Robert Bristow MD PhD FRCPC Clinician-Scientist and Professor,

1. Robert Bristow MD PhD FRCPC Clinician-Scientist and Professor, Radiation Oncology and Medical Biophysics, Princess Margaret Hospital & University of Toronto Translational Studies and Clinical Outcome: Can We Personalized Prostate Cancer Treatment ? Princess Margaret Hospital University Health Network MBP1008-March 2011

2. General References: Basic Science of Oncology www.cancer.ca Cancer Stats www.cancer.gov Clinical Trials www.cancerguide.org Lay clinical trials Princess Margaret Hospital University Health Network

3. Lecture Outline • The Problem of Prostate Cancer • The Need for Translational Science • TNM Staging-a common language • Clinical Trials • Types and why they fail • Trial Endpoints • Survival Curves • Phase I, II and III trials • Biomarkers • PK and PD • Prognosis and Prediction • The tension between pre-clinical and clinical • science in biomarker development Princess Margaret Hospital University Health Network

4. Canadian ProstateCancer Statistics • In 2011: close to 25,000 men will be diagnosed with prostate cancer and more than 4,000 will die from it • On average, more than 400 men are diagnosed each week • Test at age 40-50 depending on risk factors • But there are different types of prostate cancer Princess Margaret Hospital University Health Network

5. The New Era of Prostate Cancer Research • The 20th century approach to cancer: Seek and destroy • The 21st century approach: target and control • Personalized genetic medicine • New diagnostic tests • New drugs • Best treatment for all patients • To treat patients with fewer side effects. • To prevent deaths in patients who are currently incurable. Princess Margaret Hospital University Health Network Princess Margaret Hospital University Health Network

6. The Last 10 Years “Decreased mortality for men with prostate cancer” • New technologies in biology and imaging • Fluorescence In Situ Hybridization (FISH) and DNA/RNA/Protein CHIPs to diagnose mutations (FISH and CHIPs !) • Use of MR techniques to predict tumour spread and response pre- and post-therapy • New biologic targets and new drugs • Challenge is to have individual biomarkers of response • Better use of PSA-DT and kinetic analyses to predict local resistance and systemic spread • Choose those patients who require local and systemic therapy • Select best patients for best salvage therapies • 10 years of improved technology: • Hypofractionation, precision targeting, IMRT, robotics, HIFU, cryotherapy, sub-prostate targeting, less side-effects A CATALOGUE OFPERSONAL GENETICS Princess Margaret Hospital University Health Network

7. Treatment Options & Side Effects Indolent Disease Active Disease Aggressive Disease Hormone Therapy (injections/tablets) Surgery = Radical Prostatectomy WATCH THE PSA CAREFULLY Robots or laprascopic “Active Surveillance” Radiotherapy or brachytherapy (seeds) Chemotherapy Combinations Increasing Stage and Aggression Princess Margaret Hospital University Health Network

8. Prostate Cancer Basics: DRE and PSA Age and race-adjusted cut-off values for PSA Age Caucasians Blacks Asians 40-49 2.5 2.0 2.0 50-59 3.5 4.0 3.0 60-69 4.5 4.5 4.0 70-80 6.5 5.5 5.0 Source: Prostate Cancer A Guide for Patients, by Dr. Laurence Klotz Princess Margaret Hospital University Health Network

9. PSA and Official NIH Definition of “Biomarkers” • A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacological responses to a therapeutic intervention Biomarkers Definitions Working Group, 2001 Princess Margaret Hospital University Health Network

10. Prostate Cancer: Some Basics Risk factors: age, family history, high-fat diet, African ancestry Currently, the extent and prognosis of prostate depends on: (1) a digital rectal exam (DRE) and spread of disease (TNM) (2) the prostate specific antigen (PSA) blood test (3) the pathologic grade (Gleason score) Princess Margaret Hospital University Health Network

11. TNM Staging Princess Margaret Hospital University Health Network

13. Translation: What Other Pieces of Information Do We Need ? Princess Margaret Hospital University Health Network

14. Failure ~ 30 % Metastatic: Aggressive Disease Low Risk = Indolent Disease Intermediate/High Risk: Active Disease “Active Surveillance” Hormone Therapy & Chemotherapy Surgery or Radiotherapy DO NOT TREAT ! Current: PSA, TNM and Gleason Score Predict occult metastases for adjuvant Tx Provide best local treatment Additional Role Of Genetic Analyses: Predict indolent disease Prevent over-treatment Predict castrate resistant disease Personalize chemotherapy Princess Margaret Hospital University Health Network

