Phase III Trial of Enzalutamide (NSC# 766085) Versus Enzalutamide, Abiraterone and Prednisone for Castration Resistant Metastatic Prostate Cancer
Phase: PHASE3
Conditions: Adenocarcinoma of the Prostate, Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer
Sponsor: Alliance for Clinical Trials in Oncology



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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data directly to the 
Lead National Clinical Trial 
Network (NCTN) Group unless 
otherwise specified in the protocol:  
Regulatory documentation 
must 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 for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_
SYSTEM/ 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 study protocol and all related forms and documents must be downloaded from the protocol-
specific page of the CTSU Member website 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 assignments house in the CTSU RSS. 
 
For clinical questions 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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TABLE OF CONTENTS 
SECTION 
PAGE 
1.0 
INTRODUCTION.......................................................................................................................... 8 
1.1 
Targeting AR Activation: ................................................................................................................ 8 
1.2 
Targeting Androgen Synthesis ......................................................................................................... 9 
1.3 
Rationale for combining abiraterone/prednisone and enzalutamide in the chemotherapy naïve 
population ........................................................................................................................................ 9 
1.4 
Rationale for the correlative studies............................................................................................... 10 
1.5 
Rationale for the conduct of this trial in the cooperative groups ................................................... 10 
1.6 
Registration fatigue/uniscale assessment ....................................................................................... 10 
2.0 
OBJECTIVES .............................................................................................................................. 11 
2.1 
Primary Objective .......................................................................................................................... 11 
2.2 
Secondary Objectives..................................................................................................................... 11 
3.0 
ON-STUDY GUIDELINES ......................................................................................................... 12 
4.0 
ELIGIBILITY CRITERIA ......................................................................................................... 13 
4.1 
Documentation of Disease: ............................................................................................................ 13 
4.2 
Patients must have Measurable or Non-measurable Disease ......................................................... 13 
4.3 
Progressive disease ........................................................................................................................ 13 
4.4 
Prior Treatment .............................................................................................................................. 14 
4.5 
Patient History ............................................................................................................................... 15 
4.6 
Age and performance status ........................................................................................................... 16 
4.7 
Required Initial Laboratory Values: .............................................................................................. 16 
5.0 
REGISTRATION/RANDOMIZATION AND STRATIFICATION ...................................... 16 
5.1 
CTEP Investigator Registration Procedures .................................................................................. 16 
5.2 
CTEP Associate Registration Procedures / CTEP-IAM Account.................................................. 16 
5.3 
CTSU Site Registration Procedures ............................................................................................... 17 
5.4 
Patient Registration Requirements ................................................................................................. 18 
5.5 
Patient Registration/Randomization Procedures ............................................................................ 18 
5.6 
Registration to Correlative and Companion Studies ...................................................................... 19 
5.7 
Stratification Factors and Treatment Assignments ........................................................................ 19 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................. 19 
6.1 
Data submission ............................................................................................................................. 19 
6.2 
Specimen Submission for Correlative Studies: .............................................................................. 22 
6.3 
Imaging credentialing and submission ........................................................................................... 25 
7.0 
REQUIRED DATA ...................................................................................................................... 28 
8.0 
TREATMENT PLAN .................................................................................................................. 29 
8.1  Arm A: Enzalutamide alone ........................................................................................................... 29 
8.2 
Arm B: Enzalutamide, abiraterone, and prednisone ...................................................................... 29 
8.3 
Maintenance of castrate testosterone levels ................................................................................... 30 
8.4 
Bone protection .............................................................................................................................. 30 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ...................................... 31 
9.1 
Hepatic Toxicity ............................................................................................................................ 31 
9.2 
Neurologic toxicity ........................................................................................................................ 31 
9.3 
Reversible posterior leukoencephalopathy syndrome (RPLS) ...................................................... 31 
9.4 
Other Non-Hematologic Grade 3 or 4 Toxicity ............................................................................. 31 
10.0 
CORRELATIVE STUDIES ........................................................................................................ 32 

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10.1 Biomarker development/validation of technetium bone scintigraphy and sodium fluoride (NaF) 
PET/CT for CRPC ......................................................................................................................... 32 
10.2 Serum Androgen Levels ................................................................................................................ 36 
10.3 Development and validation of a circulating RNA profile as a prognostic and predictive 
biomarker of AR-targeted therapy in men with CRPC .................................................................. 38 
10.4 Development and validation of a circulating microRNA profile as a prognostic and predictive 
biomarker of AR-targeted therapy in men with CRPC .................................................................. 40 
10.5 Analysis and Confirmation of Prognostic Blood-based Angiokine Biomarkers in Men with 
Metastatic Castration-Resistant Prostate Cancer ........................................................................... 43 
10.6 To develop and validate prognostic and predictive models of overall survival and will include 
baseline clinical and molecular markers. ....................................................................................... 45 
10.7 Pharmacogenomic studies .............................................................................................................. 46 
10.8 Population Pharmacokinetics of abiraterone and enzalutamide ..................................................... 48 
11.0 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION ................................... 53 
11.1 Qualified personnel ........................................................................................................................ 53 
11.2 Enzalutamide (NSC #766085) ....................................................................................................... 53 
11.3 Abiraterone Acetate ....................................................................................................................... 55 
11.4 Prednisone ...................................................................................................................................... 56 
12.0 
ANCILLARY THERAPY ........................................................................................................... 56 
12.1 Supportive Care ............................................................................................................................. 56 
12.2 Treatment with other chemotherapeutic agents ............................................................................. 57 
12.3 Radiation therapy ........................................................................................................................... 57 
12.4 Growth Factors .............................................................................................................................. 57 
12.5 Zoledronic acid and denosumab .................................................................................................... 57 
13.0 
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE (SOLID TUMORS) .... 57 
13.1 Prostate Cancer Working Group 2 (PCWG2) response criteria..................................................... 57 
13.2 Target Lesions ................................................................................................................................ 58 
13.3 Non-target Lesions ......................................................................................................................... 59 
13.4 Evaluation of Best Overall Response............................................................................................. 60 
13.5 Guidelines for Evaluation of Measurable Disease ......................................................................... 60 
13.6 Confirmation Measurement/Duration of Response ....................................................................... 62 
14.0 
END OF TREATMENT .............................................................................................................. 63 
14.1 Duration of treatment ..................................................................................................................... 63 
14.2 Disease progression ....................................................................................................................... 63 
14.3 Extraordinary Medical Circumstances: .......................................................................................... 63 
15.0 
STATISTICAL CONSIDERATIONS ....................................................................................... 63 
15.1 Sample Size Determination ............................................................................................................ 63 
15.2 Interim Analysis ............................................................................................................................. 64 
15.3 Toxicity Monitoring ....................................................................................................................... 64 
15.4 Data Analysis ................................................................................................................................. 65 
15.5 Accrual Rate .................................................................................................................................. 65 
15.6 Inclusion of Women and Minorities .............................................................................................. 66 
16.0 
EXPEDITED ADVERSE EVENT REPORTING .................................................................... 66 
16.1 Alliance A031201 Reporting Requirements .................................................................................. 67 
16.2 Additional Instructions or Exclusions ............................................................................................ 68 
17.0 
REFERENCES ............................................................................................................................. 70 
APPENDIX I: REGISTRATION FATIGUE/UNISCALE ASSESSMENT ........................................ 74 

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APPENDIX II: BPI-SF QUESTION #3 AND PHARMACOKINETICS PATIENT 
QUESTIONNAIRE ................................................................................................................................... 76 
APPENDIX III: PATIENT MEDICATION LOGS .............................................................................. 79 
APPENDIX IV: GUIDE TO THE HALABI NOMOGRAM ON-LINE CALCULATOR ................ 86 
APPENDIX V: PCWG2 BONE SCAN ASSESSMENT TOOL GUIDE ............................................. 87 
APPENDIX VI: PCWG2 PROGRESSION SCENARIOS ................................................................... 91 

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1.0 
INTRODUCTION 
Prostate cancer is the second leading cause of cancer-related death in American men. In 2011, it is 
anticipated that 33,720 men will die of this disease, nearly all of them from bone metastases that are 
responsible for pain, spinal cord compression, bone fractures, and blood dyscrasias.1  
Prostate cancer growth is dependent on androgens and androgen receptor activation. Depleting or 
blocking androgen action has been a mainstay of treatment for over 6 decades. Traditional hormonal 
therapies include GnRH analogues, anti-androgens, androgen synthesis inhibitors, and estrogens. 
Despite the early sensitivity of tumors to hormonal strategies, tumors that progress despite androgen 
deprivation generally represent a transition to the terminal form of the disease, for which limited 
treatment options are available. Docetaxel and prednisone prolong survival on the order of 2-3 
months in such patients when compared to mitoxantrone and prednisone, and to this day, docetaxel 
is a standard first-line chemotherapy for patients with CRPC.2 Cabazitaxel was recently shown to 
prolong survival for patients with progressive disease following docetaxel, but cabazitaxel has 
significant side effects, including a 5% toxic death rate due to neutropenic sepsis.3 The vaccine 
sipuleucel-T also prolongs survival in CRPC, but patients with pain, visceral disease, or who use 
steroids are precluded from receiving treatment. Alternatives to chemotherapy and immune therapy 
for treatment of patients with CRPC are greatly needed. 
Results of clinical trials and studies on the molecular profiles of progressing tumors have shown that 
the androgen receptor actively signals and induces tumor growth throughout the natural history of 
prostate cancer, even in patients with CRPC. The mechanisms by which the AR continues to actively 
signal in the castration-resistant state are multifold, but include upregulation of androgen 
biosynthesis, overexpression of androgen receptors, and mutation.4-6 These pathways have provided 
a wide variety of potential therapeutic approaches targeting the AR axis, with two approaches (and 
two specific agents, abiraterone acetate [hereafter, “abiraterone”] and enzalutamide) shown to 
prolong life in these patients: 
1.1 
Targeting AR Activation: 
The fact that the AR actively signals despite castrating therapy makes the AR-axis a prime 
therapeutic target. First-generation non-steroidal anti-androgens such as bicalutamide, 
nilutamide, and flutamide have long been part of the clinical armamentarium, and have been 
extensively explored in conjunction with castration or as second line therapy after patients have 
progressed through castration.7 These relatively low-affinity ligands bind to the C-terminal 
portion of the AR ligand-binding domain, and function both by passively competing with 
patients’ endogenous androgens, or by active mechanisms such as recruiting corepressor or 
inhibiting coactivator binding.8-10 However, these agents have the capacity to function as 
agonists as well as antagonists via diverse mechanisms.  
Novel antiandrogens, however, have been developed to overcome these mixed 
agonist/antagonist properties. Enzalutamide is an oral agent that appears to bind to the AR with 
five to eight times the affinity of bicalutamide and two to three times the affinity of DHT. The 
anti-tumor effects of enzalutamide appear to be mediated by inhibiting AR nuclear translocation, 
DNA binding, and coactivator peptide recruitment. In contrast to bicalutamide, enzalutamide 
exhibits no agonistic properties and does not recruit coactivator proteins. In a human prostate 
cancer cell line that overexpresses AR, termed VCaP, enzalutamide suppressed growth and 
induced apoptosis, even when bicalutamide did not. Similarly, in vivo tumor suppression was 
evidenced in castration-resistant AR-overexpressing LNCaP/AR xenograft models, revealing 
tumor reduction. Mice treated with enzalutamide had prolonged time to tumor progression 
relative to bicalutamide as well.6   

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Enzalutamide was tested in a recently reported phase III trial involving patients with CRPC who 
had received prior treatment with docetaxel. The primary endpoint of the study was overall 
survival, with secondary endpoints of time to progression, radiographic progression-free 
survival, and post-treatment PSA and circulating tumor cell alterations. The study was positive, 
demonstrating that the patients who had received enzalutamide enjoyed a risk of death 37% 
lower than those who received a placebo (HR 0.63, 13.6 vs. 18.4 months median survival for 
each arm), conferring a 4.8 month overall survival advantage.11 The FDA has approved 
enzalutamide for patients with metastatic CRPC who have received prior docetaxel. 
1.2 
Targeting Androgen Synthesis 
Although androgen deprivation therapy (using luteinizing hormone-releasing hormone agonists 
or antagonists) decreases total serum testosterone levels by approximately 95%, this intervention 
primarily inhibits gonadal androgen synthesis and does not affect extra-gonadal androgens. It is 
now established that, in CRPC, there is continuous production of androgens by the adrenal 
glands as well as the prostate cancer itself.12,13 Moreover, in the castrate state, intraprostatic 
concentrations of testosterone and dihydrotestosterone remain sufficient to stimulate AR. The 
main mechanisms by which CRPC is able to overcome low circulating androgen levels are local 
conversion of adrenal androgens (e.g. androstenedione) to testosterone, and de novo 
intratumoral synthesis of androgens through increased expression of steroidogenic enzymes 
such as cytochrome P450 17 (CYP17).14,15  
Abiraterone is a selective inhibitor of androgen biosynthesis that potently blocks CYP17, which 
is critical to testosterone synthesis by the adrenals, testes, and within the prostate tumor.16,17 In 
phase 1-2 trials, treatment with abiraterone resulted in significant antitumor activity in both 
taxane naïve and taxane treated patients.18,19 The most common adverse events were associated 
with increased mineralocorticoid levels, including hypokalemia, fluid retention, and 
hypertension; these were largely abrogated by co-administering low-dose glucocorticoids. Two 
phase III trials have been undertaken with abiraterone. In Cougar 301, patients with progressive 
CRPC following treatment with docetaxel were treated with abiraterone and prednisone or 
prednisone alone. A total of 1195 men were randomized, with a primary endpoint of overall 
survival. Men who received the abiraterone enjoyed a significant reduction in the risk of death, 
with a hazard ratio of 0.65, associated with a median survival of 14.8 months as opposed to 10.9 
months (P<0.001).20 As a result, abiraterone and prednisone was approved by the FDA for 
patients with CRPC who have progressed despite prior treatment with docetaxel in April 2011. 
In Cougar 302, 1088 patients with CRPC who were chemotherapy naïve were randomized to 
abiraterone and prednisone vs. prednisone alone. On March 8, 20121 the independent data 
monitoring committee (IDMC) unblinded the study as a planned interim analysis. Patients who 
received a placebo and prednisone had a median survival of 27.2 months. Patients who received 
abiraterone and prednisone had at 25% risk reduction for dying (median OS not reached, HR 
0.75 (0.61-0.39, p = 0.0097). The FDA has expanded the indication of abiraterone to include 
patients with CRPC who are chemotherapy naïve.21 
1.3 
Rationale for combining abiraterone/prednisone and enzalutamide in the chemotherapy 
naïve population 
Both abiraterone/prednisone and enzalutamide prolong survival in patients with CRPC that have 
progressed despite prior treatment with docetaxel. These drugs work by two distinct 
mechanisms, both of which reduce AR signaling: the former, by reducing the primary ligand of 
the AR and the latter, by inhibiting AR activation. Both drugs prolong survival in patients who 
have been treated with prior docetaxel. 
The rationale for this trial is predicated on the demonstrated pathway addiction in CRPC, and 
the hypothesis that inhibition of the involved pathway (AR signaling) with two separate 

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inhibitors that act at different levels of the pathway will be more effective than single inhibition 
at one level. In addition, there is no a priori reason to believe that the impact of these agents 
would be different in patients who have or have not been treated with prior docetaxel, and it is 
generally recognized that the testing of these agents in the post-docetaxel setting was largely a 
regulatory construct. Support for the value of anti-AR strategies in the chemotherapy naïve 
population has been evidenced by an interim analysis of Cougar 302, in which patients with 
CRPC who were chemotherapy naïve received abiraterone/prednisone vs. prednisone alone. The 
interim analysis suggested an improved PFS and OS in favor of abiraterone/prednisone.21 Based 
on these data, the IDMC recommended unblinding of this study in order to allow the men 
receiving placebo to receive abiraterone/prednisone. The labeled indication of abiraterone has 
been expanded to include chemotherapy naïve patients. Abiraterone is now commonly used in 
chemotherapy naïve patients as part of routine practice. A phase III study of enzalutamide in the 
pre-chemotherapy population has completed accrual, although results are not anticipated to be 
available for several years. Furthermore, most investigators generally agree that the most 
rational place for the use of these agents is in the pre-chemotherapy setting. Certainly, the 
capacity to delay the use of chemotherapy would be considered to represent significant clinical 
benefit by patients and physicians alike.  
The combination of abiraterone/prednisone and enzalutamide has not yet been tested. However, 
both drugs have highly favorable safety profiles individually, and historically do not have 
overlapping toxicity profiles that should preclude therapy. The immediacy of the need to develop 
combinatorial strategies of these agents is strong enough, and the likelihood of seeing toxicity 
marginal enough, to justify up-front testing in the phase III setting in order to preserve precious 
patient resources. However, a safety early stopping rule is built into the study. 
1.4 
Rationale for the correlative studies 
Correlative studies embedded in this trial will provide insight into sub-populations within the 
broader CRPC population that might optimally benefit from one of the specific treatment 
strategies being tested, as well as begin to define the processes at play at the time of developing 
resistance to these therapies. These studies will involve analyses of circulating androgen levels, 
microRNA, RNA profiles, and serum angiokine levels that will identify independent prognostic 
biomarkers of overall survival and progression-free survival in men with metastatic CRPC, as 
well as potentially predict for the benefit associated with combined enzalutamide/abiraterone 
therapy over single agent sequential therapy. In addition, in collaboration with the Alliance 
Imaging Committee, the study contains a correlative study of bone imaging by Tc-99 or sodium 
fluoride F-18 (NaF) PET/CT imaging techniques, to develop optimized prognostic and 
predictive imaging biomarkers for castration-resistant metastatic disease. The background and 
details, rationale, and statistical plan are found in an Appendix to this document. 
1.5 
Rationale for the conduct of this trial in the cooperative groups 
From a clinical standpoint, the question of whether enzalutamide vs. enzalutamide and 
abiraterone/prednisone should be the treatment of choice as first-line therapy for CRPC is one 
that the cooperative groups can well answer. Both drugs are highly sought by patients at 
academic centers and in the community, especially before chemotherapy.  
The clinical and scientific importance of this study has also been recognized by the other 
cooperative groups beyond the Alliance. SWOG and ECOG will be participants in the study, 
and the study has been endorsed by NCIC as well. 
1.6 
Registration fatigue/uniscale assessment 
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study. Evidence has arisen indicating that 

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baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two separate meta-analyses recently presented at ASCO, the first involving 23 NCCTG and 
Mayo Clinic Cancer Center oncology clinical trials, the second involving 43 clinical trials. 
Routine inclusion of these measures should be considered similar to that of including 
performance status, either as stratification or prognostic covariates. (50) 
2.0 
OBJECTIVES  
2.1 
Primary Objective 
To compare the overall survival of patients with progressive metastatic CRPC treated with either 
a) enzalutamide only or b) enzalutamide with abiraterone and prednisone 
2.2 
Secondary Objectives 
2.2.1 
To assess the grade 3 or higher toxicity profile and compare safety by treatment arm 
2.2.2 
To assess and compare post-treatment PSA declines by treatment arm  
2.2.3 
To compare radiographic progression free survival defined by Prostate Cancer Working 
Group 2 (PCWG2), and objective response rate, by treatment arm. 
2.2.4 
To test for rPFS treatment interaction in predicting overall survival. 
2.2.5 
To assess pre- and post-treatment measures of tumor burden and bone activity using NaF 
PET/CT and Tc MDP bone scintigraphy and correlate these measures with overall survival. 
2.2.6 
To develop and validate prognostic and predictive models of overall survival that include 
baseline clinical and molecular markers.  
Correlative Study objectives 
2.2.7 
To determine whether pre-treatment serum adrenal androgen (SA) levels are prognostic 
factors of overall survival and to test whether SA levels are predictive factors of overall 
survival. 
2.2.8 
To evaluate specific pre-treatment RNA levels as prognostic factors for OS, including the 
6- and 9-gene signatures, the CTC RNA profile, and the circulating tumor stem cell RNA 
profile. 
2.2.9 
To evaluate the predictive ability of specific pre-treatment and post-treatment RNA, levels 
on the OS and PFS. 
2.2.10 To evaluate specific pre-treatment microRNA levels as prognostic factors for OS. 
2.2.11 To test whether the microRNA are predictive factors for overall survival. 
2.2.12 To determine whether pre-treatment angiokine levels are prognostic factors for OS and 
PFS. 
2.2.13 To test whether pretreatment angiokine levels are predictive factors for OS and PFS and to 
assess whether post-treatment angiokine levels are predictive factors for OS and PFS. 
2.2.14 To investigate a drug by CYP17A1 interaction with respect to overall survival. 
2.2.15 To assay candidate variants and loci hypothesized to be associated with other clinical 
phenotypes (e.g., progression-free survival or toxicity) or other eQTLs. 

