADT alone: 32.2 months Sweeney C J et al. Clin Oncol 32:5s, 2014 (suppl; abstr LBA2) Sweeney C J et al. N Engl J Med. 2015;373(8):

16 Hazard Ratios for Death in Subgroups. Sweeney CJ et al. N Engl J Med 2015;373: Sweeney CJ et al. N Engl J Med 2015;373:

17 CHAARTED: Overall QoL on FACT-P Of interest the final improvement of qol for ADT +Docetaxel: dual interpretation Patrick-Miller al. J Clin Oncol 2016;34(suppl): abstract 5005

18 E-3805 CHAARTED UPDATED SURVIVAL POINTS TO HETEROGENEITY High volume disease First data (NEJM 2015) Updated data (ESMO 2016) HR=0.60 (95%CI ) HR=0.63 (95%CI ) Updated Survival Analysis : Low Volume mhnpc Does not derive benefit from Addition of Docetaxel HR=0.60 (95%CI ) HR=1.04 (95%CI ) Low volume disease Sweeney et al #720

19 Attempt 3 : STAMPEDE Nicholas James University of Warwick and Queen Elizabeth Hospital Birmingham on behalf of Matthew Sydes, Malcolm Mason, Noel Clarke, David Dearnaley, Melissa Spears, Robin Millman, Chris Parker, Alastair Ritchie, J. Martin Russell, John Staffurth, Robert Jones, Shaun Tolan, John Wagstaff, Andrew Protheroe, Rajaguru Srinivasan, Alison Birtle, Joe O'Sullivan, Richard Cathomas, Mahesh Parmar and the STAMPEDE Investigators Lancet dec

20 Docetaxel & ZA comparisons: patients

21 Docetaxel: Survival SOC SOC+Doc 405 deaths 165 deaths HR (95%CI) 0.76 (0.63, 0.91) P-value Non-PH p-value 0.51 Median OS (95% CI) SOC 67m (60, 91m) SOC+Doc 77m (70, NR) Restricted mean OS time SOC 58.8m SOC+Doc 63.4m Diff (95%CI) 4.6m (1.8, 7.3m)

22 2015 Standard of care for men with mhnpc ADT + Docetaxel Overall Survival ADT + DOC Media n (mos) ADT Median (mos) HR (95% CI) P Value GETUG ( ) 0.3 CHAARTED ( ) STAMPEDE ( ) Gravis G, et al. Eur Urol. 2016:70: Sweeney C, et al. N Engl J Med. 2015;373: ; Sweeney C, et al. Ann Oncol. 2016;27(Suppl 6): James N, et al. Lancet. 2016;387: and Vale C, et al. Lancet Oncol ;17:

23 Docetaxel in mhnpc Conclusions & Questions Conclusions : PRACTICE SHAPING Docetaxel exhibits an overall survival benefit in hormone sensitive metastatic disease in two studies and does not in one Docetaxel added to ADT in hormone naïve metastatic disease with high volume prolongs survival (CHAARTED) De novo metastatic disease derives consistent benefit in both positive studies Marrow Toxicity remains a concern Questions Is there meaningful benefit in low volume disease? How do we objectively select men who will benefit? Subsequent access to treatment important How do we address the ~20% of highly aggressive disease not benefiting

24 Rationale for Abiraterone added to ADT in mhnpc Mechanisms of resistance to ADT may develop early 1-3 ADT does not inhibit adrenal or intracrine/ paracrine androgen synthesis; inhibits testicular synthesis but less profoundly than abiraterone A more robust wild type androgen signaling driver of disease Abiraterone + Prednisone improves OS in mcrpc 4,5 reduces tumor burden in high-risk, localized PC 6,7 Tumor Volume (cc) P = Tumor Epithelium Volume: Tumor Cell Density Volume Tumor Cell Density (%) P < P < These data suggest a potential role for inhibiting extragonadal androgen biosynthesis prior to the emergence of castration resistance 1. Gravis G, et al. Eur Urol. 2016:70: Sweeney C, et al. N Engl J Med. 2015;373: James N, et al. Lancet. 2016;387: de Bono JS, et al. N Engl J Med. 2011;364: Ryan CJ, et al. Lancet Oncol. 2015;16: Taplin ME, et al. J Clin Oncol. 2014;32: Efstathiou E, et al. J Clin Oncol. 2015;33(suppl):15s. Abstract

