A Prospective Multi-center Observational Trial to Assess Persistence on Active Surveillance When Using the OncotypeDX® Prostate Cancer Assay
Conditions: Prostate Cancer
Sponsor: Genomic Health®, Inc.

NCT NUMBER: NCT03502213 
STUDY TITLE: A PROSPECTIVE MULTICENTER 
OBSERVATIONAL TRIAL TO ASSESS PERSISTENCE 
ON ACTIVE SURVEILLANCE WHEN USING THE 
ONCOTYPE DX® PROSTATE CANCER ASSAY 
DATE OF DOCUMENT 24APR2014 

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STUDY PROTOCOL 
A PROSPECTIVE MULTICENTER OBSERVATIONAL TRIAL TO ASSESS 
PERSISTENCE ON ACTIVE SURVEILLANCE WHEN USING THE 
ONCOTYPE DX® PROSTATE CANCER ASSAY  
Development Study Number: 
09-023 
Medical Monitor: 
Béla Denes, M.D. 
Sr. Director, Medical Affairs, Urology 
Genomic Health, Inc.  
Phone: (650) 569-5692 
Fax: (650) 556-1132 
Email:  bdenes@genomichealth.com 

 
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STUDY PROTOCOL 
A PROSPECTIVE MULTICENTER OBSERVATIONAL TRIAL TO ASSESS 
PERSISTENCE ON ACTIVE SURVEILLANCE WHEN USING THE 
ONCOTYPE DX® PROSTATE CANCER ASSAY  
 
 
 
Genomic Health Approvals: 
 
 
 
 
 
_________________________________________  
____________________ 
Phillip Febbo, M.D.  
 
 
 
 
 
Date 
Chief Medical Officer 
Genomic Health, Inc. 
 
 
 
 
 
_________________________________________  
__________________ 
Carl Yoshizawa, Ph.D. 
 
 
 
 
 
Date 
Vice President, Clinical Biostatistics 
Genomic Health, Inc. 
 
 

 
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STUDY PROTOCOL 
A PROSPECTIVE MULTICENTER OBSERVATIONAL TRIAL TO ASSESS 
PERSISTENCE ON ACTIVE SURVEILLANCE WHEN USING THE 
ONCOTYPE DX® PROSTATE CANCER ASSAY  
Signature of Agreement for Protocol 
 
I declare that I have read this protocol and I agree to conduct the study as described in the 
following document. 
I will provide a copy of this protocol and all pertinent and relevant information to all those 
persons responsible for collaborating in the execution of the study.  I will review and discuss the 
material with all of them in order to assure myself of their cognizant and complete information 
with respect to the study and its execution. 
 
 
 
 
____________________________________________ 
_______________ 
 
Béla Denes, M.D. 
  
Date 
Senior Director, Medical Affairs, Urology 
Genomic Health, Inc. 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY 
 
The information contained in this document is the confidential and proprietary information of 
Genomic Health, Inc. 
Except as may be required by Federal, State, or local laws or regulations, this document 
may not be disclosed to others without written permission of Genomic Health. 
 
 

 
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DOCUMENT HISTORY 
Version 
Date 
Replaces 
Description of Change 
1.0 
 
N/A 
New issue 

 
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TABLE OF CONTENTS 
1. 
BACKGROUND INFORMATION .....................................................................................8 
1.1 
Overview ......................................................................................................................8 
1.2 
Oncotype DX Prostate Cancer Assay Development and Validation ...............................8 
2. 
OBJECTIVES .................................................................................................................... 10 
2.1 
Primary Objective ....................................................................................................... 10 
2.2 
Secondary Objectives .................................................................................................. 11 
3. 
Physician and Patient Eligibility ......................................................................................... 12 
3.1 
Pre-Study Physician Requirements .............................................................................. 12 
3.2 
Patient Management Plan ............................................................................................ 12 
3.3 
Inclusion Criteria ........................................................................................................ 12 
3.4 
Exclusion Criteria ....................................................................................................... 13 
3.5 
Target Enrollment ....................................................................................................... 13 
3.6 
Selection of Treatment Sites ........................................................................................ 14 
4. 
STUDY DESIGN............................................................................................................... 14 
4.1 
Duration of Study ........................................................................................................ 14 
5. 
MATERIALS AND METHODS........................................................................................ 15 
5.1 
Pathology Assessment ................................................................................................. 16 
6. 
STUDY CALENDAR and assessments .............................................................................. 16 
7. 
Statistical analysis METHODS .......................................................................................... 18 
7.1 
Risk group and endpoint definitions ............................................................................ 18 
7.2 
Statistical Analysis of Primary Endpoint ..................................................................... 19 
7.3 
Statistical Analysis of the Impact of GPS on the Shared Decision ............................... 19 
7.4 
Statistical Analysis of Other Secondary Endpoints ...................................................... 20 
7.5 
Planned Interim Analyses ............................................................................................ 21 
8. 
SAMPLE SIZE JUSTIFICATION ..................................................................................... 21 
9. 
DATA MANAGEMENT ................................................................................................... 22 
9.1 
Data Delivery .............................................................................................................. 22 
9.2 
Data Administration .................................................................................................... 22 

 
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9.3 
Data Security .............................................................................................................. 22 
10. ETHICS AND REGULATORY ISSUES ........................................................................... 22 
10.1 
Informed Consent .................................................................................................... 22 
10.2 
Committees on Ethics and Research ........................................................................ 22 
10.3 
Protocol Amendments ............................................................................................. 23 
10.4 
Confidential Information ......................................................................................... 23 
11. REFERENCES .................................................................................................................. 24 
Appendix A:  SITE INVESTIGATOR INITIATION FORM .................................................. 26 
Appendix B:  
Principal Investigator Protocol Signature page .................................................. 27 
Appendix C:  
Actuarial Life Table ......................................................................................... 28 
 
 
 
 

 
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DEFINITIONS AND ACRONYMS 
 
Term 
Definition 
ADT 
Androgen Deprivation Therapy 
AS 
Active Surveillance 
ASCO 
American Society of Clinical Oncology 
AUA 
American Urological Association 
CaPSURE™ 
Cancer of the Prostate Strategic Urologic Research Endeavor  
CI 
CRF 
Confidence Intervals 
Case Report Form 
DX 
Diagnosis 
EBRT 
External Beam Radiation Therapy 
 