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2.2.16 To identify specific SNPs and/or copy number variations that are associated with the 
response to and toxicity associated with therapy 
2.2.17 To define the effect of abiraterone on reducing enzalutamide metabolic clearance (i.e. 
increasing enzalutamide AUC) when the drugs are used in combination. 
2.2.18 To define the exposure (AUC) toxicity and exposure (AUC) anti-tumor effect relationship, 
including biomarkers for enzalutamide alone and enzalutamide combined with abiraterone 
in prostate cancer patients. 
2.2.19 To develop a population pharmacokinetic model for enzalutamide alone and enzalutamide 
combined with abiraterone taking account of relevant intrinsic and extrinsic factors. 
2.2.20 To determine the intrapatient and interpatient variability of abiraterone exposure (AUC) in 
prostate cancer patients receiving abiraterone when combined with enzalutamide 
2.2.21 To determine the intra-patient and inter-patient variability of enzalutamide exposure 
(AUC) in prostate cancer patients receiving enzalutamide alone and abiraterone plus 
enzalutamide. 
3.0 
ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of 
any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although they 
will not be considered formal eligibility (exclusion) criteria, 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 condition 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. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers or 
non-invasive bladder cancers or other in-situ or non-invasive malignancies. Patients are not 
considered to have a “currently active” malignancy if they have completed therapy and are free 
of disease for ≥ 3 years.  
• 
Estimated life expectancy of < 6 months. 
In addition, 
• 
Men of reproductive potential should agree to use an appropriate method of birth control 
throughout their participation in this study due to the teratogenic potential of the therapy utilized 
in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, 
implantable hormonal contraceptives (Norplant), or double barrier method (diaphragm plus 
condom). 
• 
Abiraterone is an inhibitor of CYP2D6. Avoid coadministration of abiraterone with substrates of 
CYP2D6 with a narrow therapeutic index (e.g., thioridazine). Abiraterone is a substrate of 
CYP3A4. Avoid strong inhibitors and inducers of CYP3A4. 
• 
Co-administration of enzalutamide with strong CYP2C8 inhibitors should be avoided. Co-
administration of enzalutamide with strong or moderate CYP2C8 inducers (e.g., rifampin) should 
also be avoided. In addition, concomitant use of enzalutamide with narrow therapeutic index 
drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, 

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ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, 
warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided.  
• 
Because of the potential risk of seizures (0.9% of patients in the randomized trial) with 
enzalutamide, the use of drugs that may lower seizure threshold potential should be minimized if 
possible. 
• 
Patients should have the ability to swallow study medications. 
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility criteria should be directed to the Alliance Study Chair. Please note 
that the Study Chair cannot grant waivers to eligibility requirements.  
4.1 
Documentation of Disease: 
Progressive castration-resistant metastatic prostate cancer with histologically or cytologically 
confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell 
features. 
4.2 
Patients must have Measurable or Non-measurable Disease 
4.2.1 
Measurable Disease 
For visceral or extra-nodal lesions to be considered measurable, they must be ≥ 10 mm 
in one dimension, using spiral CT. 
For lymph nodes to be considered measureable (i.e., target or evaluable lesions), they must 
be ≥ 20 mm in at least one dimension, using spiral CT. 
4.2.2 
Non-measurable Disease 
All other lesions, including small lesions (longest diameter < 20 mm with conventional 
techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions.  
Lesions that are considered non-measurable include bone lesions (only). 
4.2.3 
Patients with node only disease (i.e. no presence of visceral, extra nodal lesions or 
bone lesions) must have node(s) that measure ≥ 15 mm in short axis. 
4.3 
Progressive disease 
Patients must have progressive disease at study entry defined as one or more of the following 
three criteria that occurred while the patient was on androgen deprivation therapy. For patients 
enrolling on the basis of soft tissue or bone progression, the baseline scan must show progression 
relative to a comparison scan. If the comparison scan is not available, the baseline scan report 
must reference the previous scan to document progression. 
4.3.1 
PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 
1 week between each determination. Patients who received an anti-androgen must have 
progression documented by a minimum of two rising PSA levels with an interval of ≥ 1 
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since last flutamide, bicalutamide or nilutamide. The PSA value at the screening should be 
> 2 µg/L (2 ng/mL) 
 
 
(from PCWG2) 22 
4.3.2 
Soft tissue disease progression defined by Section 13.2.3. 
4.3.3 
Bone disease progression defined by PCWG2 with two or more new lesions on bone 
scan 
4.4 
Prior Treatment 
4.4.1 
No treatment with prior taxane-based chemotherapy for metastatic disease. 
i. 
Patients who received prior taxane-based chemotherapy as neoadjuvant or adjuvant 
therapy for local disease, or who received taxane-based therapy in the PSA clinical 
(non-metastatic) state is allowable provided that the total duration of exposure was six 
cycles or less and chemotherapy was completed more than 6 months prior to 
registration. 
ii. Taxane-based chemotherapy that was aborted due to allergic reactions or intolerance 
to chemotherapy and therefore received 1 cycle of prior therapy is allowable. 
4.4.2 
No prior enzalutamide, abiraterone, or other novel antiandrogen or androgen synthesis 
inhibitor  
4.4.3  No treatment with any of the following for prostate cancer within 4 weeks prior to 
enrollment: 
• 
Hormonal therapy (e.g., AR antagonists, 5 alpha reductase inhibitors, estrogens). 
Note: Treatment with bicalutamide and nilutamide within 4 weeks prior to enrollment 
is not allowed. Treatment with flutamide within 4 weeks prior to enrollment is 

Alliance A031201 
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Update #05 
not allowed. Treatment with all other GnRH analogues or antagonists is 
allowed. 
• 
Chemotherapy 
• 
Biologic therapy 
• 
Investigational therapy 
• 
Immunotherapy  
4.4.4 
No use of herbal products that may decrease PSA levels within 4 weeks prior to enrollment 
4.4.5 
No chronic use of systemic steroids greater than the equivalent of 10 mg of 
prednisone/prednisolone per day within 4 weeks prior to enrollment  
4.4.6 
No prior use of ketoconazole for greater than 7 days. 
4.4.7 
No prior radiation therapy or radionuclide therapy for the treatment of metastasis within 
four weeks prior to enrollment 
4.4.8 
Patients receiving bisphosphonate therapy or denosumab must have been on a stable dose 
for at least 4 weeks prior to enrollment 
4.4.9 
Patients must maintain ongoing androgen deprivation therapy with a GnRH analogue, 
antagonist, or bilateral orchiectomy (i.e., surgical or medical castration) 
4.5 
Patient History 
4.5.1 
No known or suspected brain metastases (NOTE: patients with treated epidural disease are 
allowed) 
4.5.2 
No planned palliative procedures for alleviation of bone pain such as radiation therapy or 
surgery 
4.5.3 
No structurally unstable bone lesions suggesting impending fracture 
4.5.4 
No history of seizure or any condition that may increase the patient’s seizure risk (e.g., 
prior cortical stroke, significant brain trauma). No history of TIA within 12 months of 
enrollment. 
4.5.5 
No clinically significant cardiovascular disease including: 
• 
MI within 6 months 
• 
Uncontrolled angina within 3 months 
• 
CHF with NYHA class 3 or 4, or patients with NYHA class 3 or 4 in the past, unless a 
screening echo or MUGA performed within three months demonstrates an EF>45% 
• 
History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, torsades de pointes) 
• 
History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place 
• 
Hypotension  (systolic BP <86 mmHg) or bradycardia (<50 bpm) at screening  
• 
Uncontrolled hypertension (systolic BP >170 mmHg or diastolic BP >105 mmHg at 
screening) 
4.5.6 
No GI disorder that negatively affects absorption 
4.5.7 
No major surgery within 4 weeks prior to enrollment 

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4.6 
Age and performance status 
4.6.1 
Age ≥ 18 years of age 
4.6.2 
ECOG Performance Status 0-1 
4.6.3 
Asymptomatic or mildly symptomatic from prostate cancer.  
A score of 0-1 on BPI-SF Question #3 (worst pain in last 24 hours) will be considered 
asymptomatic, and a score of 2-3 will be considered mildly symptomatic (see Appendix II) 
4.7 
Required Initial Laboratory Values: 
Granulocytes 
≥ 1,500/µL 
Platelet count 
≥ 100,000/µL 
Hemoglobin 
≥ 9 g/dL 
Creatinine 
≤ 2 x upper limits of normal (ULN) 
Bilirubin 
≤ 1.5 x ULN 
AST or ALT 
≤ 2 x ULN 
Albumin 
> 3 g/dl 
Total Testosterone 
≤ 50 ng/dL (1.7 nmol/L) 
5.0 
REGISTRATION/RANDOMIZATION AND STRATIFICATION 
5.1 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all investigators participating in any NCI-sponsored clinical trial to register and to renew 
their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
  For questions, 
please 
contact 
the 
CTEP 
Investigator 
Registration 
Help 
Desk 
by 
email 
at 
 
5.2 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved 
in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and annual 
re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, including the CTSU members’ website. 

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5.3.4 Checking Your Site’s Registration Status 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
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 at the top of your screen 
Click on the Site Registration tab 
Enter your 5-character CTEP Institution Code and click on Go 
5.4 
Patient Registration Requirements 
• 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. 
Current human protection committee approval of this protocol and a consent form is 
required prior to patient consent and registration. 
• 
Determination of Risk Using Halabi Nomogram: patients will be categorized into one of 
three risk groups using the following link: 
https://www.cancer.duke.edu/Nomogram/firstlinechemotherapy.html 
See Appendix IV for instructions for using the nomogram.  
Variables for the nomogram include: ECOG performance status (0, 1, or 2), baseline PSA, 
LDH, alkaline phosphatase, albumin, hemoglobin, opioid analgesic use, presence of bone 
metastases, presence of lymph node metastasis, and presence of visceral metastases (defined 
as lung, liver, or adrenal). 
• 
Assurance of drug provision: As abiraterone will be used on-label, patients and their 
treating physicians will secure their own supply of the drug. Arrangements with third party 
insurers, private or public, should be made prior to registration/randomization. The patient 
must be willing to pay for the balance of the drug’s cost that is not covered by third party 
insurance. 
5.5 
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://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
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 and, upon enrollment, initializes the patient in 
the Rave database. 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. A user manual is available for 
OPEN users on the CTSU site. 
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). 

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Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 
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 
 
5.6 
Registration to Correlative and Companion Studies 
5.6.1 
Registration to Substudies described in Section 10  
There are four substudies within Alliance A031201: 
• 
Alliance A031201-IM1: Imaging science studies in Alliance A031201 (Section 10.1) 
• 
Alliance A031201-ST1: Correlative science studies in Alliance A031201 (Sections 10.2 
– 10.6) 
• 
Alliance A031201-PP1: Pharmacogenomic studies in Alliance A031201 (Section 10.7) 
• 
Alliance A031201-PP2: Pharmacokinetic studies in Alliance A031201 (Section 10.8) 
Mandatory companion study: 
Participation in A031201-IM1 is required for all patients enrolled to A031201. All patients 
enrolled to this treatment trial will be registered to this companion at the same that he is 
registered to A031201. 
Optional companion studies: 
The three additional substudies A031201-ST1, A031201-PP1, A031201-PP2, must be 
offered to all patients enrolled on Alliance A031201 (although patients may opt not to 
participate).  
If a patient answers “yes” to “I agree that my specimens may be used for the research 
studies described above.” (Question #1) in the Model Consent, he has consented to 
participate in the biomarker, pharmacogenomic, and pharmacokinetic studies described in 
Sections 10.2 through 10.8. The patient should be registered to Alliance A031201-ST1, 
A031201-PP1, and A031201-PP2 at the same time that he is registered to the treatment 
trial (Alliance A031201) and samples submitted per Section 6.2. 
5.7 
Stratification Factors and Treatment Assignments 
Randomization will be stratified on: 
1) Prior chemotherapy:  
Yes, No 
2) Risk Group determined using the nomogram developed by Halabi, et al55 (See Section 
5.1.2): 
Low, Intermediate, High 
6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://eapps-ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-

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Only, Site Investigator) on either the LPO or participating organization roster at the enrolling 
site. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent 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. 
Users who have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (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 a
.   
A Schedule of Forms is available on the Alliance study webpage, within the Case Report Forms 
section. The Schedule of Forms is also available on the CTSU site within the study-specific 
Education and Promotion folder, and is named Time & Events. 
All radiology reports must be uploaded via the Supporting Documentation page associated with 
the current cycle folder in Medidata Rave® (See Section 7.0). 
6.1.2 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. Section 16.0 provides information about expedited reporting. 
Institutions that do not submit adverse event forms in a timely manner may be denied future 
registrations to this study. 
Common Terminology Criteria for Adverse Events: This study will utilize the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 for toxicity and adverse 
event reporting. However, beginning April 1, 2018, CTCAE v5.0 must be used for 
expedited adverse event reporting via CTEP-AERS. 
 
 

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6.1.3 
Routine Adverse Event Reporting 
Solicited Adverse Events: The following adverse events are considered “expected” and 
their presence/absence should be solicited, and severity graded, at baseline and for each 
cycle of treatment.  
• 
Fatigue (see CTCAE General disorders and administration site conditions) 
• 
Diarrhea 
• 
Constipation 
• 
Vomiting 
• 
Dyspepsia 
• 
Edema limbs (see CTCAE General disorders and administration site 
conditions) 
• 
Arthralgia 
• 
Bone pain 
• 
Myalgia 
• 
Seizure 
• 
Headache (see CTCAE Nervous system disorders) 
• 
Insomnia (see CTCAE Psychiatric disorders) 
• 
Hot flashes (see CTCAE Vascular disorders) 
• 
Hypertension 
• 
Cough 
• 
Dyspnea 
• 
Hyperglycemia (see CTCAE Metabolism and nutrition disorders) 
• 
Hypokalemia (see CTCAE Metabolism and nutrition disorders) 
• 
Alanine aminotransferase increased (see CTCAE Investigations) 
• 
Aspartate aminotransferase increased (see CTCAE Investigations) 
• 
Blood bilirubin increased (see CTCAE Investigations) 
 
 
 

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Plasma (for angiokine SearchLight assay, Section 10.5):  
1. For EDTA plasma, draw 8-10 mL of peripheral blood into a lavender top 
vacutainer(s) (K2EDTA anticoagulant). Invert approximately 8 times and centrifuge 
for 15 minutes at approximately 2500 x  g at room temperature. Remove plasma 
and transfer to a clean tube (plastic or glass). Repeat centrifuge at 2500 x g for 
15 minutes at room temperature. Aliquot 1 mL plasma into each 1.8 mL cryovial.* 
2. For citrate plasma, draw 8-10 mL of peripheral venous blood into a light blue top 
vacutainer(s) (3.2% sodium citrate anticoagulant). Invert approximately 8 times and 
centrifuge for 15 minutes at approximately 2500 x g at room temperature. 
Remove plasma and transfer to a clean tube (plastic or glass). Repeat centrifuge at 
2500 x g for 15 minutes at room temperature. Aliquot 1  mL plasma into each 1.8 
mL cryovial.* 
3. 
Label and freeze cryovials at –70°C or colder. Samples should be shipped within 30 
days on dry ice by overnight shipping service to the appropriate Alliance 
biorepository. If –70°C or colder freezer is not available, temporary storage at  
-20°C prior to shipment is acceptable for up to 72 hours. 
* 
Cryovial Choices: Some examples of acceptable 1.8 mL cryovials are: Nalgene (Cat 
#5012-0020), Fisher (Cat #05-669-57), Corning (Cat #430488), VWR (Cat #16001-
102). 
Whole blood (for pharmacogenomics sample, Section 10.7): Collect 10 mL of venous 
blood in lavender top (EDTA anticoagulant) vacutainer tube(s). The tubes should be 
inverted approximately 10 times to mix the EDTA.  Refrigerate sample until shipping. 
The sample should be placed in a biohazard bag and shipped according to IATA guidelines 
the same day as the blood is drawn on a cold pack by overnight courier service to the 
appropriate Alliance biorepository. 
Note: It is strongly encouraged that samples for pharmacogenomics testing are collected 
prior to the initiation of study treatment. However, sample collection and registration to a 
pharmacogenetic sub-study may take place within 60 days of registration to the treatment 
trial if permitted by the study protocol. 
Plasma (for pharmacokinetics sample, Section 10.8): 
Prior to Cycles 2 through 6, patients enrolled to the pharmacokinetics substudy will be 
asked to complete a questionnaire form (see Appendix II), which will provide information 
about the prior 48-hour dosing of enzalutamide or abiraterone and enzalutamide (details of 
dose, time and relationship to food).  
Collect 4 mL of blood in lavender top tubes at baseline, prior to first enzalutamide or 
abiraterone/enzalutamide dose, and at each subsequent clinic visit through Cycle 6 while 
on study treatment. 
Samples should be collected into 4 mL lavender top vacutainers (BD367862). Fill the tubes 
completely. Mix immediately by gently inverting the tube at least 8 to 10 times to ensure 
thorough mixing of the anticoagulant and then tubes should be placed on ice for less than 
30 minutes during the sampling period. Samples should be centrifuged at 4°C at 2,000 g x 
for 10 minutes to separate plasma from red cells. Aliquot 1 mL plasma into 1.8 mL 
cryovials that are clearly labeled with appropriate patient ID, the date of the sample, and 
the time of sample acquisition. Sample timing should be indicated as actual time the sample 
was obtained. Sample handling from collection to storage should not exceed 60 minutes. 

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To complete the training, the PI/designated local investigator is to view a webinar 
recording describing the PCWG2 interpretation procedures. This recording is available as 
a download on the A031201 study page on the Alliance and CTSU web sites.  Additionally, 
this recording is available for download to all sites that are able to submit data 
electronically through the Alliance Imaging Core Lab.  Upon completion, the Alliance 
Imaging Core Lab should be notified via e-mail to 
 
by the PI/designated local investigator that they have viewed the webinar.  A pdf of the 
presentation slides seen in the webinar can be provided for reference.  This pdf is also 
available on the A031201 study page on the Alliance and CTSU web sites. 
If the designated reference radiologist, local PI or designated local investigator who is to 
interpret the bone scans of patients on study changes, the institution must inform the 
Alliance ICL. Additionally, the Alliance ICL should be provided notification that the 
PCWG2 webinar training has been completed for the new bone scan interpreter designee. 
Sites that lack the resources for either a designated reference radiologist or a local 
investigator at their institution to interpret bone scans using PCWG2 criteria and that 
require the Alliance Imaging Core Lab to perform the interpretation need to inform the 
Alliance ICL of this arrangement prior to the enrollment of their first patient. The request 
and 
rationale 
for 
the 
request 
should 
be 
sent 
via 
e-mail 
to 
 for review and consideration. 
For sites that utilize the Alliance Imaging Core Lab to interpret the bone scans, the ICL 
will provide results to the site using the PCWG Bone Scan Assessment Tool Guide found 
in Appendix V. Once received, the site is responsible for entering the results and data into 
Medidata Rave. 
6.3.3 
Scan submission instructions 
All MRI, CT, PET/CT and planar/SPECT images will be collected digitally for archival 
and retrospective central review purposes. The following images will be collected digitally: 
• 
Baseline (within 28 days prior to patient registration) 
Chest x-ray, PA & Lateral, or Chest CT (MRI), Bone Imaging (Tc-99m MDP 
planar/SPECT or NaF PET/CT) and CT or MRI abd/pelvis 
• 
Treatment monitoring (every 8 weeks for the first 6 cycles, then every 12 weeks, 
and at end of treatment) 
Chest x-ray, PA & Lateral, or Chest CT (MRI), Bone Imaging (Tc-99m MDP 
planar/SPECT or NaF PET/CT) and CT or MRI abd/pelvis 
• 
Post-treatment follow-up (every 12 weeks after discontinuation of treatment until 
progression or 5 years after randomization)  
Chest x-ray, PA & Lateral, or Chest CT (MRI), Bone Imaging (Tc-99m MDP 
planar/SPECT or NaF PET/CT) and CT or MRI abd/pelvis 
The complete CT, MRI, PET/CT and/or planar/SPECT scan data in digital DICOM format 
will be submitted to Alliance Imaging Core Laboratory within 5 business days once the 
image acquisition is completed at site. BMP files, JPG files, or hard copies (films) are not 
acceptable. The raw data of the entire study should be saved until the scan is accepted by 
the Imaging Core Laboratory. The Imaging Core Lab will notify site and Alliance A031201 
imaging committee within 2 business days of the data receipt, and then, within 3 business 
days following the data receipt, of the quality check report.  

