Phase II Randomized Placebo-Controlled Double-Blind Study of Salvage Radiation Therapy (SRT) Plus Placebo Versus SRT Plus Enzalutamide in Men With High-Risk PSA-Recurrent Prostate Cancer After Radical Prostatectomy
Phase: PHASE2
Conditions: Adenocarcinoma of the Prostate
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Salvage XRT +/- Enzalutamide 
Protocol Chair: Daniel Song, MD 
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NCT02203695
February 15, 2022 
Johns Hopkins University 
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Phase II Randomized Placebo‐Controlled Double‐Blind Study of Salvage Radiation 
Therapy (SRT) Plus Placebo Versus SRT Plus Enzalutamide in Men with High‐Risk PSA‐
Recurrent Prostate Cancer after Radical Prostatectomy (SALV‐ENZA) 
PCCTC LOI #: c14-138
IND #: 121891 -Exempt 
The Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University 
Principal Investigator 
Statistician 
Daniel Song (Radiation Oncologist) 
Emmanuel Antonarakis (Medical Oncologist) 
Hao Wang 
1550 Orleans St 
CRB2 Rm 406 
Baltimore, MD 21231 
410-614-3880
550 N. Broadway St 
550 Building Rm 1101 
Baltimore, MD 21231 
email: dsong2@jhmi.edu & eantona1@jhmi.edu 
email: hwang76@jhmi.edu
Co-investigators 
Michael Carducci 
Mario Eisenberger 
Tamara Lotan 
Sam Denmeade 
Hans Hammers 
Channing Paller 
Theodore L. DeWeese 
The Sidney Kimmel Comprehensive Cancer 
Center 
Johns Hopkins Hospital 
401 N. Broadway 
Baltimore, MD 21287 
Prostate Cancer Clinical Trials Consortium 
55 Fifth Avenue, 13th Floor 
New York, NY 10003 
Participating Site 
Lead Investigator 
Role 

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CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information 
contained herein will not be disclosed to others without written authorization from the lead 
site/sponsor, except to the extent necessary to initiate the study or conduct study-related 
activities. 

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February 15, 2022 
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INVESTIGATOR’S APPROVAL OF PROTOCOL 
 
Title: Phase II Randomized Placebo‐Controlled Double‐Blind Study of Salvage Radiation 
Therapy (SRT) Plus Placebo Versus SRT Plus Enzalutamide in Men with High‐Risk PSA‐
Recurrent Prostate Cancer after Radical Prostatectomy (SALV‐ENZA) 
 
 
 
 
 
Principal Investigator Signature:  
_______________________________________________________ 
Principal Investigator Print:  
Daniel Song/Emmanuel Antonarakis_________ 
Date:   
 
 
 
_______________________________________________________
SYNOPSIS 
Title 
Phase II Randomized Placebo-Controlled Double-Blind Study of Salvage Radiation Therapy (SRT) 
Plus Placebo Versus SRT Plus Enzalutamide in Men with High-Risk PSA-Recurrent Prostate Cancer 
after Radical Prostatectomy 
Lead site 
The Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University 
Sponsor 
Investigator Initiated Johns Hopkins University IND Exempt trial 
Investigational 
agent 
Enzalutamide 160 mg PO once daily for 6 months 
Phase 
II 
Target 
population 
Patients with biochemical recurrence after prostatectomy who are considered candidates for 
salvage radiation therapy (XRT) 
 
Adult male >18 years of age 
 
Patients must have histologically confirmed adenocarcinoma of the prostate gland 
 
Patients must have received primary treatment with radical prostatectomy. 
 
Patients must have evidence of biochemical (PSA) relapse after prostatectomy, defined by one 
rise in PSA above a baseline detectable value (≥0.05 ng/mL) using measurements taken at least 
4 weeks apart from each other (all PSA values must be within 12 months of study entry). 

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 
Patients must have pathological Gleason (pG) sum 8-10; or pG sum 7 and either pT3 or R1 
disease (i.e. positive margins.). 
 
Patients must have an absolute PSA level between >0.05 and <0.7 ng/mL at the time of study 
entry. 
 
Patients must have non-metastatic (M0) disease, as defined by a lack of metastases seen on CT 
scan of the abdomen/pelvis and whole-body radionuclide 99Tc bone scan, (or sodium fluoride 
PET scan) taken within 3 months of study entry. 
 
Patients must have had node negative (pN0) disease found at the time of surgery.  If a nodal 
dissection was not performed at the original surgery then patients must be N0, as defined by a 
lack of radiographic or clinical evidence of local-regional tumor recurrence, including lack of 
pelvic lymph nodes ≥2 cm in short-axis diameter.  
 
