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NY Prostate Cancer Conference - M.H. Hussain - Highlights of Day 2 breakout sessions (Oncology room)
 

NY Prostate Cancer Conference - M.H. Hussain - Highlights of Day 2 breakout sessions (Oncology room)

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  • 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.

NY Prostate Cancer Conference - M.H. Hussain - Highlights of Day 2 breakout sessions (Oncology room) NY Prostate Cancer Conference - M.H. Hussain - Highlights of Day 2 breakout sessions (Oncology room) Presentation Transcript

  • 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
  • Nine FDA Approvals for Metastatic Castration Resistant Prostate Cancer in 15 Years
    • Survival
      • Docetaxel, Provenge, Cabazitaxel
      • “ abiraterone”
    • Pain
      • Mitoxantrone, Strontium,
      • Samarium
    • Skeletal related events
      • Zoledronic acid, Denusomab
  • Minimize the Number of Negative Trials
    • Nine Negative Phase III trials over the last 6 years
    • Atrasentan (X2)
    • GVAX (X2)
    • Taxotere +/- DN101
    • Satraplatin
    • Taxotere +/- Bevacizumab
    • Taxotere +/- Sunitinib
    • Zibotenan
  • 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
  • Prognosis and Prediction
    • A Biomarker is:
    • Prognostic: correlates with outcome, independent of treatment effects ( PS, stage, Gleason’s score, PSA )
    • Predictive: Provides evidence about the probability of benefit or toxicity from a specific intervention ( ER/PR, HER-2, KRAS mutations )
    • A factor can be:
      • Prognostic but not predictive
      • Predictive but not prognostic
      • Predictive and prognostic
      • Neither
    Modified from Clin cancer research 16 (6) 1745-55, 2010 & C. Tangen.
  • Challenges for Drug Development in the “Era of Targeted Therapies & Personalized Medicine”
    • Re-define “definitions” of diseases
      • Morphology or Molecular Profile
      • How to define a “relevant target”?
        • where is the marker to be measured, what expression rate is meaningful, tumor heterogeneity ?
    • Greater efficacy in selected population
      • Will result in smaller patient populations
    • Alternative study designs and Endpoints
      • Unselected, enriched, biomarker/target stratified, Adaptive
      • Endpoints and new outcome surrogates to be validated
  • AR signaling and DNA Damage/Repair
    • AR-mediated transcription is directly coupled with the induction of DNA damage
    • PARP1 function is critical to the pro-tumorigenic functions of the androgen receptor
    • A ddition of the PARP inhibitor ABT888 improves the response to hormone therapy in preclinical prostate cancer models
    Haffner MC, et al: Nat Genet 42:668-75, 2010, Lin C, et al: Cell 139:1069-83, 2009 Haffner M, et al: Clin Cancer Res, 2011
  • Individualized Medicine in prostate Cancer Conclusions
    • Personalized therapy lags significantly behind other solid tumors
      • The bulk of the efforts are focused on “prognosis” in the setting of early stage disease
    • Timely & better drug development requires:
      • High quality/ impact translational science with a focus on:
        • disease biology
        • Defining relevant pathways & Validated predictive biomarkers
        • Adequate preclinical characterization of agents and combinations