ECOG 
EDC 
Eastern Cooperative Oncology Group 
Electronic Data Capture 
FDR 
False Discovery Rate 
GG 
Gleason Grade 
GHI 
Genomic Health, Inc. 
GPS 
Genomic Prostate Score 
GS 
Gleason Score 
IRB 
Institutional Review Board 
LND 
LTFU 
Lymph Node Dissection 
Lost to Follow Up 
NCCN 
National Comprehensive Cancer Network 
OR 
Odds Ratio 
PRO 
PSA 
Patient Reported Outcomes 
Prostate Specific Antigen 
QoL 
RNA 
Quality of Life 
Ribonucleic Acid 
RP 
Radical Prostatectomy 
RT-PCR 
Reverse transcription polymerase chain reaction 
UCSF-CAPRA 
University of California San Francisco- Cancer of the 
Prostate Risk Assessment 

 
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1. BACKGROUND INFORMATION 
1.1 Overview 
Prostate cancer remains the most common solid organ malignancy in American men, with an 
estimated 238,590 new cases diagnosed in 2013 and an estimated 29,720 cancer-related 
deaths.(1) Prostate cancer screening through the use of prostate specific antigen (PSA) has 
dramatically increased the number of men diagnosed with prostate cancer annually, with 
most of the additional cases representing early stage disease.  A large majority of men with 
early stage prostate cancer are receiving definitive treatment with radical prostatectomy (RP) 
or radiation therapy.  Although some studies indicate that the early diagnosis and treatment 
of prostate cancer is associated with a decrease in prostate cancer specific mortality,(2) over 
1,000 men had to be screened and 37 cancers detected to prevent a single death from prostate 
cancer.(3) This has led to controversy around over-treatment of many cases of indolent 
disease, resulting in needless morbidity and increased healthcare costs.  These concerns 
regarding the over-diagnosis and over-treatment of early-stage prostate cancer have 
contributed to the recent recommendation by the US Preventive Task Force against PSA 
screening.(4) 
Thus, many men diagnosed with prostate cancer in the PSA-screening era have a clinically 
indolent form of cancer that does not require immediate treatment and could instead be 
managed with active surveillance (AS) withholding treatment for curative intent if there are 
signs of progression.   The uptake of this strategy, however, has been  limited, with  < 10 % 
of patients diagnosed with low-risk prostate cancer  managed with AS according to a recent 
CaPSURE™ registry survey.(5) A significant limitation to the use of AS is the uncertainty 
amongst clinicians regarding the accuracy of the current tools used to identify patients with 
low-risk disease (see (6) for review).  A major limitation is the limited nature of biopsy 
sampling with several studies demonstrating GS upgrading in a substantial proportion of 
cases (20-60%), from GS 6 on biopsy to GS 7 and even GS 8 at RP. (7-9)  
There is clearly a need for the development of new clinical tools that will allow for 
identification of biological characteristics that translate to a more accurate risk assessment for 
an individual patient’s prostate cancer.   A tool to reliably identify patients with clinically 
indolent prostate cancer would improve selection of patients with low risk disease who can 
be confidently managed by AS, have greater confidence and improved persistence on AS, 
and avoid the potential side effects and complications of unnecessary interventions. 
Alternatively, men found to be at increased risk of harboring aggressive disease could be 
directed towards immediate treatment with curative intent.  
1.2 Oncotype DX Prostate Cancer Assay Development and Validation  
Genomic Health has applied the development approach from its prior breast and colon cancer 
programs to develop a biopsy-based genomic assay to discriminate clinically indolent from 

 
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aggressive prostate cancer.  These development efforts were initiated with a series of 
feasibility studies which (1) established the ability to extract ribonucleic acid (RNA) of 
sufficient quantity and quality from prostate tumor tissue, (2) demonstrated the need for 
manual microdissection to enrich for prostate tumor tissue, and (3) identified prostate tissue-
specific reference genes. Subsequent studies were used to identify genes associated with 
aggressive prostate cancer, refine the gene list based on the analytic and performance 
characteristics in prostate biopsies, and the selection of a defined set of genes and algorithm 
to produce a Genomic Prostate Score (GPS). The GPS was subsequently tested and found to 
provide independent information beyond the conventional clinical and pathologic factors to 
confidently identify men with low risk features who are appropriate candidates for AS.   
These later development studies are discussed below. 
Gene identification study 
 
A study was conducted to identify genes whose expression was associated with clinical 
recurrence, biochemical recurrence and death from prostate cancer.(10)  Of 2,641 subjects 
with clinical stage T1/T2 cancer who underwent RP at Cleveland Clinic from 1987 to 2004, a 
cohort sampling design was used to select 127 subjects with clinical recurrence (both local 
and metastatic) and 374 subjects without clinical recurrence after surgery. RNA was 
extracted from fixed paraffin-embedded tissue sections obtained from the prostatectomy 
specimens; two regions of each tumor were sampled – one representing the predominant 
Gleason Grade (GG) and the other representing the highest GG.  The expression of 732 
cancer-related and 6 reference genes was quantified using Reverse Transcription Polymerase 
Chain Reaction (RT-PCR) in 441 subjects with evaluable tumor blocks.   
 
After adjustment for baseline PSA, biopsy GS, and clinical stage, 288 genes remained 
strongly associated (False Discovery Rate (FDR) < 10%) with clinical recurrence in both 
specimens.  Gene groups representative of pathways including stromal response, cellular 
organization, androgen, and proliferation also predicted high-grade/non-organ-confined 
disease at RP, biochemical recurrence and prostate cancer-specific survival. Thus, gene 
expression analysis using quantitative RT-PCR identified a large number of genes that were 
strongly associated with aggressive disease, whether assessed in the predominant or highest 
GS pattern tumor.   
 