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7.0 
REQUIRED DATA 
Pre-Study Testing Intervals  
To be completed within 16 DAYS before registration: 
- All laboratory studies, history and physical 
To be completed within 28 DAYS before registration: 
- ECG, Chest CT or x-ray (CT is preferred); CT/MRI chest/abd/pelvis; and Bone imaging. PET scans are 
not allowed for tumor measurement.  
Evaluations may be performed +/- 3 days except for imaging and correlative substudies, for which a 7-day 
window is allowable. 
 
Prior to 
Registration 
Day 1 of each cycle and at 
end of treatment* 
Post Treatment 
Follow up** 
Tests & Observations 
 
 
 
History and Physical Exam 
X 
X 
X 
Pulse, Blood Pressure 
X 
X 
 
Height, Weight 
X 
 
 
Performance Status 
X 
X 
 
12-Lead ECG 
X 
 
 
BPI (Question 3 only) 
X 
 
 
Fatigue/Uniscale Assessment 
C 
 
 
Drug Toxicity Assessment  
 
X 
 
Opioid Analgesic Use Assessment 
X 
 
 
Laboratory Studies 
 
 
 
CBC, Differential, Platelets 
X 
X 
 
Creatinine, NA, K, glucose 
X 
X 
 
PSA 
A 
A 
 
Total Testosterone 
X 
 
 
AST/ALT, Alk. Phos., Bili 
X 
X (1) 
 
Albumin, LDH 
X 
 
 
Staging  
 
 
 
Chest CT (preferred); or Chest x-ray, PA & Lateral 
B 
B (2) 
X 
Bone Imaging*** 
X 
X (2) 
X 
CT or MRI abd/pelvis† 
X 
X (2) 
X 
Correlative studies‡ 
See Section 6.2. 
Blood samples 
* 
Pre-registration labs and H&P may be used for day 1 of cycle 1 tests if obtained within 16 days prior to day 1 of Cycle 1. 
For subsequent cycles labs may be obtained within 48 hours prior to day of treatment. 
**  Imaging must be repeated after the end of protocol treatment unless performed within the prior 4 weeks; then every 12 
weeks until progression or until 5 years after randomization, whichever comes first. After progression, follow the patient 
for survival and second malignancy every 6 months until death or 5 years after registration. 
*** Patients can obtain either sodium fluoride (NaF) PET/CT imaging or Tc-99 bone scintigraphy at the discretion of the 
treating physician. However, all follow-up bone imaging must be the same modality as the baseline modality.  
†  
Either diagnostic CT or MRI, however, follow-up studies should be the same modality as the baseline study. CT scan 
obtained as part of the NaF PET/CT does not substitute for the CT done for staging/response evaluation unless it is 
performed using standard diagnostic algorithms. 
‡ 
For patients who consent to each substudy. 
A 
PSA is to be collected at pre-registration, Day 1 of each cycle, and at end of treatment. Additional pre-registration PSA 
values are required for those patients demonstrating PSA progression for eligibility. The last PSA value recorded prior to 
the initiation of treatment will be considered the baseline PSA for this study. PSA will not be used for documenting 
progressive disease. No patient is to end treatment on the basis of a change in PSA only. 
B 
Chest imaging is required at baseline and at all restaging time points. Patients who have received a chest CT (or MRI) 
need not have a chest x-ray. Patients who have findings suspicious for metastatic disease on a chest x-ray at baseline 
should have a confirmatory CT of the chest at baseline. Patients who have findings suspicious for metastatic disease at 
baseline on CT should have CT scans at follow-up tumor assessments. 
C 
Within 21 days prior to registration (see Appendix I). 
1 
Arm A: Day 1 of each cycle. Arm B: For patients receiving abiraterone, every two weeks for the first 3 months of treatment, 
then Day 1 of each cycle. 
2 
Tumor assessments will be performed every 8 weeks for the first 6 cycles (i.e., weeks 9, 17, 25 +/- 1 week), then every 12 
weeks (i.e., weeks 37, 48, etc. +/- 1 week) from the initiation of treatment regardless of treatment interruptions or holds 
until the PCWG2 or RECIST criteria in Section 13.0 have been met. Note: Upload all radiology reports via the Supporting 
Documentation page associated with the current cycle folder in Medidata Rave® (See Section 6.1). 
 

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reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. 
Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. 
8.2.1 
Enzalutamide 
Patients will be instructed to take 160 mg enzalutamide by mouth daily, every 
morning. Enzalutamide should be taken as close as possible to the same time each day. 
Study patients will take four capsules of enzalutamide once daily. Enzalutamide can be 
taken with or without food.  
8.2.2 
Abiraterone  
Patients will be instructed to take 1000 mg Abiraterone daily, every evening. 
Abiraterone must be taken on an empty stomach. No food should be consumed for at least 
two hours before, and for at least one hour after the dose of abiraterone is taken. The tablets 
should be swallowed whole with water. 
8.2.3 
Prednisone:  
Patients will be instructed to take 5 mg p.o. twice daily, once in the morning and once 
in the evening. The dose of prednisone will be gradually reduced if clinically indicated. It 
is not required for the prednisone to be taken at the same time as enzalutamide and 
abiraterone. The dose of prednisone will remain unchanged in the event that the 
enzalutamide and/or abiraterone doses are changed.  
8.3 
Maintenance of castrate testosterone levels  
All patients who have not undergone an orchiectomy must be maintained on either a GnRH 
analogue or GnRH antagonist during treatment. 
8.4 
Bone protection 
Bisphosphonates or other approved bone-targeting agents for the treatment of metastatic 
prostate cancer should be maintained during the screening period and while actively being 
treated on the study regimen as clinically indicated for patients with bone metastases. 
 
 
 

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9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
The following general guidelines apply to all dose modifications listed below 
• 
Doses will not be re-escalated once reduced 
• 
If dose reduction below dose level -2 is required, treatment with that agent will be discontinued.  
• 
The dose of prednisone can be gradually reduced if clinically indicated. 
• 
If treatment is held for more than four weeks due to toxicity, discontinue protocol therapy 
• 
Each cycle is always 28 days regardless of dose interruption. (i.e., a 7 day interruption of a dose 
starting on day 15 of a cycle would mean that the dose is restarted on day 22 of the same cycle) 
Dose level table for enzalutamide  
 
Dose Level 
enzalutamide 
0 (starting dose) 
160 mg/day 
-1 
120 mg/day 
-2 
80 mg/day 
 
Dose level table for abiraterone  
 
Dose Level 
abiraterone  
0 (starting dose) 
1000 mg/day 
-1 
750 mg/day 
-2 
500 mg/day 
9.1 
Hepatic Toxicity 
For ≥ grade 3 ALT or AST or Bilirubin (see Investigations in CTCAE v. 4.0), interrupt 
enzalutamide and abiraterone. Check liver function labs weekly. Restart both enzalutamide and 
abiraterone at one dose level reduction when ALT, AST, and bilirubin recover to grade 1. 
Monitor serum transaminases and bilirubin every two weeks for three months and monthly 
thereafter.  
For hepatic failure (see Hepatobiliary Disorders in CTCAE v. 4.0), discontinue protocol 
therapy. 
9.2 
Neurologic toxicity 
Discontinue protocol treatment for any seizure. 
9.3 
Reversible posterior leukoencephalopathy syndrome (RPLS) 
For signs and symptoms suggestive of reversible posterior leukoencephalopathy syndrome 
(RPLS) such as confusion, headache, seizures, and cortical blindness, hold enzalutamide for up 
to 4 weeks. Suspected RPLS should be investigated with MRI. If diagnosis of RPLS is 
confirmed, enzalutamide should be permanently discontinued. If RPLS is ruled out via MRI and 
signs and symptoms attributed to another cause, enzalutamide should resume. If enzalutamide 
is held or permanently discontinued for RPLS, continue abiraterone and prednisone. 
9.4 
Other Non-Hematologic Grade 3 or 4 Toxicity  
For patients on both arms who experience a grade 3 or greater toxicity attributed to 
enzalutamide, enzalutamide should held for one week or until symptoms improve to ≤ grade 2. 
Patients may be re-started on enzalutamide at one dose level reduction. If treatment is held for 
more than 4 weeks, discontinue protocol therapy.  

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For patients on Arm B who experience a grade 3 or greater toxicity attributed to abiraterone, 
abiraterone should held for one week or until symptoms improve to ≤ grade 2. Patients may be 
re-started on abiraterone at one dose level reduction. If treatment is held for more than 4 weeks, 
discontinue abiraterone and continue enzalutamide. 
For non-hematologic grade 3 or 4 toxicity where the attribution to either abiraterone or 
enzalutamide cannot be determined, both drugs should be held for one week or until symptoms 
improve to ≤ grade 2. Patients may be re-started on abiraterone and prednisone at one dose level 
reduction. If appearance of previous toxicity does not reappear, then patients may be re-started 
on enzalutamide at one dose level reduction. 
10.0 CORRELATIVE STUDIES 
Correlative studies embedded in this trial will provide insights into sub-populations within the 
broader CRPC population that might optimally benefit from one of the specific treatment strategies 
being tested, as well as begin to define the processes at play at the time of development of resistance 
to these therapies. These studies will involve analyses of circulating androgen levels, microRNA, 
RNA profiles, and serum angiokine levels that will identify independent prognostic biomarkers of 
overall survival and progression-free survival in men with metastatic CRPC, as well as potentially 
predict for the benefit associated with combined enzalutamide/abiraterone therapy over single agent 
sequential therapy. These biomarkers will be associated with both AR-dependent and AR-
independent signaling pathways and are described briefly below. In addition, in collaboration with 
the Alliance Imaging Committee, the study contains an imaging correlative study of bone imaging 
by Tc-99 MDP or sodium fluoride F-18 (NaF) PET/CT imaging techniques, to develop optimized 
imaging prognostic and predictive biomarkers for castration-resistant metastatic disease.  
10.1 
Biomarker development/validation of technetium bone scintigraphy and sodium fluoride 
(NaF) PET/CT for CRPC 
10.1.1 Background and hypotheses 
Despite decades of use, bone imaging has never been developed as either a prognostic or 
predictive biomarker for prostate cancer. The Prostate Cancer Working Group 2 (PCWG2) 
criteria were formulated as a semiquantitative scale for examining post-treatment bone scan 
changes, with a standard definition for progression and a standard means of controlling for 
flare. The PCWG2 standard for defining progression is two new confirmed lesions, except 
during the early post-treatment period when flare may occur during which two new lesions 
must be followed by two additional lesions on the next scan to qualify for progression. 
PCWG2 is the first successful attempt to create a set of criteria for data collection and 
interpretation for the purposes biomarker development and clinical trial conduct. PCWG2 
criteria were standardized for reproducibility of imaging measurements but not necessarily 
optimized for biologic relevance and correlation with outcome. PCWG2 criteria, however, 
were developed using standard Tc-99 bone scintigraphy. Sodium fluoride (NaF) PET/CT 
imaging, however, is increasingly being used as routine bone imaging in the community. 
The potential advantages of NaF PET/CT bone imaging include the ability to quantitate 
the amount of tracer uptake in each lesion and of the patient’s disease burden, and more 
precise anatomic localization. Both Medicare and many private insurances are reimbursing 
for NaF PET/CT bone imaging. From a clinical trial standpoint, the imaging is integral to 
the conduct of the study, and the study will not dictate to the treating physician which type 
of bone imaging to order, but will leave the choice of Tc-99 or NaF PET/CT to the 
physician in accordance with his/her institutional or community standards. We anticipate 
that approximately 25% of the patients will undergo NaF PET/CT imaging. The imaging 
data will collected in real time and audited. Retrospectively, the optimal definitions of 

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progression and the optimal quantitative imaging biomarker for prediction and 
prognostication using NaF PET/CT or Tc-99 bone definition will be established, by 
comparing the imaging data with overall survival. 
We hypothesize that clinical bone imaging, integral to the conduct of the clinical trial for 
assessing eligibility and response, can be used to develop prognostic and predictive 
biomarkers for metastatic CRPC using optimized quantitative assessments. 
We hypothesize that the definitions of progression embedded in PCWG2 can be applied to 
NaF PET/CT, and that these definitions can be similarly optimized in order to serve as 
prognostic and predictive biomarkers. 
PCWG2 was developed with Tc bone scintigraphy as a standard. Clinicians are 
increasingly using NaF PET/CT without a reference database or analysis to associate these 
imaging findings with clinical outcomes, and that at present there is no plan other this 
proposal to associate and validate these findings. We do not know a priori which parameter 
of NaF PET/CT will most closely be prognostic or predictive.  
We hypothesize NaF PET/CT can be used to develop fully quantitative measures of tumor 
burden (such as MTV) or of bone activity (such as SUVmax), and these measures will be 
prognostic and that changes with treatment will be predictive. 
PCWG2 is only semi-quantitative in that it relies on lesion counting to establish disease 
progression. A major advantage of NaF PET/CT is that as a positron emitter, lesional 
uptake can be fully quantitated, which is not routinely possible with Tc bone scintigraphy. 
These quantitative measures of baseline bone activity and disease burden at baseline and 
after treatment, offer the potential to create prognostic and predictive models for survival, 
which previously were not possible with imaging data. 
At the same time, such questions apply to Tc bone scanning as well. However, NaF 
PET/CT and Tc bone scanning are different technologies and measure different biologic 
processes. They cannot be compared head to head. We hypothesize that the basic measure 
of burden will be prognostic and predictive and will therefore examine lesion number, and, 
if feasible, bone scan index. 
10.1.2 Objectives 
To assess pre- and post-treatment measures of tumor burden and bone activity using NaF 
PET/CT and Tc bone scintigraphy and correlate these measures with overall survival. 
10.1.3 Methods 
A. Image acquisition: Patients in this study must undergo bone imaging in order to 
establish eligibility criteria for this trial, and further, they will undergo bone imaging as 
part of standard response assessments at regularly scheduled intervals (Every 8 weeks for 
the first 6 cycles, then every 12 weeks). The patient’s treating physician will order the type 
of bone imaging that represents standard practice at their institution. These scans may 
either be NaF PET/CT or traditional technetium bone scintigraphy. According to current 
practice, we anticipate that 25% of these will be NaF PET/CT and 75% will be bone 
scintigraphy.  
Individual sites will perform the imaging studies and investigators will complete the 
specialized CRF that incorporates PCWG2-dictated data capture. In close collaboration 
with the Alliance Imaging Committee, under the leadership of Dr. Lawrence Schwartz, and 
in conjunction with the Alliance imaging core facility, we will collect in real time the 
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elements. The image acquisition quality of the bone imaging will be performed in real time. 
The accuracy of the response assessments will be audited by an expert panel in real time.  
B. Analysis of PCWG2 progression criteria and optimizing the definition of 
progression to predict for survival: We will compare PCWG2 definition of progression 
with alternative imaging definitions of progression on both NaF PET/CT and technetium 
bone scintigraphy. These alternate definitions of progression will include, but may not be 
limited to, differing lesion numbers to define progression, the need for confirmatory scans, 
and quantitative measures of tumor burden. 
C. Analysis of quantitative imaging assessments of NaF PET/CT and Tc bone 
scintigraphy as measured by: 
i. 
For NaF PET/CT we will analyze SUVmax, SUVmaxavg, SUV peak, metabolic tumor 
volume, and other parameters to determine which of these best associates with survival 
as a baseline prognostic biomarker and the change analysis as a dynamic post-treatment 
predictive parameter.  
ii. For bone scintigraphy, we will examine lesion number, skeletal distribution, and bone 
scan index as a prognostic and predictive biomarker. 
iii. For both studies, we will examine flare on the first post-treatment scan as a potential 
positive prognostic biomarker. 
10.1.4 Statistical design 
One of the two main objectives is to test whether rPFS defined per PCWG2 at 6 months 
will predict overall survival.  
Using the data from COU-302, rPFS rates at 3-months and at 6-months in patients treated 
with AA plus prednisone are estimated to be 98% and 80%, respectively. Thus, the 
landmark at 6 months is chosen based on the bone scan assessment and clinical relevance. 
We do not know the proportion of rPFS rate at 6 months in patients treated with 
enzalutamide plus/or minus AA, but it will be assumed to be the same as in COU-302. It 
is expected that 25% of the patients will undergo NaF/PET scan imaging and the remaining 
75% will undergo scan using the standard Tc-99. It is assumed that the hazards of death in 
institutions where patients will undergo NaF/Pet scan will be the same as institution where 
the patients will undergo Tc-99 scan. For simplicity in the power computation, rPFS rate 
at 6 months will be used as a binary variable. We do not know the number of deaths among 
the patients who will undergo either NaF/Pet or Tc-99 bone scan. A total of 616 deaths are 
expected at the end of the trial and rPFS at 6 months is 80%. Accounting for censoring and 
deaths before 6 months, it will be assumed that there are 129 deaths and 385 deaths for 
patients undergoing NaF/PET scan and Tc_99, respectively.  
The table below provides the minimum hazard ratio detectable, assuming power of 0.80, 
and proportion of radiographic progression at 6-months ranging from 0.20-0.35, a two-
sided type I error rate of 0.05, and 129 and 385 patients undergoing NaF/PET and Tc-99, 
respectively for the NAF/PET and Tc-99 imaging modalities.  
 
 

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Proportion who progress 
radiographically at 6-months 
NaF/PET 
(129 deaths) 
Tc-99 
(385 deaths) 
0.20 
1.88 
1.42 
0.25 
1.79 
1.39 
0.30 
1.74 
1.36 
0.35 
1.69 
1.34 
Table 1 
In addition, the other main objective is to test for treatment-rPFS interaction using 
NAF/PET and Tc-99 scans in predicting overall survival.  
The sample size for this study is 1,224 patients. Power calculations based on testing 
treatment by rPFS at 6 months using NaF/PET scans interaction is provided in the table 
below and will be exploratory. It is assumed that the OS distribution follows an exponential 
distribution, an accrual rate of 306 patients (25% of 1,224 patients) over 36-months period, 
and 24 months post-accrual follow-up. Adequate power will be detected for only large 
interactions terms. The table below presents the power for testing the null of no treatment 
by rPFS interaction using a two-sided type I error rate of 0.05. Let ∆1 and ∆2 be the hazard 
ratios for treatment effect within patients who do not (non-progressors) and do progress 
(progressors) radiographically at 6-months, respectively. The assumed median OS is 33 
months for the enzalutamide arm. No discrepancy in OS distributions of the non-
radiographic progressors and radiographic progressors at 6-months is expected for this 
treatment arm.  
 
Proportion of patients who progress 
radiographically at 6-months by 
NaF/PET scans 
∆1 
∆2 
∆ 
Power 
0.25 
1.2 
3.0 
2.5 
0.67 
 
1.2 
3.5 
2.9 
0.78 
 
1.2 
3.6 
3.0 
0.80 
0.30 
1.2 
3.0 
2.5 
0.70 
 
1.2 
3.5 
2.9 
0.82 
 
1.2 
3.6 
3.0 
0.83 
Table 2 
In addition, power calculations based on testing treatment by rPFS at 6 months interaction 
using the Tc-99 scans is provided in the table below and will exploratory because of the 
limited sample size. It is assumed that the OS endpoint follows an exponential distribution, 
an accrual rate of 918 patients (75% of 1,224 patients) over 36-months period, and 24 
months post-accrual follow-up. Adequate power will be detected for moderate to large 
interactions terms. The table below presents the power for testing the null of no treatment 
by rPFS interaction using a two-sided type I error rate of 0.05. Let ∆1 and ∆2 be the hazard 
ratios for treatment effect for non-progressors and progressors at 6 months, respectively. 
The assumed median OS is 33 months for the enzalutamide arm. No discrepancy in OS 
distributions of the non-radiographic progressors and radiographic progressors at 6-months 
is expected for this treatment arm.  
 

