A Randomized Phase III Study of Neo-Adjuvant Docetaxel and Androgen Deprivation Prior to Radical Prostatectomy Versus Immediate Radical Prostatectomy in Patients With High-Risk, Clinically Localized Prostate Cancer
Phase: PHASE3
Conditions: Prostate Cancer
Sponsor: Alliance for Clinical Trials in Oncology

 
1 
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Update #10 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 90203 
 
A RANDOMIZED PHASE III STUDY OF NEO-ADJUVANT DOCETAXEL AND ANDROGEN DEPRIVATION 
PRIOR TO RADICAL PROSTATECTOMY VERSUS IMMEDIATE RADICAL PROSTATECTOMY IN PATIENTS 
WITH HIGH-RISK,
 CLINICALLY LOCALIZED PROSTATE CANCER 
Commercial agent docetaxel (NSC #628503) distributed by CTEP, DCTD, NCI. 
ClinicalTrials.gov Identifier: NCT00430183 
 
Study Chair 
James A. Eastham, MD 
Memorial Sloan-Kettering Cancer Center 
 
 
 
 
 
 
Correlative Science Co-Chair and  
 
Medical Oncology Co-Chair GU Committee Corr. Sci. Cadre Leader Diet and Lifestyle Co-chair 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
GU Committee Chair 
GU Committee Vice-Chair 
Pathology Co-chair 
 
 
 
 
 
 
 
  
 
   
 
 
 
  
 
 
 
 
 
GU Primary Statistician 
Protocol Coordinator 
Data Manager 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating Organizations:  
ALLIANCE / Alliance for Clinical Trials in Oncology; ECOG-ACRIN / ECOG-ACRIN Cancer Research Group; 
NRG / NRG Oncology; SWOG / SWOG; CCTG / Canadian Cancer Trials Group 

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Update #10 
Alliance Central Protocol Operations 
Program Office 
 
 
 
 
 
Adverse Event Reporting 
 
 
Medidata RAVE® iMedidata Portal 
 
 
Alliance Statistics and Data Center 
 
 
  
 
 
 
 
Alliance Registration/Randomization Office 
 
 
 
CALGB 90203 Pharmacy Contact 
 
 
 
 
Alliance Biorepository  
at Ohio State University 
 
 
 
 
 
CALGB 90203 Nursing Contact 
 
  
 
 
 
 

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Update #10 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 
CONTACT INFORMATION 
 
For regulatory requirements: For patient enrollments: 
For study data submission 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 
 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at 
. 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS.   
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 2. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 

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Update #10 
A RANDOMIZED PHASE III STUDY OF NEO-ADJUVANT DOCETAXEL AND ANDROGEN DEPRIVATION 
PRIOR TO RADICAL PROSTATECTOMY VERSUS IMMEDIATE RADICAL PROSTATECTOMY IN PATIENTS 
WITH HIGH-RISK,
 CLINICALLY LOCALIZED PROSTATE CANCER 
Patient Eligibility 
Required Initial Laboratory Values 
Histologic documentation of prostatic adenocarcinoma 
ANC 
≥ 1500/L 
Patients with small cell, neuroendocrine, or transitional 
Platelets 
≥ 150,000/L 
cell carcinomas are not eligible 
Bilirubin 
≤ ULN* 
No evidence of metastatic disease on cross sectional 
AST/ALT 
≤ 1.5 x ULN 
imaging and bone scan (see Sec. 4.2) 
PSA 
≤ 100 ng/mL 
Patients must have EITHER:  
Creatinine 
≤ 2.0 mg/dL 
1) a Kattan nomogram predicted probability of being  
* See Section 4.9 
disease free 5 years after surgery of < 60%  
 
 
OR 
 
 
2) Gleason sum ≥ 8 (see Sections 4.3 and 5.1) 
No prior treatment for prostatic adenocarcinoma including prior surgery (excluding TURP), radiation 
therapy, or chemotherapy 
Patients may have received up to 4 months of androgen deprivation prior to randomization. 
Patients must be appropriate candidates for radical prostatectomy (see Sec. 4.5) 
Patients with a history of deep venous thrombosis, pulmonary embolism, and/or cerebrovascular accident 
or currently requiring systemic anticoagulation are eligible provided they are surgical candidates for 
radical prostatectomy.  
ECOG performance status 0-2 
≥ 18 years of age 
Schema 
 
 
 
ARM A1 
 
 
R  
 
 
Surgical Intervention 
A  
LHRH agonist x 18 to 24 weeks 
 
Staging pelvic 
N  
Docetaxel 75 mg/m2 every 21 days x 6 cycles 
 
lymphadenectomy 
D  
 
 
Radical prostatectomy* 
O  
 
 
 
M  
ARM B2 
 
 
I 
 
Surgical Intervention 
 
 
Z  
Staging pelvic 
 
 
E  
lymphadenectomy 
 
 
 
 
Radical prostatectomy* 
 
 
 
1 
Chemohormonal therapy is to begin within 14 days of randomization. Surgery will take place 
within 60 days following the completion of neoadjuvant therapy. 
2 
Surgery is to take place within 60 days of randomization. 
* 
Patients with positive surgical margins, extraprostatic extension, and/or seminal vesicle 
invasion are allowed to receive adjuvant external beam radiation to the prostatic fossa at the 
discretion of the treating physician; adjuvant radiation must be initiated within 6 months of the 
date of surgery. 
 
Patients in both arms who consent to participate will be asked to complete a diet and lifestyle 
questionnaire 3 months following surgery. 
 
Nomogram probability: See Appendix III for information about calculating the nomogram predicted 
probability of 5-year progression-free survival. 

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Guide to Companion Study Registration 
The following "roadmap" is meant to assist clinical research associates in companion study registration 
and sample procurement. 
 
Type of Submission 
 
Diet and Lifestyle 
Questionnaire 
(see Section 6.2) 
 
Paraffin Blocks/cores 
(Initial submission for 
pathology review 
required for all patients, 
see Sections 6.4 & 6.5) 
 
Blood 
(see Section 
6.6) 
 
Fresh Frozen 
Tissue 
(see Section 6.7) 
 
 
 
 
 
 
 
Consent 
Question #1* 
"I choose to take part 
in the Diet and 
Lifestyle study and 
agree to complete the 
diet and lifestyle 
questionnaire." 
 
Consent Question #2* 
"I agree that my specimen(s) may be used for research studies to learn 
about the effects that the experimental treatment may be having." 
 
 
 
 
 
 
 
 
 
All institutions: 
 
All institutions: 
 
Required for 
Alliance Member 
institutions only; 
optional for all other 
institutions: 
 
  
  
  
If "Yes," additional 
registration is not 
required 
 
If "Yes," register to substudy CALGB 
150413 (see Section 11.2) 
 
If "Yes," also 
register to substudy 
CALGB 150412 
(See Section 11.3) 
 
  
  
  
 
 
* Please note that model informed consent questions are mapped to the OPEN registration 
system. As a result, it is highly recommended that the wording and order of the model 
informed consent questions be retained in order to facilitate patient registration. 

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Update #10 
TABLE OF CONTENTS 
SECTION 
PAGE 
1.0 INTRODUCTION 
9 
1.1 Background and rationale ............................................................................................................. 
9 
1.2 Identifying High-Risk Prostate Cancer Patients 
............................................................................ 
9 
1.3 Neoadjuvant Treatment Prior To Radical Prostatectomy [RP] 
................................................... 
10 
1.4 Taxane-based Chemotherapy in Advanced Prostate Cancer 
....................................................... 
11 
1.5 Neoadjuvant chemotherapy 
......................................................................................................... 
12 
1.6 Trial design rationale 
................................................................................................................... 
13 
1.7 PSA Doubling Time 
.................................................................................................................... 
13 
1.8 Inclusion of women and minorities 
............................................................................................. 
14 
2.0 OBJECTIVES 
15 
2.1 Primary Objective 
....................................................................................................................... 
15 
2.2 Secondary Objectives 
.................................................................................................................. 
15 
2.3 Diet and Lifestyle Objective ....................................................................................................... 
15 
2.4 Correlative Science Objectives 
................................................................................................... 
15 
3.0 ON-STUDY GUIDELINES 
16 
4.0 ELIGIBILITY CRITERIA 
16 
4.1 Histologic documentation ........................................................................................................... 
16 
4.2 Clinically localized disease 
......................................................................................................... 
16 
4.3 Determination of high-risk status 
................................................................................................ 
17 
4.4 Prior treatment 
............................................................................................................................. 
17 
4.5 Appropriate surgical candidates 
.................................................................................................. 
17 
4.6 Clotting history............................................................................................................................ 
17 
4.7 ECOG performance status: 0-2 
................................................................................................... 
17 
4.8 Age: ≥ 18 years of age. ............................................................................................................... 
17 
4.9 Required Initial Laboratory Values: 
............................................................................................ 
17 
5.0 REGISTRATION/RANDOMIZATION AND STRATIFICATION 
18 
5.1 CTEP Registration Procedures 
.................................................................................................... 
18 
5.2 CTSU Registration Procedures 
................................................................................................... 
18 
5.3 Randomization Requirements 
..................................................................................................... 
20 
5.4 Patient Registration/Randomization Procedures 
......................................................................... 
21 
5.5 Registration to companion studies 
.............................................................................................. 
21 
5.6 Stratification Factors: 
.................................................................................................................. 
22 
6.0 DATA AND SAMPLE SUBMISSION AND MODALITY REVIEW 
23 
6.1 Data submission 
.......................................................................................................................... 
23 
6.2 Diet and Lifestyle Questionnaire................................................................................................. 
24 
6.3 Sample Submission 
..................................................................................................................... 
25 
6.4 Submission of paraffin blocks and/or slides for central pathology review; 
................................ 
27 
6.5 Tissue submission requirements for patients enrolled to sub-study 150413 
............................... 
29 
6.6 Blood sample submission requirements for patients enrolled to sub-study 150413 
................... 
30 
6.7 Fresh frozen tissue sample submission requirements for patients enrolled to sub-study 150412 
30 
6.8 Surgical Quality Assurance Requirements 
.................................................................................. 
32 
7.0 REQUIRED DATA 
34 
8.0 TREATMENT PLAN 
35 
8.1 Neoadjuvant chemohormonal therapy (Arm A only).................................................................. 
35 
8.2 Radical Prostatectomy (Arms A and B) 
...................................................................................... 
36 

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8.3 Potential Minor and Major Complications of Surgery 
................................................................ 
38 
9.0 CHEMOTHERAPY DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 39 
9.1 Dose modifications for hematologic toxicity 
.............................................................................. 
39 
9.2 Hepatic Dysfunction 
.................................................................................................................... 
39 
9.3 Neurotoxicity............................................................................................................................... 
39 
9.4 Gastrointestinal Toxicity 
............................................................................................................. 
39 
9.5 Fluid retention 
............................................................................................................................. 
39 
9.6 Skin Toxicity 
............................................................................................................................... 
40 
9.7 Hypersensitivity Reactions 
.......................................................................................................... 
40 
9.8 Corticosteroid Toxicity ............................................................................................................... 
40 
9.9 Other Toxicities 
........................................................................................................................... 
40 
9.10 Dose Modification for Obese Patients ........................................................................................ 
40 
10.0 DIET AND LIFESTYLE SUBSTUDY 
41 
10.1 Background 
................................................................................................................................. 
41 
10.2 Methods 
....................................................................................................................................... 
41 
11.0 CORRELATIVE SCIENCES COMPANION STUDIES 
42 
11.1 Background to Correlative Sciences Companion Studies – CALGB 150413 and 150412 
......... 
42 
11.2 Objectives 
.................................................................................................................................... 
42 
11.3 Methods 
....................................................................................................................................... 
43 
12.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
46 
12.1 Qualified personnel 
..................................................................................................................... 
46 
12.2 Unused drug 
................................................................................................................................ 
46 
12.3 Calculation of dose 
...................................................................................................................... 
46 
12.4  Docetaxel (NSC #628503) 
.......................................................................................................... 
47 
12.5 LHRH agonists 
............................................................................................................................ 
49 
13.0 ANCILLARY THERAPY 
52 
13.1 Supportive care............................................................................................................................ 
52 
13.2 Other chemotherapeutics agents.................................................................................................. 
52 
13.3 CALGB 90203 Policy Concerning the Use of Growth Factors 
.................................................. 
52 
14.0 CRITERIA FOR DISEASE PROGRESSION AND RELAPSE 
52 
14.1 Progression Free Survival (PFS) 
................................................................................................. 
52 
14.2 Criteria for metastatic disease-free survival and overall survival 
............................................... 
54 
14.3 Criteria for biochemical response to chemo-hormonal therapy 
.................................................. 
54 
15.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
54 
15.1 Duration of Treatment 
................................................................................................................. 
54 
15.2 Extraordinary Medical Circumstances 
........................................................................................ 
54 
15.3 Study Endpoints 
.......................................................................................................................... 
54 
16.0 STATISTICAL CONSIDERATIONS 
54 
16.1 Statistical Considerations for the Clinical Study 
......................................................................... 
55 
16.2 Statistical Considerations for the Diet and Lifestyle Study ........................................................ 
57 
16.3 Statistical Considerations for the Correlative Sciences Studies 
.................................................. 
58 
17.0 ADVERSE EVENT REPORTING (AER) 
63 
18.0 REFERENCES 
65 
APPENDIX I 
72 
APPENDIX II 
74 

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APPENDIX III 
76 
APPENDIX IV 
77 
 

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1.0 INTRODUCTION 
1.1 Background and rationale 
Prostate cancer is a heterogeneous disease. While disease progresses slowly with a prolonged 
natural history in some patients, others are destined for rapid progression and failure of definitive 
local therapy. (1) Some low risk patients may not be appropriate candidates for local therapy 
due to advanced age or co-morbid conditions. In contrast, patients with intermediate or high-
risk disease characteristics may benefit from more extended local therapy or systemic 
treatments, respectively, to decrease risk of recurrence. Therefore, the goal of risk assessment 
in patients with localized prostate cancer is to distinguish between patients not requiring 
treatment, patients for whom local therapy alone produces long-term disease-free survival, and 
patients who require early initiation of systemic therapy due to a high likelihood of occult 
metastatic disease.  
1.2 Identifying High-Risk Prostate Cancer Patients  
There are a number of models or nomograms available to aid clinicians with pre-treatment risk 
assessment. For patients newly diagnosed with prostate cancer, there are three well-defined 
predictors of disease extent and outcome following treatment. These factors are clinical tumor 
stage, Gleason grades of the diagnostic biopsy specimen, and serum PSA level. However, each 
of these factors alone has not proven useful in predicting disease extent and outcome for an 
individual patient. Clinical staging by digital rectal examination may underestimate the presence 
of extracapsular disease extension in 30-50% of patients. (2) Although biopsy Gleason score 
may be helpful in predicting pathologic stage and outcome following treatment at either end of 
the spectrum (i.e. Gleason sum 2-4 or Gleason sum 7-10 tumors), it is not as helpful for the 
majority of patients who present with Gleason sum 5-8 tumors. In addition, the incidence of 
undergrading of the diagnostic biopsy specimen reaches 45% in some series. (2, 3) Finally, 
although serum PSA levels correlate with tumor volume and stage, the determination of serum 
PSA is also influenced by the volume of benign prostatic hyperplasia and the degree of tumor 
differentiation. In an effort to maximize the predictive value of each individual variable, several 
investigators have combined these variables into models that are designed to better predict 
pathologic tumor stage, the presence or absence of lymph node metastases and outcome 
following treatment. (4-6) 
The nomogram developed by Kattan et al (4) predicts the probability that a man will remain free 
from disease recurrence for 5 years. It has been externally validated on over 6000 men treated 
at 7 different institutions spanning three continents (7) as well as in African-American men. (8) 
By computing a continuous probability of failure, the nomogram predicts outcome more 
accurately than by placing the patient into one of two or three risk groups (9, 10), a finding 
confirmed in other modalities (11, 12) and cancers (13-16). Work by Carroll and colleagues 
using the CapSURE database illustrates the heterogeneity of patients within a traditional risk 
group, which argues for the use of nomograms for more precise assessment of recurrence risk. 
In particular, this work illustrates that some patients in a traditional "high-risk" category are not 
of truly high risk when assessed by a more accurate approach (i.e., the nomogram), and that 
some patients in an "intermediate risk" group are actually high risk. Thus, using the nomogram 
to define eligibility should allow truly high risk patients to enroll on this trial while excluding 
those patients who are not of sufficient risk. Extensive details regarding the design of the 
nomogram are reported elsewhere. (17) 
With use of the nomogram, a man
's probability of recurrence can be calculated using clinical 
stage, primary and secondary Gleason grades, and serum PSA level immediately prior to 
prostate biopsy. High-risk patients will be defined as those having a less than 60% probability 

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of remaining free from recurrence 5 years after surgery as determined by the preoperative 
nomogram. 
[Added with Update #3] When this study was conceptualized in 2002, approximately 15% of 
patients undergoing radical prostatectomy would have been eligible for this study using the 
Kattan Pre-Treatment Prostate Nomogram criteria (< 60% predicted probability of 5-year 
biochemical-free progression). Since that time, because of the earlier use of PSA high-risk 
prostate cancer patients are more likely to be identified because of biopsy Gleason score, rather 
than by PSA. However, risk definition in the Kattan nomogram is driven largely by PSA. Thus, 
in 2008, clinicians find that approximately 5% of patients undergoing radical prostatectomy 
meet the Kattan Nomogram-defined eligibility criteria for this study; a much smaller patient 
population than the 15% originally predicted. This reduced pool of potentially eligible patients 
led to a discussion of alternative characterizations of high-risk cancer by the CALGB GU 
Committee at the June 27th, 2008 Group Meeting. It was agreed to amend the eligibility criteria 
to add patients with Gleason score ≥ 8 on diagnostic prostate biopsy. 
The rationale for this change is that patients with biopsy Gleason score ≥ 8 are certainly 
considered high-risk, having a reported biochemical recurrence rate 10 years after radical 
prostatectomy of 60-70%. The databases of two CALGB institutions have been examined to 
evaluate the 5 year bPFS rate after prostatectomy for Gleason score 8-10 patients (regardless of 
other features such as stage or PSA level.) These rates are 44% for Memorial Sloan-Kettering 
Cancer Center and 45% for the Roswell Park Cancer Institute. By including patients with biopsy 
Gleason score ≥ 8 in Update #3, eligibility will be expanded so that approximately 15% of 
patients undergoing surgery will be targeted for participation in this study. Since the Kattan 
nomogram definition of high risk will also remain an eligibility criterion, these patients will 
continue to be eligible for the study as well as those patients enrolled prior to the approval of 
Update #3. 
1.3 Neoadjuvant Treatment Prior To Radical Prostatectomy [RP] 
While it is apparent that local therapy alone is inadequate for many patients with high-risk, 
clinically localized prostate cancer, the optimal treatment strategy has not yet been defined. For 
high-risk patients choosing external beam radiation, the use of neoadjuvant and/or concomitant 
androgen deprivation appears to have had a beneficial impact on disease-free and overall 
survival in several published studies. (18) Unfortunately, this has not been the case for patients 
undergoing radical prostatectomy. The objectives of neoadjuvant androgen deprivation prior to 
radical prostatectomy include stage reduction ("downstaging"), decreasing the incidence of 
positive surgical margins, and effecting salutary changes in long-term local and distant cancer 
recurrence rates with the ultimate goal of improving cancer-specific survival. There have been 
more than 20 published studies evaluating neoadjuvant androgen deprivation in patients with 
clinical stage T3 prostate cancer undergoing radical prostatectomy. (19) While effective in 
decreasing serum PSA and prostate volume, there have been conflicting results with respect to 
downstaging and there has been no apparent benefit in disease-free survival. Neoadjuvant 
androgen deprivation has also been tested in a variety of phase II and III studies of patients with 
clinically localized (stage T1-2) prostate cancer in an attempt to decrease positive surgical 
margin rates and improve biochemical disease-free survival. (20-23) While all series to date 
have reported significantly lower positive surgical margin rates in those receiving neoadjuvant 
androgen deprivation, this reduction has not translated into better biochemical disease-free 
survival. There are several possible explanations for this discrepancy. First, these studies were 
designed to detect differences in positive margin rates and, therefore, may not have been 
powered to detect differences in biochemical disease-free survival. Second, too many low-risk 
patients may have been included in these studies. Third, the duration of neoadjuvant therapy, 
usually 3 months, may have been too short. Recent studies suggest that serum PSA continues to 