Gene refinement study in prostate biopsy specimens 
 
For gene refinement, a second study was performed in diagnostic biopsy tissue from 167 
subjects with American Urological Association (AUA) low- (92 subjects) and intermediate-
risk (75 subjects) disease who had undergone RP.  Eighty-one genes selected from the gene 
discovery study were assessed for their association with high-grade and/or non-organ-
confined disease at subsequent RP.  Of the 176 subjects in this study, 58 (35%) had adverse 
pathologic features at RP, including 36 with high grade (major pattern 4 or any pattern 5) 

 
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disease and 42 subjects with non-organ-confined (pathologic T3) disease.  Quantitative RT-
PCR analysis of tumor from fixed paraffin-embedded prostate needle biopsy tissue revealed 
that most of the genes (58/81, 72%) identified in the gene discovery study were also 
predictive of high-grade or non-organ confined disease at RP from this separate cohort of 
subjects (FDR<10%).(11) 
 
The UCSF clinical validation study 
 
Using the data from these prior studies, a final algorithm with 12 prognostic and 5 reference 
genes was constructed to yield an individualized Genomic Prostate Score (GPS) from 
prostate needle biopsy tumor tissue.  This finalized assay (Oncotype DX Prostate Cancer 
Assay) was recently evaluated in a clinical validation study in collaboration with the 
University of California, San Francisco (UCSF).  Biopsy specimens from men with early 
stage prostate cancer who underwent subsequent RP were tested with the Oncotype DX 
Assay to determine if the GPS was predictive of adverse pathological findings at RP, 
specifically high grade (major pattern 4 or any pattern 5), and/or non-organ confined disease 
(pT3, lymph node positivity).   
 
Prostate cancer patients who were treated with RP for low or low-intermediate risk prostate 
cancer were eligible. Central review of biopsy and RP pathology was required. GPS, on a 0-
100 scale, was assessed by quantitative RT-PCR in manually microdissected biopsy tumor 
tissue.  Univariate and multivariable logistic regression was used to test association with 
adverse pathology (high grade and/or non-organ confined disease). Of 412 eligible men, 123 
(31%) had adverse pathology.  GPS predicted adverse pathology (p=0.002) controlling for 
biopsy GS.  GPS predicted both high grade (Odds Ratio (OR) 2.3 per 20 GPS units, p<0.001) 
and pT3 (OR 1.9 per 20 GPS units, p=0.003) disease. In multivariable analysis, GPS strongly 
predicted adverse pathology (p<0.005) after controlling for the University of California- 
Cancer of the Prostate Risk Assessment (UCSF-CAPRA) score or other standard 
pretreatment factors (alone or in combination). Thus, the GPS is a validated, biopsy-based 
predictor of adverse prostate cancer pathology in men with clinically apparent low risk 
disease.  
2. OBJECTIVES 
The primary goal of this prospective study is to assess the rate of persistence on Active 
Surveillance (AS) in men who choose AS after receiving the Oncotype DX Prostate Cancer GPS. 
2.1 Primary Objective 
2.1.1 
To assess the rate of persistence on AS at 1 and 2 years after receiving the 
Oncotype DX Prostate Cancer GPS 
 

 
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2.2 Secondary Objectives 
2.2.1 
To assess persistence rates on AS at 1 and 2 years by biologic risk grouping as 
determined by NCCN and GPS 
2.2.2 
To assess persistence rates on AS at 1 and 2 years by NCCN risk group (Very 
Low, Low and Low-Intermediate) risk disease 
2.2.3 
To estimate the incidence of specific outcomes during surveillance, including 
progression based on biopsy pathology, exit from study, and death from all 
causes  
2.2.4 
To characterize physician and patient reported perceived value of GPS at the 
time of physician-patient shared treatment decision 
2.2.5 
To assess the association between initial treatment selection and risk 
assessment based on NCCN and GPS  
2.2.6 
To characterize the impact of GPS on the physician-patient shared decision 
2.2.7 
To assess change in quality of life (QoL) patient reported outcomes (PRO) in 
AS patients at 12 and 24 months compared to baseline and in patients choosing 
immediate treatment at 12 months 
2.2.8 
To compare measures of QoL in patients selecting AS to patients selecting 
immediate treatment at 12 months 
2.2.9 
To characterize the intensity of surveillance as measured by frequency and time 
intervals of clinical assessments and their relationship to GPS 
2.2.10 To assess the association between GPS and locally determined adverse RP 
pathology in men choosing immediate treatment   
 
 
 

 
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3. PHYSICIAN AND PATIENT ELIGIBILITY 
Prior to enrolling any patients into the study, the principal investigator (PI) and all participating 
investigators at each site must complete the Site PI Initiation Form (see Appendix A).  The site 
PI must acknowledge and sign the Protocol Signature Page (see Appendix B).  These forms must 
be completed at the beginning of the study.   
3.1 Pre-Study Physician Requirements  
In order to review the implications of GPS on treatment decisions at all sites regardless 
of prior use of GPS, each participating physician will be required to take part in a 
review of the clinical development and validation data of the assay and a detailed 
review of the protocol.  After participating physicians have completed their training 
sign-off and have IRB approval, the site may begin to enroll patients in this study. 
3.2 Patient Management Plan 
3.2.1 
Identification of Potentially Eligible Subjects:  Patients with very low, low, 
and low-intermediate risk prostate cancer (as defined in section 3.3.2 below) 
may be eligible for this study. 
3.3 Inclusion Criteria 
3.3.1 
Physicians: Each of the criteria in the following section must be met in order 
for a physician to be considered eligible for registration:  
3.3.1.1 The physician is a urologist who makes primary treatment 
recommendations for patients with localized prostate cancer. 
3.3.1.2 The physician must practice at a facility or group practice that consults 
on at least 25 newly diagnosed prostate cancer patients per year who 
are very low, low, or intermediate risk as per NCCN guidelines 
(NCCN V3, 2012)  
3.3.1.3 The physician must practice in a group or setting that is experienced in 
offering AS.  The Principal Investigator (PI) at each participating site 
must complete the Site Principal Investigator Initiation Form and 
Protocol signature page. 
3.3.1.4 The physician must participate in a review of Oncotype DX Prostate 
Cancer Assay information and training materials, including assay 
development and validation data. 
3.3.1.5 The physician and participating site staff (including pathology if 
available) must participate in a review of this protocol including 
patient eligibility and protocol related training materials. 
3.3.2 
Patients: Patients eligible for this study will have been newly diagnosed with 
prostate cancer within the last 3 months, with no treatment decision made, and 