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Proportion of patients who 
progress radiographically at 6 
months by Tc-99 scans 
∆1 
∆2 
∆ 
Power 
0.25 
1.2 
2.0 
1.7 
0.67 
 
1.2 
2.1 
1.7 
0.74 
 
1.2 
2.2 
1.8 
0.80 
0.30 
1.2 
2.0 
1.7 
0.71 
 
1.2 
2.1 
1.7 
0.78 
 
1.2 
2.2 
1.8 
0.84 
Table 3 
Data Analysis for imaging objectives 
The proportional hazards model will be used to assess whether the rPFS rate at 6 months 
as defined by the PCWG2 will predict overall survival. In addition, the PH model will be 
used to test for treatment by rPFS rate at 6-month interaction. If there is a suggestion that 
there are treatment by rPFS interactions, then the estimates of HR and 95% CI will be 
presented separately within each treatment group. 
Exploratory analyses will be performed with the proportional hazards model will be used 
to assess the prognostic importance of SUVmax, SUVmaxaveg, SUVpeak, metabolic 
tumor volume, and other parameters as predictors of overall survival. Potential markers 
will be identified based on their associations with PFS where the c-index will be the 
primary measure of predictive discrimination. The c-index will be used to compare whether 
the predictions of rPFS at 6 months from NaF/PET scans will be higher than the standard 
Tc-99 scans. 
Exploring the association between rPFS and OS is a complex problem. Part of the difficulty 
of assessing this relationship is that both endpoints are time to event outcomes with 
censoring. This is statistically challenging because of issues related to interval censoring 
and informative censoring. The problem is simplified by assuming that there is no 
informative censoring and thereby we can apply the Kendall tau to explore the relationship 
between OS and rPFS rate at 6 months. 
10.2 
Serum Androgen Levels 
Validation Study of the Prognostic and Predictive Significance of Baseline and on-
Treatment Serum levels of Testosterone, DHEA and Androstenedione 
10.2.1 Background and specific hypotheses 
Patients with higher baseline androgens treated with abiraterone/enzalutamide have a 
superior median survival than patients with a similar androgen level who are treated with 
enzalutamide alone This hypothesis is based on need to validate the observations made in 
patients treated with abiraterone versus placebo on the COU-301 study in which all three 
androgens (testosterone, DHEA and androstenedione), when stratified at the median, were 
associated a difference in survival. For example the hazard ratio for survival was 0.64 
(<0.0001) comparing high versus low testosterone in abiraterone treated patients. In 
placebo treated patients the hazard ratio was 0.51 (p=0.0004) suggesting that even in 
patients who did not receive abiraterone therapy that there is a prognostic importance of 
baseline androgen levels. However, a caveat with that study was that the control arm 
received both placebo and prednisone, and prednisone is associated with modest reductions 
in androgens, therefore it is not possible to conclude that baseline androgen levels are 
completely independent of therapy, as all patients in that trial received some form of 

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androgen reduction therapy. The current study will compare both abiraterone/ 
enzalutamide treated patients to those who receive enzalutamide alone allowing for the 
opportunity to test whether OS is impacted to a similar extent in patients who are not treated 
with an agent that lowers androgen levels. Prospective validation of the data from the 
abiraterone versus placebo data will serve to determine if future studies with androgen 
synthesis inhibitors and androgen receptor antagonists will require stratification on the 
basis of androgen levels in addition to confirming that this statistical association exists in 
the pre-chemotherapy setting as well as in the post chemotherapy setting.  
Reduction in androgen levels during treatment with Abiraterone/enzalutamide therapy to 
undetectable levels is associated with higher proportions of PSA response, longer 
progression free survival than in patients treated with enzalutamide monotherapy. Data 
from the randomized placebo controlled trial of abiraterone and prednisone compared to 
prednisone and placebo demonstrated that abiraterone therapy leads to a reduction in 
average serum androgen levels for the treated population and to undetectable levels in a 
large proportion of patients, and that this is associated with PSA decline. Despite this 
association it was observed that there were patients who experienced a PSA decline while 
on abiraterone who did not experience a decline in serum androgens to undetectable levels 
and there were others who experienced a significant decline in androgens who did not 
experience a 50% decline in PSA. Subsequent analyses have confirmed that androgen 
decline occurs as a continuous variable. In this analysis we will determine the associations 
between treatment arms, change in androgen on treatment, and clinical outcome.  
10.2.2 Objective 
To determine whether pre-treatment serum adrenal androgen (SA) levels are prognostic 
factors of overall survival and to test whether SA levels are predictive factors of overall 
survival. 
10.2.3 Methods 
Serum androgen levels will be measured during screening and will be measured by Liquid 
Chromatography/Mass Spectroscopy. Subsequently serum androgen levels will be 
measured after 8 weeks on therapy to determine the change in androgen levels over time. 
Androgen quantification will be performed by Esoterix incorporated, who has performed 
a similar analysis on COU-301, a phase III study of abiraterone/prednisone versus 
placebo/prednisone.  
10.2.4 Statistical design: 
The primary objective is to test and validate the prognostic significance of SA in predicting 
of overall survival in men with CRPC. We expect to have 75% available serum samples of 
patients who will consent to their specimen being used for this objective. We do not know 
the number of deaths among patients with anticipated samples, but it will be assumed to be 
462 deaths (75% of 616 deaths the target deaths). The samples will be randomly divided 
into training (n=308 deaths) and testing (n=154 deaths) datasets. Using the training dataset, 
we will test if SAs will predict OS. For simplicity in the power computation, SA levels will 
be dichomotized at the median value and patients will be classified as having low (below 
or equal to the median value) or high (above the median) levels. Assuming that the OS 
follows an exponential distribution, 308 deaths, a two-sided type-I error rate of 0.0167 (= 
0.05/3), power = 0.80, and prevalence of 0.50, the minimum detectable hazard ratio is 1.44. 
Data Analysis: The Kaplan-Meier product-limit approach will be used to estimate the OS 
and PFS distributions. In addition, the proportional hazards (PH) model will be used for 
assessing the prognostic significance of SA for predicting OS. Furthermore, the PH model 

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will be used to assess the prognostic importance of SAs in predicting OS adjusting on 
treatment arm, baseline characteristics and stratification factors.  
Moreover, stratified PH regression models will be performed to test for treatment-SA 
biomarker interaction. Estimates of HR of OS (and 95% CI of the HRs) will be presented 
separately within each treatment arm if there is a suggestion that there is a treatment-SA 
interaction. Using the testing dataset, the time-dependent area under the curve (tAUC) will 
be computed as a measure of prognostic discrimination and the 95% CI will be computed 
by the bootstrapped approach. In addition, the PH model will be used to assess whether 
changes in SA at 8-weeks from baseline are associated with OS. 
10.3 
Development and validation of a circulating RNA profile as a prognostic and predictive 
biomarker of AR-targeted therapy in men with CRPC 
10.3.1 Background and hypothesis 
Circulating tumor cells are known to be prognostic in metastatic CRPC and multiple other 
tumor types.24-26 However, their utility requires human pathology review and real time 
analysis (i.e. < 72 hours) and is expensive and not readily exportable to community sites. 
In addition, the currently FDA-approved methodology for CTC capture and enumeration 
(Veridex Cellsearch method) relies on EpCAM expression in circulating tumor cells and 
CTCs are not reliably detected in over 50% of men with docetaxel-naïve metastatic 
CRPC.27 More sensitive methods for CTC detection that are exportable, simple, and have 
less subjective variability are needed. In addition, we have shown that men with metastatic 
CRPC have CTCs that co-express stem cell-like biomarkers such as CD133 and epithelial-
mesenchymal transition (EMT) biomarkers such as N and O cadherin and vimentin, 
suggesting that these CTCs may have a variety of phenotypes that may be variably sensitive 
to targeted therapies.28 It has been demonstrated that androgen-deprivation therapy (ADT) 
leads to induction of EMT and stem cell-like biomarkers in prostate cancer cell lines, 
xenografts, and patient specimens, and may thus be a mechanism of ADT resistance and 
CRPC progression.29 In addition, the development of a stable RNA profile that is able to 
associate with prognosis to the same degree or better than the current FDA approved 
Cellsearch assay would be a significant advance that may also permit biologic insight into 
mechanisms of tumor progression. 
We have also developed and validated a multiplex PCR based assay for PAXgene samples 
that detects CTC RNA in patients with favorable (4 or fewer cells/7.5 mL of blood) CTC 
counts using the Veridex CellSearch assay. The assay is currently being evaluated on 
samples from patients enrolled on trials of abiraterone and enzalutamide. The results will 
enable more precise estimates of the number of samples needed to explore associations 
with prognosis at baseline and following treatment with these agents. Potential predictive 
markers are also under study. We will evaluate this multiplex assay in the current trial as 
both a prognostic and predictive biomarker. In addition, whole blood RNA biomarker 
panels (6 and 9 gene) that have been developed and externally validated in men with 
mCRPC will be analyzed in this trial for similar prognostic and predictive value using the 
same PAXgene samples.33,34 
Linuma et al., have developed and validated an rtPCR-based strategy for the detection of 
cytokeratin (CK) + CD133+ CEA + CTCs from the whole blood of colorectal cancer 
patients undergoing adjuvant therapy.30 This stem-like CTC biomarker was highly 
prognostic in this setting and validated in several external data sets. RTPCR for PSA has 
been validated in CRPC and the evaluation of CK+/PSA+/CD133+ expression in whole 
blood from patients is thus feasible.31 Finally, prostate stem cells have been shown to 
express CD133 in preclinical models, suggesting that this biomarker may be an indicator 

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of stemness in prostate cancer stem cells, linking stemness to prostate growth and treatment 
resistance.28, 30-32 We will test this RNA profile and other validated RNA profiles in 
mCRPC33, 34 in a test dataset within this trial and validate their prognostic and predictive 
role in the entire available trial dataset. For the nine-gene and six-gene signatures, we 
hypothesize that the high risk predictive population identified by these biomarkers will 
have a poor prognosis in this trial, but will also be predictive of the benefit of combination 
abiraterone/enzalutamide therapy over single agent therapy. 
We hypothesize that high levels of CK+/PSA+/CD133 (circulating prostate cancer stem 
cell (CSCs) biomarker levels) and other RNA profiles associated with prostate cancer will 
be adversely prognosis in men with metastatic CRPC from each arm and have a shorter 
time on study drug (shorter PFS and OS). We hypothesize that high levels of CSCs will be 
predictive of the benefit of combination enzalutamide/abiraterone over enzalutamide alone, 
given that these patient will have a poorer prognosis that will be improved with more 
aggressive combination therapy.  
10.3.2 Objectives 
• 
To evaluate specific pre-treatment RNA levels as prognostic factors for OS, including 
the 6- and 9-gene signatures, the CTC RNA profile, and the circulating tumor stem cell 
RNA profile. 
• 
To evaluate the predictive ability of specific pre-treatment and post-treatment RNA, 
levels on OS and PFS.  
10.3.3 Methods 
Duplicate baseline, cycle 3, and progression blood samples for rtPCR analysis of 
circulating tumor RNA will be collected with 2.5 mL PAXgene tubes and stored and 
analyzed for both prognostic and potentially predictive value. Thus a total of 6 PAXgene 
tubes will be collected per patient on this study. [See Section 6.2.2 for PAXgene sample 
collection and submission procedures.] 
An independently run 40-sample pilot feasibility study using whole blood from existing 
studies in CRPC will be performed to evaluate the reliability and ranges for the circulating 
CTC stem cell assay in CRPC and establish values that will permit estimates for sample 
size calculations and power estimates for the larger development and validation cohorts 
within this trial. In these 40 subjects, the duplicate samples at baseline and each time point 
will be collected and analyzed for an association with outcome. Several indicators of 
reproducibility will be computed; such as coefficient of variation, correlation coefficient, 
limits of agreement, and the Bland-Altman plots. If the correlation coefficient between the 
replicates is at least 0.9, then the assay will be considered “reproducible.” However, if the 
correlation coefficient is less than 0.90, the study team will discuss how to proceed with 
these assays. Recommendations may include modifying the assay, or training the 
laboratory personnel who are performing these assays. The reproducibility rates will be 
reported at the end of the study. 
External validation of this cancer stem cell and circulating tumor RNA biomarker in the 
current trial is planned, evaluating both prognostic and predictive associations.  
Extraction of total RNA and cDNA synthesis will be performed as a batch using primers 
established against known prostate cancer, EMT, and stemness genes (PSA, CK, CD133, 
others). The expression of PSA, CK19, CK20, and CD133mRNA of blood samples will be 
examined; target genes of CTCs and glyceraldehydes-3-phosphate-dehydrogenase 
(GAPDH) mRNA were used as internal control genes. The expression levels of these 
mRNA were measured by real-time quantitative RT-PCR. All baseline samples will be 

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measured in duplicate. The levels of PSA, CK19, CK20, and CD133 mRNA will be 
normalized by GAPDH mRNA and their association with outcomes will be performed. 
mRNA profiles validated in CRPC will also be tested at baseline for prognostic 
associations with PFS and OS as well as predictive of PFS and OS in the current trial.33, 34 
10.3.4 Statistical design: 
The primary objective is to identify and validate the prognostic significance of CSC RNA 
profile in predicting overall survival in men with mCRPC. We expect to have 75% 
available RNA PAXgene samples of patients who will accept that their specimen be used 
for this objective. We do not know the number of deaths among patients with anticipated 
samples, but it will be assumed to be 462 deaths (75% of 616 deaths). The samples will be 
randomly divided into training stratified by deaths (n=308 deaths) and testing (n=154 
deaths) datasets. Using the training dataset, we will test if CSCs predict OS. For simplicity 
in the power computation, RNA expression will be dichotomized at the median value and 
patients will be classified as having low (below or equal to the median value) or high (above 
the median) levels. Assuming that OS follows an exponential distribution, 308 deaths, a 
two-sided type-I error rate of 0.0125 (type I error rate = 0.05/4 biomarkers), power = 0.80, 
and prevalence of 0.50, the maximum detectable hazard ratio is 1.46. 
Data Analysis: The Kaplan-Meier approach will be used to estimate the OS and PFS 
distributions. In addition, the proportional hazards (PH) model will be used for assessing 
the prognostic significance of individual RNA biomarker for predicting OS. The PH model 
will be used to assess the prognostic importance of individual RNA in predicting OS 
adjusting on treatment arm, baseline characteristics and stratification factors.  
Moreover, stratified PH regression models will be performed to test for treatment-RNA 
biomarker interaction. Estimates of HR of OS (and 95% CI of the HRs) will be presented 
separately within each treatment arm if there is a suggestion that there is a treatment-RNA 
biomarker interaction. Using the testing dataset, the time-dependent AUC as a measure of 
prognostic discrimination will be computed and the 95% CI for the time-dependent AUC 
will be computed by the bootstrapped approach. 
10.4 
Development and validation of a circulating microRNA profile as a prognostic and 
predictive biomarker of AR-targeted therapy in men with CRPC 
10.4.1 Background and hypothesis 
Circulating microRNA provide a robust potential prognostic and predictive biomarker.35 
Our group has recently developed and validated a fluid-capillary, quantitative polymerase 
chain reaction (qPCR) platform to robustly measure circulating microRNA from the serum 
of men with prostate cancer.36 In this study, patterns of circulating microRNA were found 
to be associated with the presence of prostate cancer and, importantly, distinguished 
between low and high risk localized prostate cancer based upon the CAPRA scoring 
system.36 In castration resistant prostate cancer, persistent AR activity despite low levels of 
circulating testosterone is a common mechanism driving persistent growth.37,38 The 
common dependence on persistent AR activity likely explains the success of drugs such as 
abiraterone.39 and enzalutamide40 in castration resistant prostate cancer. However, not all 
patients with metastatic castration resistant prostate cancer have a sustained response to 
these agents (Median time to progression is about 4 months with abiraterone) and 
biomarkers that anticipate the dependence of a tumor on persistent AR activity may 
improve our ability to choose the most appropriate treatment for patients in a timely 
manner. While PSA is androgen regulated, it has been found insufficient as a predictive 
biomarker for hormonal therapy in prostate cancer. Similarly, circulating adrenal 

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androgens are associated with prognosis in men with mCRPC who receive abiraterone and 
were found to be predictive to response to ketoconazole in a CALGB correlative study,41 
they do not have sufficient specificity and sensitivity to be used to guide therapy.  
Specific microRNAs are known to both control AR activity (e.g. Let-7 microarray family)42 
and others are known to be regulated by AR (such as miR-101 and miR-21).43,44 
Importantly, Let-7 family members have been found to antagonize self-renewal in stem 
cells and higher levels may not only impact AR activity but impact the ability of mCRPC 
to adapt during enzalutamide with or without abiraterone by manifesting stem cell-like 
characteristics. These microRNAs are reliably detected in the serum of men with prostate 
cancer36 and we will test the hypothesis that pre-treatment and dynamic levels of AR 
associated microRNAs will be predictive for response to enzalutamide and/or the 
combination of enzalutamide and abiraterone.  
Specific hypotheses: Patients with high levels of androgen-regulated miRNA will have 
greater benefit from AR targeted therapy. 
We hypothesize that: 
1) Patients with circulating levels of miR-21 that are above the median of expression for 
men with mCRPC will have a greater benefit from enzalutamide and enzalutamide + 
abiraterone than patients with circulating levels of miR-21 below the median. 
2) Patients with circulating levels of miR-101 that are above the median of expression for 
men with mCRPC will have a greater benefit from enzalutamide and enzalutamide + 
abiraterone than patients with circulating levels of miR-101 below the median. 
3) Patients with circulating levels of Let-7 miRNA family members that are above the 
median of expression for men with mCRPC will have a greater benefit from 
enzalutamide and enzalutamide + abiraterone than patients with circulating levels of 
Let-7 miRNA family members below the median. 
10.4.2 Objectives 
• 
To evaluate specific pre-treatment microRNA levels as prognostic factors for OS. 
• 
To test whether the microRNA are predictive factors for overall survival. 
10.4.3 Methods 
[See Section 6.2.2 for serum sample collection and submission procedures.] 
Thaw a single 500 μL sample on ice and mix 300 μL with an equal volume (300 μL) of 2X 
Denaturing Solution (at room temperature); re-freeze and store the residual 200 μL. 
Additional aliquots of serum may be used if the yield of RNA is too low. Follow the 
MirVana PARIS Kit manufacturer's protocol as previously published [Mitchell et al, 2008]. 
Concentrate RNA using Microcon reservoirs; elute into 20 μL final volume. Perform the 
reverse transcription (RT) with MMLV-RT and reverse stem-loop primers to amplify 
specific 
microRNA 
species 
(List 
of 
primers 
can 
be 
found 
at 
http://urology.ucsf.edu/blellochlab/protocols.htm). Pre-Amplification is necessary to 
enhance signal strength and the input RNA level determines the optimal number of Pre-
PCR cycles. Using serum as starting material, 12 cycles results in detectable miRNA levels, 
but 15 cycles appeared to be superior. For our protocol, we will use 15 cycles of pre-
amplification 
using 
previously 
developed 
primers 
(Forward 
primers 
at 
http://urology.ucsf.edu/blellochlab/protocols.htm). Product from the 15 cycles is gel 
purified, re-extracted, and purified after gel extraction with MinElute columns. Final eluted 
volume is 10 μL in DEPC treated water. The 10 μL is then used to assay microRNA levels 
with the Fluidigm 96.96 qRT-PCR Profiling platform. After samples are loaded onto the 

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chip it is placed in the BioMark system for amplification and analysis. After RT- PCR the 
proprietary software provides amplification curves, heat maps and Ct values for each well. 
A detailed protocol including all steps is provided in Moltzahn et al., J Vis Exp (2011); 
54:2552. 
10.4.4 Statistical design 
The primary objective is to test and validate the prognostic significance of microRNA in 
predicting of overall survival in men with CRPC. We expect to have 75% available serum 
samples of patients who will accept that their specimen be used for this objective. We do 
not know the number of deaths among patients with anticipated samples, but it will be 
assumed to be 462 deaths (75% of 616 deaths the target deaths). The samples will be 
randomly divided into training (n=308 deaths) and testing (n=154 deaths) datasets. Using 
the training dataset, we will test if microRNA predict OS. For simplicity in the power 
computation, microRNA will be dichotomized at the median value and patients will be 
classified as having low (below or equal the median value) or (above the median) levels. 
Assuming that OS follows an exponential distribution, 308 deaths, a two-sided type-I error 
rate of 0.0167, power = 0.80 and prevalence of 0.50, the minimum detectable hazard ratio 
is 1.44. 
In addition, power calculations based on testing micro-RNA treatment interaction is 
provided in Table 4, below, and will be exploratory because of the limited sample size. It 
is assumed that the OS endpoint follows an exponential distribution, and accrual rate of 
1224 patients over a 36-month period, and 24-month post-accrual follow up. Adequate 
power will be detected for moderate to large interactions terms. Table 4 presents the power 
for testing the null of no treatment by micro-RNA interaction using a two-sided type I error 
rate of 0.05 and assuming positive marker prevalence of 50% (since the micro-RNA is 
dichotomized at the median). The assumed median OS is 36 months for Arm A. No 
discrepancy in OS distributions is expected for this arm. 
 