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decrease for as long as 8 months after the initiation of neoadjuvant androgen deprivation, (24) 
providing the impetus for a randomized, phase III study of 3 versus 8 months of neoadjuvant 
androgen deprivation prior to radical prostatectomy by the Canadian Urologic Oncology Group. 
However, preliminary results from this trial also suggest no significant impact of long-term 
androgen deprivation on long term outcomes. Fourth, most studies have suffered from short 
follow-up times. Finally, neoadjuvant androgen deprivation alone may provide no benefit over 
surgery alone for patients with clinically localized prostate cancer.  
An alternative to neoadjuvant androgen deprivation would be the addition of early cytotoxic 
chemotherapy prior to local therapy for patients with high-risk prostate cancer. Systemic 
chemotherapy, long believed to be ineffective in men with prostate cancer, has more recently 
been shown to improve quality of life, cause measurable disease and PSA responses, and 
improve survival in men with hormone-refractory prostate cancer (HRPC). (25-27) Moreover, 
recent studies have demonstrated the feasibility of neoadjuvant chemotherapy prior to radical 
prostatectomy in high-risk prostate cancer patients (see below). If such a strategy was shown to 
be effective, future clinical practice could be altered significantly, as there is currently no 
accepted treatment strategy for patients with high-risk disease characteristics, and failure rates 
with local therapy alone remain high. The goal of such treatment is to prolong disease-specific 
and overall survival in patients at high risk for disease progression despite local therapy. 
1.4 Taxane-based Chemotherapy in Advanced Prostate Cancer 
Prior studies have demonstrated the effectiveness of chemotherapy in patients with advanced 
prostate cancer and the feasibility of administering chemotherapy in the neoadjuvant setting 
prior to radical prostatectomy. Randomized trials performed in both the United States and 
Canada using corticosteroids, with or without mitoxantrone, have shown that these regimens 
improve quality of life endpoints in patients with hormone-refractory prostate cancer (HRPC). 
(25, 27) More recently, taxane-based regimens have shown anti-tumor activity in men with 
advanced prostate cancer. Estramustine (EMP) dysregulates normal microtubule assembly, 
resulting in growth inhibition in human prostate cancer cell lines. (28-32) Moreover, 
estramustine has estrogenic effects that produces anorchid levels of testosterone similar to other 
forms of medical or surgical castration. (33) Although estramustine as a single agent appears to 
have limited anti-tumor activity in men with HRPC, prior studies suggest that estramustine may 
act synergistically with other microtubule agents including vinblastine, etoposide, paclitaxel and 
docetaxel. (34-38) 
A multicenter Cancer and Leukemia Group B phase II trial reported by Savarese and colleagues 
examined docetaxel, estramustine and low-dose hydrocortisone in 47 men with HRPC. (26) In 
44 patients with an elevated pre-treatment PSA, 68% experienced 50% or greater PSA decline. 
The measurable disease response rate was 50%, with 3 complete and 9 partial responses. 
Therapy was well tolerated. Neutropenia was the most common adverse effect with 30% of 
patients having grade 3 and 26% grade 4 granulocytopenia. There were no episodes of febrile 
neutropenia. Thromboembolic events occurred in 9% of patients, although patients were not 
routinely anticoagulated. Quality of life of these patients was assessed in tandem with this study, 
which demonstrated the feasibility of studying quality of life in clinical trials involving 
chemotherapy in men with prostate cancer. (39) 
To confirm the clinical benefits of the microtubule agents, docetaxel-based regimens were 
compared to mitoxantrone plus prednisone in two multicenter phase III randomized trials 
(SWOG 9916 and TAX327). SWOG 9916 was an intergroup trial led by the Southwest 
Oncology Group that randomized 770 men to estramustine (280 mg po TID days 1-5) and 
docetaxel (60 mg/m2) every 3 weeks or mitoxantrone (12 mg/m2) every 3 weeks and prednisone 
5 mg po BID. Patients treated with estramustine and docetaxel had a significant improvement 

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in median overall survival (17.5 vs. 15.6 months, p = 0.02) and progression free survival (6.3 
vs.3.2 months, p = 0.02) compared to patients treated with mitoxantrone and prednisone. (40) 
TAX 327 was an industry-sponsored trial that compared single agent docetaxel (75 mg/m2) 
every 3 weeks plus prednisone 5 mg b.i.d. to docetaxel (30 mg/m2) on a weekly schedule plus 
prednisone 5 mg b.i.d. to mitoxantrone (12 mg/m2) every 3 weeks and prednisone 5 mg p.o. 
b.i.d. When compared to the mitoxantrone-treated patients, men that received docetaxel every 3 
weeks had a hazard ratio for death of 0.76 (p = 0.009) and those administered weekly docetaxel 
had a hazard ratio of 0.91 (p = 0.36). The median survival was 16.5 months for the mitoxantrone 
treated patients, 18.9 months for the patients that received docetaxel every 3 weeks and 17.4 
months for patients that were given docetaxel weekly. (41) These results show that docetaxel-
based therapy is superior to mitoxantrone and prednisone. While these trials did not address the 
relative contribution of EMP to docetaxel, the data suggests that EMP adds little to improve 
overall survival, increases morbidity and that docetaxel would be the most commonly used first 
line chemotherapeutic regimen in the community. Docetaxel and prednisone has become the 
first line standard therapy for patients with metastatic hormone refractory prostate cancer. 
1.5 Neoadjuvant chemotherapy 
The feasibility of taxane-based chemotherapy prior to radical prostatectomy has been 
demonstrated in several phase II trials. Konety and colleagues recently evaluated neoadjuvant 
paclitaxel, estramustine and carboplatin (TEC) in 36 patients with high-risk prostate cancer (99) 
who were treated for 16 to 24 weeks prior to radical prostatectomy. Patients were enrolled from 
2 CALGB sites, Memorial Sloan-Kettering Cancer Center and the Dana Farber Cancer Institute. 
Thirty-four patients completed 4 cycles of chemotherapy, while 1 patient each completed 2 or 6 
courses of chemotherapy. Neoadjuvant treatment resulted in lower clinical stage in 39% of 
patients while 36% of patients were assigned higher clinical stage following neoadjuvant 
chemotherapy. The most frequent significant chemotherapy-related toxicity was deep venous 
thrombosis in 22% of patients. Surgery was well tolerated with a median operative time of 270 
minutes and a median estimated blood loss of 1250 cc. Immediate peri-operative complications 
occurred in 6 (17%) patients. The positive surgical margin rate was 22%, and at a median follow-
up of 20 months, 50% of these high-risk patients remained free of biochemical recurrence, which 
was defined as a serum PSA >0.05 ng/ml on 3 separate occasions.  
Clark and colleagues treated 18 patients with locally advanced, non-metastatic prostate cancer 
with three cycles of estramustine and etoposide before radical prostatectomy. (42) All 18 
patients completed the three planned cycles of chemotherapy, with 16 patients choosing radical 
prostatectomy and two patients choosing external beam radiation. Pre-operative serum PSA was 
undetectable in 50% of patients and 94% demonstrated a local response to chemotherapy prior 
to surgery. Twenty eight percent of patients experienced grade 3 toxicity from the chemotherapy 
and one patient (6%) had grade 4 toxicity with a pulmonary embolus. Surgical outcomes 
including operative time, median blood loss, hospital stay and complications did not appear to 
be adversely affected by the neoadjuvant chemotherapy. Organ confined disease was found in 
31% and specimen-confined disease in 56% of these high-risk patients. All patients achieved an 
undetectable serum PSA nadir after surgery. 
Pettaway and colleagues demonstrated the feasibility of neoadjuvant chemotherapy in 33 
patients with high-risk prostate cancer. (43) Patients were treated with 12 weeks of ketoconazole 
and doxorubicin alternating with vinblastine and estramustine (KAVE), then underwent radical 
prostatectomy. Ninety four percent of patients completed the two planned courses of KAVE 
prior to surgery. Most adverse effects were mild, with grades 3 or 4 hematologic toxicity in 12% 
of patients and three (9%) patients requiring hospitalization during systemic therapy. One patient 
refused surgery after systemic therapy. No major intraoperative complications were reported. 
Pathology demonstrated organ-confined disease or extracapsular disease extension in 33% and 

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Update #10 
66% of patients, respectively. Lymph node metastases were detected in 37% of these high-risk 
patients and 17% of patients had a positive surgical margin. All patients achieved undetectable 
serum PSA levels after surgery. 
In preliminary results from Gleave and colleagues from the Canadian Urology group, 2 of 64 
patients treated with docetaxel plus androgen deprivation therapy for 24 weeks had a complete 
pathological response and 14 patients had organ-confined disease. (44) 
Oh and colleagues administered neo-adjuvant docetaxel for 6 months without estramustine or 
other forms of androgen deprivation therapy safely to 19 high risk localized prostate cancer 
patients. (45) Fifty-eight percent of these patients had a post-therapy decline in PSA greater than 
50% from baseline with testosterone level remaining in the normal range. Sixteen of the 19 
patients had a radical prostatectomy performed. While no complete pathologic responses were 
seen, 38% had organ-confined disease and none had lymph node involvement.  
This trial illustrates the feasibility, safety and biologic effect of administering neo-adjuvant 
docetaxel without estramustine or androgen deprivation therapy. Whether the addition of 
androgen deprivation therapy to cytotoxic therapy will derive a greater clinical benefit is not 
known. Recently, preclinical data evaluating the optimal timing and combination of androgen 
deprivation therapy with cytotoxic chemotherapy in LNCaP and Shionogi prostate cancer 
xenografts showed that mice receiving simultaneous chemohormonal therapy had significant 
improvement in median time to progression versus best sequential therapy. (46) Lack of 
response to castration was observed after initial paclitaxel therapy and transcriptional profiling 
identified increased expression of several survival genes known to play a role in androgen 
independence after paclitaxel exposure. These findings support the use of simultaneous 
chemohormonal therapy in future neoadjuvant and adjuvant trials. 
1.6 Trial design rationale 
This randomized trial tests whether the addition of chemohormonal therapy improves PSA-
progression free survival in patients with high risk, clinically-localized prostate cancer as 
defined by the Kattan nomogram. The neo-adjuvant approach is taken since there appears to be 
a higher acceptance rate in the prostate population for this type of therapy and several phase II 
trials have demonstrated its safety. While multiple chemotherapeutic therapies have shown 
efficacy in advanced prostate cancer, recent phase III data suggests that estramustine may not 
contribute to the overall improvement in survival but increases the morbidity of the treatment. 
Thus, docetaxel has become the community standard. Many high risk patients are initiated on 
LHRH agonists at or near the time of diagnosis of their prostate cancer. In order to allow the 
inclusion of these patients in the protocol, enhance enrollment and maintain compliance with 
therapy, up to 3 months of androgen deprivation therapy prior to enrollment will be permitted. 
This study will therefore be able to test the hypothesis that targeting both androgen-sensitive 
and chemotherapy-sensitive prostate cancer cells will improve outcomes in these high-risk 
patients. 
1.7 PSA Doubling Time 
A variety of clinical and pathological factors, including serum PSA level at diagnosis, biopsy 
Gleason score, clinical staging and pathological staging, have been associated with disease 
progression after treatment for clinically localized prostate cancer. More recently, PSA doubling 
time (PSADT) has been identified as a predictor of outcomes in men with prostate cancer. 
PSADT prior to treatment has been associated with biochemical failure after RP or radiation 
therapy as well as the time to development of distant disease and death from prostate cancer. 
(47-52) The association between a specific PSADT and time to metastatic disease and death 
from prostate cancer is as follows (D
'Amico A, personal communication): 
 

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2.0 OBJECTIVES  
2.1 Primary Objective 
To determine whether treatment with neoadjuvant docetaxel and androgen deprivation therapy 
prior to radical prostatectomy will increase the rate of 3-year biochemical progression-free 
survival (bPFS) compared to treatment with immediate radical prostatectomy alone for high-
risk prostate cancer patients.  
2.2 Secondary Objectives 
2.2.1 To compare the 5-year bPFS rate, bPFS, disease progression, disease-free survival, and 
overall survival of patients randomized to the two arms of this trial. 
2.2.2 To determine the safety and tolerability of neoadjuvant docetaxel and androgen deprivation 
therapy prior to surgery for high-risk patients undergoing radical prostatectomy.  
2.2.3 To compare the impact of neoadjuvant docetaxel and androgen deprivation therapy on time 
to clinically apparent local disease recurrence and metastatic disease in high-risk patients 
undergoing radical prostatectomy for clinically localized prostate cancer. 
2.2.4 To compare the impact of neoadjuvant docetaxel and androgen deprivation therapy relative 
to RP on pathologic tumor stage, frequency of lymph node metastases and positive margin rates for 
high-risk patients undergoing radical prostatectomy for clinically localized prostate cancer. 
2.2.5 To determine if changes in serum testosterone levels will predict bPFS. 
2.2.6 To determine prospectively whether PSA doubling time (PSADT) is a surrogate endpoint 
for time to clinical metastases and overall survival. 
2.3 Diet and Lifestyle Objective 
To evaluate associations between post-diagnosis diet and lifestyle, change in food group intake, 
and risk of prostate cancer recurrence, independent of treatment. 
2.4 Correlative Science Objectives 
[See Sections 11.2.2 and 11.3.2 for correlative science objectives.] 
 
 

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3.0 ON-STUDY GUIDELINES 
The following guidelines are to assist physicians in selecting patients for whom protocol therapy is 
safe and appropriate. Physicians should recognize that the following may seriously increase the risk 
to the patient entering this protocol: 
• Psychiatric illness which would prevent the patient from giving informed consent 
• Medical conditions such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
• Unwillingness to use an appropriate method of birth control throughout their participation in this 
study due to the teratogenic potential of the chemotherapy utilized in this trial. Appropriate 
methods of birth control for participants and their female partners of child-bearing potential 
include, but are not limited to, oral contraceptives, implantable hormonal contraceptives 
(Norplant), or double barrier method (diaphragm plus condom). 
• Patients with a "currently active" second malignancy other than non-melanoma skin cancers. 
Patients are not considered to have a "currently active" malignancy if they have completed 
therapy and are considered by their physician to be at less than 30% risk of relapse.  
4.0 ELIGIBILITY CRITERIA 
All questions regarding eligibility should be directed to the Alliance Study Chair. Please note that 
the Study Chair cannot grant waivers to eligibility requirements. 
4.1 Histologic documentation 
Histologic documentation of prostatic adenocarcinoma. Patients with small cell, 
neuroendocrine, or transitional cell carcinomas are not eligible.  
All eligible patients must have a known Gleason sum based on biopsy or TURP at the time of 
registration. 
4.2 Clinically localized disease 
Patients must have clinical stage T1-T3a and no radiographic evidence of metastatic disease as 
demonstrated by: 
• • EITHER CT or MRI of the abdomen and pelvis, OR endorectal MRI of the pelvis 
that demonstrate no nodes > 1.5 cm. 
If one or more pelvic lymph node(s) measures > 1.5 cm, a negative biopsy is required. If 
more than one lymph node is > 1.5 cm, the largest or most accessible node should be 
biopsied; 
AND 
•  • Negative bone scan (with plain films and/or MRI and/or CT scan confirmation, if 
necessary). 
Positive PET and Prostascint scans are not considered proof of metastatic disease. 
 
 

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4.3 Determination of high-risk status 
Patients must have either:  
• 1) A Kattan nomogram predicted probability of being free from biochemical 
progression at 5 years after surgery of < 60%. [6] See Appendix III for instructions for 
calculating this probability. Please note that for the purposes of the nomogram 
calculation, the pre-biopsy PSA value must be used. 
OR 
• 2) Prostate biopsy Gleason sum ≥ 8  
• (NOTE: The Kattan nomogram probability must be calculated for all patients, including 
those eligible based on Gleason sum ≥ 8 only.) 
4.4 Prior treatment 
No prior treatment for prostate cancer including prior surgery (excluding TURP), pelvic lymph 
node dissection, radiation therapy, or chemotherapy. Patients may have received up to 4 months 
of androgen deprivation therapy (LHRH agonists, antiandrogens, or both) prior to being enrolled 
on the study. 
4.5 Appropriate surgical candidates 
Patients must be appropriate candidates for radical prostatectomy with an estimated life 
expectancy > 10 years as determined by a urologist. Evidence of underlying cardiac disease 
should be evaluated prior to enrollment to ensure that patients are not at high risk of cardiac 
complications. 
4.6 Clotting history 
Patients with a history of deep venous thrombosis, pulmonary embolism, and/or cerebrovascular 
accident or currently requiring systemic anticoagulation are eligible provided they are 
determined to be candidates for radical prostatectomy. 
4.7 ECOG performance status: 0-2 
4.8 Age: ≥ 18 years of age. 
4.9 Required Initial Laboratory Values: 
ANC ≥ 1500/L 
Platelet count ≥ 150,000/L 
Creatinine ≤ 2.0 mg/dL 
Pre-registration serum PSA level ≤ 100 ng/mL 
Bilirubin ≤ Upper limit of institutional normal 
(ULN)* 
AST/ALT ≤ 1.5 X ULN 
* For patients with Gilbert
's Disease, ≤ 2.5 X ULN is allowed. 

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IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients.  Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
5.2.1 Downloading Site Registration Documents:   
Site registration forms may be downloaded from the CALGB 90203 protocol page located 
on the CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed 
in the CTSU RSS. 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Protocols tab in the upper left of your screen 
• Either enter the protocol # in the search field at the top of the protocol tree or click on 
the By Lead Organization folder to expand 
• Click on the Alliance link to expand, then select trial protocol CALGB 90203. 
• Click on LPO Documents, select the Site Registration Documents link, and download 
and complete the forms provided 
5.2.2 Requirements for CALGB 90203 Site Registration: 
• IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 

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5.2.3 Submitting Regulatory Documents:  
Submit completed forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org (members’ area)  Regulatory Tab 
Regulatory Submission  
When applicable, original documents should be mailed to: 
 
 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 
 in order to receive further instruction 
and support. 
5.2.4 Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website. 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab  
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated networks. 
5.3 Randomization Requirements 
• • Informed Consent: The patient must be aware of the neoplastic nature of his 
disease and willingly consent to participate after being informed of the procedures to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, side-
effects, risks, and discomforts. Human protection committee approval of this protocol 
and a consent form are required. 
• • Kattan nomogram predicted probability: The Kattan nomogram-predicted 
probability of being biochemical disease free 5 years after surgery must be calculated 
for all patients, including those eligible based on Gleason sum ≥ 8 only. [6] See 
Appendix III for instructions for calculating this probability. A printout of this 
calculation, with the CALGB study number and patient ID number noted, must be 
submitted with on-study data for all patients. 
• • Clinical staging, serum PSA level, and Gleason sum for the purpose of Kattan 
nomogram calculation: The patient must have a clinical stage documented by the 
treating urologist within 90 days prior to randomization using the 2002 TNM staging 
system (53) (see Appendix IV). Clinical stage is based on digital rectal examination 
results and NOT on imaging studies, such as transrectal ultrasound, CT scan, and/or 
MRI. The clinical stage must be T1-T3a. For study purposes, the serum PSA prior to 
the prostate biopsy will be the PSA used for randomization. The serum PSA level must 
have been drawn within 3 months prior to the prostate biopsy and must be ≤ 100 ng/mL. 