25 LATITUDE Study Design Patients Newly diagnosed adult men with high-risk mhnpc Stratification factors Presence of visceral disease (yes/no) ECOG PS (0, 1 vs 2) R A N D O M I Z E D 1:1 ADT + Abiraterone acetate 1000 mg QD + Prednisone 5 mg QD (n = 597) ADT + placebos (n = 602) Efficacy end points Co-primary: OS rpfs Secondary: time to pain progression PSA progression next symptomatic skeletal event chemotherapy subsequent PC therapy Conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada Designed and fully enrolled prior to publication of CHAARTED/STAMPEDE results Fizazi et al NEJM 2017

26 F Fizazi et al NEJM 2017 Fizazi et al NEJM 2017 Treatment arms: GS >=8 and bone lesions main criteria ADT + AA + P (n = 597) ADT + Placebos (n = 602) Median age, years (range) 68.0 (38-89) 67.0 (33-92) Gleason score 8 at initial diagnosis 98% 97% Patients with 3 bone metastases at screening 98% 97% Extent of disease Bone Liver Lungs Node Baseline pain score (BPI-SF Item 3) % 5% 12% 47% 50% 22% 29% 98% 5% 12% 48% 50% 24% 27%

27 Latitude: 38% risk reduction of death 100 Hazard ratio, 0.62 (95% CI, ) P< ADT + AA + P, not reached Overall Survival (%) ADT + placebos, 34.7 mo OS rate at 3 years: ADT + AA + P: 66% ADT + placebos: 49% 20 No. of events: 406 (48% of 852) ADT + AA + P: 169 ADT + placebos: No. at risk Months Median follow-up: 30.4 months ADT + AA + P ADT + placebos Fizazi et al NEJM 2017

28 53% risk reduction of radiographic progression or death 100 Hazard ratio, 0.47 (95% CI, ) P< Progression-Free Survival (%) No. of events ADT + AA + P: 239 ADT + placebos: 354 ADT + placebos, 14.8 mo ADT + AA + P, 33.0 mo Months No. at risk ADT + AA + P ADT + placebos Fizazi et al NEJM

29 Subsequent life-prolonging therapy for prostate cancer Not enough AA on control arm? Patients eligible* Patients who received life- prolonging therapy ADT + AA + P (n = 597) ADT + placebos (n = 602) n (%) n (%) n = 314 (53%) n = 469 (78%) 125 (40) 246 (52) Docetaxel 106 (34) 187 (40) Enzalutamide 30 (10) 76 (16) AA-P 10 (3) 53 (11) Cabazitaxel 11 (4) 30 (6) Radium (4) 27 (6) *Patients who discontinued treatment and were eligible for subsequent therapy. Fizazi et al NEJM 2017

30 STAMPEDE ARM G REPORT 2017 Docetaxel & ZA comparisons: patients Trial includes localised and M1 HSPC Localised receive AA for 2years

31 STAMPEDE Patient characteristics 1% WHO PS 2 [s] 21% WHO PS 1 [s] 67yr Median age [s] (min 39, max 85) 52% Metastatic [s] (88% Bony mets) 20% N+M0 28% N0M0 99% LHRH analogues [s] 41% Planned for RT [s] (96% of N0M0 pts; 62% of N+M0 pts) 5% Previous local therapy Balanced by arm James N, et al. ASCO LBA5003 and Oral Abstract Session 3 0 James et al NEJM 2017

32 OS STAMPEDE abiraterone plus prednisone comparison Events 262 Control 184 abiraterone plus prednisone SOC+AA P This represents a 37% improvement in survival SOC HR % CI 0.52 to 0.76 P-value James N, et al. ASCO LBA5003 and Oral Abstract Session James et al NEJM 2017