 
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meet all Inclusion criteria and no Exclusion criteria. Eligible patients include 
those with:  
• Clinical stage T1/T2 
• PSA < 20ng/mL 
• Biopsy GS < 6 with any number of cores positive, or Biopsy GS 3+4 
disease with ≤3 positive cores or ≤ 33% positive cores 
• The patient must be > 50 years of age 
• The patient must have a life expectancy of > 10 years, based on the 
Social Security Actuarial Life Table (see Appendix C). 
• The patient must be able to give consent in English or Spanish 
3.4 Exclusion Criteria   
3.4.1 
Physicians are excluded from participating if they are: 
3.4.1.1 Not responsible for the care of newly diagnosed prostate cancer 
patients who are candidates for AS 
3.4.2 
Patients are excluded from participating if they have/are any one of the 
following: 
3.4.2.1 Clinical stage T3a or above  
3.4.2.2 PSA > 20ng/mL 
3.4.2.3 Biopsy GS 4+3 or > 8 
3.4.2.4 Known metastatic prostate cancer (bone, lymph node etc.) 
3.4.2.5 Positive biopsy for prostate cancer > 3months ago  
3.4.2.6 Treatment decision has already been made 
3.4.2.7 Insufficient tumor in prostate biopsy tissue to perform the assay 
3.4.2.8 Treatment with androgen deprivation therapy (ADT) prior to prostate 
biopsy 
3.4.2.9 Diagnosis made by transurethral resection of prostate (TURP) shavings 
3.4.2.10 Any psychiatric or psychological condition, such as depression or 
anxiety, that would impede the patient’s ability to give informed 
consent 
3.4.2.11 Contraindications to primary treatment according to physician’s 
judgment 
3.5 Target Enrollment  
3.5.1 
This study is targeted to enroll approximately 1200 patients, with no 
investigator contributing more than 50 patients. 
 

 
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3.6 Selection of Treatment Sites 
This study will be conducted at approximately 25 large community based urology group 
practices and 5 academic sites in the United States.  Site selection was based on: 
3.6.1 
Projected volumes of new prostate cancer cases per month who meet inclusion 
criteria 
3.6.2 
Experience with AS 
3.6.3 
The site’s ability to conduct clinical studies in prostate cancer, including 
sufficient research personnel, experience, and infrastructure to obtain patient 
consent, manage questionnaires, and capture and transmit data to a central 
research coordinator 
3.6.4 
Expeditious contracting and IRB process 
4. STUDY DESIGN 
This is a multicenter observational study that evaluates eligible patients who will submit 
prostate cancer diagnostic biopsy tissues for Oncotype DX Prostate Cancer Assay testing. At 
visit 1a, the patient consents to the trial, a pre-assay physician treatment recommendation 
will be made along with additional assessments defined in Section 6, Table 1, and the assay 
is ordered.  At Visit 1b, the physician will review clinical data, the GPS report and discuss 
treatment options with the patient.  At the following visit, Visit 1c, a shared physician-patient 
treatment decision (immediate treatment or AS) will be made. 
 
Men selecting immediate treatment will be contacted one year from date of diagnosis biopsy 
to document treatment received and to assess treatment satisfaction and Quality of Life 
(QoL) metrics. 
 
Men selecting AS as primary treatment will be followed to assess persistence on AS.   
There is no required or standardized AS protocol for this study and the intensity of 
surveillance will be at the discretion of the investigator. Patients will not be required, but 
may undergo a standard TRUS guided surveillance biopsy at one year. In this study, the 
Oncotype DX Prostate Cancer Assay will be assessed on the diagnostic biopsy only and will 
not be assessed on subsequent biopsies.  Patients will be queried at 12 and 24 months for 
assessment of decision satisfaction and Quality of Life metrics. 
 
4.1 Duration of Study 
Patients will be participating in the study from the time of consent until Visit 2 (Year 1) 
for those patients in the Immediate Treatment arm, and to Visit 4 (Year 2) for those 
patients in the AS arm.  Patient questionnaires will be completed at those defined time 
points in the schedule of assessments for this study.   

 
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4.1.1 
Early Termination/Withdrawal Procedures 
The following patient situations will result in screen failures and these patients 
will not be included in any analysis: 
• Patients who have signed a consent form, but for whom a sample was not 
sent to GHI 
• Patients who have signed a consent form and had a sample submitted to 
GHI, but for whom no GPS was generated 
 
Patients who sign a consent form and receive a valid GPS but do not choose 
either AS or immediate treatment at Visit 1c will be considered unevaluable. 
 
Patients who enter the study on the AS arm, and who subsequently decide to 
undergo treatment, will be required to complete the End of Study (EOS) visit 
assessments.  Those patients who are Lost to Follow Up (LTFU) will also have 
the EOS form completed.  LTFU patients are defined as those that have had at 
least 3 contact attempts over a one-month period.  Those patients who have 
been reported deceased or withdraw consent will also have the EOS form 
completed.   
5. MATERIALS AND METHODS 
The Oncotype DX Prostate Cancer Assay is a commercially available diagnostic test that is 
designed to aid in a physician’s treatment recommendation to a newly diagnosed prostate 
cancer patient.  All the necessary elements for the study (requisition forms, sample 

 
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preparation kits, shipping materials) will be provided by GHI and testing of all specimens 
will be performed at GHI at no charge to the patients or the clinical sites. Standard operating 
procedures will be followed at GHI when processing the specimens. 
 