Patients must have non-castrate levels of serum testosterone (≥ 150 ng/dL), as evidence by 
any testosterone taken within six (6) months of enrollment 
 
Patients must not have previously received hormonal therapy (LHRH agonist/antagonist, 
antiandrogen, or both), with the exception of neoadjuvant or adjuvant hormones given in 
conjunction with prostatectomy. In such cases, hormone therapy must have been administered 
for ≤6 months, discontinued ≥6 months ago, and serum testosterone must be ≥150 ng/dL. 
 
Patients must have ECOG performance status of 0-1, and life expectancy ≥ 3 years. 
 
Patients must have laboratory test results within the ranges listed below: 
o WBC ≥ 3000/mm³ 
o Granulocytes ≥ 1500/mm³ 
o Hemoglobin ≥ 9 g/dL 
o Platelets ≥ 100,000/mm³ 
o Bilirubin ≤ 1.8 mg/dL 
o ALT and AST ≤ 2.5 times the institutional upper limit of normal 
o Creatinine ≤ 1.8 mg/dL OR a calculated creatinine clearance ≥ 60 mL/hr 
 
 
Patients must be disease-free from prior malignancies for ≥3 years, with the exception of non-
melanoma skin cancers and superficial urothelial cancers. 
 
Patients must have the ability to swallow the study drug whole as a tablet or capsule. 
 
Willingness to use adequate methods of contraception throughout study participation and for 
at least 3 months after completing therapy 
 
The patient was informed about the positive survival results of the RTOG 96-01 clinical trial, 
and has elected to forgo treatment with high-dose bicalutamide 
Study centers 
Six sites in the United States, including the lead site (SKCCC, Johns Hopkins University) 
Start 
date/Duration 
First patients are expected to be enrolled in March 2015. Accrual has been slower than originally 
estimated but we will end accrual March 2020 with additional 21 months of follow-up after the last 
patient has been entered. 
Expected 
enrollment 
96 patients 
Rationale 
The primary hypothesis of this study is that outcomes for patients with biochemically recurrent 
prostate cancer following radical prostatectomy will be improved by the addition of enzalutamide 

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for 6-months compared to standard-of-care salvage radiation therapy to allow for further study in 
the definitive phase III setting. This study builds on the prior success of high-dose bicalutamide (for 
24 months) when combined with salvage XRT, while using a newer more potent anti-androgen for a 
shorter duration of time (6 months) in an effort to minimize adverse effects. 
Objectives 
Primary 
 
The primary objective of the study is to evaluate the efficacy of the two treatment regimens in 
terms of freedom-from-PSA-progression (FFPP). FFPP is defined as the time from randomization to 
the date of PSA progression. In patients who achieve an undetectable PSA value (defined as ≤0.1 
ng/mL), PSA progression is defined as a detectable PSA value (≥0.2 ng/mL) that is confirmed by a 
second consecutive PSA value obtained ≥8 weeks later which is higher (and ≥0.4 ng/mL).  In 
patients who do not achieve an undetectable PSA, PSA progression is defined as a 0.2 ng/mL 
increase from nadir that is confirmed by a second consecutive PSA value obtained ≥8 weeks later 
which is higher. 
Secondary 
 
Time to local recurrence within the radiation field (confirmed pathologically). 
 
Metastasis-free survival (radiographic MFS). Metastasis-free survival will be defined as the time 
interval from the date of registration to date of evidence of systemic disease on bone scan or 
cross sectional imaging or death, whichever occurs first. 
 
Safety as determined by frequency and severity of adverse events (AEs), feasibility, and 
tolerability. 
 
Study design 
This is a randomized, double-blind, phase II, prospective, multicenter study in male adults with 
biochemically recurrent prostate cancer following radical prostatectomy. Following registration, 
androgen receptor blockade (ARB) in the form of enzalutamide 160 mg PO once daily (or placebo 
PO once daily) for 6 months will be administered. Following 2 months of study drug therapy, 
external beam radiotherapy to 66.6-70.2 Gy will be administered to the prostate bed (no pelvic 
nodes) over 7-8 weeks. Radiotherapy will be initiated starting on day 61, with allowance up to day 
92 for resolution of study drug-related adverse effects. 
 

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Treatment Arms and Study Procedures 
Patients will be randomized equally (1:1) to one of two arms – 
 
Arm A (control): Salvage radiation therapy (3D-CRT/IMRT)                66.6-
70.2 Gy given 1.8 Gy M-F for 37 -39 fx 
PLUS Placebo PO daily for 6 months (2 months prior to SRT, 2 
months during SRT and 2 months following SRT) 
 
Arm B (experimental): Salvage radiation therapy (3D-CRT/IMRT) 66.6-70.2 
Gy given 1.8 Gy M-F for 37-39 fx 
PLUS Enzalutamide (MDV3100) 160 mg PO once daily for 6 months 
(2 months prior to SRT, 2 months during SRT and 2 months 
following SRT) 
 
Criteria for 
evaluation: 
Primary Endpoint: 
–Freedom-from-PSA-progression (FFPP). 
 