33 Failure Free Survival STAMPEDE Events 535 Control 248 abiraterone plus prednisone SOC+AAP This represents a 71% improvement in time to failure SOC HR % CI 0.25 to 0.34 P-value 0.377x10-61 James N, et al. ASCO LBA5003 and Oral Abstract Session James et al NEJM 2017

34 Subsequent Treatments More Frequent use of Docetaxel post AA and limited use of AA in ADT arm James et al NEJM 2017

35 Abiraterone in 2017 Conclusions : PRACTICE SHAPING Abiraterone added to ADT in high risk hormone naïve metastatic disease prolongs survival (LATITUDE) Abiraterone exhibits an overall survival benefit in hormone sensitive metastatic disease in two studies De novo metastatic disease derives consistent benefit in both positive studies No new safety concerns with the use of Abiraterone Questions Is the observed benefit based only on biology or window of opportunity? as well : Consistently who gets more does better Is there meaningful benefit in low risk and M0 disease? How do we objectively select men who will benefit from one of the other agent? How do we address the ~20% of highly aggressive disease not benefiting with either choice

36 Decision Making in mhnpc Docetaxel (6cs) Low Cost High Volume CHARTEED definition Abiraterone acetate with consistent long term monitoring androgen signaling driven biology is dominant Fear of chemo frailty The Breast Cancer Model albeit without the molecular classification Docetaxel 6cs followed by Abiraterone Acetate : TOO EARLY BUT : Monitor Closely Patients on both agents lived longer consistently on all trials Different Mechanism of Action Particularly High Volume disease may warrant more aggressive approach High risk LATITUDE definition (majority) to be distinguished from High Volume CHARTEED definition: High volume is a subset of high risk ADT A minority of men with slowly progressive disease (eg gleason 7 but no tertiary 5) Heart failure and comorbidities limiting survival

37 Failure-free survival STAMPEDE points to Equivalence Is it a loss vs gain balance Favours ADT+AA+P Favours ADT+DOC Head-to-head data in 566 pts (Nov-2011 to Mar-2013) Progression-free survival Metastatic progression-free survival Symptomatic skeletal events Cause-specific survival Overall survival Strong evidence favouring AA+P Weak evidence favouring AA+P No good evidence of a difference in OS Proportionately different time spent in each disease state Hazard ratio Toxicity profiles quite different and well known Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017 AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel Sydes et al Annals of Oncology

38 Conclusions for now HNPC treatment options Intermittent ADT a valid option for biochemical recurrence of m0 HNPC Continuous vs Intermittent ADT preferred for m HNPC Six Cycles of Docetaxel 75mg/m2 or Abiraterone Acetate (continuously) combined with ADT recommended for m HNPC patients

39 Prostate Cancer Treatment Paradigm Androgen deprivation therapy (ADT) in 2010 Death Local therapy Therapies after ADT Hormone sensitive mcrpc asymptomatic (failed ADT) mcrpc mildly symptomatic mcrpc symptomatic mcrpc postdocetaxel ADT Docetaxel

40 A New Therapy landscape in Advanced Prostate Cancer (2018) Death Hormone Sensitive Prostate Cancer Localized / Metastatic ADT mhspc ADT + Abiraterone Advanced metastatic Prostate Cancer Apalutamide Abiraterone Enzalutamide mhspc ADT + Docetaxel Sipuleucel-T Docetaxel Radium 223 Cabazitaxel supportive care (denosumab/bisphosphonates)

41 Non-Metastatic CRPC : Is this a real disease state? Certain patients with prostate cancer receiving ADT will eventually develop castration-resistant disease. 1,2 Patients with CRPC who present with: Rising PSA* while on ADT 3 Serum testostero ne levels below 50 ng/dl 3 No evidence of detectable metastasis 3 Non-metastatic 3 or M0 CRPC No evidence of detectable metastases with convenitonal imaging Please see Important Safety Information throughout this presentation. Please nmcrpc see includes full Prescribing local recurrence Information prostate available bed at this + pelvic presentation. nodes

42 Apalutamide Mechanism of Action Apalutamide is an AR inhibitor that binds directly to the ligand-binding domain of the AR 1 Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription Please see Important Safety Information throughout this presentation. Please see full Prescribing Information available at this presentation.