Patient Reported Outcomes (PROs) will be assessed at specified visits.  These are 
questionnaire based, have been used in this disease state and include a pre and post GPS 
Decisional Conflict Scale, EPIC-CP; FACT-G and Decision Regret (12-15).  These are 
validated, self-administered, recall instruments and will be available in English and Spanish.   
5.1 Pathology Assessment 
Pathology review and specimen preparation will be performed according to GHI standard 
processes.  Biopsy specimens will be centrally reviewed at GHI to ensure that they meet 
histologic inclusion criteria.  RP specimens will not be centrally reviewed in this study.  The 
local assessment of Gleason score and pathologic stage will be collected.   
 
6. STUDY CALENDAR AND ASSESSMENTS 
Site Specific Assessments and Forms: 
The following forms will be collected during the course of the study: Site Principal 
Investigator Initiation Form, Site Principal Investigator Protocol Signature Page, Enrollment 
Log and Non-Enrollment Log. Instructions for the completion and submission of these forms 
will be provided by GHI.   
 
Assessments and Forms for each Enrolled Patient: 
After a patient consents to participate in this study, the assessments and forms listed in the 
table below will be completed by the treating physician and submitted to GHI as instructed.  
The Oncotype DX Prostate Cancer Assay is expected to report results within a 13-21 day 
turnaround time upon receipt of the tumor specimen at GHI’s laboratory. 
 
Completion of Forms for each Enrolled Patient: 
• Data is expected to be entered into the EDC (Electronic Data Capture) system within 
5 business days of the patient’s visit.   
• Queries are expected to be addressed and responded to within 5 days of issue.  
       Table 1:  Study Schema 
 
• Visits 1b and 1c may occur anytime within 4 months of consent (Visit 1a), as is 
suitable for the patient.  Subsequent visits (Visits 2, 3 and 4) are based on the duration 
from the date of biopsy, not from Visit 1a.   
 

 
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Assessments 
  
Visit 1a 
1b 
1c  
2 
M12  
3  
M18 
4 
M24 
End of 
Study      
Eligibility Criteria 
X 
  
  
  
  
  
  
Informed consent 
X 
  
  
  
  
  
  
GPS ordered 
X 
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
Clinical T-Stage and Physician 
Risk Assessment 
X 
  
  
 
  
 
  
Biopsy
1 
X 
  
  
X 
X 
X 
X 
PSA
1 
X 
  
  
X 
X 
X 
X 
DRE
1 
X 
  
  
X 
X 
X 
X 
FACT-G 
X 
 
  
X 
  
X 
  
EPIC-CP 
X 
 
  
X 
 
X 
  
Decisional Conflict Scale 
 
X
 2 
X
3 
  
  
  
  
Patient informed of GPS result 
  
X 
  
  
  
  
  
Decisional aids provided 
 X
4 
X5 
  
  
  
  
  
Physician Treatment 
Recommendation 
 X6 
  
  
  
  
  
Physician –Patient Shared 
Decision 
 
 
X 
 
 
 
 
Physician perceived value of 
GPS 
  
  
X 
 
  
  
  
Patient perceived value of GPS 
  
  
X 
 
  
  
  
Persistence on Active 
Surveillance 
  
  
  
X 
X 
X 
 
Regret 
  
  
  
X 
 
X 
  
End of Study7 
  
  
  
  
  
  
X 
Surgical Pathology8 
  
  
  
X 
  
  
  
 
1 completed at Visit 1a and any subsequent visit, if new results are available since prior visit 
2 administered before the patient sees the physician and obtains the GPS report. 
3 administered at completion of the visit after discussing the treatment options with physician 
4 disease specific decisional aid provided (i.e. AUA Prostate Cancer Brochure) 
5 Oncotype DX specific decisional aid provided (i.e. GPS Patient Brochure) 
6 completed before ordering the Oncotype DX prostate cancer assay 
7completed if a patient moves to immediate treatment, withdraws consent, does not get a valid GPS score, dies or is 
LTFU 
8 completed if surgery was performed on a patient who chose immediate treatment 
 

 
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7. STATISTICAL ANALYSIS METHODS 
7.1 Risk group and endpoint definitions 
7.1.1 
NCCN-based risk groups 
Clinical risk groups, based on the NCCN criteria (modification of NCCN V.3, 
2012), are defined as follows: 
Very Low: Gleason Score ≤6 and PSA<10 ng/ml and Clinical T1c and ≤2 
positive cores and <50% tumor in any core and PSA density <0.15 ng/ml/g. 
Low: Gleason Score ≤6 and PSA<10 ng/ml and Clinical T1c and not meeting 
criteria for Very Low 
Low-Intermediate:  Gleason Score 3+4 or PSA 10-20 ng/ml or Clinical T2 with 
either ≤3 positive cores or ≤33% positive cores. 
 
7.1.2 
Biological NCCN and GPS-based risk groups 
Biological risk groups, based on NCCN and GPS, are defined as follows: 
Very Low: probability of favorable pathology ≥79% 
Low: probability of favorable pathology 68-78% 
Low-Intermediate: probability of favorable pathology ≤67% 
Note that the probability of favorable pathology will be rounded to the nearest 
whole percent. 
 
7.1.3 
Adverse RP pathology 
RP pathology assessments will include Gleason score and pathologic T-stage. 
Adverse pathology is defined as high-grade and/or non-organ-confined disease 
as shown in the table below, where Gleason Score ≤ 3+3 or 3+4 and pT2 is the 
baseline category and all other categories are compared to the baseline 
category. 
 
Table 1: Definition of Adverse Pathology 
RP Gleason Score 
Pathologic T2 Stage 
Pathologic T3 Stage 
≤3+3 
Baseline Category 
Non-organ confined 
Disease 
3+4 
Major pattern 4 or 
any pattern 5 
High-grade 
High-grade and Non-
organ confined Disease 
 
High-grade disease at RP is defined as the presence of any major pattern 4 or 
any pattern 5 at RP. 

 
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Non-organ-confined disease is defined as pathologic T-stage (pT) pT3a or 
pT3b or nodal involvement where pT3a signifies extraprostatic extension 
(EPE) and pT3b signifies seminal vesicle involvement (SVI). 
 