Secondary Endpoints: 
–Local recurrence within the radiation field (confirmed pathologically). 
–Metastasis-free survival (MFS). 
–Frequency and severity of adverse events (AEs). 
 
Statistical 
method: 
Primary Analysis: 
 
Freedom-from-PSA-progression (FFPP) will be summarized using Kaplan-Meier method by 
treatment arms. FFPP curves will also be displayed graphically. Differences in FFPP between 
treatment arms will be compared by the log rank test. The Cox proportional hazards regression 
model will be fitted, and the estimated hazard ratio (Arm B/Arm A) and corresponding 95% CI will 
be provided.  FFPP probability will be estimated using the Kaplan-Meier method.  Additionally, Cox 

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regression models will be used to explore the potential influences of the other prognostic factors on 
the primary FFPP endpoints. 
 
Secondary Analysis: 
 
Time-to-event endpoints (time to local recurrence and MFS) will be analyzed similarly as described 
for the primary endpoint (FFPP). 
 
For safety analysis, overall safety profile and toleration of Arm A and Arm B will be characterized 
by type, frequency, severity, timing and relationship of study therapy of adverse events and 
laboratory abnormalities. Adverse events will be summarized by the frequency of patients 
experiencing treatment emergent adverse events corresponding to body systems and by worst NCI 
CTCAE (version 4.0) grade. 
Safety 
analysis: 
Standard safety summaries will be provided for treatment exposure, patient disposition, adverse 
events leading to discontinuation, serious adverse events, and all events resulting in death, 
including those up to 30 days after treatment discontinuation. The incidence of adverse events will 
be tabulated and reviewed for potential significance and clinical importance. 

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TABLE OF CONTENTS 
[Press F9 to update] 
1. INTRODUCTION .............................................................................................................................................................. 10 
1.1 
Disease Background .......................................................................................................................................................... 10 
1.2 
Treatment Background .................................................................................................................................................... 10 
1.3 
Rationale for Combination SRT and Enzalutamide Treatment Postoperatively .................................... 11 
2.1 
Primary Objective ............................................................................................................................................................... 13 
2.2 
Secondary Objectives ........................................................................................................................................................ 14 
3. 
PATIENT SELECTION ............................................................................................................................................. 14 
3.1 
Target Population ............................................................................................................................................................... 14 
3.2 
Expected Enrollment ......................................................................................................................................................... 14 
3.3 
Inclusion Criteria ................................................................................................................................................................ 14 
3.4 
Exclusion Criteria ............................................................................................................................................................... 16 
3.5 
Inclusion of Minorities ...................................................................................................................................................... 16 
4. 
PATIENT REGISTRATION AND ENROLLMENT PLAN .................................................................................... 17 
4.1 
Registration Procedure .................................................................................................................................................... 17 
5. 
TREATMENT/INTERVENTION PLAN ................................................................................................................. 18 
5.1 
Screening/Baseline Assessment .................................................................................................................................. 21 
5.2 
Treatment Period ................................................................................................................................................................ 22 
5.3 
Treatment-Limiting Adverse Event ............................................................................................................................ 24 
5.4 
Dose Modifications ............................................................................................................................................................. 24 
5.5 
End of Treatment/Treatment Discontinuation Visit (+/- 30 days from last dose) ............................... 25 
5.6 
Follow-up (Every 3 months for >24 months or until death) ........................................................................... 25 
5.7 
Concomitant Medications ............................................................................................................................................... 25 
6. 
THERAPEUTIC AGENTS ......................................................................................................................................... 27 
6.1 
Enzalutamide ........................................................................................................................................................................ 27 
6.1.1  Pharmacokinetics ................................................................................................................................................................ 28 
6.1.2.  Dosage Selected .................................................................................................................................................................... 28 
6.1.2.1 Preparation, and Schedule of Administration ......................................................................................................... 28 
6.1.3.1Dosing Delays and Treatment Modifications for Toxicity ................................................................................... 29 
6.2 
Salvage Radiation Therapy (SRT) ................................................................................................................................ 29 
6.3 
Removing Patients from the Protocol........................................................................................................................ 33 
6.4 
Concomitant Medications and Supportive Care .................................................................................................... 33 
7. 
ADVERSE EVENTS ................................................................................................................................................... 33 
7.1 
Definitions .............................................................................................................................................................................. 33 
7.2 
Expectedness ........................................................................................................................................................................ 35 
7.3 
Recording and Grading ..................................................................................................................................................... 36 
7.4 
Reporting Adverse Events .............................................................................................................................................. 37 
8. 
CRITERIA FOR OUTCOME ASSESSMENT .......................................................................................................... 38 
8.1 
Outcome Assessment ........................................................................................................................................................ 38 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS ............................................................................ 41 
9.2 
Data Entry .............................................................................................................................................................................. 42 
9.3 
Data Management ............................................................................................................................................................... 43 
9.4 
Study Monitoring and Quality Assurance ................................................................................................................ 43 
9.5 
Clinical Trial Agreement .................................................................................................................................................. 44 
9.6 
End of Study .......................................................................................................................................................................... 44 
10. 
STATISTICAL CONSIDERATIONS ........................................................................................................................ 44 
10.1  Study Endpoints .................................................................................................................................................................. 44 
10.2  Analysis Populations ......................................................................................................................................................... 45 
10.3  Safety Analysis ..................................................................................................................................................................... 46 
10.4  Statistical Procedures ....................................................................................................................................................... 47 
11. 
PROTECTION OF HUMAN SUBJECTS ................................................................................................................. 48 