43 Metastasis-Free Survival in nmcrpc improved with Apalutamide Apalutamide + ADT Apalutamide FDA Approval on Valentine s Day 2018

44 Proposed Treatment Algorithms for mcrpc reflective of lack of precision NCCN Guidelines v2 2016;

45 Gerhardt Attard UK Johann De Bono UK Rosalind A. Eeles UK Tomasz M. Beer US Himisha Beltran US Arul M. Chinnaiyan US Nicholas D. James UK Anwar Padhani UK Chris Parker UK Charles G. Drake US Eleni Efstathiou US Susan Halabi US Maha H.A. Hussain US Christopher J. Logothetis US Peter Nelson US Frédéric Lecouvet BE Bertrand Tombal BE William K. Oh US Mark A. Rubin US Oliver A. Sartor US Jack A. Schalken NL Howard I. Scher US Neal Shore US Eric Small US Axel Heidenreich DE Sten Nilsson SE Matthew R. Smith US Christopher Sweeney US Gedske Daugaard DK Maria De Santis AT Avishay Sella IL Hideyuki Akaza JP Martin E. Gleave CA Ian Tannock CA Karim Fizazi FR David Olmos ES Stefano Fanti IT Silke Gillessen CH Ian Davis AU Cora N. Sternberg IT Hiroyoshi Suzuki JP APCCC St Gallen Meeting Offering Guidance urologist medical oncologist radiation oncologist others

46 Therapeutic agents for Advanced Prostate Cancer /mcrpc Trial Regimen Pts HR N Survival (months) Delta (months) IMPACT 1 Sipuleucel-T CRPC vs TAX TROPIC 3 COU-AA ALSYMCA 5 AFFIRM 6 Docetaxel+Prednisone vs Mitoxantrone+Prednisone Cabazitaxel+Prednisone vs Mitoxantrone+Prednisone Abiraterone +Prednisone vs Prednisone Alpharadin vs Placebo Enzalutamide vs Placebo CRPC Chemonaive CRPC Post-docetaxel CRPC Post-docetaxel vs vs vs CRPC vs CRPC Post-docetaxel vs Survival prolongation on average 3.5 months! 1. Kantoff PW et al. N Engl J Med 2010;363: Tannock IF et al. N Engl J Med 2004;351: de Bono JS et al. Lancet 2010;376: Fizazi K et al. Lancet Oncol Parker C et al. ASCO 2012 (LBA 4512). 6. Scher H et al. N Engl J Med 2012;367:

47 Docetaxel in Metastatic Castrate Resistant Prostate Cancer Tannock et al NEJM 2004

48 CRPC Remains Driven by Androgen Receptor Signaling AR Alterations Selected During Therapy AR splice variants 2 AR overexpression 2 AR mutants 2 PI3K/AKT/ERK/mTOR Androgen production by adrenal glands and prostate tumor 2 AR PI3K/AKT/ERK/mTOR T/DHT NUCLEUS Upregulation of AR cofactors 1,2 Signaling crosstalk 1,2 Up to 80% of CRPCs elevated AR gene copy number, 30% high-level amplification of the gene AR mutations common10-30% of the CRPC treated with antiandrogens 1 Heinlein CA et al. Endocr Rev. 2004;25(2): Hu R et al. Expert Rev Endocrinol Metab. 2010;5(5):

49 Abiraterone Acetate: Androgen Biosynthesis Inhibitor Μechanism of Action Tip : Endocrine Side Effects Low-dose steroid replacement minimizes mineralocorticoid-related toxicity- NOT SUPRAPHYSIOLOGIC DOSING