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Update #10 
The highest Gleason sum from the prostate biopsy will be used to calculate the 
nomogram probability of being free from biochemical disease recurrence at five years. 
The clinical stage, serum PSA level, and biopsy Gleason sum will be used to calculate 
the nomogram probability. 
5.4 Patient Registration/Randomization Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user must have an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam >) and 
a 'Registrar
' role on either the LPO or participating organization roster. Registrars must hold a 
minimum of an AP registration type.  
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data. OPEN can be accessed at https://open.ctsu.org 
or from the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 
in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable) 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.   Please print this confirmation for your records.  
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol 
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional 
questions contact the CTSU Help Desk at 
. 
5.5 Registration to companion studies 
There are three substudies included within CALGB 90203:  
• • Diet and Lifestyle substudy (Section 10.0) 
• • Tumor and serum protein correlative substudy: CALGB 150413 (Section 11.2) 
• • Tumor RNA and DNA analysis substudy: CALGB 150412 (Section 11.3) 
All English-speaking patients will be asked to complete the Diet and Lifestyle Survey. If a 
patient answers "yes" to "I choose to take part in the Diet and Lifestyle study and agree to 
complete the diet and lifestyle questionnaire," (Question #1) in the Model Consent, he has 
consented to participate in the Diet and Lifestyle study described in Section 10.0. There is no 
separate registration for this substudy. 
For Alliance Members: If a patient answers "yes" to "I agree that my specimen(s) may be used 
for research studies to learn about the effects that the experimental treatment may be having," 
(Question #2) in the Model Consent, the patient should be enrolled to CALGB 150413 and 
150412 at the same time that he is registered to the treatment trial (90203) and tissue blocks, 
frozen prostate samples, and blood samples submitted per Sections 6.4.2, and Sections 6.5—
6.7. These companion studies are described in Sections 11.2 and 11.3. 

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• • NOTE: Materials required to prepare and ship the frozen OCT specimens are 
available at site request for submission of the fresh frozen samples required for sub-
study 150412 and should be ordered from the Alliance Biorepository at OSU prior to 
radical prostatectomy. See Section 6.7. 
For all other participating institutions: If a patient answers "yes" to "I agree that my 
specimen(s) may be used for research studies to learn about the effects that the experimental 
treatment may be having," (Question #2) in the Model Consent, the patient should be registered 
to CALGB 150413 at the same time that he is registered to the treatment trial (90203) and tissue 
blocks and blood samples submitted per Sections 6.4.2, 6.5, and 6.6. This companion study is 
described in Section 11.2.  
Those institutions who wish to participate in the additional correlative science study, 150412, 
may also register to that study (described in Section 11.3) and submit additional prostate samples 
per Section 6.7. 
See the “Guide to Companion Study Registration on page 4 of this protocol for a diagram 
outlining registration to the companion studies of this trial. 
5.6 Stratification Factors:  
5.6.1 Nomogram-predicted biochemical progression-free survival at 5 years: 
• Group 1: 0%-20.9% 
• Group 2: 21%-39.9% 
• Group 3: 40%-59.9% 
• Group 4: ≥ 60% 
5.6.2 Androgen deprivation therapy prior to randomization (≤ 4 months): 
• - no 
• - yes 
 
 

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6.0 DATA AND SAMPLE SUBMISSION AND MODALITY REVIEW 
6.1 Data submission 
As of Update #10 to the protocol, this study will use Medidata Rave® for remote data capture 
(RDC) of all future data collection. All data originally received by the Alliance and Statistics 
and Data Center (SDC) (either electronically using the “Print and/or Submit to CALGB” button 
[i.e. Teleform form] or by mail) has been transferred to Medidata Rave ® and can be accessed 
via the Medidata Rave ® system. If necessary, data originally submitted to the SDC 
electronically (or by mail) can be amended via the Medidata Rave ® system. 
The Rave system can be accessed through the iMedidata portal at https://login.imedidata.com. 
To access Rave via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA 
Lab Admin, SLA, or Site Investigator) on either the LPO or participating organization roster at 
the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type. To hold the Rave 
Site Investigator role, the individual must 
be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave.  
For additional information regarding account setup or training, please visit the training section 
of the Alliance website. Forms should be submitted in compliance with the table below, and a 
copy of the All Forms Packet can be downloaded from the Alliance and CTSU websites. 
Site personnel with Rave roles assigned on the appropriate roster may receive a study invitation 
e-mail from iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and 
click on the “accept” link in the upper right-corner of the iMedidata page. Please note, site users 
will not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Personnel 
who did not receive an invitation should contact the Alliance Service Center. 
Users who have not previously activated their iMedidata/Rave account at the time of an initial 
site registration approval for a study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website’s Rave tab under the Rave Resource Materials heading (Medidata Account Activation 
and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 
or by e-mail at 
. 
For the most up-to-date data forms, please visit the Alliance website at 
www.allianceforclinicaltrialsinoncology.org or the CTSU CALGB-90203 study page. 
 
 

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Update #10 
 
 
Form 
Submission Schedule 
 
Baseline 
 
 
 
 
C-1239 
Report 
Kattan prostate nomogram print-out1 
90203 Registration Worksheet 
90203 Eligibility Checklist 
90203 On-Study Form 
Pathology report from biopsy 
Within 1 week of registration 
During chemohormonal treatment (Arm A only) 
C-1240 
C-1241 
90203 Chemohormonal Treatment Form 
90203 Adverse Event Form-Chemohormonal Therapy 
After every cycle of chemohormonal therapy until 
chemohormonal therapy ends. If chemotherapy ends 
early, submit at the end of hormonal therapy. 
 
Pre- and Post-surgery 
 
C-1145 
EPIC Short Form 
At the last pre-surgery clinic visit and every 6 months 
after surgery for 3 years. 
 
 
 
C-714 
C-744 
CALGB Prostate Specific Antigen Form 
CALGB Testosterone Form 
Per Required Data for PSA and testosterone (Sec. 7.0). 
 
 
 
C-1242 
 
C-1243 
C-2021 
Report 
90203 Surgical Complications and Morbidity Form2 
90203 Surgery and Pathology Form 
90203 Op Report Addendum Form 
Operative and Pathology reports from surgery 
Within 1 month after surgery 
 
 
 
C-1244 
90203 Follow-up Form 
Within 1 and 3 mos after surgery; then every 3 mos for first 3 yrs; then 
every 6 mos until 6 yrs after surgery; then annually until 15 yrs after 
registration or until progression (Sec. 14.1.1, 14.1.2). If patients 
experience treatment failure (Sec. 14.1.3, 14.1.4) within 3 yrs after 
surgery, submit every 6 mos. Also, at new primary; and at death. 
 
 
 
 
Diet and Lifestyle questionnaire3 
At 3 months after surgery, see Sec. 6.2. 
 
 
 
C-1275 
90203 Late Postoperative 
Complications 
3, 6, 9, and 12 months after surgery 
 
 
 
 
Pathology and scan reports 
At the time of first local and first metastatic disease progression 
 
Other 
 
C-260 
CALGB Remarks Addenda 
When needed 
1 See Appendix III. 
2 To be completed twice, Day 3 and Day 30 after surgery. 
3 For patients participating in Diet and Lifestyle Survey. 
Common Toxicity Criteria: This study will use the NCI Common Terminology Criteria for Adverse 
Events version 3.0 for routine toxicity reporting on study forms. However, adverse events reported 
via CTEP-AERS must use CTCAE version 5.0 (See Section 14.0). 
6.2 Diet and Lifestyle Questionnaire 
Diet and lifestyle questionnaires will be given to all consenting patients enrolled on CALGB 
90203 at 3 months following surgery. It is preferred that the questionnaire be completed during 
the 3-month clinic visit and given to institutional staff for submission to the Alliance Statistics 
and Data Center. However, patients may complete the questionnaire at home and either mail the 
completed questionnaire to institutional staff or bring it with them to the 6-month visit.  
Completed original questionnaires must be mailed (not faxed) to:  

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6.3 Sample Submission 
Questions regarding sample collection or submission should be directed to the Alliance 
Biorepository at the Ohio State University at 
. 
All Patients registered to CALGB 90203: Retrospective histopathology review will be 
conducted using the paraffin prostate tissue from the diagnostic prostate biopsies and the radical 
prostatectomy specimens. The submission of these samples for histopathology review is 
required for all patients registered to this study, including those who are found to be 
ineligible and those who do not receive protocol therapy. When available, these specimens 
will also be used for correlative analyses described in Section 11.3. 
Patients registered to sub-study 150413: All participating institutions must ask patients for 
their consent for the use of their specimens for the biomarker analysis study described in Section 
11.2. For patients who consent, submit tissue and blood samples as described below. 
Patients registered to sub-study 150412: In addition to the tissue and blood samples required 
for 150413, for patients who have consented to the use of their specimens at Alliance Member 
Institutions, frozen prostate tissue will also be submitted for the RNA and DNA studies 
described in Section 11.3. 
Specimen Collection Time Points: 
 
Within 90 
days of 
registration 
Prior to chemo-
hormonal 
treatment (Arm 
A pts only) 
Prior to 
surgery 
At 
surgery 
After surgery, every 3 months 
for 3 yrs, then every 6 months 
for the next 3 yrs, then yearly 
until treatment failure or 
progression*, and at treatment 
failure or progression† 
For patients all patients registered to 90203 submit: 
Paraffin block/slides for 
histopathology review  
X 
 
 
X 
 
 
For patients registered to 150413, also submit the following: 
Paraffin block/cores of 
prostate tissue from radical 
prostatectomy1 
 
 
 
X1 
 
 
Number and volume of tubes to draw 
Serum SST (marble top)2 
 
2 x 5 mL** 
2 x 5 mL** 
 
2 x 5 mL** 
Plasma (lavender top)
2 
 
1 x 10 mL 
1 x 10 mL 
 
1 x 10 mL 
 
 
For patients registered to Substudy 150412, submit all of the specimens above, PLUS: 
Frozen prostate tissue from 
RP3 
 
 
 
X 
 
* As defined in Sections 14.1.1 through 14.1.4. 
† Treatment failure/progression samples may be collected and submitted up to 3 months after 
treatment failure or progression. 
** Or, 1 x 10 mL. 

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1 Blocks/cores to be used for biomarker/TMA analysis (substudy 150413). Additional submission 
of RP blocks/cores is not necessary if blocks are submitted for histopathology review. 
2 Serum and plasma to be used for biomarker analysis (substudy 150413) 
3 To be used for RNA and DNA analyses (substudy 150412) 
Specimen submission using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BIOS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance 
trials. Authorized individuals 
may access BioMS at the following URL:  
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers (Safari, 
Firefox, Internet Explorer). For information on using the BioMS system, please refer to the 
‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, and training 
videos. To report technical problems, such as login issues or application errors, please contact: 
. For assistance in using the application or 
questions or problems related to specific specimen logging, please contact
 
 
After logging collected specimens in BioMS, the system will create a shipping manifest.  This 
shipping manifest must be printed and placed in the shipment container with the specimens. 
All submitted specimens must be labeled with the protocol number (90203), Alliance patient 
number, patient’s initials and date and type of specimen collected (e.g., serum, whole blood). 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in the 
shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method of 
shipping that is secure and traceable. Extreme heat precautions should be taken when necessary.  
Shipment on Monday through Thursday by overnight service to assure receipt is encouraged. 
All specimens should be sent to the following address: 
 
 
 
 
 
 
 
Alliance Block Submission Policies: The goal of the Alliance Biorepository at OSU is to 
provide investigators with quality histology sections for their research while maintaining the 
integrity of the tissue. All paraffin blocks that are to be stored at the Alliance Biorepository at 
OSU will be vacuum packed to prevent oxidation and will be stored at 4ºC to minimize 
degradations of cellular antigens.  
For these reasons it is preferred that the Alliance Biorepository at OSU bank the block until 
correlative studies have been initiated and the study investigator requests thin sections. Please 
contact the Alliance Biorepository at OSU if additional assurances with your hospital pathology 
department are required. 
The Alliance has instituted special considerations for the small percentage (5%) of hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage (4%) of hospitals 
whose policies prohibit release of any block. If, due to institutional policy, a block cannot be 

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sent, please call the Alliance Biorepository at OSU at 
 to obtain a protocol to cut 
the sections or to obtain the cores at your institution. 
Pathology Reports: When shipping tissue samples to the Alliance Biorepository at OSU, a copy 
of the responsible pathologist's pathology report 
must be included.  
This report should specify: 
• - The number of pelvic lymph nodes identified, 
• - presence or absence of cancer in each of the identified pelvic lymph nodes, 
• - presence or absence of extranodal tumor, 
• - prostate tumor histologic type and Gleason grade, 
• - presence and location of positive margins [defined as apical, anterior, bladder 
neck, and posterolateral], 
• - tumor size which can be quantitated as percentage of the gland involved by 
carcinoma, as determined by visual inspection, or as tumor volume, as measured by 
computer-assisted morphometry, 
• - presence or absence of capsular invasion [none, invasion into but not through the 
capsule, focal extracapsular extension, established extracapsular extension], 
• - presence or absence of tumor in the seminal vesicles, 
• - invasion of cancer into the bladder neck, 
• - specification of whether the tumor is unilateral or bilateral, and 
• - tumor pathologic stage, according to the 2002 TNM system, must also be specified. 
6.4 Submission of paraffin blocks and/or slides for central pathology review;  
Required for all patients registered to this study. 
Consistent and accurate histologic grading using the Gleason grading system is important for 
this study. Submission of histologic slides from the diagnostic prostate biopsy and of paraffin 
blocks, cores, or slides (see below) from the radical prostatectomy is required for all patients 
enrolled to CALGB 90203.  
While institutional Gleason scoring will be used to determine patient eligibility, a retrospective 
review of the histologic slides used for diagnosis of prostate cancer on these patients will be 
performed. Central pathology review is not required prior to registration.  
Central histopathology review of radical prostatectomy blocks/slides should provide a more 
accurate picture of the comparative tumor Gleason grades as well as an assessment of treatment 
effects on tumor, including qualitative cytologic effects and quantitative amount of prostate 
cancer via image analysis.  
6.4.1 Block/slide preparation 
Label all blocks and/or slides with the following identification: 
a) Procurement date 
b) Institutional surgical pathology number 
c) Patient study ID number 
d) CALGB study number (i.e., 90203) 
e) Specimen source (according to location within the prostate) 

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Pathology reports: When shipping samples to the Alliance Biorepository at OSU, include 
copies of the responsible pathologist
's pathology report from the TREATING institution, 
and, if applicable, the REFERRING institution.  
Follow shipping instructions outlined in Section 6.3. 
6.4.2 Diagnostic biopsy sample submission  
Within 90 days of patient registration/randomization, submit to the Alliance Biorepository 
at OSU the following materials: 
• 1) One H&E slide from every prostate biopsy tissue block regardless of region or 
pathology,  
AND:  
• 2) One paraffin-embedded block with REPRESENTATIVE PRIMARY TUMOR  
• OR 
• Ten (10) unstained slides from a tumor-bearing block that will be suitable for 
immunohistochemical staining. 
6.4.3 Radical prostatectomy sample submission for histopathology review 
Within 90 days of radical prostatectomy, submit to the Alliance Biorepository at OSU the 
following materials: 
• 1) One H&E slide from every prostate tissue block taken from the prostate regardless 
of region or final pathology,  
AND  
• 2) One paraffin-embedded block with REPRESENTATIVE PRIMARY TUMOR 
from each of the following regions: 
• - Prostate 
• - Seminal vesicle, if tumor present 
• - Lymph node, if tumor present 
OR 
• Ten (10) unstained slides from a tumor-bearing block that will be suitable for 
immunohistochemical staining from each of the following regions: 
• - Prostate 
• - Seminal vesicle, if metastatic 
• - Lymph node, if metastatic 

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6.5 Tissue submission requirements for patients enrolled to sub-study 150413  
Formalin-fixed paraffin-embedded blocks or cores of prostate tissue are required for tissue 
microarray analysis for all patients enrolled to sub-study 150413. If a block(s) from the 
surgical sample were submitted for histopathology review per Section 6.4.3, it is not 
necessary to submit additional tissue. 
For blood sample requirements for patients enrolled to 150413, see Section 6.6. 
Please contact the Alliance Biorepository at OSU at 
 with additional questions 
PRIOR to submitting materials.  
6.5.1 Radical prostatectomy tissue sample requirements: Within 90 days of radical 
prostatectomy, submit to the Alliance Biorepository at OSU the following materials: 
• 1) Blocks: One paraffin-embedded block with REPRESENTATIVE PRIMARY 
TUMOR from each of the following tumor-bearing regions: 
• - Prostate 
• - Seminal vesicle, if tumor present 
• - Lymph node, if tumor present 
OR 
• 2) Cores: If blocks cannot be provided, tissue core extraction (punches) are required. 
Punches (at least two) will be taken from tumor-rich areas as well as from benign areas 
(at least two). For each block with REPRESENTATIVE PRIMARY TUMOR, submit 
two cores from each of the following tumor-bearing regions: 
• - Prostate 
• - Seminal vesicle, if tumor present 
• - Lymph node, if tumor present 
Please contact the Alliance Biorepository at OSU at 
, to obtain instructions 
for tissue core extraction (punches). The punches will be used by the submitting 
institution
's pathologist to extract tissue cores suitable for protocol requirements. 
6.5.2 Radical prostatectomy tissue sample submission: Label each section or core with the 
following: 
a) Procurement date 
b) Institutional surgical pathology number 
c) Patient study ID number 
d) CALGB study number (i.e., 90203) 
e) Specimen source (according to location within the prostate) 
Within 90 days of the radical prostatectomy, submit samples to the Alliance 
Biorepository at OSU. Include the responsible pathologist
's pathology report and follow 
shipping instructions outlined in Section 6.3. 

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6.6 Blood sample submission requirements for patients enrolled to sub-study 150413  
For patients who consent to participate, in addition to the tissue samples collected and submitted 
as described above, serum and plasma samples will be used for the correlative science substudy 
described in Section 11.2 (150413). Blood samples should be collected prior to the initiation of 
chemohormonal therapy (for patients randomized to Arm A), prior to radical prostatectomy (or 
pelvic lymph node dissection for patients undergoing perineal prostatectomy), and every 3 
months during the first three years after surgery, every 6 months for the next three years, and 
annually thereafter until treatment failure or progression as defined in Sections 14.1.1—14.1.4, 
and at treatment failure or progression. 
For serum, a total of 10 mL of venous blood will be drawn in two red/black top serum separator 
tubes. Gently invert 5 times to mix clot activator with blood. Let blood clot for up to one hour. 
Observe a dense clot. Centrifuge at 1300g for 10 minutes. The sample should be refrigerated 
until shipped on cool pack by overnight mail to the Alliance Biorepository at OSU. The sample 
should be shipped the same day that the blood is drawn.  
For plasma, 10 mL of venous blood will be drawn in purple top EDTA containing tubes. Invert 
tube 8-10 times, and refrigerate until shipped on cool pack by overnight carrier to the Alliance 
Biorepository at the Ohio State University. The sample should be shipped the same day that the 
blood is drawn.  
Label samples with the following identification: 
• 1)  Procurement date 
• 2)  Patient study ID number 
• 3) CALGB study number (i.e., 90203) 
• 4)  Serum or Plasma 
6.7 Fresh frozen tissue sample submission requirements for patients enrolled to sub-study 
150412 
In addition to the tissue samples described in Sections 6.4.2 and 6.5, and blood samples 
described in Section 6.6, submission of FRESH prostate tissue is required for all patients from 
Alliance Member Institutions who have consented to the use of their specimen(s). All other 
institutions are encouraged, but not required, to submit fresh prostate tissue. 
Materials required to prepare and ship the frozen OCT specimens are available for this sub-
study upon site request. The materials may be requested by contacting the Alliance 
Biorepository at Ohio State University at 
. 
6.7.1 Specimen submission requirements 
The following samples should be submitted for patients registered to sub-study 150412 at 
Alliance Member Institutions: 
• 1) Two OCT specimens collected from the site of cancer within the prostate. If 
present, the dominant tumor should be sampled; if no cancer is obvious on visible 
inspection of the prostate, then the area of the prostate positive on biopsy should be 
sampled. 
• 2) One OCT specimen collected from 1 area of normal/benign prostate. 
• 3) One OCT specimen collected from a lymph node positive for tumor, if available. 
(If lymph nodes are negative for tumor, no specimen should be submitted. 