7.2 Statistical Analysis of Primary Endpoint 
Persistence at 1 year will be described as the proportion of patients who remain on AS 
as of their 12 month visit. Specifically, this is defined as the number of patients who are 
documented as intervention-free at their 12-month visit (Visit 2) divided by the number 
of patients who chose AS at Visit 1c. Persistence at 2 years will be calculated in a 
similar manner.  Additional analysis will exclude the subjects who were lost to follow-
up or died before the 12-month (Visit 2) and 24-month (Visit 4) visits for analysis of 
the 1-year and 2-year persistence rates respectively.   Exact 95% confidence intervals 
for proportions will be calculated using the F-distribution method (16).   
 
Additionally, the proportion of men who experienced specific outcomes during 
surveillance, including definitive treatment, physician-reported biopsy findings, exit 
from the study, and death from all causes will be calculated as a crude proportion.  
Similar analyses will be conducted to estimate the proportion of patients who persist on 
AS by NCCN-based risk group (very low, low, and low-intermediate) and by biological 
risk group defined by NCCN and GPS (probability of favorable pathology ≥79%, 68-
78%, ≤67%). 
 
Kaplan-Meier methods will be used to estimate time on surveillance free of definitive 
treatment. Time zero will be defined as the diagnostic biopsy date and time on 
surveillance free of definitive treatment will be defined as time from diagnostic biopsy 
to definitive treatment. Patients who withdraw without evidence of definitive treatment 
or are lost to follow-up will be censored at the time of their last visit and those who died 
will be censored at the time of death.   
 
The aforementioned methods have been used in prominent AS literature to assess 
persistence on AS (17).  Because patients lost to follow-up could be drop-outs due to 
seeking definitive treatment elsewhere, alternative methods that account for informative 
censoring will be explored to evaluate the consistency of results.   
 
7.3 Statistical Analysis of the Impact of GPS on the Shared Decision 
The primary assessment of the impact of GPS on the shared treatment decision will be 
performed in the NCCN Low-risk subset of the first 300 patients enrolled in the study 
with valid GPS results.  The analysis will summarize the proportion of patients for 
whom the treatment recorded on the CRF changed from pre-assay to post-assay along 

 
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with a two-sided 95% confidence interval (CI). All treatment decision changes, 
including immediate treatment to AS and vice versa and changes in treatment modality 
will be characterized.  Additional analysis of decision changes will include changes to 
and from AS only.  Similar analysis will also be performed for all 300 patients to 
estimate an overall change rate across all NCCN risk groups. This analysis will be 
conducted as soon as 300 patients with valid GPS results and completed pre- and post-
assay CRFs have been accrued.  
 
7.4 Statistical Analysis of Other Secondary Endpoints 
 
Physician and patient-reported perceived value of GPS and patient-reported QOL 
outcomes will be summarized descriptively.  For QOL, comparisons over time and 
comparisons between patients selecting AS and patients selecting immediate treatment, 
will be summarized descriptively. 
 
To assess the association between initial treatment selection and risk assessment based 
on NCCN and GPS, the proportion of patients selecting AS will be summarized by 
NCCN-based risk group (very low, low, and low-intermediate) and biological risk 
group defined by GPS (probability of favorable pathology ≥79% , 68-78%, ≤67%).  
The expectation is that the observed proportion of patients selecting AS will decrease as 
both NCCN-based risk group and GPS biological risk increase.  Exploratory analysis 
will include evaluation of alternative biologic risk groupings based on different cut-
points for probability of favorable pathology. 
 
Descriptive statistics will be used to characterize the intensity of surveillance as 
measured by number of repeat biopsies, duration between initial and first surveillance 
biopsy, number of PSA tests, and number of DRE examinations,. The biopsy rate, PST 
testing rate, and DRE rate for patients who elect AS will be calculated as the number of 
biopsies, PSA tests, and DRE examinations per person per year, respectively.  The 
relationship between each of the aforementioned intensity measures and biological risk 
(NCCN and GPS) will also be graphically depicted. 
 
To assess the relationship between GPS and local adverse pathologic findings at RP in 
patients who chose RP after receiving the GPS, we will fit a univariable binary logistic 
regression model to the endpoint of adverse RP pathology as defined in section 7.1.3 
above.  We will also fit multivariable logistic regression models to assess the 
relationship of GPS to local adverse pathology at RP after adjusting for biopsy Gleason 
score, baseline PSA, or NCCN-based risk group.  From these analyses, we will obtain 
odds ratios with corresponding 95% confidence intervals.  We will use a likelihood ratio 

 
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test to evaluate if the GPS is significantly associated with the likelihood of adverse 
pathology at RP. A p-value <0.05 will be considered statistically significant.  Unlike the 
UCSF validation study where all specimens had central review of RP pathology, the 
endpoint being evaluated in this analysis is local RP pathology.  
 
7.5 Planned Interim Analyses  
Planned Interim analysis will be conducted at two additional time points: 
1. When all enrolled patients have completed Visit 1C, selection of AS versus 
immediate treatment will be analyzed. The impact of GPS on shared treatment 
decision, as described in Section 7.3 will be conducted on all enrolled patients at 
this time.   
2. When all enrolled patients have completed Visit 2, persistence on AS at 1 year and 
quality of life measures will be analyzed. 
 
8. SAMPLE SIZE JUSTIFICATION 
The sample size was calculated with the intent of showing a drop-out rate on AS of 20% or 
less when GPS is incorporated into treatment decisions.  A rate of 20-30% is what is reported 
in the literature (17,18).  Assuming a true drop-out rate of 17% by 2 years a sample size of 300 
patients will be required to achieve 90% probability that the observed drop-out rate will be 
20% or less.  We expect that if 1200 patients are enrolled, approximately 30%, or 360 of the 
patients will choose active surveillance and after accounting for patients with insufficient 
tissue, approximately 300 will be evaluable for the primary endpoint. 
 
For the secondary endpoint of assessing the impact of GPS on treatment decisions, the 
sample size considerations are driven by the anticipated number of changes in recorded 
treatment from the pre-assay CRF to the post-assay CRF. We anticipate that the 
approximately 50% of the first 300 patients enrolled will be NCCN Low-risk.  Furthermore, 
we estimate a 10% drop-out rate due to loss to follow-up or laboratory/pathology failures.  
We anticipate that the proportion of NCCN Low-risk patients for whom there is a change 
from pre-assay to post-assay, will be at least 30%.  Based on probabilities derived from the 
binomial distribution, for an expected 35% change rate, a minimum of 140 patients will be 
required to provide 90% probability to observe a change rate above 30%.  
 