50 Enzalutamide : Antiandrogen mechanism of action Enzalutamide is an AR signalling inhibitor that inhibits AR signalling in three distinct ways: 1. Blocks AR binding 2. Impairs nuclear translocation 3. Blocks DNA binding and activation DHT Cytoplasm Nucleus Enzalutamide AR Enzalutamide Enzalutamide TIP: Crosses brain blood barrier Centrally driven adverse event profile; fatigue Steady State 28 day Tran et al. Science 2009;324:787 90; Watson et al. Proc Natl Acad Sci USA 2010;107: AR, androgen receptor; DHT, dihydrotestosterone

51 COU-AA-301: Abiraterone Acetate Improves Overall Survival in Metastatic CRPC post docetaxel 100 HR = ( ) P < FDA Approved Apr 28, 2011 EMEA Approved Sep 2011 Survival (%) Placebo: 10.9 months (95% CI: ) AA Placebo Abiraterone acetate: 14.8 months (95% CI: ) Median age: 69 yrs 75 years: 28% Time to Death (Months) Tip PSA increase should be a trigger for further evaluation but not discontinuation CRPC, castrate resistant prostate cancer. De Bono et al. N Engl J Med.

52 AFFIRM Enzalutamide Improves Overall Survival in Metastatic CRPC post docetaxel Survival (%) HR = (0.529, 0.752) P < % Reduction in Risk of Death Placebo: 13.6 months (95% CI: 11.3, 15.8) FDA Approved Aug 2012 EMA Dec 2012 MDV3100: 18.4 months (95% CI: 17.3, NYR) Scher et al NEJM 2012 Enzalutamide Placebo

53 Overall Survival (%) Targeting Androgen Signaling Earlier Two large trials in line in chemo naïve mcrpc : Both positive Prednisone, 30.3 mos HR (95% CI): 0.81 ( ) p Value: Abiraterone, 34.7 mos Time to Death (Months) Survival (%) Placebo: 30.2 (95% CI 28.0, NYR) Enzalutamide Placebo Enzalutamide: 32.4 (95% CI 30.1, NYR) HR: (95% CI: 0.60,0.84) P< Ryan et al. NEJM 2014, Beer et al NEJM 2014

54 Alpharadin Mechanism of action: microenvironment targeting? Minimal damage to surrounding bone marrow and tissue Range of alpha particle (small volume) 2-10 cell diameter Tumor Bone marrow Radionuclide Bone Bone surface

55 Alpharadin increases Overall Survival in mcrpc patients ineligible for or who refused chemo Median Age 70 Parker et al Lancet 2013

56 How to Train your Immune system

57 Sipuleucel T improves overall survival in mcrpc Tips : No PSA response no rpfs improvement anticipated Sub-analysis in favor of prechemo smaller volume disease with stability FYI two large ipilimumab trials negative in mcrpc Small et al 2010

58 TROPIC: Cabazitaxel improves overall survival vs Mitoxantrone in post docetaxel mcrpc HR 0.70 (95% CI ) p < Proportion surviving (%) Cabazitaxel Mitoxantrone 28% Median age: 68 yrs 75 years: 18% 20 17% Time (months) De Bono et al. Lancet, 2010, 376:

59 FIRSTANA: Overall survival no difference Conclusion : Cabazitaxel not superior to docetaxel in first line mcrpc Cabazitaxel 20mg/m2 less toxic than 25mg/m2 FDA issued new dosing instruction : 20mg /m2 in 2017 Sartor et al. J Clin Oncol 2016

60 Supportive Treatment for bone mcrpc Bone Health Vit D (+Calcium) a mandate for PCa patients Zoledronic acid 4mg iv q 3-4 wks vs Denosumab 120mg /q 4wks Both only approved for mcrpc in such regimen

61 Denosumab vs zoledronic acid in mcrpc

62 SIOG recommendations for senior men Treatment recommendations for older men with prostate cancer should be based: health status (mainly driven by comorbidities) patient preferences NOT on chronological age!!! Droz JP et al, Lancet Oncology. 2015,