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11.1  Ethical Considerations ...................................................................................................................................................... 48 
11.2  Protocol Amendments ...................................................................................................................................................... 49 
11.3  Written Informed Consent .............................................................................................................................................. 49 
11.4  Protection of Privacy ......................................................................................................................................................... 49 
11.5  Terminating or Modifying the Study .......................................................................................................................... 50 
12. 
REFERENCES ............................................................................................................................................................. 51 
APPENDIX A: PERFORMANCE STATUS CRITERIA ..................................................................................................... 54 
APPENDIX B: MEDICATIONS WITH THE POTENTIAL FOR DRUG‐DRUG INTERACTIONS ............................ 55 
APPENDIX C: GLOSSARY OF ABBREVIATIONS AND ACRONYMS .......................................................................... 56 
APPENDIX D: DSMP ............................................................................................................................................. 61 
 
List of Tables 
Table 1 
Study Calendar 
19 
Table 2 
Agents Studied in this Protocol 
27 
Table 3 
Relationship of Adverse Event to Study Drug 
35 
 
List of Figures 
Treatment Schema 
5 
Figure 1 
Clinical states of prostate cancer 
9 
Figure 2 
Treatment Schema 
22 
Figure 3 
Chemical Structure of Enzalutamide 
26 

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1. INTRODUCTION 
1.1 
Disease Background 
Prostate cancer is the second leading cause of cancer deaths in men. According to American 
Cancer Society estimates in 2012, as many as 241,740 American men were diagnosed with 
prostate cancer, and nearly 28,170 died of the disease1. 
The course of prostate cancer from diagnosis to death is best categorized as a series of 
clinical states (Fig. 1). These clinical states involve the complex interplay of a network of 
signaling molecules that collectively promote net cell proliferation relative to cell death. 
Based on the extent of disease, hormonal status, and absence or presence of detectable 
metastases on an imaging study, the states are localized disease, rising levels of prostate-
specific antigen (PSA) after radiation therapy or surgery with no detectable metastases, and 
clinical metastases in the non-castrate or castrate state.  Most men that ultimately die of 
prostate cancer die from metastatic castrate-resistant disease1.  However, of the 
approximately 30,000 men that die of prostate cancer per year, the vast majority of these 
men originally presented with localized prostate carcinoma which failed local therapy such 
as radical prostatectomy and progress along the pathway as shown in Fig. 1.  Importantly, 
these men at the time of initial PSA relapse following surgery still represent potentially 
curable patients with salvage radiation (see Fig. 1 – “Rising PSA”). 
 
 
Figure 1 
Clinical states of prostate cancer – In red highlights the focus group of this 
trial. 
 
1.2 
Treatment Background 
While a significant proportion of patients with clinically localized prostate cancer will be 
cured with definitive local therapy, those patients with high-risk features such as Gleason 
grade 8-10, positive lymph nodes, positive surgical margins or positive seminal vesicles 
have a 50-75% chance of disease recurrence in 10 years 2-7.  Men who undergo 
prostatectomy and are found to have any of these features have cure rates of less than 25% 
after long-term follow-up 3,7,8. As the use of prostatectomy has increased substantially over 
the last 10 years, so has the application of post-prostatectomy salvage radiotherapy (SRT). 
SRT is the mainstay of salvage treatment for men with a persistently detectable PSA or a 
delayed rise in PSA without evidence of metastasis 9-17.  Because there are no published SRT 
randomized trials, the rationale for this treatment is derived mostly from retrospective 
series. The largest retrospective analysis was a multi-institutional effort reported by 

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Stephenson et al.17 They examined predictors of response to SRT and found that high 
Gleason score, high pre-SRT PSA, negative prostatectomy surgical margins, short PSA 
doubling time (PSADT), and seminal vesicle involvement were independently associated 
with adverse outcome. Similar factors have been reported in many of the other 
retrospective series as well18. Despite gains in understanding how to select patients for 
salvage treatment, higher level prospective clinical evidence on the outcome of patients 
receiving well-delineated treatment (e.g., RT technique, use of androgen 
deprivation/androgen receptor blockade) is still lacking.  Regardless, it is clear that SRT 
alone is not likely to afford high levels of Freedom from PSA progression (FFPP) or cure in 
high-risk individuals. 
1.3 
Rationale for Combination SRT and Enzalutamide Treatment Postoperatively 
1.3.1 
Rationale for improving SRT outcomes with hormonal therapy 
Several randomized trials have demonstrated that the addition of hormone therapy 
improves overall survival in men receiving primary radiotherapy for prostate 
cancer8,19-23. There is no consensus on how to apply hormonal therapy or in what 
patients in the postoperative setting24-29 and until recently there were no reported 
randomized controlled trials addressing the role of hormone therapy in men 
receiving post-operative radiotherapy. 
 