15. Lecture Outline • The Problem of Prostate Cancer • The Need for Translational Science • TNM Staging-a common language • Clinical Trials • Types and why they fail • Trial Endpoints • Survival Curves • Phase I, II and III trials • Biomarkers • PK and PD • Prognosis and Prediction • The tension between pre-clinical and clinical • science in biomarker development Princess Margaret Hospital University Health Network

16. Factors Determining Trial Design Availability of Resources Degree of Certainty Number of Experimental Agents/Regimens Adequacy of Historical Experience Princess Margaret Hospital University Health Network

17. Stages of New Drug Development Drug Discovery Preclinical Evaluation (In vitro/in vivo testing; toxicity; pharmacology; formulation) Phase I (dose and toxicity finding) Phase II (efficacy testing) Phase III (comparative) Phase IV (post marketing) Princess Margaret Hospital University Health Network

18. Clinical Trials • Prevention trials: What kinds of interventions—such as lifestyle • modifications, dietary supplements, or drugs—can prevent • cancer from occurring? • • Screening and early detection trials: What tests can find cancer • as early as possible in healthy people? • • Diagnostic trials: How can new tests or procedures identify a • suspected cancer earlier or more accurately ? • • Genetics trials: Can gene-transfertherapybeusedtotreatcancer? • • Treatment trials: What new interventions (e.g., drugs, biologics, • surgical procedures, radiation) can help people who have cancer? • • Quality-of-life and supportive care trials: What kinds of • interventions can improve the comfort and quality of life of people who have cancer? Princess Margaret Hospital University Health Network

19. Response Criteria (RECIST criteria): Measures tumor shrinkage in response to treatment and how long that shrinkage lasts. Response is the typical main endpoint for phase II trials, and is frequently measured in other trials as well.
 * Complete Response (CR): Disappearance of all target lesions * Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD * Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Princess Margaret Hospital University Health Network

20. T3 Prostate Cancer: Surgery Alone Van Poppel and colleagues, Eur Urol, 2007 Princess Margaret Hospital University Health Network

21. High-Risk CaP and Radiotherapy Alone >2000pts; Zelefsky et al; IJROBP-2008) • Better local control led to decreased metastases Princess Margaret Hospital University Health Network

22. Every Week the Same Question SO WHICH IS BETTER ? SURGERY OR RADIOTHERAPY FOR PROSTATE CANCER ? And why? Princess Margaret Hospital University Health Network

23. Clinical Trial Response Endpoints Response; but also…….. Local Control: For local therapies (radiotherapy and surgery), complete removal or ablation of the tumour without any regrowth at the local site. Disease-Specific and Overall Survival: A typical main endpoint (survival is important!) for phase III and adjuvant trials.
 Progression Free Survival (disease is there without progression) and Disease Free Survival (disease is not there-adjuvant setting; then it recurs): Measures the length of time that a patient is both alive and without worsening of their cancer. These are typical endpoints for phase III and adjuvant trials.
 Quality of Life: Based on subjective measures of how well the patient is functioning and enjoying life. Princess Margaret Hospital University Health Network

24. Kaplan-Meier Curves for Survival Series of “steps” in which each step is a patient who drops out of the study cohort due to an “event” (death, recurrence). A “tick” shows where the data where censored for a patient lost to follow-up Princess Margaret Hospital University Health Network

25. Kaplan-Meier Analysis • The goal is to estimate survival within a population of patients from • sampling patients over time • If every patient is followed until death, the survival curve would be • estimated by computing the fraction surviving at any one time • However in most studies, patients tend to drop out and therefore the • time of study will differ between patients (why is there drop out?) • A Kaplan-Meier analysis allows estimation of survival over time, • even when patients drop out or are studied for different lengths of time Princess Margaret Hospital University Health Network