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6.7.2 Specimen collection, preparation, and submission procedures  
In the case of grossly positive pelvic lymph nodes, a portion of the involved node(s) should 
be frozen. Fresh prostate tissue may be harvested using a protocol in place at one
's hospital, 
one of the published protocols (74-78), or, as follows:  
• 1) After inking of the entire outer surface of the prostate gland, incision or sectioning 
of the whole prostate gland may be performed using the local standard of care. 
Care must be taken not to disrupt or harvest the outer surface of the gland as this may 
compromise histopathologic evaluation of extraprostatic extension of carcinoma 
and/or surgical margin status. Fresh tissue may be procured by taking tissue sections 
from underneath the prostatic "capsule" or by taking punch biopsies (74-78).  
• 2) Sampling of several sites, including sites of any palpable or gross abnormalities, is 
desirable. For example, if large tissue sections are taken, sampling of both right and left 
sides of the prostate is recommended. For needle core sampling, 10 cores should be 
taken (75). Suspicious sites can be identified by induration on palpation, hyperemia, or 
other color irregularities from normal-appearing prostate gland. 
Sample one normal and two suspicious sites within the prostate by either: 
a) (Preferred) Incise prostate sections and remove samples approximately 20 to 30 
mg (size of an eraser head on a pencil). DO NOT DISRUPT OR HARVEST THE 
OUTER SURVACE OF THE GLAND. 
Or 
b) (Alternate) Perform needle core sampling using an 18 gauge needle. 10 cores 
should be taken. 
• 3) Label frozen samples sequentially with the following codes: 
• FT1: Tumor sample one; 
• FT2: Tumor sample two; 
• FB1: Benign sample one; 
• FB2: Benign sample two (optional) 
• Label with the respective region using the following codes: 
• From the prostate: FT1 and FT2, (targeting tumor); FB1 and FB2 (targeting benign 
tissues), RB (right prostate), RM (right mid), RA (right apex), LB (left base), LM (left 
mid), LA (left apex) 
• From the lymph node(s): RO (right obturator), RII (right internal ileac), REI (right 
external ileac), LO (left obturator), LII (left internal ileac), LEI (left external ileac) 
• 4) Place collected material, incised specimens or cores, onto a pre-frozen pallet of 
Optimal Cutting Temperature (OCT) compound.  
• Pre-frozen pallets of OCT can be created by placing sufficient OCT to cover the bottom 
of a pre-labeled, plastic cryomold. The importance of having pre-frozen OCT is that the 
fresh tissue rapidly freezes when it contacts the frozen OCT. Cover sample with 
additional OCT and freeze rapidly in cryostat (at -20˚ C) or on dry ice. 
• If an alternative method of freezing (i.e. liquid nitrogen submersion) is used, after the 
specimen is frozen, place sample in pre-labeled cryomolds, cover with OCT, and freeze 
OCT in dry ice or in a cryostat. 

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• 5) Label cassettes with the following identification: 
a) Institutional surgical pathology number 
b)  Procurement date 
c)  Sample type (e.g., FT1, FT2, or FB1) 
d) Respective region (e.g., RB, RM, RA, LB, LM, RO, RII, LO, LII, or LEI) 
e)  Patient study ID number 
f) CALGB study number (i.e., 90203) 
• 7) Temporarily place on dry ice (to move to storage). 
• 8) Store in liquid nitrogen-vapor phase (ideal) or at -80˚ C (if necessary). 
• 9) Ship on dry ice by overnight mail to the Alliance Biorepository at OSU at the 
address listed in Section 6.3. Please notify the Alliance Biorepository at OSU by fax 
or email 
 of intended shipments. Shipments to 
the Alliance Biorepository at OSU can be made on a monthly basis by overnight carrier. 
• Remember to include the responsible pathologist
's pathology report as described in 
Section 6.3 when submitting samples to the Alliance Biorepository at OSU. 
6.8 Surgical Quality Assurance Requirements  
6.8.1 General Guidelines 
All patients will undergo standard surgical intervention that will consist of: (1) staging 
pelvic lymphadenectomy and (2) radical perineal or retropubic prostatectomy. If the 
retropubic approach is chosen, lymphadenectomy will be performed concurrently with 
prostatectomy. In the case of perineal prostatectomy, lymphadenectomy should be 
performed no more than 2 weeks before prostatectomy.  
Resection of the prostate gland will not be performed in the case of gross, macroscopic, 
histologically confirmed lymph node metastases. If nodal involvement is microscopic, 
surgery may proceed at the discretion of the surgeon. Following radical prostatectomy, 
pathology will be reviewed centrally to evaluate the pathologic endpoints. Radical 
prostatectomy specimens will be handled and sampled in a uniform fashion, with complete 
embedding of the entire prostate gland. 
6.8.2 Surgical Quality Assurance 
The surgical goals of the study are: 
• • To perform a standard bilateral pelvic lymph node dissection including the external 
iliac, obturator and hypogastric lymph nodes 
• • To perform a radical prostatectomy with complete removal of all gross tumor. The 
dissection should include complete removal of both seminal vesicles 
• • To determine if neoadjuvant chemotherapy results in a more difficult surgical 
dissection 
To ensure that these goals are met, and facilitate compliance with Surgical Quality 
Assurance Committee requirements, the following seven (7) items should be specifically 
commented on in the operative procedure: 
• 1. A description of the extent of the lymph node dissection including specific mention 
of whether or not the external iliac, obturator, and/or hypogastric nodes were removed. 
• 2. Were the nodes grossly positive or negative? 

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• 3. Was a frozen section of the lymph nodes and/or prostate sent at the time of surgery? 
If yes, what was the result? 
• 4. An intraoperative assessment of the extent of disease within the prostate given 
using the “T” part of the TNM system (classified as T1c through T4). 
• 5. A description of whether or not all gross disease was resected. 
• 6. A statement regarding the difficulty of the procedure. 
• 7. A statement of whether or not there were intraoperative complications. 
Submission of the operative report is required (see Section 6.1) A sample dictation is 
as follows (the note would be adjusted based on the actual case): 
“Findings: The patient is enrolled in CALGB 90203 and was randomized to receive 
neoadjuvant chemo-hormonal therapy. He is brought to the operating room within 60 days 
of his last treatment cycle. A bilateral pelvic lymph node dissection including the external 
iliac, obturator and hypogastric areas was performed. The nodes were grossly negative for 
metastatic disease. The prostate was indurated bilaterally without evidence of 
extraprostatic disease (intraoperative stage T2c). Both seminal vesicles were removed and 
all visual evidence of disease was resected. There were no intraoperative complications.” 
6.8.3 Monitoring of Surgical Quality 
The Alliance study chair will assign relative weights (points) to the various surgical aspects 
of the procedure. If these elements are not performed, points are deducted during case 
review from a perfect score of 100% of all available points. Key events of the procedure 
are rated so that major protocol deviations require point deductions > 20%. Less important 
deviations have a smaller deduction. A passing score of 75% of total points is required for 
each patient and if not achieved initiates an interactive quality improvement process for the 
institution or investigator as appropriate. 
Major Deviations 
• • Failure to perform a pelvic lymphadenectomy 
• • Performing a radical prostatectomy in the setting of grossly positive lymph nodes  
• • Performing surgery outside the 60 day guideline after randomization (surgery only 
arm) or the completion of chemohormonal therapy (neoadjuvant chemohormonal 
therapy arm) 
Minor Deviations 
• • Performing a limited pelvic lymphadenectomy (not sampling the external iliac, 
obturator, AND hypogastric lymph nodes) 
• • Failure to report extent of tumor based on intraoperative findings using 2002 TNM 
staging system in the operative report 
• • Failure to report intraoperative complications in the operative report 
• • Failure to remove the entire seminal vesicles 
• • Failure to report completeness of resection 
 

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7.0 REQUIRED DATA 
Guidelines for Pre-Study Testing  
To be completed within 90 DAYS before registration: 
- Diagnostic prostate biopsy confirming prostatic adenocarcinoma 
To be completed within 42 DAYS before registration: 
- Computed tomography or MRI scan of the abdomen and pelvis or endorectal MRI, and bone scan (with plain film 
or MRI confirmation, if necessary).  
To be completed within 14 DAYS before registration: 
- All blood work, physical examination, history 
 
Prior to 
registration 
ARM A 
Day 1 of each cycle† 
Pre-
surgery‡ 
At 
surgery 
Post-surgery 
follow-up* 
Tests & Observations 
 
 
 
 
 
History and Progress Notes 
X 
X 
X 
 
X 
Physical Examination 
X 
X 
X 
 
X 
Pulse, Blood Pressure 
X 
X 
X 
 
X 
Weight/BSA∞ 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
Performance Status 
X 
 
X 
 
 
Drug Toxicity Assessment 
 
X 
X# 
 
 
EPIC Short Form (C-1145) 
 
 
D 
 
D 
Pathology review 
A 
 
 
B 
 
Laboratory Studies  
 
 
 
 
 
CBC, Differential, Platelets 
X 
X 
X 
 
 
Serum Creatinine 
X 
X 
X 
 
 
ALT, AST, Bilirubin 
X 
X 
X 
 
 
LDH, Alk. Phos. 
X 
 
 
 
 
Serum PSA 
X 
X 
X 
 
E 
Serum Testosterone 
X 
 
X 
 
X 
EKG 
 
 
X 
 
 
Staging 
 
 
 
 
 
Bone Scan 
X 
 
 
 
C 
CT Scan or MRI of abd./pelvis 
OR erMRI of pelvis 
X 
 
 
 
 
Companion Studies** 
 
 
 
 
 
Diet/Lifestyle Assessment 
At 3 months following surgery 
Prostatectomy tissue samples  
To be collected at surgery, see Sections 6.4, 6.5 and 6.7. 
Blood samples 
See Section 6.6 
** For patients who consent to participate. See also, Sections 6.2—6.7. 
† Labs may be obtained within 48 hours prior to each cycle of chemohormonal therapy. For cycle 1, baseline history and 
physical and labs may be used in place of Day 1 H & P and labs provided they are obtained within 14 days prior to treatment. 
‡ Labs obtained within 30 days prior to surgery need not be repeated. Pre-registration physical exam may be used for pre-
surgery PE if obtained within 14 days prior to surgery. 
* Patients will be evaluated within 1 month and within 3 months after surgery, then every 3 months for the first 3 years 
following surgery, every 6 months for the next 3 years, and annually thereafter until 15 years after randomization. If patients 
experience treatment failure per Sections 14.1.3 or 14.1.4 during the first 3 years following surgery, evaluations may be done 
every 6 months. Follow all patients until biochemical or metastatic disease progression per Sections 14.1.1 or 14.1.2, then 
follow patients for survival until 15 years after registration. 
∞ The dose of chemotherapy need not be changed unless the calculated dose changes by ≥ 10%. 
# For patients randomized to Arm A only. 
A Diagnostic prostate blocks or slides, see Sections 6.4. 
B Prostatectomy and pelvic lymph node blocks or slides, see Sections 6.4 and 6.5. 
C Bone scans are to be performed on any patient with complaints of bone pain that cannot be attributed to intercurrent disease. 
Also, after PSA progression, scans are to be performed every 6 months until distant progression. 
D The EPIC short form is required at the last pre-surgery clinic visit and every 6 months after surgery for 3 years regardless of 
disease or treatment status. 
E Every 3 months until protocol progression of any type (per Section 14.1): confirmed biochemical disease progression 
(Section 14.1.1); radiographic disease (Section 14.1.2); post-operative radiotherapy started later than 6 months post-surgery 
(Section 14.1.3); or post-surgery systemic therapy (ADT) (Section 14.1.4). After any of these qualifying events, PSA 

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measurements are optional and may be taken at the discretion of the treating physician.  Please continue to report all PSA 
measurements on the C-714 PSA form 
via Medidata Rave® and non-protocol therapies on the C-1244 Follow-up form 
via 
Medidata Rave® even after progression. 
8.0 TREATMENT PLAN 
Questions regarding treatment should be directed to the Alliance Study Chair or Co-chair. 
Patients will be randomized to receive either 18 to 24 weeks of androgen deprivation therapy plus 
chemotherapy followed by radical prostatectomy OR immediate radical prostatectomy.  
For patients randomized to Arm A, neoadjuvant treatment is to begin within 14 days of 
randomization. One cycle will be defined as 3 weeks of treatment. Surgery will then take place within 
60 days following the completion of neoadjuvant therapy (i.e., sixty days plus 3 weeks after the last 
docetaxel dose was given). 
For patients randomized to Arm B, surgery is to occur within 60 days of randomization. 
 
 
ARM A1 
 
 
R  
 
 
Surgical Intervention 
A  
LHRH agonist x 18 to 24 weeks 
 
Staging pelvic 
N  
Docetaxel 75 mg/m
2 every 21 days x 6 cycles 
 
lymphadenectomy 
D  
 
 
Radical prostatectomy* 
O  
 
 
 
M  
ARM B2 
 
 
I  
Surgical Intervention 
 
 
Z  
Staging pelvic 
 
 
E  
lymphadenectomy 
 
 
 
 
Radical prostatectomy* 
 
 
* 
Patients with positive surgical margins extraprostatic extension, and/or seminal vesicle 
invasion are allowed to receive adjuvant external beam radiation to the prostatic fossa at 
the discretion of the treating physician. Adjuvant radiation must be initiated within 6 
months of the date of surgery. 
8.1 Neoadjuvant chemohormonal therapy (Arm A only) 
Patients who have been randomized to Arm A will receive 6 cycles of docetaxel administered 
every 3 weeks combined with 18 to 24 weeks of androgen deprivation therapy. 
8.1.1 Docetaxel: Docetaxel 75 mg/m2 will be administered intravenously over 1 hour on Day 1 of 
each cycle, every 21 days. 
Dexamethasone: During each cycle of chemotherapy, all patients should undergo 
premedication with dexamethasone 8 mg orally approximately 12 hours, 3 hours, and 1 
hour prior to docetaxel (i.e., 8 mg of dexamethasone the night before, the morning of, and 
just prior to the infusion of docetaxel). 
Alternatively, dexamethasone may be given twice daily the day before, the day of, and the 
day after docetaxel (i.e., 6 doses of 8 mg of dexamethasone during each cycle of therapy). 
Lastly, dexamethasone may also be given intravenously according to institutional 
guidelines. 

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8.1.2 Androgen deprivation: Androgen deprivation will include 18 to 24 weeks (measured from 
the date of starting docetaxel) of an LHRH agonist (e.g., leuprolide acetate, goserelin acetate). 
Oral antiandrogens may not be used, and must be discontinued prior to the initiation of 
protocol treatment. 
8.1.3 Additional pre-medication and antiemetics may be given at the physician's discretion. 
However, the use of aprepitant as an antiemetic is not allowed. Use of additional medications should 
be recorded on the CALGB C-260 Remarks Addenda. 
8.2 Radical Prostatectomy (Arms A and B) 
All patients will undergo standard surgical intervention that will consist of:  
(1) staging pelvic lymphadenectomy and  
(2) radical perineal, retropubic, laparoscopic, or robotic-assisted prostatectomy.  
In the case of perineal prostatectomy, lymphadenectomy should be performed no more than two 
weeks prior to prostatectomy. If the retropubic, laparoscopic, or robotic-assisted approach is 
chosen, lymphadenectomy will be performed concurrently with prostatectomy.  
The surgical procedures will be performed within 60 days of the completion of neoadjuvant 
therapy for patients on Arm A. For patients randomized to Arm B, surgery is to be performed 
within 60 days of randomization. The procedure may be performed under general, regional, or 
general and regional anesthesia. 
See Section 6.8 for surgical quality assurance requirements. 
8.2.1 Staging Lymphadenectomy 
Bilateral pelvic lymphadenectomy should include complete removal of all fibroadipose 
tissue dorsal to the external iliac vein, caudal to the hypogastric artery and vein, cephalad 
to Cooper
's ligament and the pelvic floor, medial to the obturator muscular sidewall of the 
pelvis, lateral to the bladder, and ventral to the sciatic nerve. (54, 55) 
Resection of the prostate gland will not be performed in the case of gross, macroscopic, 
histologically confirmed lymph node metastases. Because patients in the chemohormonal 
therapy arm may have a decreased chance of having/detecting positive lymph nodes, no 
frozen sections will be performed on the lymph nodes intraoperatively. This is required to 
keep the study arms balanced and to avoid selection bias. No frozen sections of visually 
and palpably negative nodes will be performed. 
Androgen Deprivation: Patients with lymph node metastases at staging pelvic 
lymphadenectomy or radical prostatectomy will be followed. Although a matter of debate, 
recent data from Messing and colleagues suggests a significantly better outcome with 
respect to overall and progression-free survival for radical prostatectomy patients with 
pathologically proven lymph node metastases who receive immediate androgen 
deprivation therapy compared to those undergoing delayed treatment. (56) Therefore, these 
patients will be allowed to have immediate androgen deprivation therapy, if desired. Since 
androgen deprivation therapy will affect time to biochemical and metastatic disease 
progression, and possibly survival, these patients will be considered treatment failures at 
the time of initiation of androgen deprivation therapy. Investigators are encouraged to delay 
postoperative systemic therapy, including androgen deprivation therapy, until the patient 
has documented evidence of biochemical failure (defined as a serum PSA level > 0.2 
ng/mL and rising on 2 separate occasions at least 3 months apart following radical 
prostatectomy). 

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8.2.2 Radical perineal prostatectomy 
The patient is placed in an exaggerated lithotomy position, taking care to pad any pressure 
points. The incision is made from one ischial tuberosity to the other, with the apex of the 
incision approximately 1.5 cm above the anus. The incision is deepened through the 
adipose tissue, and the central tendon is divided. The rectal wall is retracted inferiorly and 
the pedicles to the prostate are identified lateral to the seminal vesicles and divided. 
The urethra is identified and divided just distal to the apex of the prostate. The plane 
between the anterior aspect of the prostate and the dorsal venous complex is developed to 
the level of the bladder neck. The bladder neck is divided distal to the ureteral orifices. The 
dissection of the seminal vesicles is completed. The seminal vesicles should be removed 
in toto. 
The bladder neck is reconstructed as needed and anastomosed to the urethra over a catheter. 
A drain is placed deep to the reconstructed central tendon following which the 
subcutaneous tissue and skin are closed.  
8.2.3 Radical retropubic prostatectomy 
A lower midline abdominal incision is made and a pelvic lymphadenectomy [see above 
description for limits of dissection] is performed. The endopelvic fascia is incised and the 
levator muscles are dissected off the lateral aspect and apex. The dorsal venous complex is 
divided with appropriate hemostatic control. The decision whether or not neurovascular 
bundle (NVB) preservation should be performed is at the discretion of the operating 
surgeon. At centers where nerve grafting is performed, this is permitted as part of routine 
surgical care. After either NVB mobilization or division at the apex, the urethra distal to 
the apex of the prostate is transected. Denonvilliers
' fascia should be kept intact over base 
and posterolateral aspect of the prostate. The dissection, whether nerve sparing or not, 
proceeds in a retrograde fashion from the apex to the base of the prostate. The lateral 
vascular pedicles are divided. The seminal vesicles are dissected free in their entirety and 
resected intact with the prostate. The vasa are divided. The bladder neck should be 
circumferentially incised and the specimen removed. 
The bladder neck is reconstructed as needed and anastomosed to the urethra over a catheter. 
The fascia and skin are closed in routine fashion. 
A laparoscopic or robotic-assisted approach is permitted and should follow a similar 
anatomical approach as outlined with intact specimen delivery. 

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8.2.4 Positive surgical margins 
Patients with positive surgical margins, extraprostatic extension, and/or seminal vesicle 
invasion will be allowed to receive adjuvant external beam radiation to the prostatic fossa 
based on the judgment of the treating physician. Although the efficacy and timing of such 
treatment is a matter of debate, physicians and patients may desire this treatment based on 
the available data. Such patients will not be considered treatment failures, but will continue 
on standard follow-up and will be included in the analysis. The decision for adjuvant 
radiation therapy must be made and started within 6 months of the date of surgery. See 
Section 14.1.3 for post-operative radiotherapy. 
8.2.5 Handling of the pathologic material 
Specimen submission of formalin-fixed, paraffin-embedded tissue (blocks or slides) from 
the radical prostatectomy (RP) specimen and metastatic pelvic lymph nodes for centralized 
pathology review is required for all patients.  
Submission of frozen tissue is required for all patients enrolled at Alliance Main Member 
and At-Large institutions except for those who indicate on the consent form that they 
decline to participate in this companion study (150412). All other institutions are strongly 
encouraged, but not required, to submit this tissue. See Sections 6.5 and 6.7 for details 
regarding preparation of these samples for submission. 
8.3 Potential Minor and Major Complications of Surgery 
8.3.1 Potential minor complications include: wound infection, urinary tract infection, 
pelvic/scrotal/lower extremity edema, ileus, urinary frequency/urgency/nocturia, urinary retention, 
incisional or pelvic pain. 
8.3.2 Potential major complications include: Rectal injury, ureteral injury, major vascular or 
nerve injury, hemorrhage requiring transfusion of non-autologous blood products, urinary 
incontinence, erectile dysfunction, bladder neck contracture, deep venous thrombosis, pulmonary 
embolism, myocardial infarction, stroke, life threatening complications, and death. 