One study has recently reported, RTOG 96-01 compared SRT alone to SRT plus 2 
years of androgen receptor blockade (ARB), accomplished using 150 mg/day of 
Casodex.  RTOG 96-01 has shown significantly improved overall survival by 5% at 
12-years and reduced incidence of metastatic prostate cancer and death from 
prostate cancer by half without adding significantly to radiation toxicity. Post hoc 
analysis demonstrated that most of the benefit came from patients with PSA >0.7 
and that men with PSA < 0.7 appeared to not benefit and in fact survival was worse 
in these men placed on high-dose bicalutamide.  A few notable criticisms of this trial 
that was conducted over 15 years ago was the use of a much lower salvage radiation 
therapy dose of 64.8 Gy, and the study population does not represent the majority of 
men with rising PSA following surgery seen in the modern era where most men 
present with PSA <1.  In addition, the use of RTOG 96-01 does also not provide 
information on the use of short-term hormonal therapy in combination with SRT. 
 
Another trial that has reported recently is GETUG-16 that compared SRT alone to 
SRT plus 6-mos of androgen deprivation therapy using an LHRH analog.  GETUG-16 
showed an improvement of 5-year any progression-free survival of 62% vs 80%.  
The follow-up was too short to determine overall or prostate cancer specific 
survival at this time. 
 
Three retrospective non-randomized studies have compared the outcome of SRT 
alone versus SRT plus short-term (4-6 months) hormone therapy, and have 
observed improved biochemical control rates with the addition of hormone 
therapy24,26,29. 
 
RTOG 05-34 is a Phase III three-arm clinical trial designed to address multiple 
questions regarding SRT.  The most germane question to our proposed trial, 
attempts to determine whether short-term androgen deprivation (AD) of 4-6 
months plus SRT is superior to SRT alone.  RTOG 05-03 specifies AD as combined 

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androgen deprivation in the form of LHRH agonist and first generation ARB such as 
flutamide or bicalutamide. 
 
RADICALS is an international, multi-center, open-labeled, randomized trial of 
prostate cancer patients with two separate randomizations for overlapping patient 
groups.  The first randomization is between early post-operative or adjuvant 
radiotherapy and deferred SRT (for PSA failure). The other randomization is 
performed shortly before the administration of postoperative radiotherapy and is 
either no hormone therapy, short-term (6-mos) or long-term (2-years) hormone 
therapy in combination with SRT. 
1.3.2 
Rationale for dose and fractionation used with SRT 
Our proposal prescribes 66.6-70.2 Gy total given in 1.8 Gy fractions, which is a 
commonly used dose range although we do acknowledge the use of 2 Gy and higher 
total doses in the salvage radiation setting.  The largest RTOG Phase III salvage 
radiation trial RTOG 05-34 uses 64.8-70.2 Gy in 1.8 Gy.  The RADICALS trial is 
another Phase III adjuvant/salvage radiation trial which is using 66 Gy in 2 Gy 
fractions.  The biologically equivalent dose (BED) assuming the linear quadratic 
formalization suggests that 66 Gy in 2 Gy fractions is equivalent/similar to 70.2 Gy 
in 1.8 Gy fractions over a range of alpha/beta 1.5, 3 and 10 [(BED10 = 2 Gy x 33 = 
79.20; BED3 = 2 Gy x 33 = 110; BED1.5 = 2 Gy x 33 = 154) vs. (BED10 = 1.8 Gy x 39 = 
82.84; BED3 = 1.8 Gy x 39 = 112.32; BED1.5 = 1.8 Gy x 39 = 154.44.  Doses higher 
than 70.2 Gy such as 74 Gy although used by some in the community and for which 
there is some retrospective data31 is not a standard. 
1.3.3 
Rationale for enzalutamide versus combined androgen deprivation in combination 
with SRT 
Androgen receptor signaling promotes dysregulated growth in the majority of 
untreated prostate cancers.  Androgen deprivation (AD) via medical or surgical 
castration can induce apoptosis or senescence in prostate cancer cells however 
those cells that do not die will ultimately become castration-resistant and will grow 
despite androgen deprivation.  Molecular profiling studies have demonstrated 
progressive changes that occur in the androgen receptor after development of 
castrate-resistance, most frequently overexpression of the androgen receptor, 
which can occur via several mechanisms following AD 32.  AD is also associated with 
long term metabolic adverse effects (adverse changes in fat body mass, lipid and 
glycemic profiles) and decreases in bone mineral density (BMD).  Given this, more 
potent androgen receptor blockade (ARB) is desirable.  First-generation ARB with 
bicalutamide has been used in combination with SRT as discussed above.  
Bicalutamide is easy to administer, well tolerated and has a favorable side effect 
profile, however as with all first-generation androgen receptor antagonists, displays 
weak agonist properties, particularly in the setting of increased androgen receptor 
levels.  These agents also demonstrate relatively weak binding affinity for the 
androgen receptor when compared to novel agents in development 33,34. 
 
