1. Biomarkers in Prostate Cancer, part II Prostate Cancer Symposium September 17, 2011 Clara Hwang, MD Internal Medicine Hematology/Oncology

2. Biomarkers – the holy grail of personalized medicine? Advances in technology (genomics, proteomics) have offered the promise of personalized medicine, where therapies and medical decision making can be finely tailored to patients.Advances in technology (genomics, proteomics) have offered the promise of personalized medicine, where therapies and medical decision making can be finely tailored to patients. Potential benefits include improving clinical efficacy and decreasing toxicity by better treatment selection and patient selection.Potential benefits include improving clinical efficacy and decreasing toxicity by better treatment selection and patient selection.

3. Phases of biomarker development Discovery – ~Phase IDiscovery – ~Phase I Identify relationship between molecular marker and clinical outcome; ideally identify causal relationshipIdentify relationship between molecular marker and clinical outcome; ideally identify causal relationship Analytic Validation – ~Phase IIAnalytic Validation – ~Phase II Develop lab SOP/QC, reliability in clinical samplesDevelop lab SOP/QC, reliability in clinical samples Selectivity, sensitivity, CR, precision, accuracySelectivity, sensitivity, CR, precision, accuracy Clinical Qualification – ~Phase IIIClinical Qualification – ~Phase III Confirm correlation with clinical outcomesConfirm correlation with clinical outcomes Clinical implementation - ~Phase IVClinical implementation - ~Phase IV

4. Clinical utility of biomarkers in prostate cancer Clinical scenarioExample DetectionPSA for early diagnosis PrognosisGleason score PredictionER positivity and hormone Rx; none exist for prostate cancer PharmacodynamicTestosterone for GnRH agonist Clinical surrogatePSA decline as tumor marker

5. Prostate cancer clinical states and treatment decisions Localized disease Metastatic disease Should I start treatment? (Prognostic biomarker) Which treatment should I use? (Predictive biomarker) Is my treatment working? (Pharmacodynamic biomarker) Is my treatment helping the patient? (Surrogate biomarker)

6. Current landscape of treatments for castrate- resistant metastatic prostate cancer Minimally symptomatic – sipuleucel-TMinimally symptomatic – sipuleucel-T 1 st line – docetaxel1 st line – docetaxel 2 nd line –2 nd line – AbirateroneAbiraterone CabazitaxelCabazitaxel 3 rd line – mitoxantrone3 rd line – mitoxantrone

7. Biomarkers to assess response to systemic therapy Limitations of systemic therapy – all patients will ultimately progressLimitations of systemic therapy – all patients will ultimately progress Some patients will not have an initial response to therapySome patients will not have an initial response to therapy Are there predictive or surrogate biomarkers to guide treatment decisions?Are there predictive or surrogate biomarkers to guide treatment decisions?

8. Response markers in prostate cancer In current clinical useIn current clinical use PSAPSA PainPain Bone scanBone scan CT scan/ MRI scan (RECIST)CT scan/ MRI scan (RECIST) ExperimentalExperimental Circulating tumor cellsCirculating tumor cells

9. The difficulty of assessing response to therapy in mCRPC “PCWG2 advises that, in the absence of clinically compelling indicators of disease progression, early changes (within 12 weeks) in indicators such as serum PSA, patient-reported pain, and radionuclide bone scan be ignored.” Scher et al JCO 2008 v26(7) p 1148

10. Clinical examples of using PSA as biomarker for treatment response PSA responses from three patients started on chemotherapy with CRPCPSA responses from three patients started on chemotherapy with CRPC On occasion, PSA will rise prior to falling (PSA flare response)On occasion, PSA will rise prior to falling (PSA flare response)

11. PSA response as surrogate marker Retrospective analysis of patients on Ph III comparision of D+E vs M+P (S9916)Retrospective analysis of patients on Ph III comparision of D+E vs M+P (S9916) 3 month 30% PSA decline defined to have occurred if lowest PSA within first three months <=50% of baseline value3 month 30% PSA decline defined to have occurred if lowest PSA within first three months <=50% of baseline value By this definition – occurred in 76% in D+E arm vs 40% in M+PBy this definition – occurred in 76% in D+E arm vs 40% in M+P Petrylak 2006 JNCI 98:516

12. PSA decline as surrogate marker in S9916 Original figure of MP vs. DE compared to OS curve of patients with PSA decrease >=30% in 3 mo vs < 30% Petrylak 2006 JNCI 98:516

13. Circulating tumor cells (CTC) In patients with solid tumors, circulating tumor cells can be detected in circulationIn patients with solid tumors, circulating tumor cells can be detected in circulation Rare (1 in 10 9 nucleated cells)Rare (1 in 10 9 nucleated cells) Provide a source of tumor cells for molecular profilingProvide a source of tumor cells for molecular profiling For Cellsearch assay, cutoff for favorable vs unfavorable is 5 CTC per 7.5 mL bloodFor Cellsearch assay, cutoff for favorable vs unfavorable is 5 CTC per 7.5 mL blood

14. CTC detection with CellSearch Only FDA approved, analytically validated CTC assay

15. Baseline CTC is prognostic in mCRPC patients treated with cytotoxic therapy

16. Conversion of CTC as predictor of overall survival

17. CTC enumeration vs PSA decline as predictor of overall survival

18. Clinical utility of biomarkers in prostate cancer, revisited Clinical scenarioExample DetectionPSA for early diagnosis PrognosisGleason score PredictionER positivity and hormone Rx; none exist for prostate cancer PharmacodynamicTestosterone for GnRH agonist Clinical surrogatePSA decline as tumor marker

19. Markers that correlate with docetaxel- sensitivity underexpressed in sensitive cell linesoverexpressed in sensitive cell lines

20. Actin SKP2 si-SKP2 si-NonTarget Causal relationship between SKP2 and docetaxel response

21. Conclusions PSA decline may be used as a surrogate marker for response (after 12 weeks)PSA decline may be used as a surrogate marker for response (after 12 weeks) Baseline levels of CTC are prognostic for OSBaseline levels of CTC are prognostic for OS Conversion of CTC correlates with OS but have not yet been qualified for individual patient useConversion of CTC correlates with OS but have not yet been qualified for individual patient use Further studies are needed to identify and validate predictive markersFurther studies are needed to identify and validate predictive markers