∆1 
∆2 
∆ 
Power 
0.5 
1.2 
2.0 
1.7 
0.42 
 
1.2 
2.1 
1.8 
0.50 
 
1.2 
2.2 
1.8 
0.57 
 
1.2 
3.0 
2.5 
0.84 
 
1.2 
3.3 
2.9 
0.96 
Table 4 
Data Analysis: The Kaplan-Meier approach will be used to estimate the OS and PFS 
distributions. In addition, the proportional hazards (PH) model will be used for assessing 
the prognostic significance of individual microRNA for predicting OS. The PH model will 
be used to assess the prognostic importance of individual microRNA in predicting OS 
adjusting on treatment arm, baseline characteristics and stratification factors.  
Moreover, stratified PH regression models will be performed to test for treatment-
microRNA interaction. Estimates of HR of OS (and 95% CI of the HRs) will be presented 
separately within each treatment arm if there is a suggestion that there is a treatment-
microRNA interaction. Using the testing dataset, the tAUC as a measure of prognostic 
discrimination will be computed and the 95% CI for the tAUC will be computed by the 
bootstrapped approach. 
 
 

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10.5 
Analysis and Confirmation of Prognostic Blood-based Angiokine Biomarkers in Men with 
Metastatic Castration-Resistant Prostate Cancer  
10.5.1 Background and hypothesis 
Evolving data strongly suggests that genetic alterations within the tumor epithelium, as 
well as variations in host microenvironment factors in the setting of chronic castration, lead 
to prostate cancer progression through multiple divergent biologic pathways. Serum and 
plasma prognostic factors may help to identify subgroups of metastatic castration-resistant 
prostate cancer (CRPC) with prognostic significance. In prior CALGB studies we have 
identified plasma vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), 
chromogranin A (CgA), and hepatocyte growth factor (HGF) to have independent 
prognostic significance.46-49 In particular, these factors are part of a larger set of angiogenic 
and cytokine factors that may play an important role in the prognosis of CRPC, independent 
of the testosterone – androgen receptor (AR) signaling axis.  
Recently, multiplex ELISA approaches have been utilized for the analysis of a broader 
array of plasma and serum of cancer patients. Compared to tumor biopsies, analyses of 
blood samples have the marked advantages of minimal risk, greater convenience, reduced 
cost, universal availability in clinical trials, and the ability to be collected at multiple time-
points, including before treatment and along the continuum of disease response and 
progression. Building off of our previous studies, we have performed broad analysis of 32 
angiogenic and cytokine analytes in 2 cooperative group studies (CALGB 80303 and 
CALGB 90206) with plans to run samples across our recently completed Phase III study 
in patients with mCRPC (CALGB 90401) to identify potential prognostic analytes for 
overall survival in patients receiving either docetaxel/prednisone/bevacizumab or 
docetaxel/prednisone.50  
Angiokine and cytokine analytes have independent prognostic significance in patients with 
mCRPC, independent of androgen and AR inhibition.  
10.5.2 Objectives 
• 
To determine whether pre-treatment angiokine levels are prognostic factors for OS and 
PFS. 
• 
To test whether pretreatment angiokine levels are predictive factors for OS and PFS 
and to assess whether post-treatment angiokine levels are predictive factors for OS and 
PFS. 
10.5.3 Methods 
Proposed analytes: These cover multiple categories of angiogenic factors: VEGF family 
members, non-VEGF classical angiogenic factors, inflammatory factors, stromal factors, 
and coagulation factors as shown in the following Table below. Overall, assays had 
excellent sensitivity and low variability. Several factors were highly prognostic for 
outcome in general, including IGBP-1, ICAM-1, Ang-2, CRP, IL-8, TSP-2, VCAM-1, 
PAI-1 active, IGF-1, and IL-6.  
Assay: From a quality control standpoint, our multiplex array has been optimized for use 
in cancer patients and utilizes the SearchLight® multiplex ELISA platform (Aushon 
Biosystems, Inc.). This novel multiplexing technology allows for the measurement of up 
to 16 different analytes simultaneously in a single microplate well. The assay design is 
similar to a sandwich ELISA where the capture antibodies are pre-spotted into individual 
wells of a 96-well plate. We have developed the current profile via extensive collaboration 
with Aushon, both in the selection of important angiogenic factors and in the technical 

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validation of the assay in plasma of cancer patients. All plate designs have already been 
validated in order to 1) limit cross-reactivity of the antibodies 2) optimize sensitivity and 
specificity and 3) maximize the linearity of the assay’s dynamic range. Any study samples 
that fall outside the linear portion of the standard curve are retested. Samples that read 
below the limit of detection are retested, if possible. Samples that read above the linear 
portion of the standard curve are serially diluted and retested to obtain accurate 
measurements. Any analyte that does not meet the aforementioned criteria will result in the 
sample being re-evaluated.  
 
Soluble angiogenic 
Factors 
Matrix-derived 
Angiogenic Factors 
Markers of 
Coagulations 
Markers of vascular 
activation and 
Inflammation 
bFGF 
TGFb1 
PAI-1 Active 
Gro-a 
HGF 
TGFb2 
PAI-1 Total 
IL-6 
PlGF 
Osteopontin 
CRP 
IL-8 
VEGF-A 
BMP9 
 
P-selectin 
VEGF-C 
TSP2 
 
SDF-1b 
VEGF-D 
PEDF 
 
ICAM-1 
ANG-2 
sEndoglin 
 
VCAM-1 
PDGF-AA 
 
 
MCP-1 
PDGF-BB 
 
 
 
IGFBP1 
 
 
 
IGFBP2 
 
 
 
IGFBP3 
 
 
 
sVEGFR1 
 
 
 
sVEGFR2 
 
 
 
Table 5: Angiogenic and Cytokine factors 
10.5.4 Statistical design 
The primary objective is to identify and validate the prognostic significance of analytes in 
predicting overall survival in men with CRPC. We expect to have 75% available plasma 
samples of patients who will accept that their specimen be used for this objective. We do 
not know the number of deaths among patients with anticipated samples, but it will be 
assumed to be 462 deaths (75% of 616 deaths). The samples will be randomly divided into 
training (n=308 deaths) and testing (n=154 deaths) datasets. Using the training dataset, we 
will identify analytes that significantly predict OS. For simplicity in the power 
computation, analyte levels will be dichotomized at the median value and patients will be 
classified as having either low (below or equal to the median value) or high (above the 
median) levels. Assuming that OS follows an exponential distribution, 308 deaths, a two-
sided type I error rate of 0.00125 (type I error rate = 0.05/40), power = 0.80, and prevalence 
of 0.50, the minimum detectable hazard ratio is 1.59. 
The primary objective of the prognostic studies will be to explore the association of 
angiokine biomarker levels with overall survival, and secondary endpoints will be 
progression-free survival. The Kaplan-Meier product-limit approach will be used to 
estimate the OS and PFS distributions. In addition, the proportional hazards (PH) model 
will be used for assessing the prognostic value of individual and combination blood 
analytes for predicting OS. The PH model will be used to assess the prognostic importance 

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of individual and combination analytes in predicting OS adjusting on treatment arm, 
baseline characteristics and stratification factors.  
Moreover, PH regression models will be performed to test for treatment-analyte interaction 
in predicting overall survival. As a first step, models with individual analytes will be 
considered. The interaction terms for treatment analytes that have p-values less than 0.10 
will be jointly modeled adjusting for treatment and stratification factors. Estimates of HR 
of OS (and 95% CI of the HRs) will be presented separately within each treatment arm if 
there is a suggestion that there is a treatment-analyte interaction. The parameter estimate 
from the final model will be applied to the testing set and the tAUC as a measure of 
prognostic discrimination will be computed and the 95% CI for the tAUC will 
bootstrapped. 
10.6 
To develop and validate prognostic and predictive models of overall survival and will 
include baseline clinical and molecular markers.  
Currently, there are three prognostic models of overall survival that have been developed and 
validated in chemotherapy naïve patients.51-53 The CALGB model is developed in a large multi-
center cohort and was based on 760 patients enrolled on six trials, and identified seven variables: 
LDH, PSA, alkaline phosphatase, hemoglobin, performance status, presence of visceral disease 
and Gleason score. The model developed by Smaletz et al. was based on data from 409 men 
treated at the Memorial Sloan Kettering Cancer Center and also identified seven prognostic 
factors: age, Karnofsky performance status, LDH, albumin, alkaline phosphatase, and 
hemoglobin. Armstrong and colleagues developed and validated a prognostic model that was 
based on the TAX 327 trial. In addition to the known prognostic factors, they identified pain, 
PSADT, liver metastases and number of metastatic sites as independent factors of OS. 29 It is 
noteworthy that the model developed by Armstrong et al. was based on patients treated with 
docetaxel and yielded a c-index of 0.69. The difference in the parameters in the final models 
may have arisen from different patient population, different sample sizes, and different sets of 
assumptions made in model building and in the data that were available. Nevertheless, all models 
selected variables that were representative of host factor and tumor burden and had similar 
statistics in terms of predictive accuracy. The predictive discrimination (the area under the 
receiver operating characteristic [ROC] curve was 0.68 in both models) was not close to one, 
suggesting that models need to improve their predictive accuracy. 
Power Computation 
We would like to accurately estimate the tAUC and the 95% CI for the tAUC will be 
bootstrapped. Using Gonen and Heller approach,23 extensive simulations studies were 
performed to estimate the c-index and variance of the c-index were conducted. The results of 
these simulations showed that the c-index ranged from 0.69-0.99 depending on the individual 
parameters and the shape parameter of the Weibull distribution. Regardless the c-index can be 
estimated with simulated variance of 0.0041. 
Data Analysis 
The trial dataset will be randomly divided into a 2:1 allocation ratio with 2/3 of the patients 
going into the training set and 1/3 will be used in the validation.  
A penalized Cox proportional hazard models using adaptive LASSO penalty will be considered. 
Unlike other methods, the main advantage of using penalized methods is that they 
simultaneously select important prognostic factors and estimate their associated regression 
coefficients. Furthermore, the identification of prognostic factors is not based on the p-values. 
Adaptive weights were given by the reciprocal of absolute parameter estimates from an 
unpenalized Cox model fitted with all baseline covariates. The final model will be evaluated for 
its discriminative ability in two ways. First, the time dependent area under the curve (AUC) will 

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be computed in the training sample. Second, the model will be assessed for its calibration by 
plotting the predicted probability based on the final model vs. the observed probability at time 
(24, 30, 36 months). A risk score will be computed for each patient in the training set from the 
estimated regression coefficients.  
To examine the prognostic ability of the fitted model, we will apply the parameter estimates on 
the testing set and calculated the risk score for every patient in the testing data sets based on the 
estimated regression parameters from the training set. We will then evaluate its discriminative 
ability based on the time dependent AUC (21). The 95% CI for the AUC will be computed based 
on the bootstrapped method.  
10.7 
Pharmacogenomic studies 
10.7.1 Background and hypothesis 
Abiraterone is a selective inhibitor of androgen biosynthesis that potently blocks 
CYP17A1, which is critical to testosterone synthesis by the adrenals, testes, and within the 
prostate tumor. Genetic variation in expression of CYP17A1 is regulated in part by 
promoter sequence variation, including a T>C change at nucleotide -34. 
The primary statistical objective for this companion study is to investigate a drug by 
CYP17A1 interaction with respect to overall survival. Specifically, we hypothesize that 
patients on the enzalutamide/abiraterone arm (Arm B) with a homozygous −34T genotype 
(Genotypic Group 1, 43% of the population) will have an inferior overall survival to 
patients with a heterozygous or homozygous −34C genotype (Genotypic Group 2, 57% of 
population). No genotype effect is expected in Arm A (enzalutamide alone). 
As secondary objectives, we will assay candidate variants and loci hypothesized to be 
associated with other clinical phenotypes (e.g., progression-free survival or toxicity) or 
other eQTLs. 
In addition, we may use the DNA collected to consider other candidate SNPs or to conduct 
a genome-wide association study (GWAS) to validate other or identify novel candidates, 
or, as next generation sequencing platforms become more cost effective, consider exome 
or whole- genome sequencing. As a randomized trial with uniform assessment and follow-
up this represents an important opportunity to better understand the relationships among 
germline genetic variation, disease, and treatment-response phenotypes. At this time, the 
Population Pharmacology and Pharmacogenomics Committee of Alliance is conducting 
genomewide analyses of previously completed CALGB trials using The Illumina 1M 
platform in collaboration with the RIKEN Center for Genomic Medicine. More than 
1,000,000 SNPs are simultaneously genotyped. In addition, there are 4,300 SNPs in regions 
of copy number variations (CNVs), thus allowing for the detection of CNVs as well. Near 
the completion of this clinical trial, specific hypotheses based on currently evolving 
findings will be formulated and a detailed investigational plan will be submitted as an 
amendment to this investigation. This flexible, anticipatory design is not only conventional, 
but also necessary in cancer pharmacogenomics. 
10.7.2 Objectives: 
1. To investigate a drug by CYP17A1 interaction with respect to overall survival. 
2. Assay candidate variants and loci hypothesized to be associated with other clinical 
phenotypes (e.g., progression-free survival or toxicity) or other eQTLs. 
3. To identify specific SNPs and/or copy number variations that are associated with the 
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10.7.3 Methods: 
All patients enrolled in the accompanying randomized phase III study will be given the 
option to consent for germline DNA analysis. A single blood sample (10 ml in a lavender 
top) will be collected at baseline (or any follow-up visit) for pharmacogenetic analysis. 
Germline DNA will be extracted using standard techniques and genetic testing appropriate 
to specific study questions will be performed. The concentration and quality of DNA will 
be quantified by ultraviolet spectroscopy. All DNA samples and unprocessed blood will be 
frozen and will be stored at the Alliance Biorepository at Ohio State University (OSU) until 
they are distributed to the appropriate laboratory for analysis. The typical yield of DNA 
from a 10ml blood sample is 100 ug (range of 80-150 ug). For the studies described below 
we will need up to 5 ug for both the candidate gene analysis as well as the whole genome 
analysis, leaving the majority of the sample stored at the OSU and available for additional 
future genotyping projects. 
10.7.4 Statistical design 
According to the clinical design of this study the number of patients to be evaluated 
clinically is 1224. For simplicity, will assume that the median OS for Arm A is 27 months 
and that the median OS for Arm B is 35.1 months, and that the patients are accrued 
uniformly over a period of 36 months and that the last patient will be followed for at least 
14 months. This is the scenario described in the first row of Table 9 in Section 15.1 
It is assumed that at least 85% of the patients are self-reported non-Hispanic whites, and 
that at least 85% of the patients will consent and provide usable samples for the proposed 
analyses. The power calculations shown below will be based on the assumption that 884 
(1224 x 0.85 x 0.85) patients will be available for these analyses. It is noted that this the 
smallest expected sample size. All patients who provide consent and usable samples will 
be included in the proposed pharmacogenomic studies. 
The analysis will be carried out within a framework of a multiplicative two-way Cox 
proportional hazards model. The inference will be conducted with respect to the interaction 
term in this model. For the power calculation, we will assume that the time to event 
distribution for Arm B is a two-component mixture of exponential laws of the form 
0.5=0.43*exp(-lam1B*MB)+0.57*exp(-lam1B*HRB*MB) where MB is the median for 
arm B and lam1B is the exponential hazard rate for the TT genotype in Arm B. HRB 
quantifies the hazard ratio between the two genotypic groups. It is noted that the 
corresponding hazard ratio in Arm A is assumed to be one as no genotypic effect is 
expected. Therefore the effect size is HRB/HRA=HRB/1=HRB. The power, at the two-
sided 0.05 level, is 0.67 if HRB=0.63, 0.77 if HRB=0.60 and 0.82 if HRB=0.57. 
 
 

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10.8 
Population Pharmacokinetics of abiraterone and enzalutamide 
10.8.1 Background and hypothesis: 
Abiraterone Pharmacokinetics: The abiraterone pharmacokinetic parameters across dose 
levels tested in the Phase I studies show considerable variability between patients and are 
presented in the Table below. In a phase I study of abiraterone conducted across four sites 
in the US, pharmacokinetics were evaluated for all 33 patients. The parent compound, 
abiraterone, was not detected in any sample, suggesting rapid and complete conversion to 
abiraterone. Maximum drug concentrations (Cmax) were achieved within 1.5 to 4 hours 
(Tmax). When administered with food that had high-fat content (per FDA guidance), drug 
exposure was significantly increased (by 4.4-fold) compared with fasting administration 
(P=0.049; Figure 1). Less than proportional increases in both Cmax and AUC0-∞ were 
observed across dose levels in fed and fasted patients (Figure 1), but was less pronounced 
among fed patients. The small number of patients per cohort and the high degree of inter- 
patient variability, often approaching 50%, limits further interpretation. Nonetheless, 
abiraterone exposures (AUCs) appeared to be consistently higher in fed compared to fasted 
patients (Figure 1) possibly suggesting food may aid drug absorption. Abiraterone terminal 
elimination half-life across all groups ranged from 5 to 14 hours. At subsequent cycles, 
concentrations were lower (approximately 10-15%) than the highest concentration 
observed in cycle 1. 1-3 
 
Parameter 
Abiraterone Dose (mg) 
250 
500 
750 
1000 
Fasted 
(n = 3) 
Fed 
(n = 3) 
Fasted 
(n = 6) 
Fed 
(n = 3) 
Fasted 
(n = 3) 
Fed 
(n = 3) 
Fasted 
(n = 6) 
Fed 
(n = 6) 
Tmax, h 
Mean 
SD 
% CV 
 
2.0 
0 
0 
 
2.0 
0.1 
3.8 
 
1.5 
0.5 
36.5 
 
2.7 
1.2 
43.3 
 
2.0 
0.1 
2.8 
 
2.0 
0 
0 
 
1.8 
0.4 
22.3 
 
4.0 
0 
0 
Cmax, nM/L 
Mean 
SD 
% CV 
 
283 
142.2 
50.3 
 
421 
75.8 
18.0 
 
331 
204.9 
62.0 
 
676 
147.9 
21.9 
 
290 
126.6 
43.7 
 
1552 
458.1 
29.5 
 
510 
366.5 
71.9 
 
2194 
1096.9 
50.0 
AUC0-∞, nM/L•hr 
Mean 
SD 
% CV 
 
1411 
697.2 
49.4 
 
1387 
290.2 
20.9 
 
1781 
986.8 
55.4 
 
3840 
1080.9 
28.2 
 
1665 
704.6 
42.3 
 
9359 
3338.6 
35.7 
 
3478 
2012.2 
57.9 
 
14404 
5971.0 
41.5 
T1/2-λ, h 
Mean 
SD 
% CV 
 
5.3 
1.7 
31.7 
 
5.1 
1.0 
20.3 
 
10.6 
6.3 
59.8 
 
6.9 
5.7 
82.7 
 
7.1 
3.4 
48.6 
 
7.9 
2.6 
33.2 
 
14.4 
7.7 
53.3 
 
12.5 
1.2 
9.8 
Apparent 
Clearance, L/h 
Mean 
SD 
% CV 
 
 
4288 
1319.3 
30.8 
 
 
530 
99.5 
18.8 
 
 
5441 
4844.5 
89.0 
 
 
391 
99.1 
25.4 
 
 
1519 
822.7 
54.2 
 
 
247 
73.0 
29.6 
 
 
2650 
4617.0 
174.2 
 
 
231 
97.7 
42.2 
Apparent Vd, L 
Mean 
SD 
% CV 
 
654 
447.3 
68.4 
 
3940 
1275.4 
32.4 
 
10252 
12268.8 
119.7 
 
3418 
1934.4 
56.6 
 
13688 
4265.4 
31.2 
 
2740 
1084.7 
39.6 
 
25494 
18670.2 
73.2 
 
4069 
1462.6 
36.0 

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Figure 1: Effect of food intake on Abiraterone Cmax and AUC 
Abiraterone is primarily cleared by hepatic metabolism, abiraterone sulphate is formed by 
SULT2A1 and this metabolite is further metabolized to N-oxide abiraterone sulphate, by 
CYP3A4. Approximately 5% of the radioactivity of a 14C labeled dose of abiraterone is 
found in urine. In vitro studies with hepatic microsomes revealed that abiraterone is a 
strong inhibitor of CYP1A2, CYP2D6, and notably CYP2C8 (which metabolizes 
enzalutamide) [abiraterone product insert]. 
Enzalutamide (MV3100) Pharmacokinetics and Metabolism: Following oral 
administration of enzalutamide at 160 mg in patients with metastatic CRPC, the median 
time to reach maximum plasma enzalutamide concentrations is 1 hour (range 0.5 to 3 
hours). The enzalutamide mean terminal elimination half-life (T1/2), in patients with 
metastatic CRPC, following a single oral dose is 5.8 days (range 2.8 to 10.2 days). With 
daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzalutamide 
accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in 
enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady 
state, enzalutamide shows approximately dose proportional pharmacokinetics over the 
daily dose range of 30 to 360 mg. In patients with metastatic castration resistant prostate 
(MCRP) cancer, the mean (%CV) predose Cmin values for enzalutamide and its major M2 
metabolite were 11.4 (25.9%) μg/mL and 13.0 (29.9%) μg/mL, respectively. 
In vitro, enzalutamide is metabolized by CYP2C8 and CYP3A4. In vivo results further 
suggest that CYP2C8 is primarily responsible for the formation of the active metabolite - 
N-desmethyl enzalutamide (M2). In vivo, the sum of enzalutamide and M2 exposure was 
increased by 2.2-fold and 1.3-fold when it was co-administered with gemfibrozil (strong 
CYP2C8 inhibitor) or itraconazole (strong CYP3A4 inhibitor), respectively. If the co- 
administration of enzalutamide with a strong CYP2C8 inhibitor cannot be avoided, the 
daily enzalutamide dose should be reduced to 80 mg. In vitro, enzalutamide, M1 and M2 
caused direct inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5. Enzalutamide also caused time- dependent inhibition 
of CYP1A2. Among these enzymes, the IC50 of CYP2C8 was the lowest. However, 
enzalutamide at steady state did not cause a clinically relevant change in the AUC of 
pioglitazone (CYP2C8 substrate) in vivo. 
In vitro, enzalutamide caused induction of CYP3A4. In vivo, enzalutamide can be 
classified as a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. 