Enzalutamide is a second-generation androgen receptor signaling inhibitor that 
significantly prolongs survival in patients with metastatic castration-resistant 
prostate cancer who have received prior docetaxel chemotherapy 35,36.  
Enzalutamide has demonstrated activity in cells that overexpress the androgen 
receptor.  Unlike previous ARB agents, Enzalutamide does not display any agonist 
properties and blocks translocation of the ligand-receptor complex into the nucleus 

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preventing DNA binding 33.  Enzalutamide is an oral agent that is generally well 
tolerated and does not require concurrent steroid administration, which makes it an 
ideal candidate for combination with SRT. 
 
Finally, provocative preliminary Phase II data presented at the ASCO 2013 by 
Mathew Smith and colleagues assessed the efficacy and safety of 25-weeks (~6-
mos) of enzalutamide alone in prostate cancer of all stages who had never received 
hormone therapy; presenting with non-castrate testosterone levels ( 230 ng/dL).  
Enzalutamide alone for 6-mos achieved a high PSA response rate with efficacy 
similar to castration, but .in contrast to castration, BMD remained stable and 
metabolic variables were not substantially impacted. 
 
The trial described here differs from RTOG 96-01, GETUG-16, RTOG 05-34 and 
RADICALS in several ways. First, the eligibility criteria are stricter; less favorable 
patients have been selected and relative to RTOG 96-01 contemporary patients with 
modern radiotherapy dose and techniques are being used. Second, short-term ARB 
is being tested, while in RTOG 96-01 and RADICALS long-term ARB of 2-years was 
examined. Finally, and most importantly, we are testing the second generation ARB 
agent, enzalutamide, alone in combination with SRT as opposed to GETUG-16, RTOG 
05-34 and RADICALS which use AD. 
 
This trial is not intended to address the efficacy of SRT alone over observation. The 
complete response rate (a drop in PSA to undetectable levels) after SRT is 70%-80% 
and durable responses are observed in 30%-40% of patients. For these reasons, it is 
not feasible or appropriate to randomize men between observation and SRT. The 
more important issue is whether the proportion of durable responses is increased 
by altering the therapeutic approach, such as the use of enhanced ARB using 
enzalutamide.  Similarly, as described above, there is considerable controversy 
regarding the benefit of adding high-dose bicalutamide to men with rising PSA 
where there PSA is < 0.7 following surgery.  Given differences in this old trial 
consisting of lower SRT dose of 64.8 Gy, and the non-contemporary study 
population we think it is reasonable to offer SRT alone as a control arm as long as 
men are informed of the survival results of RTOG 96-01 and the controversy 
regarding this study in the modern era. 
2. OBJECTIVES 
2.1 
Primary Objective 
The primary efficacy endpoint is the rate of Freedom-from-PSA-progression (FFPP). FFPP is 
defined as the time from randomization to the date of PSA progression. A subject who does 
not have PSA progression at the time of the analysis will be censored at the last date of PSA 
measurement. 
 
In patients who achieve an undetectable PSA value (defined as ≤0.1 ng/mL), PSA 
progression is defined as a detectable PSA value (≥0.2 ng/mL) that is confirmed by a second 
consecutive PSA value obtained ≥8 weeks later which is higher (and ≥0.4 ng/mL).  In 
patients who do not achieve an undetectable PSA, PSA progression is defined as a 0.2 ng/mL 
increase from nadir that is confirmed by a second consecutive PSA value obtained ≥8 weeks 
later which is higher.  The date of PSA progression will be defined as the first date of PSA 
rise from nadir or baseline. 

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2.2 
Secondary Objectives 
 
Local recurrence within the radiation field (confirmed pathologically)  
 
Metastasis-free survival (MFS) rates. Metastasis-free survival will be defined as the 
time from the date of registration to date of evidence of systemic disease on bone 
scan or cross sectional imaging or death, which occurs first. 
 