63 Treatment should be adapted to health status Fit : Same treatment as younger patients 50% of men years 25% of men years Vulnerable : Geriatric intervention then standard treatment Frail : Geriatric intervention then adapted treatment or palliative treatment Too sick Only palliative treatment Standard treatment Geriatric intervention

64 Treatment Selection for mcrpc No available predictors of outcome No Clear selection Criteria between androgen signaling inhibitors and docetaxel....both abiraterone acetate and enzalutamide have proven survival benefit when given prior to docetaxel.. Alpharadin should be used only for bone metastases Sipuleucel T is preferred pre chemo and on lower disease burden Vintage hormones are no longer recommended given lack of survival benefit data Patient preference should be considered

65 Future Directions Do not confuse motion with progress Montalpert

66 Current Practice: Reactive Medicine Regimen + - to + + Patient success + Choice of Treatment Access to Treatment Reimbursement status- Regulatory aspects Level I evidence : originating from randomised PhIII trials Personal Experience - Discipline

67 Trial Progress Report Clinical Practice Change in mhnpc The reemergence of Chemotherapy in advanced Prostate cancer mhnpc data Failure for microenvironment agents and immunotherapy in ALL mcrpc studies: Orteronel,Tasquinimod, Cabozantinib, Ipilimumab (2) mcrpc Saturation? Lack of Selection Moving Androgen Biosynthesis Inhibition earlier in the disease spectrum mhspc positive data ( 2 positive trial)

68 Design of prostate cancer studies largely rely on uniform prognostication

69 Moving the Therapeutic Dilemma Earlier Death Local therapy Hormone sensitive mcrpc asymptomatic (failed ADT) mcrpc mildly symptomatic mcrpc symptomatic mcrpc postdocetaxel ADT mhnpc ADT + Docetaxel Apalutamide Abiraterone Enzalutamide Docetaxel Radium 223 Abiraterone Enzalutamide Cabazitaxel mhnpc ADT + Abiraterone 2017 Sipuleucel-T supportive care (eg denosumab/bisphosphonates)

70 Have we reached Saturation in mcrpc? Agents Docetaxel Cabazitaxel Sipeuleucel-T Abiraterone Enzalutamide Rad 223 Survival prolongation on average 3.5 months in mcrpc Most trials to date focused on drug development irrespective of risk category Giving Perspective : Pembrolizumab for MSI across solid tumors

71 Registration Study Failures in mcrpc Uniform Prognostication Approach Cabozantinib, Tasquinimod and Ipilimumab (2), And all Docetaxel + combinations (15) Too many questions to be answered / lack of validation of companion diagnostics Galeterone Too late Space taken / Saturation Orteronel

72 Are we missing opportunities for our patients and how can we rectify? Ipilimumab in Post-Chemotherapy mcrpc HR 0 85, 95% ; p=0 053 Proportion Alive Ipilimumab Censored Placebo Censored Months Kwon, ED et al. Lancet Oncol

73 Steps in the right direction

74 Multi-institutional integrative clinical sequencing analysis- East Coast SU2C Underscores Heterogeneity A feasibility report paving the way for predictive biomarker identification And a much needed classification ~90% of mcrpc harbor clinically actionable molecular alterations NEED FOR PROSPECTIVE VALIDATION TO PROVE A POTENTIAL BENEFIT OF ANY ACTION Robinson et al Cell 2015

75 Somatic mutation landscape in far advanced mcrpc Highly Burdened mutational landscape A tall order to identify a driver. Cell May 21;161(5)

76 DNA Repair Genes aberrations in mcrpc maybe treatable with a PARP inhibitor : A retrospective analysis providing insight the path for a prospective validation Mateo J et al. N Engl J Med 2015;373: Mateo et al 2015 NEJM

77 GENETIC TESTING: SHOULD IT BE OFFERED AND WILL IT AFFECT EARLY TREATMENT RAD51D CHOICES? 3 MRE11A NBN PMS2 BRP1 GEN1 ATR MSH6 MSH FAM175A RAD51C 6 BRCA1 7% 37 BRCA2 (45%) 10 CHEK2 (12%) 11 ATM (13%) 12% Pritchard, NEJM, 2016