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Therefore, co-administration of enzalutamide with CYP3A4, 2C9, and 2C19 substrates 
with a narrow therapeutic index should be avoided. 
Potential pharmacokinetic drug-drug interactions between enzalutamide and 
abiraterone: We hypothesize that there will be a significant pharmacokinetic drug-drug 
interaction between enzalutamide and abiraterone because abiraterone is a strong inhibitor 
of CYP2C8 (in vitro) and enzalutamide is metabolized to N-desmethylenzalutamide in via 
CYP2C8 (and CYP3A4) thus potentially increasing enzalutamide AUC due to decreased 
metabolic clearance  (enzalutamide product insert).  In vivo, gemfibrizol an inhibitor of 
CYP2C8 increased enzalutamide + N desmethyl enzalutamide by 2.2 fold without a 
significant effect on Cmax. Additionally enzalutamide is a strong inducer of CYP3A4 in 
vitro and in vivo, this will increase the degradative metabolism of abiraterone sulfate 
(abiraterone metabolite) and indirectly effect abiraterone metabolism. In vivo, strong 
CYP3A4 inducers (Rifampin) decreased abiraterone AUC by 55%. [abiraterone and 
enzalutamide product inserts] 
10.8.2 Objectives 
1. To define the effect of abiraterone on reducing enzalutamide metabolic clearance (i.e. 
increasing enzalutamide AUC) when the drugs are used in combination. 
2. To define the exposure (AUC) toxicity and exposure (AUC) anti-tumor effect 
relationship, including biomarkers for enzalutamide alone and enzalutamide combined 
with abiraterone in prostate cancer patients. 
3. To develop a population pharmacokinetic model for enzalutamide alone and 
enzalutamide combined with abiraterone taking account of relevant intrinsic and 
extrinsic factors. 
4. To determine the intrapatient and interpatient variability of abiraterone exposure 
(AUC) in prostate cancer patients receiving abiraterone when combined with 
enzalutamide 
5.  To determine the intra-patient and inter-patient variability of enzalutamide exposure 
(AUC) in prostate cancer patients receiving enzalutamide alone and abiraterone plus 
enzalutamide. 
10.8.3 Methods 
For patients in the study who are receiving enzalutamide alone or enzalutamide plus 
abiraterone, venous blood samples for abiraterone/enzalutamide concentrations will be 
obtained at baseline, and at each scheduled follow-up clinic visit for up to six months while 
still receiving study drug therapy. These samples will have the time of day they were 
obtained documented. At these follow up visits a Patient Pharmacokinetic Questionnaire 
(see Appendix II) will be filled in which will request information about the prior 48h dosing 
of abiraterone/enzalutamide. This will detail the time of day the last two doses of study 
drug were taken, and relationship of when the doses were taken in relation to meals. 
Drug concentrations will be measured using an LC-MS-MS assay validated in the Alliance 
Pharmacology/Pharmacokinetic core lab at the Univ. of Pittsburgh using a modification of 
the assay published by Gurav S., et al. Biomed Chromatogr. 2011. PMID: 22002259 for 
abiraterone, and a validated LC-MS-MS method for enzalutamide and the n-desmethyl-
enzalutamide metabolite. 
Pharmacokinetic population data modeling of the multiple drug concentrations will be 
performed using NONMEM to derive enzalutamide and abiraterone specific AUCs and the 
intra and inter-patient variability (see below for details). 

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10.8.4 Statistical design: 
The primary scientific hypothesis is that the metabolic clearance of enzalutamide is 
reduced when administered concomitantly with abiraterone. The corresponding statistical 
hypothesis is that the distribution of enzalutamide metabolic clearance is stochastically 
smaller in the combination arm.  
We will test this hypothesis formally using the Wilcoxon rank sum test. The canonical 
effect size in this context is P[X<Y] where X and Y are random variates from the two 
population respectively. We propose to evaluate all con. We anticipate that the range for 
the sample size will be between 500 and 900 but will not exceed the study sample size 
based on the primary clinical study endpoint. For the power calculation illustrations, we 
will assume that X and Y are random variables from normal distributions with unit 
variance. The power as a function of the effect size, at the two-sided 0.05 level, for 
n=500,600,700,800 and 900 is shown in Figure 2 below. Each illustration is based on 
B=10000 simulation replicates. The effect size will be visualized using a receiver operating 
characteristic (ROC) curve. 
 
Figure 2. 
We will also explore the relationship between toxicity and exposure, and anti-tumor effect 
and exposure. To incorporate additional baseline co-variates, including clinical risk factors, 
demographics and biomarkers, we will employ a standard regression framework 
Population Pharmacokinetic Modeling: We will develop parametric population 
pharmacokinetics models for the exposure of enzalutamide alone and enzalutamide 
combined with abiraterone. To capture both between and within-subject variabilities in 

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both enzalutamide and abiraterone exposures, a non-linear mixed effects model will be 
used.  In particular, we will consider models of the form  
𝑦𝑦𝑦𝑦 [𝑡𝑡] =  𝛹𝛹 [𝑡𝑡, 𝜃𝜃, 𝜂𝜂𝑖𝑖; 𝐷𝐷, 𝑥𝑥] +  𝜀𝜀𝑖𝑖 [𝑡𝑡]   
where denotes yi [t] the observed plasma concentration at time t, t (t1,…, tk), obtained 
through sparse sampling as previously described, for the i-th individual and  denotes the 
vector of population parameters of size p. The quantity D denotes the dose level and x is a 
vector of additional covariates. The random vectors i and  = (i[t1],…, i[tk]) account for the 
between and within subject variabilities respectively.  If possible, non-linearities with 
respect to time will be explored. The model will be fitted using first-order conditional 
maximum likelihood estimation in the NONMEM program (version 5) [Reference: Beal, 
S. and L. Sheiner, NONMEM Users Guide. 1992, NONMEM Project Group, University 
of California at San Francisco: San Francisco].  For this purpose it will be assumed that the 
random effects i....n are independent q-variate mean-zero normal random variables with 
common variance i where q is at most equal to p (the dimension of the population parameter 
vector ). It is also assumed that the measurement errors 1,…,n are independent k-variate 
mean-zero normal vectors with common covariance matrix. Individual pharmacokinetic 
parameter estimates will be obtained from the estimated population PK model for both 
enzalutamide and abiraterone.   
Covariate testing will be performed to identify sources of variability in exposure to 
enzalutamide and abiraterone among individuals. Covariates that will be tested include: 
demographic characteristics, organ function markers, disease severity, genetic markers, 
and concomitant medications and time relationship to ingestion of the previous meal. All 
derived PK parameters will be summarized using standard numerical and graphical 
displays. 
Pharmacometric Analyses: Patients with pharmacokinetic, efficacy and key toxicity data 
will be included in the pharmacometric analyses. First a population pharmacokinetic 
approach will be employed to analyze the concentration-time data for enzalutamide and 
abiraterone.  Relevant demographic and intrinsic/extrinsic factors will be explored for 
covariate relationship.  Different empirical Bayesian PK parameters will be correlated with 
toxicity and efficacy endpoints such as the overall survival and safety endpoints. 
Pharmacokinetic-biomarker relationships using key markers will also be conducted.  
 
 

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11.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
11.1 
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. 
11.2 
Enzalutamide (NSC #766085) 
Enzalutamide, or MDV3100, has the chemical name 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-
5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. The drug 
substance has no chiral centers and no salt forms are available at ~ pH 2 to 10. It is essentially 
insoluble in water, but partially soluble in lipid-based solutions. The drug substance is 
formulated in the surfactant Labrasol to create a self-emulsifying (or microemulsifying) dosage 
form.  
Please refer to the package insert for additional information. 
Availability 
For US Sites: 
Enzalutamide will be provided by Astellas directly to Investigators engaged in research under 
the Protocol, whose current IRB status has been verified by the Alliance.  Enzalutamide may be 
ordered by completing the US order form provided by Astellas and posted on the CTSU Web 
site study page for A031201.  For Canadian sites: Enzalutamide Enzalutamide is supplied as 40 
mg soft gelatin capsules in bottles containing 120 capsules. 
The FDA has determined that enzalutamide is IND exempt for this study. 
For Canadian Sites: 
Enzalutamide will be provided by Astellas and distributed by Biologics. Enzalutamide may be 
ordered by completing the order form found at the CTSU Web site study page for A031201. 
Enzalutamide is supplied as 40 mg soft gelatin capsules in bottles containing 120 capsules. 
The FDA has determined that enzalutamide is IND exempt for this study. 
Storage and Stability 
Enzalutamide should be stored at room temperature (68°- 77°F), with excursions permitted to 
59°F to 86°F (15°C to 30°C).  
Drug accountability and returns 
The investigator, or designated qualified personnel must maintain an accurate record of the 
receipt, dispensing and disposal of enzalutamide using the NCI Investigational Agent 
Accountability Record Form for oral agent available at http://ctep.cancer.gov/forms. Drug 
returned by patients should be recorded on the Investigational Agent Accountability Record 
Form and disposed on site per local institutional standard of practices. Unused or expired drug 
should be destroyed per local institutional practice. U.S. sites are to provide Investigational 
Agent Accountability Record Forms to Astellas upon request and at study conclusion. 
Administration 
Enzalutamide will be administered once daily, orally. It may be administered without regard to 
meals. Capsules should be swallowed whole and not chewed or crushed. If dosing is missed on 
one day for any reason, double dosing should NOT occur the following day.  
Toxicities 
Enzalutamide is generally well tolerated. 

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Fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache have been seen at higher rates 
than with placebo for any grade toxicity. In addition, 7 cases of seizure (<1%) were seen in the 
enzalutamide group in the randomized clinical trial, with no cases in the placebo group. 
The adverse events listed below are of interest to Astellas: 
• Anorexia 
• Seizure 
• Hypokalemia 
• Asthenia/fatigue 
• Fall 
• Hypertension 
• Dyspnea 
• Fracture 
• Cardiac failure  
• Renal failure/insufficiency 
• Hallucination 
• Insomnia 
• Hepatic failure/insufficiency 
• Nausea 
• Rash 
• Neutrophil count decreased 
• Vomiting 
• Diarrhea 
• Cognitive impairment 
• Edema 
• Pruritus 
• Spinal cord compression and cauda equina syndrome 
For this trial, report adverse events as described in Sections 6.1.3 and 16.0. 
Potential drug interactions 
Drugs that Inhibit or Induce CYP2C8 
Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area 
under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl 
enzalutamide in healthy volunteers. Co-administration of enzalutamide with strong CYP2C8 
inhibitors should be avoided if possible. If co-administration of enzalutamide with a strong 
CYP2C8 inhibitor cannot be avoided, reduce the dose of enzalutamide. 
The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been 
evaluated in vivo. Co-administration of enzalutamide with strong or moderate CYP2C8 inducers 
(e.g., rifampin) may alter the plasma exposure of enzalutamide and should be avoided if 
possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential 
is recommended. 
Drugs that Inhibit or Induce CYP3A4 
Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC 
of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers. 
The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been 
evaluated in vivo. Co-administration of enzalutamide with strong CYP3A4 inducers (e.g., 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the 
plasma exposure of enzalutamide and should be avoided if possible. Selection of a concomitant 
medication with no or minimal CYP3A4 induction potential is recommended. Moderate 
CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort 
may also reduce the plasma exposure of enzalutamide and should be avoided if possible. 
Effect of enzalutamide on Drug Metabolizing Enzymes 
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in 
humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 
substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant 
use of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-
mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-
administration with warfarin cannot be avoided, conduct additional INR monitoring. 

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11.3 
Abiraterone Acetate 
Abiraterone acetate (hereafter, “abiraterone”) is a CYP17 inhibitor indicated for use in 
combination with prednisone for the treatment of patients with metastatic castration-resistant 
prostate cancer who have received prior chemotherapy containing docetaxel.  
Please refer to the package insert for additional information. 
Availability 
Abiraterone is commercially available as 250-mg tablets: oval, white to off-white and contain 
abiraterone and compendial (USP/NFIEP) grade lactose monohydrate, microcrystalline 
cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, 
colloidal silicon dioxide, and purified water, in descending order of concentration (the water is 
removed during tableting).  
Dosage and Administration: 
Abiraterone 1,000 mg will be administered orally once daily in combination with prednisone 5 
mg administered orally twice daily. Abiraterone must be taken on an empty stomach. No food 
should be consumed for at least two hours before the dose of abiraterone is taken and for at least 
one hour after it is taken.  
Warnings and Precautions: 
Mineralocorticoid excess: Use abiraterone with caution in patients with a history of 
cardiovascular disease. The safety of abiraterone in patients with LVEF < 50% or NYHA Class 
III or IV heart failure is not established.  
Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. 
Increased dosage of corticosteroids may be indicated before, during and after stressful situations.  
Hepatotoxicity: Increases in liver enzymes have lead to drug interruption, dose modification 
and/or discontinuation.  
Food Effect: Abiraterone must be taken on an empty stomach. Exposure (area under the curve) 
of abiraterone increases up to 10 fold when abiraterone is taken with meals.  
Toxicities: 
The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, 
edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, 
arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. 
Drug interactions: 
Abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-
administration of abiraterone with CYP2D6 substrates that have a narrow therapeutic index. If 
an alternative treatment cannot be used, exercise caution and consider a dose reduction of the 
concomitant CYP2D6 substrate drug. 
Effects of Abiraterone on Drug Metabolizing Enzymes 
Abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 
drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were 
increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone 
1,000 mg daily and prednisone 5 mg twice daily. Avoid coadministration of abiraterone with 
substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative 
treatments cannot be used, exercise caution and consider a dose reduction of the concomitant 
CYP2D6 substrate drug. 

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Drugs that Inhibit or Induce CYP3A4 Enzymes 
Based on in vitro data, abiraterone is a substrate of CYP3A4. The effects of strong CYP3A4 
inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, 
telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of 
abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and 
inducers of CYP3A4 during abiraterone treatment. 
11.4 
Prednisone 
Please refer to the FDA-approved package insert for prednisone for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.  
Availability 
Prednisone is commercially available in 5 mg tablets.  
Storage and stability 
Prednisone should be stored at room temperature. 
Administration 
Prednisone is administered orally. 
Toxicity 
Short-term use of prednisone (e.g., ≤ 4 weeks) may be associated with gastrointestinal side 
effects (dyspepsia, ulceration); insomnia, nervousness, and occasionally, psychosis; and 
hyperglycemia. Immunosuppression with an increasing risk of infection is also seen. 
More prolonged use may be associated with, in addition to the above, muscle weakness and 
muscle wasting; osteoporosis and fractures; hirsutism, acne, skin atrophy and easy bruising; 
sodium and water retention. Adrenal suppression can occur with long-term use, necessitating 
tapering rather than abrupt discontinuation, and the need for steroid coverage during stress. 
Occasionally, a withdrawal syndrome manifest by muscle aches and pains is seen upon 
discontinuation. 
12.0 ANCILLARY THERAPY 
12.1 
Supportive Care 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate.  
In addition, treatment of chronic and/or comorbid issues as they arise are permissible as long as 
they do not interfere with study treatments. For example, the following treatments are allowed 
during the study (and do not require study drug discontinuation) including, but not limited to: 
• 
Steroids given at a maximum equivalent daily dose of 10 mg of prednisone; 
• 
Pain therapy per standard of care and institutional guidelines for pain felt not to be due to 
progressive disease (e.g., for fragility fracture or pathologic fracture of an existing bone 
lesion without documentation of new lesions); 
• 
Palliative surgical procedures to treat skeletal related events that are felt not to represent 
progressive disease (e.g., kyphoplasty for restoration of a fragility fracture or surgery and/or 
radiation therapy to address apathologic fracture of an existing bone lesion in the absence 
of other indices of progressive disease). 

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12.2 
Treatment with other chemotherapeutic agents 
The concurrent administration of any other anticancer therapy, including cytotoxic, hormonal 
(except LHRH agonists or antagonists), or immunotherapy is prohibited during protocol 
treatment. Use of other investigational drug therapy for any reason is prohibited. 
12.3 
Radiation therapy 
Radiation therapy, including external beam radiotherapy, may not be administered except for 
the specific circumstance described in Section 12.1 as part of supportive care. 
Radium-223 may not be administered. 
12.4 
Growth Factors 
The use of growth factors is not allowed for patients enrolled to this study. It is not anticipated 
that the treatments in this study will necessitate their use.  
12.5 
Zoledronic acid and denosumab 
Treatment with zoledronic acid and/or denosumab may be initiated once patients has been on 
study treatment for at least two months and tolerance to study treatment has been established. 
13.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE (SOLID TUMORS) 
For the purposes of this study, patients should be reevaluated every 8 weeks for 6 cycles, then every 
12 weeks. The timing of scans should be based off the initiation date of protocol treatment. The 
restaging schedule should be adhered to regardless of treatment holds or interruptions. In addition to 
a baseline scan, confirmatory scans should also be obtained at least 6 weeks following initial 
documentation of objective response. 
13.1 
Prostate Cancer Working Group 2 (PCWG2) response criteria 
This study makes use of the PCWG2 response criteria, which is comprised of three distinct 
evaluation schemes: 
• 
Visceral lesions will be assessed using a modified form of the RECIST 1.1 criteria as 
specified in Section 13.2. 
• 
Lymph nodes will not be assessed using RECIST 1.1; instead, customized criteria are 
specified in Section 13.2. 
• 
Bone metastases will be assessed using the PCWG2 criteria specified below in Section 
13.1. 
PCWG2 discourages the use of overall response criteria, and in this protocol, overall response 
criteria will only apply to soft tissue lesions, will not incorporate bone lesions, and will not 
incorporate changes in tumor markers. 
Tumor markers: neither PSA nor any other tumor marker will be used in this protocol for either 
defining in part or in whole progression or response. PSA will not be used to make treatment 
decisions either. 
Bone lesions: Post-treatment changes will be described as “new lesions” or “no new lesions.” 
There will be no descriptions of post-treatment “responses” for bone metastases. As such, only 
progression will be defined in regards to bone lesions, using the following table as a descriptor. 
Patients are defined as progressing when they meet bone or soft tissue progression (both are not 
required). 
Please refer to Appendix VI for specific examples of how bone lesion progressions should be 
tracked and reported. 