Safety, feasibility, and tolerability as assessed by NCI Common Toxicity Scales (v4.0), 
quality of life (EPIC survey), and achievement of accrual goals. 
3. 
PATIENT SELECTION 
3.1 
Target Population 
Prostate adenocarcinoma following radical prostatectomy with evidence of recurrent 
disease as measured only by rising PSA, without evidence of metastatic disease by bone 
scan or CT scan within 12 weeks of entry (i.e. the salvage radiotherapy population). 
3.2 
Expected Enrollment 
A total of 96 patients will be included in this study. The first patients are expected to be 
enrolled in March 2015. Accrual was expected to be completed in 18 months once the 
protocol has been approved by the IRB at each participating institution, but has been slower 
than expected at about 10 patients per 6 months. We plan to close accrual at March 2020.  
3.3 
Inclusion Criteria 
To be included in this study, patients should meet all of the following criteria: 
 
Willing and able to provide written informed consent and HIPAA authorization for 
the release of personal health information. 
NOTE: HIPAA authorization may be either included in the informed consent or 
obtained separately. 
 
Males aged 18 years of age and above 
 
Patients must have histologically confirmed adenocarcinoma of the prostate gland 
 
Patients must have received primary treatment with radical prostatectomy. 
 
Patients must have evidence of biochemical (PSA) relapse after prostatectomy, 
defined by one rise in PSA above a baseline detectable value (≥0.05 ng/mL) using 
measurements taken at least 4 weeks apart from each other (all PSA values must be 
within 12 months of study entry). 
 
Patients must have pathological Gleason (pG) sum 8-10; or pG sum 7 and either pT3 
or R1 disease (i.e. positive margins.). 
 
Patients must have an absolute PSA level between >0.05 and <0.7 ng/mL at the time 
of study entry. 
 
Patients must have non-metastatic (M0) disease, as defined by a lack of metastases 
seen on CT scan of the /abdomen/pelvis and whole-body radionuclide 99Tc bone 
scan, (or sodium fluoride PET scan) taken within 3 months of study entry. 
 
Patients must have had node negative (pN0) disease found at the time of surgery.  If 
a nodal dissection was not performed at the original surgery then patients must be 
N0, as defined by a lack of radiographic or clinical evidence of local-regional tumor 
recurrence, including pelvic lymph nodes ≥2 cm in short-axis diameter.  

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 
Patients must have non-castrate levels of serum testosterone (≥ 150 ng/dL). 
 
Patients must not have previously received hormonal therapy (LHRH agonist, 
antiandrogen, or both), with the exception of neoadjuvant or adjuvant hormones 
given in conjunction with prostatectomy. In such cases, hormone therapy must have 
been administered for ≤6 months, discontinued ≥6 months ago, and serum 
testosterone must be ≥150 ng/dL. 
 
Patients must have ECOG performance status of 0-1, and life expectancy ≥ 3 years. 
 
Patients must have laboratory test results within the ranges listed below within 4 
weeks of enrollment: 
o WBC ≥ 3000/mm³ 
o Granulocytes ≥ 1500/mm³ 
o Hemoglobin≥9 g/dL 
o Platelets ≥ 100,000/mm³ 
o Bilirubin ≤1.8 mg/dL 
o ALT and AST ≤ 2.5 times the institutional upper limit of normal 
o Creatinine ≤ 1.8 mg/dL OR a calculated creatinine clearance ≥ 60 mL/hr 
 
 
Patients must be disease-free from prior malignancies for ≥3 years, with the 
exception of non-melanoma skin cancers and superficial urothelial cancers. 
 
Patients must have the ability to swallow the study drug whole as a tablet or 
capsule. 
 
Throughout study, male patient and his female partner who is of childbearing 
potential must use 2 acceptable methods of birth control (1 of which must include a 
condom as a barrier method of contraception) starting at screening and continuing 
throughout the study period and for 3 months after final study drug administration 
or per local guidelines where these require additional description of contraceptive 
methods.  Two acceptable methods of birth control thus include the following: 
 
o Condom (barrier method of contraception); AND 
o One of the following is required: 
 Established and ongoing use of oral, injected, or implanted hormonal 
method of contraception by the female partner. 
 Placement of an intrauterine device or intrauterine system by the female 
partner. 
 Additional barrier method:  Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository by the female 
partner. 
 Tubal ligation in the female partner. 
 Vasectomy or other procedure resulting in infertility (eg, bilateral 
orchiectomy), for > 6 months. 
 
Throughout the study, patients must use a condom if having sex with a pregnant 
woman. 
 
The patient was informed about the positive survival results of the RTOG 96-01 
clinical trial, and has elected to forgo treatment with high-dose bicalutamide. 

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3.4 
Exclusion Criteria 
Patients that meet any of the criteria listed below will not be eligible for study entry: 
 
Currently active second malignancy 
 
Primary treatment with radiation therapy. 
 
