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NY Prostate Cancer Conference - M.H. Hussain - Session 7: Role of predictive biomarkers as a measure of individualized medicine
1. Role of Predictive Biomarkers as a Measure of Individualized Medicine Maha Hussain, M.D., FACP Professor of Medicine & Urology Associate Director for Clinical Research University of Michigan Comprehensive Cancer Center
2. Identification of “ active” drugs Appropriate Phase III studies Identification of active and safe combinations Adjuvant Neoadjuvant Overarching Objective “ Impact and Change the Standards of Care” This = Decades & $$$$$$
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5. Plethora of Targets and Agents in Prostate Cancer What to Pick and How Best to Test? Pathway Target Agents Angiogenesis PDGF receptor Olaratumab Unknown Tasquinimod VEGF Aflibercept VEGF receptor Ramucirumab Androgen Androgen receptor ARN-509, MDV3100 CYP17 Abiraterone, Orteronel Apoptosis BCL-2 AT-101 Clusterin Custirsen Cell division Microtubules Eribulin, nab-Docetaxel DNA repair PARP Veliparib Endothelin Endothelin receptor Atrasentan, Zibotentan Histone acetylation HDAC Vorinostat Immune modulation CTLA-4 Ipilimumab Multiple Lenalidomide Insulin-like growth factor IGF-1R Cixutumumab Other mTOR Everolimus, Temsirolimus Multiple, including Src Dasatinib Multiple, MET/VEGFR2 XL184
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7. TAX327 Overall Survival, 2004 Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Tannock et al, N Engl J Med, 2004
8. Kantoff et al, NEJM 363:411-22, 2010 Median Survival 25.8 m vs 21.7 m Sipuleucel-T vs Control Overall Survival , 2010
9. Cabazitaxel vs Mitoxantrone Overall Survival, 2010 De Bono et al, Lancet 2010 Median Survival: 15.1 vs 12.7 m )
10. COU-AA-301: Abiraterone Acetate Overall Survival, 2011 HR = 0.646 (0.54-0.77) P < 0.0001 Placebo: 10.9 months (95%CI: 10.2, 12.0 ) 0 100 200 300 400 500 600 700 0 20 40 60 80 100 Survival (%) Days from Randomization Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4) 2 Prior Chemo OS: 1 Prior Chemo OS 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo AA 797 728 631 475 204 25 0 Placebo 398 352 296 180 69 8 1
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16. How successful are we in selecting and targeting solid tumors? Target ER Her-2 EGFR C-Kit TS Disease Breast Breast Colon GIST Colon Drug Tamoxifen Herceptin Cetuximab Gleevec 5-FU Response (%) 50-60 15-26 (35) 10 60-70 15-20
17. Lung Cancer:EGFR Genotype Cannot Be Reliably Determined by Phenotype Jackman DM, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 8035. In mutation positive 71%(I-PASS) response as first-line treatment and 42% (INTEREST) as second-line Phenotype of NSCLC Patient Prevalence of EGFR Mutation, Which Enhances Sensitivity to TKIs All 10-15% Elderly 10-15% PS2 10-15% Caucasian never-smokers ~ 35% Asian never-smokers ~ 65%
22. ERG-positive Xenografts are Preferentially Sensitive to PARP inhibitors ( Olaparib) ERG (the predominant ETS gene fusion product) physically interacts with PARP1 PARP1 is required for ERG-associated function (transcription/invasion) ERG-positive xenografts are preferentially sensitive to PARP inhibitors
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24. LOI 9012: Randomized Phase II Trial of Gene Fusion-Targeted Therapy for Pts with mCRPC N=172 mCRPC 0-1 prior chemotherapy Assess ETS fusions status ETS fusion-positive (~50% of cases) Abiraterone + PARP1 inhibitor ETS fusion-negative patients (~50% of cases) Abiraterone Abiraterone Abiraterone + PARP1 inhibitor
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Notas do Editor
Novel agents pose new challenges. Rather than conventional histological criteria for diagnosis, we may need to re-define how we classify cancers based on the mechanism of pathogenesis and therapy. This may allow greater efficiency in the clinical trial process by selecting populations with a greater liklihood of responding to treatments. Novel surrogates will need validation and acceptance by the scientific community. Starting doses of agents may need to be aimed at inhibiting or interacting with a target rather than the MTD. Dose ranging studies, accepted as a norm in most other therapeutic areas, may be accepted by oncologists to avoid toxicities and optimize the therapy’s interaction with targets.
This slide emphasizes why selecting patients for EGFR TKI therapy by clinical characteristics may be less successful.
In addition to our phase I PARPi + RT study, we are also in the process of initiating a multi-center clinical trial stratifying and treating patients by their prostate cancer gene fusion status. Maha – clinical trial Me – translational component