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Documentation for Radiographic Evidence of Disease Progression 
 
Date 
Progression 
Detected 
(Visit)a 
Criteria for Progression 
Criteria for 
Confirmation of 
Progression 
(requirement and timing) 
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 9 
Bone lesions:  Two or more new 
lesions compared to baseline bone
scan by PCWG2. 
Timing: at least 6 weeks after 
progression identified or at Week 17 
visit.b 
Two or more new bone lesions 
on bone scan (compared to 
Week 9 scan). 
Soft tissue lesions: Progressive 
disease on CT or MRI per 
Section 13.2.3. 
Confirmation required for soft 
tissue disease (scan of same modality 
as demonstrated progression).b 
Confirmation of progressive 
soft tissue disease per Section 
13.2.3. 
Week 17 
Bone lesions:  Two or more 
new lesions on bone scan 
compared to Week 9 bone 
scan. 
Timing:  at least 6 weeks after 
progression identified or at Week 25 
Visit. Required for bone lesions 
observed on bone scan.b 
Persistentc or increase in 
number of bone lesions on 
bone scan compared to Week 
17 scan. 
Soft tissue lesions: Progressive 
disease on CT or MRI per 
Section 13.2.3. 
No confirmatory scan required for 
soft tissue disease progression. 
------------ 
Week 25 or 
later 
Bone lesions:  Two or more 
new lesions compared to 
Week 9 bone scan. 
Timing:  at least 6 weeks but no later 
than 12 weeks after progression 
identified. Required for bone lesions 
observed on bone scan.b 
Persistentc or increase in 
number of lesions on bone 
scan compared to prior scan. 
Soft tissue lesions: Progressive 
disease on CT or MRI per 
Section 13.2.3. 
No confirmatory scan required for 
soft tissue disease. 
------------ 
a 
Progression detected at an unscheduled visit either prior to Week 9 or between scheduled visits will require a 
confirmatory scan at least 6 weeks later and should follow confirmation criteria outlined in the table for the next 
scheduled scan. 
b 
Confirmation must occur at the next available scan. 
c 
For confirmation, at least two of the lesions first identified as new must be present at that next available scan 
(confirmation scan). 
Note: For patients with a superscan (confluence of lesions across the axial skeleton such that distinguishing any 
new lesions is not possible), progression will be defined by clinical progression or progression by RECIST 
criteria. 
13.2 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and will be recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, and should be chosen based 
on their suitability for accurate repetitive measurements. Lymph nodes need to be ≥ 20 mm in 
at least one dimension to be considered target or evaluable lesions to assess changes in size. 
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
repeated measurements in which case the next largest lesion that can be measured reproducibly 
should be selected. A sum of the diameters (longest for all lesions, including nodes) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum LD will 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease. 
13.2.1 Complete Response: Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in long axis to < 10 mm. 

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13.2.2 Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.  
13.2.3 Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new non-osseous lesions is also considered progression). Clinical lesions will only be 
considered measurable when they are superficial (e.g., skin nodules, palpable lymph nodes) 
and at least 10 mm in diameter as assessed using calipers (e.g., skin nodules). Per PCWG2 
and Cou302: Visceral (lung, liver adrenal) or extranodal lesions need to be ≥ 10 mm in one 
dimension, using spiral CT. However, lymph nodes need to be ≥ 20 mm in at least one 
dimension to be considered new. 
13.2.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as references the smallest sum diameters while on study. 
13.3 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. Non-target lesions 
include bone lesions. 
13.3.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm long axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
13.3.2 Non-complete response (non-CR)/Non-progression (non-PD): Persistence of one or 
more non-target lesion(s) and/or maintenance of tumor marker level above the normal 
limits. 
13.3.3 Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of non-target lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed later on by the review panel (or Study Chair). 
Whether new or pre-existing, lesions must be measurable per Section 13.2.3 to be used to 
measure progression. For new bone lesions, adhere to bone progression criteria specified 
in Section 13.1. 
 
 

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13.4 
Evaluation of Best Overall Response 
Measurable disease will be evaluated using the PCWG2 criteria in Section 13.1. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required 
CR 
CR 
No 
CR 
≥ 4 wks confirmation* 
CR 
Non-CR/Non-PD 
No 
PR 
 
≥ 4 wks confirmation* 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once ≥ 
4 wks from baseline* 
PD 
Any 
Yes or No 
PD 
 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
 
 
 
* 
Only for non-randomized trials with response as the primary endpoint. 
** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
For Patients with Non-measurable (Non-Target) Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
13.5 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 

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13.5.1 Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers (e.g., 
skin nodules). For the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended. 
13.5.2 Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
13.5.3 Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. Visceral (lung, liver, adrenal) or extranodal lesions need to be ≥ 
10 mm in one dimension if slice thickness is ≤ 5 mm; however, lymph nodes need to be ≥ 
20 mm in at least one dimension to be considered evaluable lesions to assess for changes 
in size. MRI is also acceptable in certain situations (e.g., for body scans). Use of MRI 
remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability 
of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
13.5.4 PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. Note, however, that the 
PET portion of the CT introduces additional data, which may bias an investigator if it is 
not routinely or serially performed.  
13.5.5 Ultrasound (US) Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances. 
13.5.6 Endoscopy and Laparoscopy The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
13.5.7 Tumor Markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  

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13.6 
Confirmation Measurement/Duration of Response 
13.6.1 Confirmation 
To confirm progressive measurable disease, it is recommended that confirmatory scans be 
performed after at least 6 weeks. 
13.6.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively documented. 
13.6.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements. 
 
 

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14.0 END OF TREATMENT 
14.1 
Duration of treatment 
Protocol therapy should be continued as long as the patient is tolerating the study drug and 
continues androgen deprivation therapy (i.e., surgical castration or ongoing GnRH analogue 
therapy) until confirmed radiographic disease progression AND one of the two following events: 
1) initiation of other standard treatments for prostate cancer or 2) initiation of investigational 
agent for treatment of prostate cancer. Initiation of bisphosphonates or other approved bone 
protective agents are allowed as supportive treatment for worsening bone mineral density or 
fragility fracture during treatment and should not result in discontinuation of study drug therapy. 
Patients who discontinue treatment will continue to be followed for radiographic progression 
(until disease progression has been confirmed, additional treatments for prostate cancer, and 
survival [5 years]).  
14.2 
Disease progression 
Patients should continue protocol treatment until confirmed radiographic or unequivocal clinical 
progression. If the patient has radiographic progression but no unequivocal clinical progression 
and alternate treatment is not initiated, the patient may continue on study treatment, at the 
investigator's discretion. However, if patients have unequivocal clinical progression without 
radiographic progression, these patients are indicated for the current standard of care. Study 
treatment should be stopped and patients advised regarding available treatment options.  
14.3 
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: 
• 
Document the reason(s) for discontinuation of therapy on forms. 
• 
Follow the patient for survival and secondary malignancy for a minimum of 5 years 
following registration. 
15.0 STATISTICAL CONSIDERATIONS 
This is a randomized, prospective phase III trial in which 1224 patients will be randomized will be 
randomized in 1:1 ratio to one of two treatment arms: arm A (enzalutamide) or Arm B (abiraterone 
plus enzalutamide). Randomization will be stratified on patients who received prior chemotherapy 
(yes, no) and risk-group stratification defined as low, intermediate, or high using the Halabi et al. 
nomogram55. Assignment to treatment arm will be performed centrally at the Alliance Statistical 
Center following determination of eligibility.  
15.1 
Sample Size Determination 
The null and alternative hypotheses can be written as H0: Δ=1 or Ha: Δ=0.77, where Δ= is the 
hazard ratio defined as 
 /
. 
 represents the hazard of death for Arm A and 
represents the hazard of death for Arm B. Under the alternative hypothesis, the expected number 
of deaths is 616 in the two arms. With this information, assuming failure time that follows an 
exponential distribution and a one-sided type I error rate = 0.025, the log-rank test has 90% 
power to detect a hazard ratio of 0.77 taking into account the planned schedule of the interim 
analyses. The median OS time in patients randomized to enzalutamide (arm A) who have not 
received first line chemotherapy is 35.3 months, but this is based on 200 events in the COU302. 
The target sample size will be 1,224. Regardless what the observed median OS time is in patients 
randomized to arm A, the final analysis will be conducted when 616 deaths has been observed. 
ArmB
λ
ArmA
λ
ArmA
λ
ArmB
λ

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Assuming a monthly accrual of rate of 34 patients, the target 616 deaths are expected to occur 
anywhere from 14 to 24 months post enrollment period depending on what the observed medians 
OS time are in patients randomized to arms A and B.  
Median OS 
time in Arm A 
(months) 
Expected Median 
OS time in Arm 
B (months) 
Sample Size 
Accrual Period 
(months) 
Follow-up 
(months) 
Trial 
Duration 
(months) 
27 
35.1 
1,224 
36 
14 
50 
30 
39 
1,224 
36 
18 
53 
33 
42.9 
1,224 
36 
21 
57 
36 
46.8 
1,224 
36 
24 
60 
Table 7:  Sample size and trial duration for various median OS time assuming a one-sided type I 
error rate of 0.025, power of 0.90, HR = 0.77, and accrual rate of 34 patients/month 
15.2 
Interim Analysis 
Efficacy (overall survival) results will be conducted on semiannual basis to coincide with the 
semiannual meetings of the Alliance Data and Safety Monitoring Board (DSMB). Under the 
alternative hypothesis, six hundred sixteen events (deaths) are expected at the end of the follow-
up period. Assuming the accrual rate and failure rate in row 1 (Table 7), the first interim analysis 
for OS will be performed at about 37% of the full information (approximately 24 months after 
study activation). Other interim analyses will be performed at 55% (approximately 30 months), 
at 72% of the total information (approximately 36 months), at 87% (approximately 42 months), 
and at 100% (approximately 48 months after study activation). No interim analysis will be 
performed if there is not at least 10% increment in the information proportion compared to the 
previous interim analysis. To help insure complete data on which to base the interim analyses, 
institutions will be asked to submit survival status updates on their patients on a semi-annual 
basis while the trial is being monitored by the DSMB. 
A Lan-Demets spending function analogue of a one-sided O’Brien-Fleming will be used to stop 
the trial early to reject the null hypothesis. Assuming the above percent information available at 
each look and a one-sided type I error rate = 0.025, the z-score boundaries for stopping for 
superiority for the OS endpoint and the z-score boundaries for stopping for futility under the 
alternative hypothesis using Friedlin et al., futility guidelines are presented in the table below. 
Should any boundary be crossed, accrual to the trial may be stopped.  
 
 
Boundaries for Interim Analysis for the OS endpoint 
Z value, nominal significance levels, and hazard ratio 
Interim Analysis 
Percent information 
(Number of deaths) 
For Superiority 
For Futility 
1 (18 months) 
22% (135) 
 
-1.645, 0.472, 1.012 
2 (24 months) 
37% (228) 
3.392, 0.0003, 0.638 
0.003, 0.501, 1.000 
3 (30 months) 
55% (339) 
2.782, 0.003, 0.739 
0.140, 0.556, 0.985 
4 (36 months) 
72% (444) 
2.431, 0.008, 0.794 
0.309, 0.621, 0.971 
5 (42 months) 
87% (536) 
2.211, 0.013, 0.826 
0.482, 0.685, 0.959 
6 (Final) 
100% (616) 
2.063, 0.020, 0.847 
2.063, 0.020, 0.847 
Table 8: Superiority and futility boundaries for each interim analysis 
15.3 
Toxicity Monitoring 
Extensive clinical data is available on enzalutamide and abiraterone/prednisone. We have no 
reason to believe that the combination of the two drugs will lead to increased toxicity, and there 
is no plan to do a separate phase I/II study of the combination. Given that the safety of 

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enzalutamide is well established, safety parameters will apply to the combination arm. Monthly 
conference calls (including the Study Chair, Committee Chair, study statisticians, data 
coordinator, protocol coordinator, and Alliance Executive Officer) will be held to monitor the 
first 120 patients randomized to the trial treated for 4 cycles due to unacceptable treatment-
related events. Unacceptable toxicity will be defined as: treatment-related death and seizures.  
It is assumed that the incidence of unacceptable toxicity in patients treated with enzalutamide is 
1%. Unacceptable toxicity rates will be compared by the two treatments arms for the first 120 
randomized patients to the study. We expect to accrue the first 120 patients at about 3.5 months 
after institutions have their IRBs approved the study. Three analyses at 50% (60 patients), 80% 
(72 patients), and 100% (120 patients) will be performed and will be discussed at all scheduled 
conference calls. If at any scheduled time of analysis the lower boundary of a one-sided 90% 
confidence interval for the difference in unacceptable toxicity exceeds 10%, accrual to the trial 
will be immediately suspended. The trial will remain closed until the review of all toxicity data 
is completed and a decision is made about whether it is safe to resume accrual. This decision 
will be made by consensus of the study team, the Alliance DSMB and CTEP. Institutions that 
do not submit adverse event forms in a timely manner may be denied future registrations to this 
study. 
15.4 
Data Analysis 
An intent-to-treat approach will be used in this phase III study to analyze clinical outcomes (OS 
PFS, radiographic PFS, post treatment decline in PSA and ORR) except toxicity. Patients who 
withdraw consent for treatment or withdraw from the study due to toxicity will continue to be 
followed for overall survival, even if they begin another therapy. The stratified log-rank statistic 
will be the primary analysis to compare the hypothesis on OS and PFS adjusting on the 
stratification factors (prior chemotherapy and risk group as determined by the Halabi 
nomogram55).  
The Kaplan-Meier product-limit estimator will be used to estimate the OS, PFS and radiographic 
PFS distributions. In addition, the proportional hazards model will be used to assess the 
importance of each comparison adjusting on patient characteristics and stratification factors in 
predicting OS, PFS, and radiographic PFS.  
Landmark analyses of rPFS at 6 months from randomization/registration will be performed to 
minimize lead-time bias. The associations between OS and PFS, and between OS and rPFS 
progression, will be investigated using a statistic that estimates Kendall’s tau measure of 
association for bivariate time to event outcomes subject to censoring. 
Furthermore, the Cochran-Mantel-Haenszel test will be used to compare the two arms on the 
proportion of patients who experience an objective response (defined as either a confirmed CR 
or a PR) and post-treatment decline in PSA adjusting on the stratification factors. 
15.5 
Accrual Rate  
Based on previous data from patients enrolled on CALGB 90401, the accrual rate was 34 
patients/month, accrual to this trial is expected to be completed in about 36 months within study 
activation as outlined in Table 10. 
 
 

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15.6 
Inclusion of Women and Minorities 
Minorities will be eligible for this study without alteration in eligibility criteria. We expect that 
the racial and ethnic composition of the patient group for the current trial will be similar to that 
seen in CALGB 90401. 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
51 
= 
51 
Not Hispanic or Latino 
0 
+ 
1173 
= 
1173 
Ethnic Category: Total of all subjects 
0 
+ 
1224 
= 
1224 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
5 
= 
5 
Asian 
0 
+ 
9 
= 
9 
Black or African American 
0 
+ 
126 
= 
126 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
1 
= 
1 
White 
0 
+ 
1083 
= 
1083 
Racial Category: Total of all subjects 
0 
+ 
1224 
= 
1224 
16.0 EXPEDITED ADVERSE EVENT REPORTING 
Investigators are required by Federal Regulations to report serious adverse events as defined below. 
Alliance investigators are required to notify the Alliance Central Protocol Operations Program Office, 
the Study Chair, and their Institutional Review Board if a patient has an adverse event requiring 
expedited reporting. All such events must be reported in an expedited manner using the NCI CTEP 
Adverse Event Reporting System (CTEP-AERS).  
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized for AE reporting 
beginning April 1, 2018. All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
Please note that toxicity and routine AE reporting through RAVE will continue to use v4.0 after 
April 1, 2018. 
The Alliance requires investigators to route all expedited adverse event reports through the Alliance 
Central Protocol Operations Program Office for Alliance coordinated studies.  
Be sure to read this entire protocol section, as requirements are described in both the table and bullet 
points following the table. Note that the additional instructions or exclusions are protocol specific, 
and in the case of a conflict, the additional instructions or exclusions supersede the table.  
 
 

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16.2 
Additional Instructions or Exclusions  
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB, according to local IRB policies. 
• 
Note: A death on study requires both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause must be provided. 
• 
After April 1, 2018, death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and administration site 
conditions.” Evidence that the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression; clinical deterioration 
associated with a disease process) should be submitted. 
• 
Treatment expected adverse events include those listed in Section 6.1.3 and in the package 
insert. 
• 
Any seizures occurring on A031201 should be reported via CTEP-AERS within 10 calendar 
days. 
• 
When evaluating hypertension, consider the description of severity grade 3 relative to the 
last AE reporting period. That is, for “more than one drug or more intensive therapy than 
previously used,” “previously” should be considered the last reporting period. A regimen 
more intensive than a previous reporting period need only prompt expedited reporting the 
first time that it is used. If BP is stable on the more intensive regimen, do not continue to 
report grade 3 HTN via CTEP-AERS. 
• 
All new malignancies must be reported through CTEP-AERS whether or not they are 
thought to be related to either previous or current treatment. All new malignancies should 
be reported, i.e., solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and 
in situ tumors. In CTCAE version 4.0, the new malignancies (both second and secondary) 
may be reported as one of the following: (1) Leukemia secondary to oncology 
chemotherapy, (2) Myelodysplastic syndrome, (3) Treatment-related secondary 
malignancy, or (4) Neoplasms benign, malignant and unspecified—other. Whenever 
possible, the CTEP-AERS reports for new malignancies should include tumor pathology, 
history or prior tumors, prior treatment/current treatment including duration, any associated 
risk factors or evidence regarding how long the new malignancy may have been present, 
when and how it was detected, molecular characterization or cytogenetics of the original 
tumor (if available) and of any new tumor, and new malignancy treatment and outcome, if 
available.  
• 
All pregnancies and suspected pregnancies occurring in the partner of a male patient during 
therapy or within 28 days after completion of treatment on A031201 must be reported via 
CTEP-AERS. In CTCAE version 4.0 (until March 31, 2018) or version 5.0 (after April 1, 
2018), use the event term, “pregnancy, puerperium, and perinatal condition-other, fetal 
exposure (grade 4)”.  
- 
CTEP-AERS reports should be amended upon completion of the pregnancy to report 
pregnancy outcome (e.g. normal, spontaneous abortion, therapeutic abortion, fetal 
death, congenital abnormalities). 
- 
The CTEP-AERS report should be amended for any neonatal deaths or complications 
occurring within 28 days of birth independent of attribution. Infant deaths occurring 

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after 28 days considered to be related to in utero exposure to the agents used in this trial 
should be reported via CTEP-AERS. 
- 
After April 1, 2018, 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. 
- 
In the case of partners of male patients, no interaction with the pregnant partner is 
required. It is anticipated that any information about these pregnancies will be obtained 
from the patient. 
• 
The reporting of adverse events described above is in addition to, and does not supplant, the 
reporting of adverse events as part of the reporting of the results of the clinical trial, e.g. 
routine reporting. 