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9.0 CHEMOTHERAPY DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
No dose modifications will be made for LHRH agonists. 
There will be no dose re-escalation once docetaxel dose is reduced. If dose reduction beyond level -
2 is required (for any reason) or if docetaxel is held for greater than 3 weeks unless otherwise specified 
below, no further docetaxel will be administered; the patient will complete at least 18 weeks of 
androgen deprivation therapy and proceed to surgery 
Dose Levels for Docetaxel 
Dose Level 
Docetaxel 
Level 0 (Starting dose) 
75 mg/m
2 
Level -1 
60 mg/m
2 
Level -2 
50 mg/m
2 
9.1 Dose modifications for hematologic toxicity 
For ANC < 1500 or platelets < 100,000, hold docetaxel, and repeat CBC weekly. Resume 
docetaxel when ANC ≥ 1500 and platelets ≥ 100,000. If docetaxel is held for hematologic 
toxicity for more than one week, resume docetaxel when toxicity resolves with one dose level 
reduction for all subsequent cycles. 
For febrile neutropenia defined as ANC < 500 and T ≥ 38.2°C (100.8°F), decrease docetaxel 
by one dose level for all subsequent cycles. 
9.2 Hepatic Dysfunction 
For bilirubin ≤ 1.5 x ULN and AST 1.5 - 5 x ULN, decrease docetaxel by 1 dose level for all 
subsequent doses. 
For bilirubin > 1.5 x ULN or AST > 5 x ULN, hold docetaxel and repeat LFT
's weekly. 
Resume docetaxel when bilirubin ≤ 1.5 x ULN and AST ≤ 1.5 x ULN, with one dose level 
reduction. 
9.3 Neurotoxicity 
For grade 3 or 4 neurotoxicity, hold docetaxel until the toxicity resolves to grade 2 or less and 
then resume therapy with docetaxel at one lower dose level. If the neurotoxicity persists or 
worsens despite dose reduction, hold docetaxel until toxicity clears to grade 2 or less then 
resume with docetaxel at one more lower dose level. If therapy is held for more than six weeks 
or ≥ grade 3 neurotoxicity persists after 2 dose reductions, discontinue docetaxel and complete 
18 weeks of androgen deprivation therapy as planned. 
9.4 Gastrointestinal Toxicity 
In this protocol, the routine use of an antiemetic is clinically appropriate. 
For ≥ grade 3 mucositis, hold docetaxel until symptoms resolve to ≥ grade 2. Then resume 
docetaxel with one dose level reduction. 
9.5 Fluid retention 
If symptomatic, treat the patient early with diuretics of the physician
's choice. If severe and 
refractory to symptomatic treatment, discontinue docetaxel. 

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9.6 Skin Toxicity 
9.6.1 Extravasation of docetaxel may cause skin necrosis; stop the infusion immediately if 
extravasation is suspected, and administer the drug at another site. 
9.6.2 Erythema, desquamation 
Grade 0-2: No change. 
Grade 3-4: Hold docetaxel until skin toxicity improves to ≤ grade 2, then decrease one 
dose level for all subsequent cycles of therapy. If grade 3-4 toxicity recurs, 
discontinue docetaxel. 
9.7 Hypersensitivity Reactions  
9.7.1 Grade 1: Interrupt infusion until resolution of symptoms, then complete infusion a the 
initial planned rate. 
9.7.2 Grade 2: Stop infusion. Give diphenhydramine 50 mg IV with dexamethasone 10 mg IV 
plus an H2 blocker, all at the physician's discretion. Resume docetaxel infusion after recovery. 
Pretreat with diphenhydramine and H2 blocker for future cycles. 
9.7.3 Grade 3 or 4: Stop infusion and discontinue docetaxel. 
9.8 Corticosteroid Toxicity 
High doses of dexamethasone may cause hyperglycemia, insomnia, and mental status changes. 
Treating physicians may modify the dose of dexamethasone as clinically indicated. 
9.9 Other Toxicities 
For grade 3 or grade 4 toxicities not listed above including fatigue (and excepting nausea and 
vomiting), all treatment should be withheld until the toxicity resolves to grade 1 or less. 
Docetaxel should be re-instituted (if medically appropriate) at one lower dose level. If treatment 
is withheld for longer than three weeks, no further chemotherapy will be administered, 18 weeks 
of androgen deprivation therapy will be completed, and the patient will proceed to surgery if 
clinically indicated. 
9.10 Dose Modification for Obese Patients  
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely 
by (1) the patient's BSA as calculated from actual weight or (2) actual weight without any 
modification unless explicitly described in the protocol. This will eliminate the risk of 
calculation error and the possible introduction of variability in dose administration. Failure to 
use actual body weight in the calculation of drug dosages will be considered a major 
protocol deviation. Physicians who are uncomfortable with administering chemotherapy dose 
based on actual body weight should not enroll obese patients on Alliance protocols.  

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10.0 DIET AND LIFESTYLE SUBSTUDY 
10.1 Background 
Overall, red meat, total and specific fats, (50, 57-71) dairy and calcium intake (72) have been 
associated with an elevated risk of prostate cancer. For each of these, stronger associations were 
observed for the development of metastatic and fatal disease, suggesting that these dietary 
factors play a role late in carcinogenesis. In contrast, total and specific vegetables, 
lycopene/carotenoids/tomato products, fruits, vitamin E supplements, and selenium 
supplements have all been inversely linked to risk of prostate cancer. In particular, while not the 
primary endpoint of the studies, vitamin E was linked to an approximate 40% reduction in 
prostate cancer incidence and mortality in a randomized clinical trial. Similarly, selenium 
supplementation was associated with an approximate 1/3 reduction in prostate cancer incidence 
in a randomized clinical trial. (73) 
In addition to the large body of evidence for incident prostate cancer, there is emerging evidence 
that post-diagnostic diet is also important for prostate cancer death. Chan and colleagues 
examined post-diagnostic diet relevant to pre-diagnostic diet and risk of prostate cancer 
recurrence in an observational, non-intervention study among 1202 incident prostate cancer 
cases, using prospectively collected dietary questionnaire data (Health Professionals Follow-up 
Study). In an analysis with 392 cases of recurrence, progression, and mortality, a positive change 
in intake of fish or tomato sauce after diagnosis (e.g. consuming more fish or tomato sauce after 
diagnosis relative to before diagnosis) appeared to be strongly protective against risk of prostate 
cancer recurrence/progression (HR = 0.73, 95% CI 0.32 - 1.02 for fish; HR = 0.56, 95% CI 0.38 
- 
0.82 for tomato sauce), independent of other food groups and total energy, and age at diagnosis. 
Adjusting for tumor stage at diagnosis and primary treatment did not affect these results (Chan, 
et al., CCC in press). In a separate analysis of 1511 incident prostate cancer cases from this 
cohort study, there were also provocative inverse associations for post-diagnostic physical 
activity and grain intake and the risk of prostate cancer-specific death (personal communication, 
JM Chan). While provocative, this sub-study was not designed to examine post-diagnostic 
clinical follow-up, and there was potentially incomplete data on clinical progression and 
treatment. Thus, food intake, exercise, and change in these behaviors pre- and post-diagnosis 
will be examined in this trial; more rigorous clinical data will be collected to confirm these 
preliminary results from the Health Professionals Follow-up Study. It is recognized that 
collection of change in diet and exercise patterns will require the retrospective assessment of 
these habits before diagnosis, and may be vulnerable to some recall bias and measurement error. 
However, the questions have purposely been phrased to inquire about a relative change in intake 
(rather than attempt an absolute assessment of previous diet), which will minimize possible 
measurement error. 
Further evidence for a post-diagnosis role of diet in prostate cancer progression comes from 
intervention studies conducted among prostate cancer survivors. While these studies have been 
small and often lacked a control group, they have reported suggestive potential benefits of 
various low-fat plant-based diets on intermediate indicators of prostate cancer progression (PSA 
levels). (74-77) 
10.2 Methods 
Participants in this sub-study will be asked to complete a diet and lifestyle questionnaire at three 
months following surgery. The dietary survey (the Willet semi-quantitative food frequency 
questionnaire) is a validated food frequency survey that has been used in several large cohort 
studies for determining associations between nutrition and chronic disease. For each food, a 
commonly used unit or portion size (e.g., one egg or slice of bread) is specified, and participants 
are asked how often, on average over the past year, they consumed that amount of each food. 
There are nine possible responses that range from never to six or more times per day. The 

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lifestyle portion of the survey includes questions regarding the patient
's physical activities and 
smoking history. (See Section 6.2 for submission instructions.) 
11.0 CORRELATIVE SCIENCES COMPANION STUDIES 
11.1 Background to Correlative Sciences Companion Studies – CALGB 150413 and 150412 
 
In 2015 multiple analyses described somatic mutations, copy number alterations and structural 
DNA rearrangements in primary prostate cancer (78-81). While many studies are not able to 
assess the clinical relevance of tumor genetic alterations, several reports have suggested 
alterations of prognostic significance (82-84). Several groups have reported that copy number 
alteration burden across the genome was associated with PSA recurrence and metastasis after 
prostatectomy (82-85). The association was independent of PSA level and Gleason grade (82). 
Similarly Lalonde et al and Levin et al. found an association of DNA based genomic instability 
(copy number profiles) and PSA recurrence after local therapy (83-84) 
 
Advanced technologies for genomic assessments are now available that are able to use smaller 
DNA/RNA inputs and available FFPE tissue and are suited to sampling obtained real time from 
clinical specimens. These technologies include whole exome and whole genome DNA 
sequencing and nanostring-RNA analyses (86-88) and RNA expression platforms (89).  
 
Alliance 90203 specimens include prostatectomy tissues from untreated and treated (androgen 
deprivation and docetaxel) patients with high risk prostate cancer. Additionally pretreatment 
prostate biopsy specimens will be available in some participants. These tissues will provide 
opportunities to for DNA and RNA based discovery with correlation to clinical endpoints such 
as PSA failure rate.  
11.2 Objectives 
11.2.1 To identify genomic aberrations in matched diagnostic needle biopsy cores and radical 
prostatectomy specimens from men enrolled in the trial using deep targeted DNA-sequencing. 
11.2.2 To identify mRNA expression changes of androgen receptor signaling genes, AR and the 
AR V7 splice variant, neuroendocrine prostate cancer, epithelial mesenchymal transition, and cell 
cycle-associated genes, TMPRSS2-ERG fusion transcript, and control/housekeeper genes in 
matched diagnostic needle biopsy cores and radical prostatectomy specimens. 
11.2.3 To correlate the presence of baseline and post-treatment expression changes and genomic 
aberration and clonality states with pathologic response and clinical outcomes. 
11.2.4 To correlate genomic and gene expression differences in prostatectomy specimens from 
treated vs. untreated cases with clinical outcomes. 
11.2.5 Validation of the Decipher metastasis signature as predictive of response to neo-adjuvant 
docetaxel and androgen deprivation prior to radical prostatectomy versus immediate radical 
prostatectomy in patients with high-risk, clinically localized prostate cancer. 
11.2.6 To test whether AR target gene signatures from clinical prostate cancer specimens obtained 
prior to administration of ADT will inform on response to ADT. This requires AR target gene 

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signatures to be summarized into AR activity scores and a quantization method to summarize AR 
target gene signatures into AR activity level. 
11.2.7 To validate GEMCaP biomarkers in predicting recurrence using the 90203 control arm 
patient set and evaluate GEMCaP as a predictive biomarker of response to neoadjuvant 
chemotherapy/ADT using the 90203 test arm patient set. 
11.2.8 To characterize expression of microRNAs in 90203 specimens. 
11.2.9 To develop and validate a comprehensive prognostic models of clinical outcomes  (3-year 
bPFS rate, bPFS metastases-free survival and overall survival) that can be used for risk 
stratification of patients with prostate cancer, using clinical and molecular markers. 
11.3 Methods 
 
DNA and RNA extractions from baseline biopsies and RP samples will be performed by 
Dr Gleave/Beltran’s team from FFPE specimens and distributed to other groups for 
analysis.  
 
We will review H&E slides from each diagnostic biopsy core.  We will select from each patient 
two positive cores (with >50% tumor content).  Each core will be assessed for Gleason score 
and other morphologic features. We will extract DNA and RNA from each FFPE biopsy core. 
DNA will be extracted using the Covaris truXTRAC FFPE DNA Kit. DNA concentration will 
be assayed using the Qubit and the Qubit dsDNA HS assay kit. RNA will be extracted using the 
Ambion RecoverAll™ Total Nucleic Acid Isolation Kit. RNA quality control will be performed 
on the Agilent 2100 Bioanalyzer system by annotating total RNA concentration and percentage 
of RNA greater than 300 nucleotides (nt) in length. For samples with more than 50% of total 
RNA greater than 300 nt, 100ng input RNA will be used; for samples with less than 50% of total 
RNA greater than 300 nt, the input RNA will be proportionally increased according to the level 
of degradation.  Pathology review will be carried out simultaneously on matched radical 
prostatectomy specimens, where tumor size, grade (if possible) and evidence of any unusual 
features (e.g. neuroendocrine differentiation) will be documented. Macrodissection of tumor and 
benign tissue, and DNA and RNA extraction, will be performed as described above. 
We will employ a deep targeted sequencing strategy for the identification of mutations and copy 
number changes using a custom NimbleGen SeqCap EZ Choice Library (specifically designed 
for aggressive prostate cancer by Dr. Wyatt) and our in-house Illumina sequencing machines. 
Our custom design includes 75 prostate-cancer relevant genes, including for example AR 
pathway genes, prostate cancer drivers (e.g. TP53, SPOP), cell cycle drivers (e.g. CCND1, RB1, 
CDK4/6), DNA repair genes (e.g. BRCA1/2, FANC family genes, ATM, MSH2/6), PI3K 
pathway genes (e.g. PIK3CA, PTEN). From each clinical specimen 10ng of DNA will be used 
for library construction using the KAPA Library Prep Kit, SeqCap EZ Reagent Kit and the 
SeqCap Adapter Kit (Roche). Target enrichment will be performed using the EZ Choice Library 
according to the manufacturer’s protocol (Roche NimbleGen). Libraries will be sequenced in 
batches of 8-48, using our Illumina MiSeq with 25M read kits.  DNA sequence reads will be 
trimmed and aligned with Bowtie-2.2.6 against GRCh37. Somatic mutations will be called by 
comparing allele read counts between tumor and benign samples, requiring a somatic mutation 
to have an allele fraction >1.0%, 20x higher allele fraction than paired benign and median of all 
benign samples, and to have a statistically significant difference in the mutant allele read count 
relative to paired benign (p<1e-20, chi-square test). All variants will be annotated for biological 
significance using ANNOVAR. Mutation candidates will be inspected visually for strand bias, 
amplicon bias, and positional bias within reads. To call copy number changes, aligned reads will 
be counted at each amplicon using bedtools-2.25.0. Sample-specific differences in overall read 
coverage will be multiplicatively corrected using medians-of-ratios calculated across regions 

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with low rates of copy number alterations in prostate cancer. After normalization, amplicon 
coverage log ratios will be calculated between tumor and paired benign samples. 
For gene expression changes, we utilize NanoString nCounter® Analysis System using 100-300 
ng RNA from FFPE tissue to quantify expression levels of a panel of 149 genes, including the 
AR signaling signature genes (n=30), AR and the AR V7 splice variant, neuroendocrine prostate 
cancer, epithelial mesenchymal transition, and cell cycle-associated genes, TMPRSS2-ERG 
fusion transcript, and control /housekeeper genes.  Samples will be run according to the 
manufacturer’s directions.  Briefly, total RNA will be hybridized overnight at 65°, then run on 
the Prep Station at max sensitivity. Cartridges will then be scanned on the Digital Analyzer at 
555 fields of view. Raw count data will be normalized using the nSolver™ analysis software 
version 2.0, which normalizes samples according to positive and negative control probes and 
the geometric mean of the 6 housekeeping primers.  
Davicioni 
Decipher has been identified (90) and independently validated for prediction of post-RP 
biochemical failure (91), metastasis (92-95), prostate cancer specific mortality (96) and benefit 
from adjuvant radiation therapy (97). However, since GC was originally developed as a 
prognostic model to predict metastasis after RP, there is no guarantee that this marker will 
validate as a predictive biomarker (i.e., a significant interaction term between the biomarker and 
treatment). Therefore, we will use the Decipher platform (i.e., a high density oligonucleotide 
microarray optimized to generate expression data from FFPE derived RNA) to enable discovery, 
evaluation and validation of published genes, signatures or key pathways in addition to 
validating the primary objective of the study. The Decipher platform is a clinical grade assay 
that interrogates over 1.4 million expressed markers from over 46,000 annotated genes and non-
coding RNAs. We will also leverage the Decipher GRID (Genomic Resource Information 
Database), consisting of RNA expression profiles of over 5,000 prostate cancer patients from 
both retrospective and prospective cohorts to augment our analyses. Leveraging the Decipher 
GRID we can determine the expression levels of key genes involved in DNA repair and AR 
signaling pathways as described previously (99-100) in order to evaluate their ability to predict 
response/sensitivity or treatment failure/resistance. In addition, we will evaluate these pathways 
in a context specific manner using prostate cancer subtypes available on the GRID as described 
previously (101-102). The GRID analyses will help us understand the relationship be prevalence 
of alterations in these key pathways with clinical outcomes of patients in both arms of the trial 
in comparison to contemporary high risk prostate cancer patients. In addition, it is anticipated 
that by the time we obtain trial patient expression data for analysis additional signatures (e.g., 
Schaeffer and Karnes et al., “A novel ADT resistance signature predicts rapid metastasis after 
postoperative adjuvant hormonal therapy”; manuscript in preparation, You S et al., “Three 
intrinsic subtypes of prostate cancer with distinct pathway activation profiles differ in prognosis 
and treatment response”; manuscript in review) currently in development using the GRID will 
have been published and available for evaluation.  
Heemers 
RNA Data from Decipher array will be obtained from Dr Davicioni’s team and analyzed as 
follows. 
1. AR target gene signatures to be summarized in AR activity scores 
a. an AR target gene profile from ADT-naïve CaP cells serves to measure response to 
first-line ADT 
b. an AR target gene profile from ADT-recurrent CaP  is included as it may mediate non-
response to primary ADT 
c. similarly-sized random gene signatures are included as additional controls  
2. Quantitation method to summarize AR target gene signatures in AR activity level  

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The expression profile of AR target gene signature(s) obtained from an individual patient’s 
CaP specimen is summarized to measure quantitatively AR activity. Specifically, singular 
value decomposition is applied to the expression profile of the AR target gene signature, 
and the resulting top principle component is fitted to the Bayesian probit regression mode. 
Leave-one-out-cross validation is used to test the accuracy of the predictive signature. 
3. Determining response to ADT  
a. a. The decline in serum PSA levels serves as an indicator of treatment response. A fall 
in serum PSA by <90% is considered no response; fall by >/= 90% good response; fall 
by >/= 90% and to< 4 ng/ml excellent response; and a fall by >/= 90% and to 
undetectable [< 0.2 ng/ml] outstanding response, and  
b. b. PCWG2 response criteria. 
Statistical considerations  
Association between AR activity score and response to ADT is assessed using Student’s t-
test. For populations with unequal variances, Welch’s t-test is used. If normality is not 
satisfied (Kolmogorov-Smirnov test) even after log-transformation, wilcoxon rank sum test 
is used. Spearman rank correlation is used also to assess the association between continuous 
variables. Multiple testing correlations are performed when appropriate. 
4. Defining the clinical utility of an AR activity assay to predict response to ADT  
The predictive potential of AR activity scores is compared to that of clinical parameters 
claimed to predict response to ADT before (performance status, age, Gleason grade, serum 
levels of PSA, alkaline phosphatase or testosterone). The clinical utility of AR activity score 
to predict response to ADT will be determined in comparison with these parameters, 
individually or in combination (combination of 2 up to 5 parameters). 
Statistical considerations 
The diagnostic utility of AR target gene expression in discriminating patients in terms of 
dichotomized measures of clinical response will be examined through the generation of the 
receiver operating characteristic (ROC) curve. The area under the ROC curve (AUC) also 
will be computed. The area under the curve is a measure of the predictive power of a 
diagnostic model and thus may be taken as a measure of the overall diagnostic accuracy of 
expression in terms of predictability of outcome. A 95% confidence interval for the AUC 
will be calculated based on bootstrap re-sampling methods. In a similar fashion, the AUC 
for other predictors (pre-treatment PSA, Gleason score, etc.) will be calculated and 
compared using a hypothesis test for correlation with AR expression. The fact that the areas 
under the curve will be derived from the same set of patient data implies that the measures 
themselves will be correlated and so testing will be based on use of bootstrap methodology 
that incorporates this information. The bootstrapping algorithm will involve re-sampling of 
the within-patient values. A nominal significance level of 0.05 will be used. 
Paris 
Using existing genomic data (TBD: NGS, aCGH or SNP microarray), we will derive copy 
number for the GEMCaP loci.  We have existing, published methods to derive GEMCaP  
copy number depending on the genomics platform used in 90203. 
 The GEMCaP predictions 
will be compared to those from both CAPRA-S and the Kattan postoperative nomogram, 
which both only use clinical variables. (84, 98) 
Tewari 
MicroRNAs are short (~22 nt) noncoding RNAs that play important roles in regulating 
multiple mechanisms underlying carcinogenesis and cancer progression. Here we will 

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characterize expression of a panel of 10 candidate microRNA markers of prostate cancer 
aggressiveness, as well as perform global profiling of miRNAs to discover additional 
markers to be integrated into a multi-parameter outcome classifier. Technology 
development for miRNA analysis on RNA prepared by Gleave/Beltran team will be carried 
out. If this material is not suitable for miRNA work then RNA will be extracted from tissue 
specimens using standard methods (Ambion, Inc.), followed by microRNA analysis using 
qRT-PCR assays based on locked nucleic acid-based primers for enhanced sensitivity and 
specificity (Exiqon, Inc.). After nonspecific filtering (e.g., miRNAs not expressed in the 
vast majority of specimens), data will be normalized using global quantile normalization as 
well as plate calibrator assays. Differential expression analysis will be done using 
parametric and non-parametric methods with groups stratified by outcome and corrections 
for multiple comparisons.  
 