78 How to Efficiently target? Would earlier treatment reduce variables that may be driving progression or resistance? What are the variables and how do they change over time and how do we track them? Development of Biomarkers : Should a biomarker be reflective of the pathway of progression rather than a by association event

79 Precision Medicine Requirements National Research Council 2012

80 Precision Medicine Requirements Knowledge Network for Biomedical Research integrating : Molecular Characterisation & Clinical Data New Taxonomy of Disease Biomedical Research Clinical Medicine

81 Precision Medicine Delivered Understand Integrate Knowledge Identify / Classify findings Anticipate Enable Risk Assessment Cure/ Secondary Prevention Treat based on Taxonomy AND patient characteristics Right treatment strategy at the right dose at the right time, with minimum ill consequences and maximum efficacy

82 A need to acquire Knowledge to make most of information

83 Make the most of data adapt to your practice Monitor patients diligently details matter Listen to the need of the patient For now : we can use available treatment strategy at the right dose, with minimum ill consequences and strive for maximum efficacy

84 Working together to support our Patients and their families

85 Questions

86 2016 question 1 An 80 yr old previously fit man with no comorbidities has recently started having back pain loss of weight and fatigue his PS is quickly deteriorating. Found to have de novo metastatic prostate cancer GS 8 with >20 bone lesions, PSA 800, LDH What would be the preferred approach? a. Start Androgen Deprivation b. Start Androgen deprivation and bone modifying agents c. Start Androgen deprivation and Docetaxel d. Start Androgen Deprivation and Abiraterone Acetate plus low dose steroids e. C or D

87 2. Please propose the appropriate 1 st line treatment for a gentleman of 78 yrs with no known comorbidities, who has mcrpc with multiple bone and lymphnode metastases. Patient remains fully active has no symptoms has a very busy social life. He is on treatment with lhrh analogue for 3 years and is now progressing by imaging and PSA criteria. Lymphnode size ranges from 2-3 cm. Novel agents are available and reimbursed or patient can afford Pick all appropriate choices a Novel Androgen Signaling Inhibitor : Abiraterone Acetate or Enzalutamide b 6-10 courses of Docetaxel c Alpharadin d 6-10 courses of Cabazitaxel e Sipuleucel T d prednisone or dexamethasone low dose e Bicalutamide 50mg /qd f Denosumab or Zoledronic acid infusion added to one of choices of systemic treatment

88 3. A patient of 73 yrs old has received prior chemo with docetaxel and is now on treatment with a novel androgen signaling inihibitor ( abiraterone or enzalutamide). For the past 12 months. He had initiated treatment because of a rising psa to 150. Initially his PSA regressed to 10. His PSA is now progressing within the past 3 months ( 05/16 : 10 06/16: 12 07/16: 14) Patient is feeling great and his imaging did not show any sign of progression Patient is concerned please advise regarding best option a. Stop an androgen signaling inhibitor b continue the androgen signaling inhibitor and monitor closely imaging and clinical symptoms while reassuring patient c continue androgen signaling inhibitor and add chemo with cabazitaxel d stop androgen signaling inhibitor and start treatment with cabazitaxel e. Stop androgen signaling inhibitor and initiate alpharadin f change from one androgen signaling inhibitor to the other (abiraterone to enzalutamide or vice versa depending on what he was on) g reassure patient nothing is wrong and send him home to continue monitoring only psa every 3 months

89 4. A 68 yr old gentleman is diagnosed with a Gleason Score 7 (3+4) Prostate Cancer in 3/8 right lobe biopsy cores and none of 0 /6 left lobe biopsy cores. No comorbidities but hypertension. Please recommend treatment options.multiparametric Choose the most appropriate selection a. Active Surveillance b. XRT + ADT for 6 months c. XRT d. Radical Prostatectomy