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68:4447-54, 2008 
39. 
de Bono JS, Logothetis CJ, Molina A, et al: Abiraterone and increased survival in metastatic 
prostate cancer. N Engl J Med 364:1995-2005 

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40. 
Tran C, Ouk S, Clegg NJ, et al: Development of a second-generation antiandrogen for treatment 
of advanced prostate cancer. Science 324:787-90, 2009 
41. 
Ryan CJ, Halabi S, Ou SS, et al: Adrenal androgen levels as predictors of outcome in prostate 
cancer patients treated with ketoconazole plus antiandrogen withdrawal: results from a cancer 
and leukemia group B study. Clin Cancer Res 13:2030-7, 2007 
42. 
Nadiminty N, Tummala R, Lou W, et al: MicroRNA let-7c suppresses androgen receptor 
expression and activity via regulation of Myc expression in prostate cancer cells. J Biol Chem 
287:1527-37 
43. 
Cao P, Deng Z, Wan M, et al: MicroRNA-101 negatively regulates Ezh2 and its expression is 
modulated by androgen receptor and HIF-1alpha/HIF-1beta. Mol Cancer 9:108 
44. 
Ribas J, Ni X, Haffner M, et al: miR-21: an androgen receptor-regulated microRNA that 
promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res 
69:7165-9, 2009 
45. 
Iinuma H, Watanabe T, Mimori K, et al: Clinical significance of circulating tumor cells, 
including cancer stem-like cells, in peripheral blood for recurrence and prognosis in patients 
with Dukes' stage B and C colorectal cancer. J Clin Oncol 29:1547-55, 2011 
46. 
George DJ, Halabi S, Shepard TF, et al: The prognostic significance of plasma interleukin-6 
levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and 
leukemia group B 9480. Clin Cancer Res 11:1815-20, 2005 
47. 
George DJ, Halabi S, Shepard TF, et al: Prognostic significance of plasma vascular endothelial 
growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and 
Leukemia Group B 9480. Clin Cancer Res 7:1932-6, 2001 
48. 
Humphrey PA, Halabi S, Picus J, et al: Prognostic significance of plasma scatter 
factor/hepatocyte growth factor levels in patients with metastatic hormone- refractory prostate 
cancer: results from cancer and leukemia group B 150005/9480. Clin Genitourin Cancer 4:269-
74, 2006 
49. 
Taplin ME, George DJ, Halabi S, et al: Prognostic significance of plasma chromogranin a 
levels in patients with hormone-refractory prostate cancer treated in Cancer and Leukemia 
Group B 9480 study. Urology 66:386-91, 2005 
50. 
Nixon AB, Pang H, Starr M, et al: Prognostic and predictive blood-based biomarkers in patients 
with advanced pancreatic cancer: J Clin Oncol 29:10508 (suppl; abstr), 2011 
51. 
Halabi S, Small EJ, Kantoff PW, et al: Prognostic model for predicting survival in men with 
hormone-refractory metastatic prostate cancer. Journal of Clinical Oncology 21:1232-1237, 
2003 
52. 
Smaletz O, Scher HI, Small EJ: A nomogram for overall survival of patients with progressive 
metastatic prostate cancer following castration. Journal of Clinical Oncology  20(19):3972-
3982, 2002 
53. 
Armstrong AJ, Garrett-Mayer ES, Ou Yang Y, et al:  A contemporary prognostic nomogram 
for men with hormone-refractory metastatic prostate cancer (HRPC). Clinical Cancer Research 
13:6396-6403, 2007. 
54. 
Tan, A. D., P. J. Novotny, et al. (2008). "A patient-level meta-analytic investigation of the 
prognostic significance of baseline quality of life (QOL) for overall survival (OS) among 3,704 
patients participating in 24 North Central Cancer Treatment Group (NCCTG) and Mayo Clinic 
Cancer Center (MC) oncology clinical trials." J Clin Oncol 26.;    Sloan JA, Liu H, Sargent DJ, 
Satele D, Schaefer PL, Halyard MY, Grothey A, Garces YI, Brown PD, Loprinzi CL, Buckner 
JC. A patient-level pooled analysis of the prognostic significance of baseline fatigue for overall 
survival (OS) among 3,915 patients participating in 43 North Central Cancer Treatment Group 
(NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials. J Clin Oncol 2009; 
27(507s). 

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55. 
Halabi S, Lin CY, Kelly WK, Fizazi KS , Moul JW, Kaplan EB, Morris MJ, Small EJ. An 
updated prognostic model for predicting overall survival in first-line chemotherapy metastatic 
castration-resistant prostate cancer patients.  Published on-line (Journal of Clinical Oncology). 

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APPENDIX I: REGISTRATION FATIGUE/UNISCALE ASSESSMENT 
 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, and 
recorded in Medidata Rave®. 
 
If needed, this appendix can be adapted to use as a source document. A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
A translator may be used to administer the assessment. Additionally, since NCIC is participating in 
A031201, a French version of the assessment has been provided on the following page. 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can 
be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad 
as it 
can be 
 
 
 
 
 
 
 
 
 
As good 
as it can 
be 
 
 
 
 

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Fatigue/Uniscale Évaluation 
 
Instructions: S'il vous plaît, pour chaque article ci-dessous, encerclez le 
numéro (0-10) qui vous décrit le mieux. 
 
Comment décririez-vous : 
 
 
1. Votre niveau de fatigue moyen au cours de la dernière semaine, aujourd'hui inclus? 
  
0  
1  
2  
3  
4  
5  
6  
7 
 8  
9  
10  
Aucune fatigue  
 
La pire fatigue possible 
 
 
 
 
 
 
 
2. Votre qualité de vie globale dans la semaine écoulée, y compris aujourd'hui? 
 
 0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
Aussi mauvaise  
 
 
 
 
 
 
Aussi bonne 
que possible   
 
 
 
 
 
 
que possible 
 
 

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APPENDIX II: BPI-SF QUESTION #3 AND PHARMACOKINETICS PATIENT QUESTIONNAIRE 
 
 
 
 

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Brief Pain Index-Short Form Question #3 
 
Prospective patients for this study should be asked the question below for the purposes of determining 
eligibility per Section 4.6.3: 
 
 
Please rate your pain by marking the box beside the number that best describes your pain at its worst 
in the last 24 hours: 
 
☐ 0 
☐ 1 
☐ 2 
☐ 3 
☐ 4 
☐ 5 
☐ 6 
☐ 7 
☐ 8 
☐ 9 
☐ 10 
     No pain 
 
 
 
 
 
 
 
          Pain as bad  
     as you can imagine 
 
 
 

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Pharmacokinetics Patient Questionnaire 
 
Date: 
 
The following questions refer to the day before yesterday (2 days ago): 
What time did you take your study medication (enzalutamide)?  
 
_ _ : _ _    AM / PM 
What time did you last eat before taking your study medication (enzalutamide)? _ _ : _ _    AM / PM 
What time did you first eat after taking your study medication (enzalutamide)?  _ _ : _ _    AM / PM 
 
The following questions refer to yesterday (1 day ago): 
What time did you take your study medication (enzalutamide)?    
 
_ _ : _ _    AM / PM 
What time did you last eat before taking your study medication (enzalutamide)? _ _ : _ _    AM / PM 
What time did you first eat after taking your study medication (enzalutamide)?  _ _ : _ _    AM / PM 
 
The following questions refer to today (ONLY APPLIES IF YOU HAVE TAKEN YOUR STUDY 
MEDICATION BEFORE BEING SEEN IN THE CLINIC TODAY): 
What time did you take your study medication (enzalutamide)?    
 
 _ _ : _ _    AM / PM 
What time did you last eat before taking your study medication (enzalutamide)?  _ _ : _ _    AM / PM 
What time did you first eat after taking your study medication (enzalutamide)?    _ _ : _ _    AM / PM 
 
 
The following questions only need to be answered if you are taking abiraterone. 
 
The following questions refer to the day before yesterday (2 days ago): 
What time did you take your study medication (abiraterone)? 
 
          _ _ : _ _    AM / PM 
What time did you last eat before taking your study medication (abiraterone)?  _ _ : _ _    AM / PM 
What time did you first eat after taking your study medication (abiraterone)?    _ _ : _ _    AM / PM 
 
The following questions refer to yesterday (1 day ago): 
What time did you take your study medication (abiraterone)?   
 
          _ _ : _ _    AM / PM 
What time did you last eat before taking your study medication (abiraterone)?  _ _ : _ _    AM / PM 
What time did you first eat after taking your study medication (abiraterone)?    _ _ : _ _    AM / PM 
 
The following questions refer to today (ONLY APPLIES IF YOU HAVE TAKEN YOUR STUDY 
MEDICATION BEFORE BEING SEEN IN THE CLINIC TODAY): 
What time did you take your study medication (abiraterone)?   
 
          _ _ : _ _    AM / PM 
What time did you last eat before taking your study medication (abiraterone)? _ _ : _ _    AM / PM 
What time did you first eat after taking your study medication (abiraterone)?   _ _ : _ _    AM / PM 
 
 
 
 

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APPENDIX III: PATIENT MEDICATION LOGS 
 
 
 

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Enzalutamide Medication Log (Arms A and B) 
 
Number of Pills Given:____________  
Pill Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of Pills returned:_____________ 
 
(To be completed by RN)  
    
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS  
1. Take enzalutamide capsules orally in the morning with or without food. The capsules should be 
swallowed whole and must not be crushed or broken. 
2. If a dose is missed, please take the dose as soon as possible, but only if there are 12 or more hours 
remaining before the next dose. 
a. If the dose is due in less than 12 hours, skip the missed dose and take the next dose as 
scheduled 
b. Remember to record missed doses 
3. If vomiting occurs after taking enzalutamide, do not take a replacement dose on that day. Resume 
at the next scheduled dose 
4. Enzalutamide capsules should be stored at room temperature 
 
 
 

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CYCLE #: _______    # of WEEKS___________ 
 
DAY 
Medication 
DATE 
TIME 
Number of 40 mg 
capsules taken 
Comments 
Example 
Enzalutamide 
07/01/2012 
9:00 
AM 
4 
 
1 
Enzalutamide 
 
 
AM 
 
 
2 
Enzalutamide 
 
 
AM 
 
 
3 
Enzalutamide 
 
 
AM 
 
 
4 
Enzalutamide 
 
 
AM 
 
 
5 
Enzalutamide 
 
 
AM 
 
 
6 
Enzalutamide 
 
 
AM 
 
 
7 
Enzalutamide 
 
 
AM 
 
 
8 
Enzalutamide 
 
 
AM 
 
 
9 
Enzalutamide 
 
 
AM 
 
 
10 
Enzalutamide 
 
 
AM 
 
 
11 
Enzalutamide 
 
 
AM 
 
 
12 
Enzalutamide 
 
 
AM 
 
 
13 
Enzalutamide 
 
 
AM 
 
 
14 
Enzalutamide 
 
 
AM 
 
 
15 
Enzalutamide 
 
 
AM 
 
 
16 
Enzalutamide 
 
 
AM 
 
 
17 
Enzalutamide 
 
 
AM 
 
 
18 
Enzalutamide 
 
 
AM 
 
 
19 
Enzalutamide 
 
 
AM 
 
 
20 
Enzalutamide 
 
 
AM 
 
 
21 
Enzalutamide 
 
 
AM 
 
 
22 
Enzalutamide 
 
 
AM 
 
 
23 
Enzalutamide 
 
 
AM 
 
 
24 
Enzalutamide 
 
 
AM 
 
 
25 
Enzalutamide 
 
 
AM 
 
 
26 
Enzalutamide 
 
 
AM 
 
 
27 
Enzalutamide 
 
 
AM 
 
 
28 
Enzalutamide 
 
 
AM 
 
 
 
 
Patient Signature: _________________________________________Date:__________ 
Consenting Professional/Research RN Signature: ______________Date:__________  
Comments:_____________________________________________________________ 
 
 
 

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Abiraterone Medication Log (Arm B) 
 
Number of Pills Given:____________  
 
Total Daily Dose:________________ 
 
 
 
(To be completed by RN)  
    
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS  
1. Abiraterone must be taken on an empty stomach. Take abiraterone tablets orally in the evening 
without food at least 1 hour before OR 2 hours after a meal. The tablets should be swallowed 
whole and must not be crushed or broken. 
2. If a dose is missed, please take the dose as soon as possible, but only if there are 12 or more hours 
remaining before the next dose 
a. If the dose is due in less than 12 hours, skip the missed dose and take the next dose as 
scheduled 
3. If vomiting occurs after taking abiraterone, do not take a replacement dose on that day. Resume 
at the next scheduled dose 
4. Abiraterone tablets should be stored at room temperature 
 
 

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CYCLE #: _______    # of WEEKS___________ 
 
DAY 
Medication 
DATE 
TIME 
Number of 250 mg 
tablets taken 
Comments 
Example 
Abiraterone 
07/01/2012 
9:00 
PM 
4 
 
1 
Abiraterone 
 
 
PM 
 
 
2 
Abiraterone 
 
 
PM 
 
 
3 
Abiraterone 
 
 
PM 
 
 
4 
Abiraterone 
 
 
PM 
 
 
5 
Abiraterone 
 
 
PM 
 
 
6 
Abiraterone 
 
 
PM 
 
 
7 
Abiraterone 
 
 
PM 
 
 
8 
Abiraterone 
 
 
PM 
 
 
9 
Abiraterone 
 
 
PM 
 
 
10 
Abiraterone 
 
 
PM 
 
 
11 
Abiraterone 
 
 
PM 
 
 
12 
Abiraterone 
 
 
PM 
 
 
13 
Abiraterone 
 
 
PM 
 
 
14 
Abiraterone 
 
 
PM 
 
 
15 
Abiraterone 
 
 
PM 
 
 
16 
Abiraterone 
 
 
PM 
 
 
17 
Abiraterone 
 
 
PM 
 
 
18 
Abiraterone 
 
 
PM 
 
 
19 
Abiraterone 
 
 
PM 
 
 
20 
Abiraterone 
 
 
PM 
 
 
21 
Abiraterone 
 
 
PM 
 
 
22 
Abiraterone 
 
 
PM 
 
 
23 
Abiraterone 
 
 
PM 
 
 
24 
Abiraterone 
 
 
PM 
 
 
25 
Abiraterone 
 
 
PM 
 
 
26 
Abiraterone 
 
 
PM 
 
 
27 
Abiraterone 
 
 
PM 
 
 
28 
Abiraterone 
 
 
PM 
 
 
 
Patient Signature: _________________________________________Date:__________ 
Consenting Professional/Research RN Signature: ______________Date:__________  
Comments:_____________________________________________________________ 
 
 

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Prednisone Medication Log (Arm B) 
 
Number of Pills Given:____________  
 
Total Daily Dose:________________ 
 
 
 
(To be completed by RN)  
    
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS  
1. Take one prednisone tablet orally in the morning and in the evening with or without food.  
2. If a dose is missed, please take the dose as soon as possible, but only if there are 6 or more hours 
remaining before the next dose 
a. If the dose is due in less than 6 hours, skip the missed dose and take the next dose as 
scheduled 
3. If vomiting occurs after taking prednisone, do not take a replacement dose on that day. Resume 
at the next scheduled dose 
4. Prednisone tablets should be stored at room temperature 
 
 

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CYCLE #: _______    # of WEEKS___________ 
 
DAY 
Medication 
DATE 
TIME 
TIME 
Number of 5 mg 
tablets taken 
(AM/PM) 
Comments 
Example Prednisone 
07/01/2012 
9:00 
AM 
9:00 
PM 
1/1 
 
1 
Prednisone 
 
 
AM 
 
PM 
 
 
2 
Prednisone 
 
 
AM 
 
PM 
 
 
3 
Prednisone 
 
 
AM 
 
PM 
 
 
4 
Prednisone 
 
 
AM 
 
PM 
 
 
5 
Prednisone 
 
 
AM 
 
PM 
 
 
6 
Prednisone 
 
 
AM 
 
PM 
 
 
7 
Prednisone 
 
 
AM 
 
PM 
 
 
8 
Prednisone 
 
 
AM 
 
PM 
 
 
9 
Prednisone 
 
 
AM 
 
PM 
 
 
10 
Prednisone 
 
 
AM 
 
PM 
 
 
11 
Prednisone 
 
 
AM 
 
PM 
 
 
12 
Prednisone 
 
 
AM 
 
PM 
 
 
13 
Prednisone 
 
 
AM 
 
PM 
 
 
14 
Prednisone 
 
 
AM 
 
PM 
 
 
15 
Prednisone 
 
 
AM 
 
PM 
 
 
16 
Prednisone 
 
 
AM 
 
PM 
 
 
17 
Prednisone 
 
 
AM 
 
PM 
 
 
18 
Prednisone 
 
 
AM 
 
PM 
 
 
19 
Prednisone 
 
 
AM 
 
PM 
 
 
20 
Prednisone 
 
 
AM 
 
PM 
 
 
21 
Prednisone 
 
 
AM 
 
PM 
 
 
22 
Prednisone 
 
 
AM 
 
PM 
 
 
23 
Prednisone 
 
 
AM 
 
PM 
 
 
24 
Prednisone 
 
 
AM 
 
PM 
 
 
25 
Prednisone 
 
 
AM 
 
PM 
 
 
26 
Prednisone 
 
 
AM 
 
PM 
 
 
27 
Prednisone 
 
 
AM 
 
PM 
 
 
28 
Prednisone 
 
 
AM 
 
PM 
 
 
 
Patient Signature: _________________________________________Date:__________ 
Consenting Professional/Research RN Signature: ______________Date:__________  
Comments:_____________________________________________________________ 
 

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APPENDIX IV: GUIDE TO THE HALABI NOMOGRAM ON-LINE CALCULATOR 
1. Access the Halabi Nomogram at: 
 https://www.cancer.duke.edu/Nomogram/firstlinechemotherapy.html 
2. In the top right, ensure that “NO” is selected for “Display Output?” This will remove redundant 
statistical details from the output and just provide the results needed for this trial. 
3. For “Risk Group Classification Question”, ensure that “3 Groups” is selected. 
4. Respond to all of the remaining questions. Note that you can view the valid lab ranges by hovering 
your pointer over the lab name.  Those valid ranges are: 
a. Albumin: 0 - 10 g/dL 
b. Hemoglobin: 6.0 - 17.0 g/dL 
c. Alkaline Phosphatase: 1.0 - 9,000.0 U/L 
d. PSA: 1.0 - 9,000.0 ng/mL 
e. Opioid Analgesic use (yes, no) 
f. LDH > 1 X ULN (yes, no) 
5. Once all questions have been answered, click the “Validate!” button. This will refresh the screen with 
the predicted risk grouping for the patient based on the provided data. 
6. Save the results as a PDF by clicking the “PDF” link and upload the PDF via Medidata Rave® into 
the form for “Supporting Documentation” in the Baseline folder. 
7. Note the risk grouping marked “Yes”: Low, Intermediate, or High. This is the value that must be 
entered as a stratification factor during Step 1 of the OPEN registration process. 

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APPENDIX V: PCWG2 BONE SCAN ASSESSMENT TOOL GUIDE 
This study will use the Prostate Cancer Working Group 2 (PCWG2) response criteria for evaluating bone 
metastases for progression. This study will use Medidata Rave® for remote data capture of all study data.  
This appendix includes the official validated forms on which the A031201 data collection is based. The 
forms within this appendix are provided for your information and guidance only. You may use these forms 
at your discretion for local record keeping, but these forms are not required for A031201 data capture and 
if used these forms should not be uploaded to Medidata Rave®. 
In the Week 9 and Post Week 9 Bone Scan Assessment Forms, the tracer uptake question is asking if 
what is viewed on the bone scan is related to metastatic disease, as opposed to arthritic lesions or 
traumatic injuries. 
If a patient has metastatic disease on the scans but no new lesions in comparison to the appropriate 
reference scan, the tracer uptake question may be answered “yes,” new regions may be left blank, 
and the number of new lesions would be zero. 
The baseline scan serves as the "reference" scan at Week 9 restaging. The Week 9 scan serves as the 
"reference" scan for all subsequent scans. Please reference Section 13.1 for further details. 
NOTE: Medidata Rave® does not collect exact locations of new metastases using a skeletal template for 
this study, as is depicted in these forms. It is sufficient to collect region of new disease in Medidata Rave®. 
 
Baseline Bone Scan Assessment Form 
 
 
 
 
 
 

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Week 9 Bone Scan Assessment Form 
 
 
 
 

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Post-Week 9 Bone Scan Assessment Form 
 
 
 
 
 

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Progression Assessment Worksheet 
 
 
 

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APPENDIX VI: PCWG2 PROGRESSION SCENARIOS