26. Patients Start and Stop Within a Clinical Trial: Need a Way to Compare the Results KM Lam, Vanderbilt

27. KM Lam, Vanderbilt Princess Margaret Hospital University Health Network

28. KM Lam, Vanderbilt

29. Plateau Time to Zero X X

30. Types of Cancer Clinical Trials In a Phase I Trial, the first phase of testing, a new drug or treatment is tried in humans for the first time ever. The goal of the Phase I trial is not to see how well a new treatment works but rather just to discover how much of the drug can be given safely, and to understand its side effects and chemistry in the body. Is it toxic ? In a Phase II Trial, the new treatment is tested to see if it can shrink tumors in patients with a particular type of cancer using the dose and schedule set during the prior Phase I trial. This is the first test of efficacy Is it worth pursuing ? In a Phase III Trial, the new treatment is compared to the standard treatment to see which produces better survival. Phase III trials are normally randomized - half the patients are randomly selected to get the new treatment, and half the standard treatment. The survival of the two groups is then compared to determine which treatment was best. In some cases, Phase III trials compare two standard treatments or two new treatments. Phase III trials are not limited to patients with advanced cancer, but may be a consideration at any stage Is it better than current treatment ? Princess Margaret Hospital University Health Network

31. Princess Margaret Hospital University Health Network

32. Randomization (Blinding and Stratification) Princess Margaret Hospital University Health Network

33. Types of Cancer Clinical Trials Adjuvant Trials are tests of additional treatment intended to reduce the risk of recurrence after initial treatment (usually surgery or radiotherapy) for apparently localized disease. There is no detectable disease and it is given after the initial treatment = extra insurance that the tumour does not recur. Most adjuvant trials are basically a special type of Phase III trial, and are randomized, but the considerations in choosing one are different enough that they deserve a separate discussion Neoadjuvant-systemic treatment before the local treatment (e.g. chemotherapy or hormone therapy before surgery or radiotherapy) (why do this ?) Concurrenttreatment-treatments given at the same time (e.g. chemotherapy or hormone therapy and radiotherapy) (why do this ?) Princess Margaret Hospital University Health Network

34. Treatment option for high-risk/locally advanced prostate cancer One standard of care is pelvic + prostatic radiotherapy + concurrent/adjuvant hormonal therapy for 2-3 years. EORTC 22863 415 pts RTOG 85-31, 977 pts RTOG 86-10, 451 pts RTOG 94-13 1310 pts SPCG-7/ 875 pts SFUO-3 Bolla et al Lancet 2002 360:103-106 Median fu 66 month; 16% OS advantage 78% vs 62% Princess Margaret Hospital University Health Network

35. Elements of a Trial Protocol Princess Margaret Hospital University Health Network

36. Princess Margaret Hospital University Health Network

37. Success Rate: from First-in-Man to Registration Data from 10 biggest drug companies from 1991-2000 Kola and Landis, Nat Rev 2004 Princess Margaret Hospital University Health Network

38. Reasons for Attrition 1991-2000 Lack of efficacy (30%) + toxicology/clinical safety (30%) = 60% Kola and Landis, Nat Rev 2004 Princess Margaret Hospital University Health Network

39. BIOBREAK Princess Margaret Hospital University Health Network

40. Lecture Outline • The Problem of Prostate Cancer • The Need for Translational Science • TNM Staging-a common language • Clinical Trials • Types and why they fail • Trial Endpoints • Survival Curves • Phase I, II and III trials • Biomarkers • PK and PD • Prognosis and Prediction • The tension between pre-clinical and clinical • science in biomarker development

41. Gaps in New Agent (Drugs, RT, Combos) Trial Development More intelligent and coordinated biomarker research Better understanding of oncogenic pathways and their potential for therapeutic targeting Preclinical models that better predict for safety and efficacy More efficient clinical trial designs and methods Clinical DevelopmentPhase I, II, III Preclinical Development Approval and Marketing Drug Discovery

42. Biology-Driven Phase II Trials Princess Margaret Hospital University Health Network Andrei et al; JCO, 2011

43. Use of Lab Correlates In Clinical Trials • Should be driven by sound scientific rationale • Phase I: • Proof-of-mechanism • Establish optimal biological dose in some trials (especially if little or no toxicity expected) • Phase II: • Predictive markers (difficult to distinguish between sensitivity to treatment vs tumor biology [i.e. prognostic markers], as all pts receive study drug if single-arm trials) • Pharmacodynamic markers in a more homogeneous population • Phase III: • Predictive markers of outcome and toxicity • Important to ensure that pts with available specimens are similar to those without

44. Lecture Outline • The Problem of Prostate Cancer • The Need for Translational Science • TNM Staging-a common language • Clinical Trials • Types and why they fail • Trial Endpoints • Survival Curves • Phase I, II and III trials • Biomarkers • PK and PD • Prognosis and Prediction • The tension between pre-clinical and clinical • science in biomarker development GET OUT THEREAND TRANSLATE ! Princess Margaret Hospital University Health Network