12.0 DRUG FORMULATION,
 AVAILABILITY,
 AND PREPARATION  
12.1 Qualified personnel  
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe disposal 
of chemotherapeutic agents in a self-contained, protective environment.  
12.2 Unused drug 
Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection 
USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial entry to minimize 
the risk of bacterial contamination. 
12.3 Calculation of dose 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% 
of the actual calculated dose. 

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12.4  Docetaxel (NSC #628503) 
Please refer to the FDA-approved package insert for docetaxel for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.  
Availability 
In the U.S., docetaxel will be provided by Sanofi-Aventis and distributed by the Pharmaceutical 
Management Branch (PMB). The one vial preparation (injection concentrate) is replacing the 
previous preparation (docetaxel plus diluent). It is supplied in a solution as 80 mg/4 mL (or 20 
mg/mL). Each mL contains 20 mg docetaxel in 50/50 (v/v) ratio polysorbate 80/dehydrated 
alcohol. 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating investigators 
at each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   
ECOG-ACRIN institutions in Peru receive the drug directly from Sanofi-Aventis. 
In Canada, docetaxel is provided and distributed by Sanofi-Aventis. Docetaxel may be requested 
by completing the Clinical Drug Request Form, found on the NCIC PRC.3 trial Web site.   
Agent Inventory Records  
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, and a “current” password 
and active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  
  
• NCI CTEP Investigator Registration:  
  
• PMB  
Online  
Agent  
Order  
Processing  
(OAOP)  
application: 
 
• CTEP Identity and Access Management (IAM) account:
   
• CTEP Associate Registration and IAM account help:  
   

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• IB Coordinator:
   
• PMB email:  
  
• PMB phone and hours of service: 
 Monday through Friday between 8:30 am 
and 4:30 pm (ET) 
Storage and Stability 
Unopened packages of docetaxel may be stored at room temperature or under refrigeration (36-
77°F). Freezing will not adversely affect the product. If stored under refrigeration, vials should 
be allowed to stand at room temperature prior to dilution. 
Infusion solutions prepared in PVC containers are reported to be stable for four days. Solutions 
for infusion prepared in polyolefin containers are reported to be stable for four weeks 
refrigerated or at room temperature. (123) 
Preparation 
The desired dose of docetaxel concentrate should be withdrawn and added to 250 mL of 0.9% 
sodium chloride or 5% dextrose for IV infusion. Doses of docetaxel of greater than 200 mg 
should be diluted in a larger volume of infusion solution in order to maintain a final 
concentration of 0.3 to 0.74 mg/mL. 
Administration 
The docetaxel infusion solution should be administered intravenously as a 1-hour infusion. 
Toxicities 
The most common adverse events expected with docetaxel include neutropenia, fluid retention, 
alopecia, myalgias and arthralgias, and asthenia. 
The usual dose limiting toxicity is neutropenia, which is dose and schedule dependent and 
rapidly reversible. Neutropenia is greater in patients with hepatic dysfunction (see Section 
9.2). 
Fluid retention: Fluid retention commonly begins in the lower extremities and may become 
generalized. Severe fluid retention may be characterized by peripheral edema, generalized 
edema, pleural effusion, dyspnea, cardiac tamponade, or ascites. The likelihood of fluid 
retention may increase with increasing cumulative dose of docetaxel. The pathophysiology 
of docetaxel induced fluid retention appears to be extensive transcapillary filtration 
proteins induced by docetaxel followed by later saturation of lymphatic drainage. 
Recommended pretreatment to prevent fluid retention consists of dexamethasone 8 mg 
b.i.d. for three days beginning the day before each docetaxel dose. Moderate fluid retention 
has been reported in 27% and severe in 6.5% of patients despite dexamethasone 
pretreatment. 
Alopecia is seen in the majority of patients treated with docetaxel. 
Myalgias and arthralgias have been reported in 10-20% of patients. Myalgias are severe in 
less than 2%. Severe asthenia has been reported in 11% of patients but has led to treatment 
discontinuation in only 2.6% of patients. Symptoms of fatigue and weakness may last a 
few days up to several weeks and may be associated with deterioration of performance 
status in patients with progressive disease. 
The following adverse events are less likely or less likely to be severe: thrombocytopenia, 
hypersensitivity reactions, neurologic toxicities, cutaneous reactions, gastrointestinal reactions, 
cardiovascular reactions, and increased lacrimation. 

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Thrombocytopenia is uncommon and rarely severe.  
Hypersensitivity reactions: Severe hypersensitivity reactions (hypotension and/or 
bronchospasm, or generalized rash/erythema) have been reported in approximately 2% of 
patients receiving dexamethasone pretreatment. Hypersensitivity reactions may be seen 
within a few minutes of starting docetaxel infusions. Minor reactions do not require 
interruption of therapy. Patients should not be re-challenged with docetaxel if they develop 
a grade 3 or 4 hypersensitivity reaction. 
Neurologic: Severe neurosensory symptoms (paresthesia, dysesthesia, pain) have been 
reported in 6% of patients. The dose of docetaxel should be modified for moderate or severe 
symptoms (see Section 9.3). Symptoms tend to be slowly reversible. 
Cutaneous: Localized erythema of the extremities with edema followed by desquamation 
has been observed. In the case of severe skin toxicity, an adjustment in dosage is 
recommended (see Section 9.6.2). Nail changes which predominantly include hypo- or 
hyper-pigmentation and occasionally onycholysis have occurred in 1-2% of patients.  
Gastrointestinal: Gastrointestinal reactions are generally mild to moderate. Severe 
reactions (nausea, vomiting, diarrhea, stomatitis) have been reported in approximately 5% 
of patients. 
Cardiovascular: Hypotension has been reported in less than 5% of patients, Heart failure, 
sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and 
hypertension have been reported rarely.  
Docetaxel has been associated with increased lacrimation that is thought to result from 
canalicular stenosis. Docetaxel concentrations were measured in tears in six patients; 
lacrimal concentration ranged from 14 to 70% of plasma concentration. This side effect 
may be more common with weekly versus three-weekly docetaxel. Artificial tears and/or 
ophthalmic steroids have been used with variable success. Although increased lacrimation 
has reportedly improved following discontinuation of docetaxel, dacryocystorhinostomy 
with placement of permanent tubes has been required in some patients. 
Potential Drug Interactions: 
The metabolism of docetaxel may be modified by the concomitant administration of compounds 
that induce (e.g., phenobarbital) or inhibit (e.g., itraconazole, ketoconazole, erythromycin) 
cytochrome P-450 3A4. Docetaxel has also been shown to inhibit CYP 3A4 in studies with 
human liver microsomes. Thus, docetaxel might increase the concentration of other drugs 
metabolized by this isoenzyme. To date, there is little documentation of such interactions in 
patients. 
12.5 LHRH agonists 
At the physician
's discretion, equivalent LHRH agonists other than those listed below may be 
used. 
12.5.1 Leuprolide Acetate  
Please refer to the FDA-approved package insert for leuprolide for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.  
Availability 
Leuprolide acetate is commercially available as a kit or prefilled dual-chamber syringe 
containing 7.5 mg or 22.5 mg and intended for administration every four weeks or every 

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12 weeks. (Lupron Depot®). The leuprolide in these single dose preparations is present as 
lyophilized microspheres. 
Sanofi-Aventis is providing the Eligard® brand of leuprolide for (some) Canadian 
institutions, based on local regulations regarding reimbursement. Refer to the PRC.3 
appendix found on the NCIC PRC.3 Web site for details. 
Storage and Stability 
Intact kits and syringes should be stored at room temperature. Once reconstituted using the 
diluent provided in the kit or syringe, leuprolide suspension is stable for 24 hours. 
Preparation 
Reconstitute the microspheres with the diluent provided in the kit or release the diluent in 
the syringe into the microspheres. Gently shake the reconstituted product to yield a uniform 
suspension. 
Administration 
Leuprolide 7.5 mg or 22.5 mg is administered via intramuscular injection every 4 weeks 
or every 12 weeks, respectively. 

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Toxicities 
Common toxicities are mostly related to the effects of decreased serum testosterone. Hot 
flashes are seen in more than 50% of patients. Gynecomastia, impotence, and decreased 
libido are also related to decreased testosterone, although they do not occur as often as hot 
flashes. Decreases in bone mineral density are seen with chronic administration (e.g., > 6 
months). Nausea/vomiting or anorexia have been reported in approximately 5% of patients, 
and cardiovascular adverse events (e.g., arrhythmias, peripheral edema) are also described. 
Injection site reactions occur infrequently. 
The FDA issued a safety communication in October, 2010 based on their ongoing safety 
review of LHRH agonists. The safety communication discusses the potential for an 
increased risk of diabetes and cardiovascular disease (myocardial infarction, sudden 
cardiac death, stroke) associated with these agents. The risk is thought to be low in men 
receiving LHRH agonists for prostate cancer. In this trial, LHRH agonists are being 
administered for a short period of time. FDA recommendations include management of 
cardiovascular risk factors according to current standards of practice. 
12.5.2 Goserelin acetate  
Please refer to the FDA-approved package insert for goserelin acetate for product 
information, extensive preparation instructions, and a comprehensive list of adverse events. 
Availability 
Goserelin acetate is commercially available as a prefilled syringe containing 3.6 mg or 10.8 
mg and intended for administration every 4 weeks or every 12 weeks, respectively. 
Storage and Stability 
Intact syringes should be stored at room temperature. 
Administration 
Goserelin 3.6 mg or 10.8 mg is administered by subcutaneous injection into the upper 
abdominal wall, every 4 weeks or every 12 weeks, respectively. 
Toxicities 
Common toxicities are mostly related to the effects of decreased serum testosterone. Hot 
flashes are seen in more than 50% of patients. Gynecomastia, impotence, and decreased 
libido are also related to decreased testosterone, although they do not occur as often as hot 
flashes. Decreases in bone mineral density are seen with chronic administration (e.g., > 6 
months). Nausea/vomiting or anorexia have been reported in approximately 5% of patients, 
and cardiovascular adverse events (e.g., arrhythmias, peripheral edema) are also described. 
Injection site reactions occur infrequently. 
The FDA issued a safety communication in October, 2010 based on their ongoing safety 
review of LHRH agonists. The safety communication discusses the potential for an 
increased risk of diabetes and cardiovascular disease (myocardial infarction, sudden 
cardiac death, stroke) associated with these agents. The risk is thought to be low in men 
receiving LHRH agonists for prostate cancer. In this trial, LHRH agonists are being 
administered for a short period of time. FDA recommendations include management of 
cardiovascular risk factors according to current standards of practice. 

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13.0 ANCILLARY THERAPY 
13.1 Supportive care 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate. However, the use of aprepitant is prohibited in 
this study The reason(s) for treatment, dosage, and the dates of treatment should be recorded on 
the CALGB C-260 Remarks Addenda. 
13.2 Other chemotherapeutics agents 
Treatment with other chemotherapeutic agents may not be administered except for steroids 
given for adrenal failure; hormones administered for non-disease-related conditions (e.g., 
insulin for diabetes); and intermittent use of dexamethasone as an antiemetic or as pretreatment 
for patients receiving docetaxel.  
13.3 CALGB 90203 Policy Concerning the Use of Growth Factors 
The following guidelines are applicable unless otherwise specified in the protocol: 
13.3.1 Epoetin 
The use of epoetin or darbopoetin is permitted at the discretion of the treating physician. 
13.3.2 Filgrastim (G-CSF), sargramostim (GM-CSF), and pegfilgrastim 
• 1. Filgrastim (G-CSF), sargramostim (GM-CSF), and pegfilgrastim treatment for 
patients on protocols that do not specify their use is discouraged. 
• 2. Filgrastim, and sargramostim, and pegfilgrastim may not be used to avoid dose 
reductions or delays as specified in the protocol. 
• 3. For the treatment of febrile neutropenia the use of CSF
's should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSF
's may 
be indicated in patients who have prognostic factors that are predictive of clinical 
deterioration such as pneumonia, hypotension, multi-organ dysfunction (sepsis 
syndrome) or fungal infection, as per the ASCO guidelines. Investigators should 
therefore use their own discretion in using the CSF
's in this setting. The use of CSF must 
be documented and reported on data forms.  
• 4. If CSFs are used, they must be obtained from commercial sources.  
14.0 CRITERIA FOR DISEASE PROGRESSION AND RELAPSE  
14.1 Progression Free Survival (PFS) 
The primary endpoint is the rate of 3-year biochemical progression-free survival (bPFS). 
Secondary endpoints include 5-year bPFS rate and bPFS. Patients will be followed with history, 
physical examination and serum PSA and testosterone levels every 3 months for the first 3 years 
following surgery, every 6 months for the next 3 years and annually thereafter until 15 years 
following registration. 
If patients experience treatment failure per Sections 14.1.3 or 14.1.4 during the first 3 years 
following surgery, evaluations will be done every 6 months. These patients will be followed 
until biochemical or metastatic disease progression per Sections 14.1.1 or 14.1.2, then followed 
for survival until 15 years after registration. 
It is expected that the majority of patients will relapse biochemically with a rising PSA.  

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Time to progression will be defined as the time from the date of randomization to the date of 
distant or local recurrence as defined below: 
• • Biochemical failure (see Sec. 14.1.1) 
• • Any new evidence of metastatic disease based on bone or CT/MRI scan. If based 
solely on PET or ProstaScint scan, it must be confirmed with a biopsy (see Sec. 14.1.2). 
• • Local recurrence in prostate bed, which must be accompanied by pathologic 
confirmation (by biopsy) in addition to CT/MRI scan evidence (see Sec. 14.1.2). 
• • Treatment with post-operative radiotherapy for a rising PSA or adjuvant radiation 
initiated more than 6 months following surgery (see Sec. 14.1.3). 
• Time to treatment failure will be defined as the time from the date of randomization 
to the date of the following: 
• • Initiation of androgen deprivation therapy (see Sec. 14.1.4). 
• • Initiation of any other investigational therapy for the treatment of the prostate 
cancer (see Sec. 14.1.4). 
Time to metastatic disease progression will be defined as time from date of randomization to 
date of evidence of systemic disease on bone scan or CT/MRI. 
14.1.1 Biochemical Failure: Biochemical failure will be defined as a serum PSA level > 0.2 ng/mL 
that increases on 2 consecutive occasions each of which is at least 3 months apart. The time of 
biochemical failure is measured from the date of randomization to the date of the first PSA level > 
0.2 ng/mL.  
14.1.2 Development of radiographic disease: Any new evidence of metastatic disease on bone or 
CT\MRI scan will constitute disease progression. Evidence of disease progression based solely on 
PET or ProstaScint scan will only be accepted if a biopsy confirms the metastatic disease. Patients 
with local recurrence in the prostate bed will also be considered as disease progression if pathologic 
confirmation by biopsy is obtained.  
14.1.3 Post-operative radiotherapy: Patients with positive surgical margins, extraprostatic 
extension, and/or seminal vesicle invasion will be allowed to receive adjuvant external beam 
radiation to the prostatic fossa based on the judgment of the treating physician; such therapy must 
be initiated within 6 months after surgery. Although the efficacy and timing of such treatment is a 
matter of debate, physicians and patients may choose this treatment based on the available data. 
These patients will not be considered treatment failures, but will continue on standard follow-up 
according to the protocol and will be included in the final analysis.  
Post-operative radiotherapy for a rising PSA or adjuvant radiation initiated more than 6 months 
following surgery will be considered disease progression. The field of radiation will be according to 
the standard of the treating institution and may include whole pelvis irradiation or limit the field to 
the prostatic fossa. Adjuvant radiation including up to four months of neoadjuvant/concurrent 
androgen deprivation therapy will be allowed. For the radiation to be considered adjuvant, the 
patient also must not have met the definition of biochemical failure. 
14.1.4 Systemic Therapy: Patients with lymph node metastases at staging pelvic lymphadenectomy 
or radical prostatectomy will be allowed to have immediate androgen deprivation therapy, if 
desired. Since androgen deprivation therapy will affect time to biochemical and metastatic disease 
progression, and possibly survival, these patients will be considered treatment failures at the time 
of initiation of androgen deprivation therapy. Investigators are encouraged to delay post-operative 

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systemic therapy, including androgen deprivation therapy, until the patient has documented 
evidence of biochemical failure. 
Any other systemic therapy, including androgen deprivation therapy that is initiated for the 
treatment of the prostate cancer, will also be considered treatment failure.  
14.2 Criteria for metastatic disease-free survival and overall survival 
14.2.1 Time to metastatic disease progression will be defined as the date of randomization to date 
of evidence of systemic disease on bone scan or cross sectional imaging or death from any cause, 
whichever occurs first. 
14.2.2 Overall survival will be defined as date of randomization to date of death due to any cause. 
14.3 Criteria for biochemical response to chemo-hormonal therapy 
Response to docetaxel and androgen deprivation therapy in the neoadjuvant arm is defined as 
those patients having a biochemical complete response (PSA < 0.1) prior to prostatectomy. 
15.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
15.1 Duration of Treatment 
Disease Progression: Patients who experience disease progression per Sections 14.1.1, 14.1.2, 
or 14.1.3 will be treated at the treating physician
's discretion. At that time, follow the patient for 
survival, new primary and secondary malignancy according to the data submission schedule. 
Treatment Failure: For patients who experience treatment failure per Section 14.1.4, submit 
full follow-up data for this study until the patient has reached an endpoint (progression) for the 
study. 
15.2 Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient
's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• • Notify the Study Chair. 
• • Document the reason(s) for discontinuation of therapy on forms. 
• • Follow the patient for survival, new primary, and secondary malignancy until 15 
years after randomization. 
15.3 Study Endpoints 
The endpoints for this study are: 
• • Biochemical progression-free survival and progression-free survival 
• • Death 
16.0 STATISTICAL CONSIDERATIONS 
This is a randomized, phase III trial where a total of 750 men will be randomized with equal 
probability to one of two arms: the standard arm being immediate radical prostatectomy and 
bilateral pelvic node dissection and experimental arm being neoadjuvant androgen deprivation 
therapy and docetaxel chemotherapy followed by radical prostatectomy and bilateral pelvic 
node dissection. The randomization will be stratified by the Kattan nomogram-predicted 5-year 
biochemical progression-free survival (bPFS) of < 21%, 21-39.9%, 40-59.9%, and ≥ 60%; and 
prior androgen deprivation therapy (no, yes). 