 
 
 

 
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9. DATA MANAGEMENT 
9.1 Data Delivery  
Forms capturing Patient Reported Outcomes (PRO) will be completed by patients on paper 
CRFs, and then entered into the Electronic Data Capture (EDC) system by study personnel, 
as per study conduct instructions provided by GHI.  Other forms will be captured initially in 
site produced source documentation, and then entered into the EDC system by study 
personnel.  Site personnel will be requested to enter data into the database within five 
business days of patient visits. 
9.2 Data Administration 
Study personnel will be trained in study procedures to ensure that all aspects of patient and 
data management are standardized throughout the duration of the study.  All study data 
should be entered by study personnel using the collection methods designed for this study.  
Data will be validated in accordance with study-specific Data Management documentation. 
9.3 Data Security 
Whenever data is first recorded on a paper CRF, that document will be considered source 
documentation and will be stored at the study site in designated areas with secure locking 
systems.  Data entered into the EDC system will be accessible to study personnel for the 
duration of their participation in the study.  Study personnel will have access to study data 
only for their particular site.  Study personnel with access to the EDC system will create their 
own password according to the instructions provided by GHI. 
10. ETHICS AND REGULATORY ISSUES 
10.1 Informed Consent 
No patient will participate in the study until they have been duly informed, have had 
sufficient time to understand the implications of the study and their participation in it, 
and freely granted their consent to participate through the signed consent form, which 
will have been previously approved by the Institutional Review Board (IRB) at the 
participating institution.  Informed consent must be obtained by a physician investigator 
or a designee who possesses the appropriate knowledge and expertise needed to obtain 
informed consent for this study.  Each participant will receive a copy of the consent 
form and the site will keep the original that has been signed and dated by the patient, 
the witnesses, and the person who requested the consent. 
10.2 Committees on Ethics and Research 
The protocol must be approved in writing by the IRB of choice for the participating 
sites.  The study will only be able to begin after this approval has been obtained.  Before 

 
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beginning the study, it is the principal investigator’s responsibility to provide a copy of 
the IRB’s approval together with the approved documentation to GHI. 
10.3 Protocol Amendments 
Amendments to the protocol or changes to the informed consent must be approved by 
GHI and should be prepared in writing and submitted for approval to the IRB.  All 
records of changes made by the IRB, both to the protocol and to documents related to 
the study, will be saved in the investigator’s files and are subject to inspection by 
regulatory authorities.  Copies of amended documents and approval letters must be 
provided to GHI. 
10.4 Confidential Information 
All information provided by GHI in association with this study and not previously 
published is considered confidential information. This information includes but is not 
limited to the protocol and other scientific data. Any data collected during the study is 
also considered confidential. This confidential information is the property of GHI, 
should not be divulged without written consent from GHI, and cannot be used, with the 
exception of use in the execution of this study. 
Information developed during the course of this study is also considered confidential. In 
order to receive permission to use the information originating from this trial, the 
investigator is required to provide GHI with the complete results of and all data 
obtained during the study. 
 

 
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11. REFERENCES 
1. 
American Cancer Society, Inc., Surveillance Research (2013).  
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acsp
c-037124.pdf. Retrieved 20Jan2014.    
2. 
Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. “Screening 
and prostate-cancer mortality in a randomized European study”. New England Journal of 
Medicine. 2009;360(13):1320-8.  
3. 
Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. “Prostate-
cancer mortality at 11 years of follow-up”. New England Journal of Medicine. 
2012;366(11):981-90. 
4. 
Moyer VA, Force USPST. “Screening for prostate cancer: U.S. Preventive Services Task 
Force recommendation statement”. Annals of Internal Medicine. 2012;157(2):120-34.  
5. 
Cooperberg MR, Broering JM, Carroll PR. “Time trends and local variation in primary 
treatment of localized prostate cancer”. Journal of Clinical Oncology. 2010;28(7):1117-23.  
6. 
Shariat SF, Kattan MW, Vickers AJ, Karakiewicz PI, Scardino PT. “Critical review of 
prostate cancer predictive tools”. Future Oncology. 2009;5(10):1555-84.  
7. 
Pinthus JH, Witkos M, Fleshner NE, Sweet J, Evans A, Jewett MA, et al. “Prostate 
cancers scored as Gleason 6 on prostate biopsy are frequently Gleason 7 tumors at radical 
prostatectomy: implication on outcome”. Journal of Urology. 2006;176(3):979-84. 
8. 
Boorjian SA, Karnes RJ, Crispen PL, Rangel LJ, Bergstralh EJ, Sebo TJ, et al. “The 
impact of discordance between biopsy and pathological Gleason scores on survival after radical 
prostatectomy”. Journal of Urology. 2009;181(1):95-104 
9. 
Amin A, Partin A, Epstein JI. ‘Gleason score 7 prostate cancer on needle biopsy: relation 
of primary pattern 3 or 4 to pathological stage and progression after radical prostatectomy”. 
Journal of Urology. 2011;186(4):1286-90.  
10. 
Klein EA, Falzarano SM, Maddala T, . LM. “Quantitative gene expression in primary and 
highest Gleason pattern cancer specimens identifies genes associated with clinical recurrence and 
prostate cancer–specific survival after radical prostatectomy”. J Clin Oncol 29, 2011(suppl; abstr 
4663). 
11. 
Klein EA, Maddala T, Millward CL, Cherbavaz D, Falzarano SM, Knezevic D, et al. 
“Development of a needle biopsy-based discrimination of clinically aggressive from indolent 
prostate cancer”. J Clin Oncol 30, 2012 (suppl; abstr 4560). 
12.   
Cella DF, Tulsky DS, Gray G, Sarafian B, et al.  “The Functional Assessment of Cancer 
Therapy (FACT) scale:  Development and validation of the general measure” J Clin Oncol, 
1993; 11(3):570-579. 
13.   
Chang P, Szymanski K, Dunn R, Chipman J, et al.  “Expanded Prostate Cancer Index 
Composite for Clinical Practice:  Development and Validation of a Practical Health Related 
Quality of Life Instrument for the Use in the Routine Clinical Care of Patients With Prostate 
Cancer”  Journal of Urology, 2011; 186(3):865-872. 
14.   
O’Connor AM. “Validation of a Decisional Conflict Scale”.  Med Decis Making, 1995; 
15(1):25-30.   

