Robert Bristow MD PhD FRCPC

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Translational Studies and Clinical Outcome Can
We Personalized Prostate Cancer Treatment ?

• Robert Bristow MD PhD FRCPC
• Clinician-Scientist and Professor,
• Radiation Oncology and Medical Biophysics,
• Princess Margaret Hospital University of Toronto

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MBP1008-March 2011
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General References Basic Science of
Oncology www.cancer.ca Cancer Stats www.cancer.g
ov Clinical Trials www.cancerguide.org Lay
clinical trials
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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

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Canadian Prostate Cancer 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

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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.

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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
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Treatment Options Side Effects
Indolent Disease
Aggressive Disease
Active Disease
Surgery Radical Prostatectomy
Hormone Therapy (injections/tablets)
WATCH THE PSA CAREFULLY
Robots or laprascopic
Active Surveillance
Radiotherapy or brachytherapy (seeds)
Chemotherapy
Combinations
Increasing Stage and Aggression
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Prostate Cancer Basics DRE and PSA
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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
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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)
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TNM Staging
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(No Transcript)
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Translation What Other Pieces of Information Do
We Need ?
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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
Predict indolent disease Prevent over-treatment
Additional Role Of Genetic Analyses
Predict castrate resistant disease Personalize
chemotherapy
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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

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Factors Determining Trial Design
Availability of Resources
Degree of Certainty
Number of Experimental Agents/Regimens Adequacy
of Historical Experience
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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)
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Clinical Trials

• Prevention trials What kinds of
  interventionssuch as lifestyle
• modifications, dietary supplements, or drugscan
  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-transfertherapybeusedt
  otreatcancer?
• 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?

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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
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T3 Prostate Cancer Surgery Alone
Van Poppel and colleagues, Eur Urol, 2007
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High-Risk CaP and Radiotherapy Alone gt2000pts
Zelefsky et al IJROBP-2008)

• Better local control led to decreased metastases

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Every Week the Same Question SO WHICH IS BETTER
? SURGERY OR RADIOTHERAPY FOR PROSTATE CANCER
? And why?
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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.
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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
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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

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Patients Start and Stop Within a Clinical
Trial Need a Way to Compare the Results
KM Lam, Vanderbilt
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KM Lam, Vanderbilt
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KM Lam, Vanderbilt
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Plateau
Time to Zero
X
X
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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 ?
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Randomization (Blinding and Stratification)
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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-systemi
c treatment before the local treatment (e.g.
chemotherapy or hormone therapy before surgery or
radiotherapy) (why do this ?) Concurrent
treatment-treatments given at the same time (e.g.
chemotherapy or hormone therapy and radiotherapy)
(why do this ?)
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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 360103-106
Median fu 66 month 16 OS advantage 78 vs 62
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Elements of a Trial Protocol
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Success Rate from First-in-Man to Registration
Data from 10 biggest drug companies from 1991-2000
Kola and Landis, Nat Rev 2004
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Reasons for Attrition 1991-2000
Lack of efficacy (30) toxicology/clinical
safety (30) 60
Kola and Landis, Nat Rev 2004
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BIOBREAK
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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

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Gaps in New Agent (Drugs, RT, Combos) Trial
Development
Clinical DevelopmentPhase I, II, III
Preclinical Development
Approval and Marketing
Drug Discovery
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Biology-Driven Phase II Trials
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Andrei et al JCO, 2011
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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

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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 !
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