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16.1 Statistical Considerations for the Clinical Study 
16.1.1 Endpoints 
The primary endpoint is the 3-year biochemical progression-free survival rate (3-year 
bPFS). Secondary endpoints are 5-year bPFS rate and bPFS. Other endpoints are time to 
clinical local recurrence, time to metastatic disease progression, unacceptable toxicity, 
prostate cancer-specific free survival, disease progression, and overall survival (OS). 
Biochemical disease failure will be defined as the time from randomization to the date of 
biochemical disease failure as defined in Section 14.1.1. Time to clinical local recurrence 
will be defined as the time from randomization to the first biopsy-proven recurrence in the 
prostatic bed (new mass). Time to metastatic disease progression will be defined as the 
date of randomization to date of evidence of systemic disease on bone scan or cross 
sectional imaging. Unacceptable toxicity will be defined as any grade 3 or higher toxicity.  
Prostate cancer-specific free survival will be defined as the time from randomization to the 
time of death due to prostate cancer. OS will be defined as date of randomization to date 
of death due to any cause. 
16.1.2 Sample Size Determination 
The following calculations assume a monthly accrual rate of about 13 patients per month 
accrued over a 60-month period, and followed for 36 months after study closure. Based on 
the experience of patients treated at MSKCC, 5-year freedom from recurrence in the 
standard arm (i.e., those patients with a nomogram prediction < 60%) is expected to be 
approximately 40%. The 3-year bPFS rate in the standard arm is expected to be 57.7%. 
This study is designed so that the two sample binomial test has 89% power assuming a 
one-sided type I error rate = 0.025 to detect almost 12% difference between the two groups, 
when the true rates of 3-year bPFS are 57.7% (standard arm) and 69.1% (experimental 
arm). 
16.1.3 Interim Analysis 
The Alliance DSMB on a semi-annual basis will review the study for safety, progress 
toward completion, and, when appropriate, interim analyses of outcome data to coincide 
with the meetings of the DSMB. In this patient population, it is anticipated that biochemical 
progression may occur within 1-2 years after the patient is treated with RP. Furthermore, 
because the primary endpoint is 3-year bPFS rate, it is expected that data will not be 
available for formal analyses before 54 months after study activation. However, toxicity 
(grade 3 or higher) and survival data (proportion of patients dead) will be presented in the 
report to the DSMB. The first interim analysis will be performed when 30% of the patients 
have been followed for at least 3 years (at about 54 months after study activation, Table 1). 
In addition, there will be seven interim analyses besides the final analysis. The remaining 
analyses will be performed when 40% of the patients have completed at least 3 years of 
follow-up (about 60 months), and when 50% (about 66 months), 60% (about 72 months), 
70% (about 78 months), 80% (about 84 months), 90% (about 90 months), and 100% of the 
patients have completed 3 years of follow up (about 96 months after study activation). It is 
not planned that accrual will be halted while the interim analyses are undertaken. To help 
insure complete data on which to base the interim analyses, progression events 
(follow-up forms) should be faxed to the Alliance Statistics and Data Center within 
one week of being reported to the institution. 

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A group sequential test design by O
'Brien and Fleming (124) will be used to stop the trial 
early both to accept and to reject the null hypothesis. The z-score boundaries for stopping 
for superiority for bPFS are: 3.809, 3.299, 2.951, 2.694, 2.494, 2.333, 2.199, and 2.087. 
The z-score boundaries for stopping for futility for bPFS at a fixed alpha level = 0.005 are: 
-0.788, -0.512, -0.268, -0.048, 0.155, 0.343, 0.520, and 2.087. Should any boundary be 
crossed, accrual to the study will be recommended to be stopped.  
 
Table 1 
Boundaries for Interim Efficacy Analyses 
Time 
(months) 
Percent of patients with 
at least 3 years of  
follow-up (number) 
z-scores 
For Superiority 
z-scores 
For Futility 
54 
30% (225) 
3.809 
-0.788 
60 
40% (300) 
3.299 
-0.512 
66 
50% (375) 
2.951 
-0.268 
72 
60% (450) 
2.694 
-0.048 
78 
70% (525) 
2.494 
0.155 
84 
80% (600) 
2.333 
0.343 
90 
90% (675) 
2.199 
0.520 
96 
100% (750) 
2.087 
2.087 
 
16.1.4 Data Analysis 
A modified intent-to-treat approach will be used in this phase III study. The primary 
analysis will be based on the comparisons of the Kaplan-Meier bPFS rate at 3 years. 
Patients who had lymph node metastases at the time of radical prostatectomy (RP) will be 
censored at the first date of initiation of androgen deprivation therapy. The Kaplan-Meier 
product-limit estimator (125) will be used to estimate the 3-year and 5-year bPFS rates, 
bPFS, time to local recurrence, time to clinical metastases and OS. In addition, the stratified 
log-rank test (126) to compare the two treatment arms on bPFS, time to clinical metastases 
and OS. 
Furthermore, the Chi-square test will be used to compare the two arms on pathologic tumor 
stage, the proportion of patients with lymph node metastases, positive margins, and grade 
3 or higher toxicity. The proportional hazards model (127) will be used to assess the effect 
of the treatment arm on bPFS, time to metastases and OS adjusting on baseline patient 
characteristics, pathologic variables and stratification factors. All secondary analyses will 
use a two-sided type I error rate of 0.05. For objective 2.4, because of competing risks, we 
will use analyses based on cumulative incidence and cumulative conditional probability 
(128). For objective 2.6, the proportional hazard model will be used to test if the change 
(increase) in serum testosterone levels will predict bPFS outcome in men treated with 
neoadjuvant androgen deprivation therapy and docetaxel chemotherapy followed by 
radical prostatectomy and bilateral pelvic node dissection. This analysis will be exploratory 
in nature and will try to generate hypotheses among this group of high risk undergoing RP 
plus/minus neoadjuvant chemohormonal therapy. 

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16.1.5 Accrual and Follow-up 
The target sample size is 750 and assuming that Alliance institutions will enroll about 13 
patients per month, accrual will be completed in about 5 years after IRB approval. Accrual 
will be completed significantly sooner if, as anticipated, there is accrual from SWOG and 
ECOG-ACRIN institutions via the CTSU. All patients will be followed for PFS and OS 
for 15 years following registration. 
16.1.6 Accrual Expansion with Update #08 
The original target sample size was 750 evaluable patients. The target of 750 patients was 
reached on 06/24/2015. Due to the fact that over 4% of the patients did not have surgery 
or withdrew consent prior to observing the biochemical failure endpoint, the total sample 
size has been increased by 5% to 788 patients to account for these events. 
16.1.7 Statistical Considerations for the PSADT as a surrogate Marker of Outcome 
Prentice
's criteria require that for an endpoint to be surrogate for the "true" endpoint, three 
conditions should be satisfied. First, there is a treatment effect with respect to the surrogate 
endpoint. Second, the surrogate endpoint is a prognostic factor of the true endpoint, and 
finally that the surrogate endpoint should capture all treatment effect on the true endpoint. 
Prentice
's criteria will be applied to determine if PSADT is a potential surrogate endpoint 
for time to metastatic disease progression and overall survival. PSADT will calculated as 
the ratio of natural log 2/slope of log PSA by time. The proportional hazards model will be 
used to test if the treatment is prognostic of overall survival and of the surrogate endpoint. 
Next, the proportional hazards model will be used to test if the surrogate endpoint is 
prognostic of overall survival. Finally, the proportional hazards model will be used to test 
if the treatment effect on overall survival is explained by the surrogate endpoint. 
16.2 Statistical Considerations for the Diet and Lifestyle Study 
16.2.1 Power Computation 
The primary objective of the dietary component of this study is to test whether fish intake 
decreases the risk of biochemical progression at 3 years. Assuming that the 80% of the 
patients (n = 600) will complete the diet and food questionnaires, power computations are 
based on the proportions of patients who are progression-free at 3 years and univariate tests 
of hypothesis testing assuming two-sided significance levels of 0.01. The power was based 
on testing the null hypothesis of independence versus the alternative of a linear trend in the 
3-year progression rate over quintiles. With 600 patients, the power is 80% to detect a 
relative risk of 2.1 (5th quintile versus 1st in fish consumption) assuming a two-sided alpha 
= 0.01.  
16.2.2 Data Analysis 
Because of the multiplicity of hypotheses and endpoints (3-year and 5-year bPFS rates and 
bPFS) being tested, we will use a type I error rate of 0.01 for all exploratory dietary 
hypotheses being tested. Physical activity will be computed into metabolic units per week 
(METs, continuous variable), and then examined as quintiles or categorical variables. 
Unconditional logistic regression will be used for the outcomes 3-year and 5-year bPFS 
rates. In addition, the proportional hazards model will be used to compare the bPFS among 
the low and high intakes groups (based on the median) and extreme quartiles of food 
consumption and change in food consumption. For example, the hazard associated with 
being in the upper 25th percentile of fish consumption vs. the lowest 25th percentile will 
be examined. Individual food groups (e.g. red meat, dairy, grains, vegetables, fruits) and 

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relative changes in intake of these food groups will be examined. The following variables 
will be adjusted on in the multivariable models: total caloric intake, physical activity, body 
mass index, smoking, age, race, family history, treatment arm, and clinical and pathologic 
variables (e.g. tumor stage, grade, Gleason score). 
16.3 Statistical Considerations for the Correlative Sciences Studies 
The target sample size for this study is 750 patients. However, we do not expect that frozen 
prostate tissue will be submitted for all patients enrolled through the CTSU. We do not have 
historical data on CTSU accrual among patients with hormone refractory prostate cancer, but 
based on a renal study (CALGB 90206) we expect that 40% of the total accrual will be through 
the CTSU. Thus, we assume that frozen tissue will be submitted for 60% of all patients enrolled 
to the study and from our experience, we expect that 65% of those samples will have enough 
tissue to make RNA. Based on other Alliance studies, we expect that tissue and blood samples 
will be submitted for 80% of patients enrolled to the study. We therefore estimate that the 
number of samples assumed to be available will be 294 for the RNA-expression analyses of 
tumor tissue, 600 samples for the DNA (SNP) analyses of tumor tissue, 600 samples for serum 
proteomic analyses, and 600 samples for tissue (TMA) protein analyses. 
16.3.1 Power Computation 
The primary endpoint in CALGB 90203 is 3-year biochemical progression-free survival 
rates. Other endpoint of interest is pathologic response and biochemical progression-free 
survival. 
Power computation is based on testing whether genes will predict pathologic response.  
We anticipate having access to 200 specimens from CALGB 90203.  We assume that the 
specimens will yield enough RNA, DNA & microRNA data. We used the method by  Yang 
et al to derive the power based on non-central F-distribution. The non-centrality parameter 
is defined as a function of the effect size 
|μ
2 - μ1
s

|/ , and the type-I error rate adjusted for 
false discovery (α*)  where α* = α (max[1, n
0]) /n
g  and α=0.05. By setting the type-I error 
= α* ensures a false discovery rate = α, and note that when n0 = 1, α* is the Bonferroni-
adjusted type-I error rate. Estimates for many of these parameters are usually unknown 
prior to the study but we use reasonable estimates from prior studies. For example, an effect 
size=2 corresponds to a two-fold difference between groups in mean expression ratios on 
2
s

a log(base 2) scale when variance between the subjects 
= 0.5. This is a typical median 
value observed in tumor samples. Table 1 provides the power estimates assuming an 
adjusted type I error rate of 0.000005682, effect size of 2, five truly differentiated genes, 
and a total sample size of 200. 
We estimated the power for comparing expression in 200 men with and without 
pathological response. Thus, the proposed sample size will give excellent power to detect 
at least 1.5-2-fold increases in expression ratios.  
Table 1. Power computation for pathological response 
Prevalence 
of Pathologic 
response  
Variance 
Ratio 
2
e

(
2
s

/
) 
Effect Size 
Power 
0.1 
0.25 
1.5 
0.843 
0.2 
0.25 
1.5 
0.998 
0.3 
0.25 
1.5 
0.999 

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0.4 
0.25 
1.5 
1.000 
0.5 
0.25 
1.5 
1.000 
0.1 
0.5 
1.5 
0.700 
0.2 
0.5 
1.5 
0.986 
0.3 
0.5 
1.5 
0.999 
0.4 
0.5 
1.5 
~1.000 
0.5 
0.5 
1.5 
1.000 
0.1 
1.0 
1.5 
0.439 
0.2 
1.0 
1.5 
0.904 
0.3 
1.0 
1.5 
0.984 
0.4 
1.0 
1.5 
0.996 
0.5 
1.0 
1.5 
0.997 
0.1 
0.25 
2 
0.997 
0.2 
0.25 
2 
1.000 
0.3 
0.25 
2 
1.000 
0.4 
0.25 
2 
1.000 
0.5 
0.25 
2 
1.000 
0.1 
0.5 
2 
0.986 
0.2 
0.5 
2 
1.000 
0.3 
0.5 
2 
1.000 
0.4 
0.5 
2 
1.000 
0.5 
0.5 
2 
1.000 
0.1 
1.0 
2 
0.904 
0.2 
1.0 
2 
0.999 
0.3 
1.0 
2 
0.999 
0.4 
1.0 
2 
1.000 
0.5 
1.0 
2 
1.000 
In addition, we present the power computations based on the binary endpoint 3-year bPFS 
rate. Let θ =probability of X
n<Xl, where X
n is risk prediction scores is normally distributed 
in men who have not progressed with mean 0 and variance 1, and Xl will be normally 
distributed with mean 0.50 and variance=1 in men with progression prostate cancer. The 
null hypothesis to be tested is that the area under the ROC curve θ =0.50 versus the 
alternative hypothesis is different than 0.5.  Table 2 presents the power for the Wilcoxon 
test to detect an area under the ROC curve (θ) =0.65 based on a 10,000 simulations 
assuming a total of 200 patients, unequal allocation between the two groups, and a two-
sided type I error rate 0.05. Thus, the proposed sample size will give excellent power to 
detect θ =0.65. We assumed also assumed different distribution for the prediction scores 
(such as beta distribution) and they yielded similar empirical power.  
Table 2. Power associated with ROC  
Number of 
patients with 
lethal prostate 
cancer 
Number of patients 
without lethal 
prostate cancer 
Simulated 
type I error 
rate 
Power 
20 
180 
0.0485 
0.5339 
40 
160 
0.0508 
0.7857 
60 
140 
0.0501 
0.8759 
80 
120 
0.0522 
0.9356 
100 
100 
0.0483 
0.9314 

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In addition, we provide power computation for validating the final model based on the a 
time-to-event endpoint, bPFS . Although the risk predictions follow a normal distribution, 
for simplicity in computing the power we dichotomize the risk scores: as less than the 
median and greater than the median. We do not know the number of events among the 200 
patients, but we assume that there will be between 50-100 events. Table 3 provides the 
minimum hazard ratio detectable, assuming a two-sided type I error rate of 0.05, sample 
size of 200, power=0.80, event rate of 25%-50%, and prevalence of 0.10-0.50. The power 
computations are based on the assumption that the bPFS follows an exponential 
distribution. The log-rank test has sufficient power to detect moderate effect sizes. 
Table 3. Minimum detectable HR under a range of conditions and assuming a two-sided 
type I error rate =0.05 and 200 patients. 
Prevalence of  risk 
prediction score    
Number of 
events 
Hazard ratio 
0.10 
50 
3.75 
0.10 
100 
2.54 
0.20 
50 
2.69 
0.20 
100 
2.01 
0.30 
50 
2.37 
0.30 
100 
1.84 
0.40 
 
50 
 2.24 
0.40 
 
100 
 1.77 
0.50 
50 
2.21 
0.50 
100 
1.75 
16.3.2 Data Analysis 
It is expected that once the designated laboratory data are generated, normalized data will 
be sent to the Alliance Statistics and Data Management Center for statistical analysis. 
There 
are several objectives in this CS study. 
1. To identify genomic aberrations in matched diagnostic needle biopsy cores and radical 
prostatectomy specimens from men enrolled in the trial using deep targeted DNA-
sequencing 
The genomic identification of significant targets in cancer (GISTIC) method will be 
used to identify genomic aberrations in matched diagnostic needle biopsy cores and 
radical prostatectomy specimens. GISTIC is a statistical method for analysis of genomic 
aberrations and was developed by Beroukhim et al.[1]. It identifies regions of the 
genome that are aberrant more often than would be expected by chance with greater 
weight given to high amplitude events (for example, high level copy number gains or 
homozygous deletions) that are less likely to be random. Each genomic aberration in 
GISTIC will be assigned a G-score that considers the amplitude of the aberration and 
the frequency of occurrence across samples [1,2] and then false discovery rate (FDR) 

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q-values  are calculated for the aberrant regions. Regions with q-values below a user 
defined threshold are considered significant. GISTIC outputs the genomic location and 
calculated q-value for the aberrant regions and identifies the samples that exhibit each 
significant gains or deletions. After obtaining the genomic aberrations, we will compare 
aberrations from biopsy cores with that from radical prostatectomy specimens to 
identify matched and unmatched regions of aberrations. The employment of FDR may 
be problematic in this framework given the potentially strong spatial dependence among 
the genomic regions. Therefore, permutation resampling will also be employed, to 
adjust for the family-wise error rate (FWER) at the 0.05 level. 
2. To identify mRNA expression changes of androgen receptor signaling genes, AR and 
the AR V7 splice variant, neuroendocrine prostate cancer, epithelialmesenchymal 
transition, and cell cycle-associated genes, TMPR-SS2-ERG fusion transcript, and 
control/housekeeper genes in matched diagnostic needle biopsy core and radical 
prostatectomy specimens. 
First, the raw data will be pre-processed and normalized using the DEseq algorithm. 
Briefly, the DEseq algorithm [3] takes the geometric mean of log values of each gene 
across samples and uses that as the reference expression data set. For each sample, a list 
of differences 
between log values of each gene expression and reference expression data 
set will be performed and then find median of a list. Then it takes exponential of the 
medians of each sample respectively and it divides gene expression values for each 
sample by each normalization factor. For the data analysis, we will use a parametric 
model based on the negative binomial distribution which explains better the technical 
and biological variance for count data and then takes permutation based multiple testing 
to detect significant expression changes. 
3. To correlate the presence of baseline and post-treatment expression changes and 
genomic aberration and clonality states with pathologic response and clinical outcome 
(bPFS). 
We will utilize the univariate negative binomial regression model of two expressions 
for each marker. To identify significantly differentially expressed markers between the 
baseline and post-treatment changes, we will utilize multiple correction methods, such 
as FDR to control for the false-positive rate: 
We will also use the GISTIC method as outline in objective #1 to identify significant 
genomic aberrations between baseline and post-treatment. 
4. To correlate genomic and gene expression differences in prostatectomy specimens from 
treated vs. untreated cases with clinical outcomes. 
We will also use simple negative binomial regression model for treated and untreated 
cases of each of expression markers. To identify significantly expressed marker between 
treated and untreated cases we will employ multiple correction methods. Similar to the 
above aims, we will use the GISTIC method to identify significant genomic aberrations 
between treated and untreated cases. In addition, the Spearman rank-correlation will be 
computed and these relationships between genes and clinical outcomes (pathologic 
response, 3-year bPFS) would be visualized with symmetric heatmaps.   
5. Validation of the Decipher metastasis signature as predictive of response to neo-
adjuvant docetaxel and androgen deprivation prior to radical prostatectomy versus 
immediate radical prostatectomy in patients with high-risk, clinically localized prostate 
cancer. 