 
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15.  Clark JA, Wray NP, Ashton CM.  “Living With Treatment Decisions:  Regrets and Quality 
of Life Among Men Treated for Metastatic Prostate Cancer”.  J Clin Oncol, 2001; 19(1):72-80. 
16.  Collett D. “Modelling Binary Data”. Chapman & Hall/CRC; 2003 
17.  Tosoian, JJ; B. J. Trock, P. Landis, Z. Feng, J. I. Epstein, A. W. Partin, P. C. Walsh and H. 
B. Carter . "Active surveillance program for prostate cancer: an update of the Johns Hopkins 
experience.". J Clin Oncol, 2011; 29(16): 2185–2190. 
18.  Dall’Era MA, Albertsen PC, Bangma D, Carroll PR, et al.  “Active Surveillance for Prostate 
Cancer: A Systematic Review of the Literature”.  European Urology Journal, 2012; 62(6):976-
83. 

 
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APPENDIX A:  
SITE INVESTIGATOR INITIATION FORM 
 
This form is to be completed by all the investigators on the study. This form should be submitted prior to enrolling any patients into the study.   
 
List all the investigators at the site who are participating in the study below.  All Investigators must have been trained and able to conduct the 
study as described in the protocol.  No more than 6 physicians at the same site may participate in the study at any given time.  
With this form you agree to offer this study to all patients who meet the protocol criteria. 
 
Physician Printed Name 
Physician 
Number 
Date of Investigator 
Initiation 
Date Completed or Dropped 
from Study 
 
01 
 
 
 
02 
 
 
 
03 
 
 
 
04 
 
 
 
05 
 
 
 
06 
 
 
 
Site PI Printed Name________________________________________ 
 
Site Number___________ 
 
Site PI Signature_____________________________________    Date:________________ 
 
 

 
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APPENDIX B:  
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
STUDY PROTOCOL 
A PROSPECTIVE MULTICENTER OBSERVATIONAL TRIAL TO ASSESS 
PERSISTENCE ON ACTIVE SURVEILLANCE WHEN USING THE 
ONCOTYPE DX® PROSTATE CANCER ASSAY  
Signature of Agreement for Protocol 
 
I declare that I have read this protocol and I agree to conduct the study as described in the 
following document. 
I will provide a copy of this protocol and all pertinent and relevant information to all those 
persons responsible for collaborating in the execution of the study.  I will review and discuss the 
material with all of them in order to assure myself of their cognizant and complete information 
with respect to the study and its execution. 
 
 
 
 
____________________________________________ 
_______________ 
 
Site Principal Investigator Signature 
             Date 
 
 
 
 
 
____________________________________________ 
 
Institution Name 
 
 
 
 
CONFIDENTIALITY 
 
The information contained in this document is the confidential and proprietary information of 
Genomic Health, Inc. 
Except as may be required by Federal, State, or local laws or regulations, this document 
may not be disclosed to others without written permission of Genomic Health. 
 

 
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APPENDIX C:  
ACTUARIAL LIFE TABLE 
Life expectancy for men age 50-82 is presented below. Life expectancy for a given person can be adjusted, using the 
clinician’s assessment of the patient’s overall health.* Patients in the best quartile of health (exceptionally healthy) 
have a 50% longer life expectancy than patients of the same age in the middle two quartiles (of average health).  
Patients in the worst quartile of health (poor health) have a 50% shorter life expectancy than patients in the middle 
two quartiles. 
The highlighted box in each of the columns represents the age below which all patients in that quartile of health 
have a life expectancy of greater than 10 years. Patients in the white and yellow boxes are eligible for this study. 
Patients in the red boxes have a life expectancy of less than 10 years and are not eligible for this study. 
Males 
Adjusted Life Expectancy** 
Based on clinician’s assessment of overall health 
Exact age 
Best Quartile 
of Health 
Middle Two Quartiles 
of Health 
Worst Quartile of 
Health 
50 
43.5 
29.0 
14.5 
51 
42.2 
28.2 
14.1 
52 
41.0 
27.3 
13.7 
53 
39.7 
26.5 
13.2 
54 
38.5 
25.7 
12.8 
55 
37.3 
24.9 
12.4 
56 
36.1 
24.1 
12.0 
57 
34.9 
23.3 
11.6 
58 
33.7 
22.5 
11.2 
59 
32.5 
21.7 
10.8 
60 
31.4 
20.9 
10.5 
61 
30.2 
20.2 
10.1 
62 
29.1 
19.4 
9.7 
63 
28.0 
18.7 
9.3 
64 
26.9 
17.9 
9.0 
65 
25.8 
17.2 
8.6 
66 
24.7 
16.5 
8.2 
67 
23.7 
15.8 
7.9 
68 
22.6 
15.1 
7.5 
69 
21.6 
14.4 
7.2 
70 
20.6 
13.7 
6.9 
71 
19.6 
13.1 
6.5 
72 
18.7 
12.4 
6.2 
73 
17.7 
11.8 
5.9 
74 
16.8 
11.2 
5.6 
75 
15.9 
10.6 
5.3 
76 
15.1 
10.0 
5.0 
77 
14.2 
9.5 
4.7 
78 
13.4 
8.9 
4.5 
79 
12.6 
8.4 
4.2 
80 
11.9 
7.9 
4.0 
81 
11.1 
7.4 
3.7 
82 
10.4 
6.9 
3.5 
* NCCN Prostate Cancer Guidelines Version 3.2012. 
** Modified from the Social Security Administration Actuarial Life Table, 2007 (http://www.ssa.gov/OACT/STATS/table4c6.html/).