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The Decipher score will be computed on all patients. A treatment arm by decipher score 
interaction will be used to detect possible predictive effect on bPFS. The Cox’s 
proportional hazard model will be used with treatment arm, Decipher score and 
treatment arm-decipher score interaction term in predicting bPFS. 
6. To test whether AR target gene signatures from clinical CaP specimens obtained prior 
to administration of ADT will inform on response to ADT. This requires AR target gene 
signatures to be summarized into AR activity scores and a quantitation method to 
summarize AR target gene signatures into AR activity level. 
Similar analyses as mentioned above will be performed.  
7. Validate GEMCaP biomarkers in predicting recurrence using the 90203 control arm 
patient set and evaluate GEMCaP as a predictive biomarker of response to neoadjuvant 
chemotherapy/ADT using the 90203 test arm patient set.  
It is assumed that among the 200 patients, 100 patients will be from the control arm 
radical prostatectomy (RP). The GEMCAP score will be computed in the 100 patients 
randomized to RP. The Cox’s proportional hazard model will be used with GEMCAP 
score as a covariate stratified on arm. The c-index will be computed as a measure of the 
predictive accuracy in predicting bPFS. In addition, the treatment arm-GEMCaP score 
interaction term will be tested using the Cox’s proportional hazards model. 
8. To characterize expression of microRNAs in 90203 specimens.  
Using the microRNA based on 376 gene expression levels. The comparative CT method 
algorithm will be used for normalization. The paired Wilcoxon test will be used to test 
for microRNA difference in matched benign and cancer tumors. 
9. To develop and validate a comprehensive prognostic models of clinical outcomes (3-
year bPFS rate, bPFS, metastases-free survival and overall survival) that can be used 
for risk stratification of patients with prostate cancer, using clinical and molecular 
markers. 
We will first perform univariate logistic regression (for the bPFS rate at 3 years) or 
Cox’s regression (for the time-to-event endpoints) to identify genomic predictors of 
clinical outcomes. We will use Sure Independent Screening (SIS) and iterative SIS as a 
pre-screening step which will reduce the dimensionality 
of the data 
and then use variable 
selection methods (ALASSO). Both unadjusted (for multiplicity) and family-wise error 
rate (FWER) adjusted exact p-values, approximated by B=10,000 permutation 
replicates will be generated. Under the control of FWER, a list of significant biomarkers 
will be identified.  Based on selected markers (expressions, RNA, microRNA, decipher 
score and GEMCap score etc.), we will build the best models which predict the clinical 
outcomes using variable selection models such as adaptive LASSO [4] and ELASTIC 
NET [5]. Because of the absence of external dataset, 5-fold cross-validation and 
bootstrapped approaches will be used to validate the final prognostic models of clinical 
outcomes. The c-index and time-dependent AUC will be computed as measures of 
predictive accuracy for the clinical outcomes. 
In addition, we plan to perform other analyses. We will employ the Kaplan-Meier 
product-limit method to estimate bPFS, MFS and OS distributions. We will also use the 
log-rank statistic to compare the bPFS, PFS, MFS and OS distribution by prediction 
levels (based on the model) categorized by quartiles. Moreover, the proportional hazards 
model will be used to assess the prognostic importance of the risk scores adjusting on 

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growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
• All grade 4 events that are unexpected and that are at least possibly related to treatment must be 
reported via CTEP-AERS within 10 calendar days. 
• Any unexpected grade 4 event that precipitates hospitalization (or prolongation of existing 
hospitalization) must be reported via CTEP-AERS within 10 calendar days. 
• Grade 4 events that are expected do not require CTEP-AERS expedited reporting, even if they 
result in hospitalization. 
• Adverse events include those listed in Section 12.0 and in the package inserts.  
• All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• The reporting of adverse events described in the table above is in addition to and does not 
supplant the reporting of adverse events as part of the report of the results of the clinical trial, 
e.g., study summary forms or cooperative group data reporting forms (see Section 6.1 
for required 
forms). 
• Secondary malignancy: A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). 
A secondary malignancy is not considered a metastasis of the initial neoplasm.  
• CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. In CTCAE version 5.0, three 
options are available to describe the event:  
• -Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• -Myelodysplastic syndrome (MDS)  
• -Treatment-related secondary malignancy  
• Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol.  
• Second malignancy: A second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting unless otherwise specified. 
• New primary malignancies should be reported using study form C-1244 via Medidata Rave®. 
• Pregnancy loss is defined in CTCAE as “Death in utero.” Any pregnancy loss should be reported 
expeditiously as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC. A pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes this 
event as a patient death. 
• A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
 

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normal prostate tissue. Nat Genet. 2015 Apr;47(4):367-72. 
82. Hieronymus H, Schultz N, Gopalan A, et al. Copy number alteration burden predicts prostate 
cancer relapse. Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):11139-44.  
83. Lalonde E, Ishkanian AS, Sykes J, et al. Tumour genomic and microenvironmental 
heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a 
retrospective cohort study. Lancet Oncol. 2014 Dec;15(13):1521-32. 
84. Levin AM, Lindquist KJ, Avila A, et al. Performance of the Genomic Evaluators of Metastatic 
Prostate Cancer (GEMCaP) tumor biomarker for identifying recurrent disease in African 
American patients. Cancer Epidemiol Biomarkers Prev. 20 14 Aug;23(8):1677-82. 

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85. Levin AM, Lindquist KJ, Avila A, et al. Performance of the Genomic Evaluators of Metastatic 
Prostate Cancer (GEMCaP) tumor biomarker for identifying recurrent disease in African 
American patients. Cancer Epidemiol Biomarkers Prev. 2014 Aug;23(8):1677-82.  
86. Beltran H, Eng K, Mosquera JM, et al. Whole-Exome Sequencing of Metastatic Cancer and 
Biomarkers of Treatment Response. JAMA Oncol. 2015 Jul;1(4):466-74.  
87. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate 
cancer. Cell. 2015 May 21;161(2):454. 
88. Tyekucheva S, Martin NE, Stack EC, et al. Comparing Platforms for Messenger RNA 
Expression Profiling of Archival Formalin-Fixed, Paraffin-Embedded Tissues. J Mol Diagn. 
2015 Jul; 17(4):374-81.  
89. Yamoah K, JCO 2015. 
90. Erho, N., Crisan, A., Vergara, I.A., et al. Discovery and Validation of a Prostate Cancer 
Genomic Classifier that Predicts Early Metastasis Following Radical Prostatectomy. PLOS 
ONE 2013; 8(6):e66855. 
91. Den, R.B., Feng, F.Y., Showalter, T.N., et al. Genomic Prostate Cancer Classifier Predicts 
Biochemical Failure and Metastases in Patients After Postoperative Radiation Therapy. Int J 
Radiat Oncol Biol Phys. 2014; 89(5):1038-46. 
92. Karnes, R.J., Bergstralh, E.J., Davicioni, E., et al. Validation of a Genomic Classifier that 
Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population. The 
Journal of Urology 2013; 190:2047-2053. 
93. Ross, A.E., Feng, F.Y., Ghadessi, M., et al. A genomic classifier predicting metastatic disease 
progression in men with biochemical recurrence after prostatectomy. Prostate cancer and 
prostatic diseases 2014; 17(1): 64-9. 
94. Ross, A.E., Yousefi, K., Trock, B., et al. Tissue Based Genomics Augment Post-Prostatectomy 
Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men European 
Urology, 2016 Jan; 69(1): 157-65. doi: 10.1016/j.eururo.2015.05.042. 
95. Klein, E. Yousefi, K., Haddad, Z., et al. A genomic classifier improves prediction of metastatic 
disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed 
by radical prostatectomy without adjuvant therapy. European Urology 2015; 67(4): 778-786. 
96. Cooperberg, M.R., Davicioni, E., Crisan, A., et al. Combined Value of Validated Clinical and 
Genomic Risk Stratification Tools for Predicting Prostate Cancer Mortality in a High-risk 
Prostatectomy Cohort. European Urology, 2015 Feb; 67(2):326-333. 
97. Den, R.B., Yousefi, K., Trabulsi, E.J., et al. A genomic classifier identifies men with adverse 
pathology after radical prostatectomy who benefit from adjuvant radiation therapy. Journal of 
Clinical Oncology 2015; 33:944-951. 
98. Lindquist, K. Paris, P. L. et al., and Witte J.S. Whole Genome Sequencing of Aggressive 
Prostate Tumors in African Americans. Cancer Research, 2015, under revision. 
99. Evans, J.R., Zhao, S.G., Chang, S.L.,  et al. Patient-Level DNA Damage and Repair Pathway 
Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer.JAMA Oncol 2016; 
7:1-10 
100. 
Goodwin, J.F., Kothari, V., Drake, J.M., et al., DNA-PKcs-Mediated Transcriptional 
Regulation Drives Prostate Cancer Progression and Metastasis. Cancer Cell 2015;28:97-113 
101. Tomlins, S.A., Alshalalfa, M., Davicioni, E., et al., Characterization of 1577 primary prostate 
cancers reveals novel biological and clinicopathologic insights into molecular subtypes. 
European Urology 2015:68;555-67. 

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102. 
Smith, B.A., Sokolov, A., Uzunangelov, V., et al., A basal stem cell signature identifies 
aggressive prostate cancer phenotypes. Proc NatlAcad Sci U S A. 2015;112:E6544-52. 
 
 
 
 

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APPENDIX I 
Collaborative Agreement Provisions 
 
The docetaxel used in this protocol is provided to the NCI and Alliance under agreements between 
the Sanofi-Aventis (hereinafter referred to as Collaborator), the NCI Division of Cancer Treatment 
and Diagnosis and the Alliance for Clinical Trials in Oncology. Therefore, the following 
obligations/guidelines, in addition to the provisions in the "Intellectual Property Option to 
Collaborator" (http://ctep.cancer.gov/industry) contained within the terms of award, apply to the use 
of docetaxel in this study: 
• 1. Docetaxel may not be used for any purpose outside the scope of this protocol, nor 
can docetaxel be transferred or licensed to any party not participating in the clinical 
study. Collaborator data for docetaxel are confidential and proprietary to Collaborator 
and shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be 
shared or distributed without permission of the NCI. If a copy of this protocol is 
requested by a patient or patient
's family member participating on the study, the 
individual should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
•  
• 2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements, the access to and use of data by each Collaborator shall be as follows (data 
pertaining to such combination use shall hereinafter be referred to as "Multi-Party 
Data"): 
• a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI
's participation in the proposed combination protocol. 
• b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
• c. Any Collaborator having the right to use Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
•  
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator, the NCI, and the FDA, as appropriate and 
unless additional disclosure is required by law or court order. Additionally, all Clinical Data and 
Results and Raw Data will be collected, used and disclosed consistent with all applicable federal 
statutes and regulations for the protection of human subjects, including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 
164. 
 

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• 4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator
's wish to contact 
them. 
• 5. Any data provided to Collaborator for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
• 6. Any manuscripts reporting the results of this clinical trial should be provided to 
CTEP by the Group Office for Cooperative Group studies for immediate delivery to 
Collaborator for advisory review and comment prior to submission for publication. 
Collaborator will have 30 days from the date of receipt for review. Collaborator shall 
have the right to request that publication be delayed for up to an additional 30 days in 
order to ensure that Collaborator
's confidential and proprietary data, in addition to 
Collaborator
's intellectual property rights, are protected. Copies of abstracts must be 
provided to CTEP for forwarding to Collaborator for courtesy review as soon as possible 
and preferably at three (3) days prior to submission, but in any case, prior to presentation 
at the meeting or publication in the proceedings. Press releases and other media 
presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract, and/or press release/media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
 
 
 
 
 
 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator
's 
confidential/proprietary information. 
 
 
 
 

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APPENDIX II 
Kattan Nomogram Information 
 
The Kattan preoperative nomogram for prostate cancer recurrence will be used to determine 
eligibility for this study.  
An on-line calculator can be accessed at http://www.nomograms.org. A guide to the electronic 
calculator can be found on the following page. 
The pre-biopsy PSA should be used for the Kattan nomogram calculator. 
 
Preoperative Nomogram for Prostate Cancer Recurrence 
 
 
Instructions for Physician: Locate the patient
's PSA on the PSA axis.  Draw a line straight 
upward to the Points axis to determine how many points towards recurrence the patient receives 
for his PSA.  Repeat this process for the Clinical Stage and Biopsy Gleason Sum axes, each 
time drawing straight upward to the Points axis.  Sum the points achieved for each predictor 
and locate this sum on the Total Points axis.  Draw a line straight down to find the patient
's 
probability of remaining recurrence free for 60 months assuming he does not die of another 
cause first. 
 
Note: This nomogram is not applicable to a man who is not otherwise a candidate for radical 
prostatectomy.  You can use this only on a man who has already selected radical prostatectomy 
as treatment for his prostate cancer. 
 
Instruction to Patient:  "Mr. X, if we had 100 men exactly like you, we would expect between 
<predicted percentage from nomogram - 10%> and <predicted percentage + 10%> to remain 
free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is 
very rare." 
© 1997 Michael W. Kattan and Peter T. Scardino 
 

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Guide to Kattan nomogram on-line calculator 
 
1. Use the link www.nomograms.org to access the Memorial Sloan-Kettering Cancer Center 
nomograms web site. 
2. Click on the bullet, “Prostate Cancer,” which will direct you to the “Prediction Tools” page. 
3. Click on “Pre-Treatment” or scroll down to “pre-treatment nomogram” and click on this link. 
4. A disclaimer will be shown; click “accept” at the bottom of the page. 
5. Complete the “Enter Your Information” section, including clicking on the “Progression Free 
Probability after Radical Prostatectomy” button. 
6. You do not need to fill in the “Planned or Non-Primary Treatment Information.” 
7. Scroll to “Enter Advanced Details (for Medical Professionals);” “Would you like to enter 
additional details” and click “no.” 
8. Click the “calculate” button. 
9. Scroll back to the top of the page and on the right-hand side, click “Historical Model,” which 
will be highlighted in blue. 
10. The nomogram-predicted result is listed as: “Progression Free Probability after Radical 
Prostatectomy, 5-year.” 
 
 
 
 

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APPENDIX III 
 
2002 TNM Classification System [47] 
Prostate 
 
T-primary tumor 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
T1 
Clinically inapparent tumor not palpable  
T1a Tumor incidental histologic finding in 5% or less of tissue resected 
T1b Tumor incidental histologic finding in more than 5% of tissue resected 
T1c Tumor identified by needle biopsy (e.g., because of an elevated serum PSA) 
T2 
Tumor confined within the prostate 
T2a Tumor involves one half of one lobe or less 
T2b Tumor involves more then half of one lobe, but not both lobes 
T2c Tumor involves both lobes 
T3 
Tumor extends through the prostatic capsule 
T3a Extracapsular extension (unilateral or bilateral) 
T3b Tumor invades seminal vesicle(s) 
T4 
Tumor is fixed or invades adjacent structures other than the seminal vesicles: 
bladder neck, external sphincter, rectum, levator muscles, or pelvic wall 
 
N-Regional Lymph Nodes 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Regional lymph node metastasis 
 
M-Distant Metastasis 
MX Distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis 
M1a Non-regional lymph node(s) 
M1b Bone(s) 
M1c Other site(s) 
 
pTNM Pathological Classification 
 
The pT, pN, and pM categories correspond to the T, N, and M categories. However, there is no 
pT1 category because there is insufficient tissue to assess the highest pT category. 

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APPENDIX IV 
 
 
DISTRIBUTION SCHEMA, AND SAMPLE COLLECTION AND TMA CONSTRUCTION 
PROCEDURES FOR CORRELATIVE SCIENCE SUBSTUDIES 
 
 
 
 
 
 
 

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TMA CONSTRUCTION PROCEDURES FOR SUBSTUDIES 
150412 AND 150413 
 
 
1. Each participating institution will submit to the Alliance Biorepository at Ohio State University 
radical prostatectomy tissue blocks and the diagnosing pathologist
's report. 
2. The PCO will face each block and minimally cut (to preserve the tissue) a 4 micrometer section 
for H&E staining. Each section will be placed on slides, stained with H&E, dried overnight and 
checked for quality. Slides will be labeled with 90203 study number followed by a dash and a 
suffix indicating the specific block from which the section was collected (the same suffix written 
in the original tissue block). This will facilitate the identification of the specific block selected 
for TMA construction. If the quality of the H&E section causes the block to be excluded by the 
pathologist or the technician, the corresponding block will be returned. 
3. The Alliance GU Pathologist will Gleason grade each region of each prostatectomy that contains 
CaP (outlining the area of cancer). The pathologist will determine those research subjects for 
whom the blocks should not be used because such research use would exhaust the specimen. S/he 
will also record Gleason primary and secondary grades directly on each H&E section/slides. 
4. H&E slides will be digitized and the H&E images will be used for quality assurance review and 
for annotation of core locations for TMA construction. Three 3-micrometer sections will be cut 
and labeled with the original number and 90203 study number. These sections will be stored in 
case TMA construction proves inadequate. 
5. In a pilot study (101), radical prostatectomy specimens yielded an average of 25 (range 2-66) 
blocks per subject. An average of 9 blocks (range 2-17) revealed cancer. Radical prostatectomy 
specimens contained an average of 2 (range 1-8) individual cancers. 
6. A template of the radical prostatectomy will be made using Microsoft Excel as a guide to 
determine core coordinates. Each core location is described by x,y co-ordinates, research subject 
study number and 90203 study number. The annotated digital image will be used to determine 
the coring locations of the tissue blocks. 
7. The location and number of punches to be made from each patient will be determined by 
consultation with Table 3 of Singh, et al. (101). TMAs will be constructed using the 2-quadrant 
technique. Each quadrant of 150 0.6 mm cores on the array will hold approximately 25 research 
subjects since each research subject has on average 5 CaP cores included on TMA (based on 
sampling strategy) and 1 "normal" tissue core. There are 300 total cores on each block that will 
include 12 "markers" (mouse lung) to determine proper orientation and 12 internal controls (rat 
liver). 
8. Data accumulated by the Alliance Biorepository at OSU will contain the following information 
as either an Excel or Word file as needed: 
• 1) Research subject study number 
• 2) Research Block number 
• 3) Punch identifier 
• 4) Benign or cancer (Gleason primary and secondary grades) 
• 5) Percent prostatectomy specimen involved by tumor 
• 6) TMA block number 
• 7) TMA location (x,y-coordinates) 

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9. All H&E slides from study tumor blocks and all TMA blocks will be archived and stored at the 
PCO. After each TMA construction, all prostatectomy blocks used for that TMA will be returned 
to the submitting institution. Upon completion of TMA construction, the Alliance Biorepository 
at OSU will be responsible for cutting the TMA and staining for the biomarkers of interest. The 
Alliance Biorepository at OSU will also cut sections as requested by other qualified laboratories. 
 
Detailed TMA construction protocol: 
10. A recipient block made with paraffin-containing plasticizers be faced on a microtome and 
screwed firmly into place in the Beecher Instruments Microarrayer. 0.6 mm needles (one for 
recipient punch and one for donor block punch) are placed in the turret of the instrument and 
placed in the proper x, y-coordinates. The usable area of a TMA block is about 3 cm x 2 cm. 
Within this area, x, y-coordinates will be assigned to each punch for each research subject and 
recorded as described above. 
11. A small core is removed from the recipient block and the turret is moved so that a punch can be 
taken from the donor block. The punch from the donor block is placed into a hole previously 
created. This process can only be done properly using the human eye and requires acquired 
technical skill. 
12. After all research subjects and controls have been placed into the recipient block, the TMA is 
warmed briefly at 37˚C for 15 minutes with a smooth weight placed on top. This allows bonding 
between the recipient block and the donor cores and flattens the surface. 
13. The newly created TMA is faced on a microtome and a slide cut for H&E evaluation. Any cores 
missing will be logged as "lost" and recorded in the database for future reference (up to 20% of 
cores may be lost). 
14. The Instrumedics Adhesive Tape Transfer system works best for cutting 0.6 mm TMAs. This 
system requires that adhesive tape is placed on the microarray block prior to cutting each section. 
The tape is aligned on an Instrumedic slide that contains a PSA polymer for adhesion. The slides 
are incubated under UV light to polymerize the paraffin to the slide. After UV incubation, the 
slides are placed in a TPC solvent to remove the tape. The slides are placed in xylene for 60 
seconds and air dried. Finally, the slides are dipped in melted paraffin once and allowed to cool. 
The TMA sections can be shipped or stored (failure to redip the TMA sections resulted in loss of 
antigenicity).