Radiographic or clinical evidence of regional tumor nodal recurrence, including 
pathological pelvic lymph nodes ≥2 cm in short-axis diameter. Radiographic 
evidence of distant metastases is also an exclusion. 
 
Concurrent use of other antiandrogens, estrogen-like agents, or 5a-reductase 
inhibitors. 
 
Use of systemic corticosteroids equivalent to prednisone 10 mg/day or higher at the 
time of study entry (inhaled corticosteroids are permitted). 
 
Concurrent use of other anti-cancer agents or treatments. 
 
Serious concurrent medical illnesses (including uncontrolled major cardiac, 
pulmonary, Child-Pugh C liver or psychiatric diseases) or active major infections 
(including HIV, Hepatitis A-C). 
 
Clinically significant cardiovascular disease including: 
o Myocardial infarction within 6 months of Screening visit. 
o Uncontrolled angina within 3 months of Screening visit. 
o Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or 
subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or 
history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a 
screening echocardiogram or multi-gated acquisition scan (MUGA) performed 
within three months of the Screening visit results in a left ventricular ejection 
fraction that is ≥ 45%. 
o History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, torsade de pointes). 
o Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on 
the screening electrocardiogram (ECG) > 470 msec. 
o History of Mobitz II second degree or third degree heart block without a 
permanent pacemaker in place. 
o Hypotension (systolic blood pressure <86 mmHg or bradycardia with a heart 
rate of <50 beats per minute on the Screening ECG, unless pharmaceutically 
induced and thus reversible (i.e. beta blockers). 
o Uncontrolled hypertension as indicated by a resting systolic blood pressure 
>170 mmHg or diastolic blood pressure >105 mmHg at the screening visit. 
 
Medications which lowers seizure threshold. 
 
History of seizure or any condition that may predispose to seizure including, but not 
limited to underlying brain injury, stroke, primary brain tumors, brain metastases, 
or alcoholism. Also, history of loss of consciousness or transient ischemic attack 
within 12months of enrollment (Day 1 visit). 
 
Patients taking medications that may have adverse interactions with enzalutamide 
(see Appendix B). 
3.5 
Inclusion of Minorities 
Men of all races and ethnic groups are eligible for this trial. 

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4. 
PATIENT REGISTRATION AND ENROLLMENT PLAN 
4.1 
Registration Procedure 
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an IRB 
approved consent form.  A centralized, 3-part registration procedure will be used.  After 
eligibility screening and confirmation that a patient is eligible, patients who are selected to 
participate will be registered centrally at the SKCCC Johns Hopkins Lead Center, at the 
participating institution, and if applicable, in the online centralized PCCTC database. A 
record of patients who fail to meet entry criteria (ie, screen failures) will be maintained. The 
patient must give informed consent before beginning any study-specific procedures. Patient 
registration must be completed by the lead coordinating center before treatment is 
initiated. A complete, signed study consent and HIPAA consent are required for registration. 
4.1.1 
Registration at SKCCC, Johns Hopkins University 
Confirm eligibility as defined in Section 3. 
Patient Selection.  
4.1.1.1 Obtain informed consent, by following procedures: 
The investigator (or his/her designee) will explain to each subject the nature 
of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved and any discomfort it may entail. Each 
subject will be informed that participation in the study is voluntary, that he 
may withdraw from the study at any time, and that withdrawal of consent 
will not affect his subsequent medical treatment or relationship with the 
treating physician(s) or institution. The informed consent will be given by 
means of a standard written statement, written in non-technical language, 
which will be IRB approved. The subject should read and consider the 
statement before signing and dating it, and will be given a copy of the 
document. No subject will enter the study or have study-specific procedures 
done before his informed consent has been obtained. 
In accordance with the Health Information Portability and Accountability Act 
(HIPAA), the written informed consent document (or a separate document to 
be given in conjunction with the consent document) will include a subject 
authorization to release medical information to the study sponsor and 
supporting agencies and/or allow these bodies, a regulatory authority, or 
Institutional Review Board access to subjects’ medical information that 
includes all hospital records relevant to the study, including subjects’ medical 
history. 
All subjects considered for enrollment in the study must complete an IRB-
approved informed consent prior to any study-specific procedures being 
performed. 
To register a patient, the participating site must contact the Lead Center’s 
Study Coordinator about a potential candidate prior to sending documents.  
Once acknowledgement is made, the following documents must be 
completed and faxed to (443-287-8354) or e-mailed to the lead site: 
 
Signed patient consent form 
 
Eligibility checklist signed by the participating center PI or Co-I 
 
Copies of all source documentation verifying eligibility criteria 
 

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The Lead Site will review the documents to confirm eligibility. To 
complete the registration process, the Lead Center will: 
 
Assign a patient study number 
 
Randomize the patient onto a treatment arm 
 
Register the patient on the study with the Sidney Kimmel 
Comprehensive Cancer Center’s Clinical Research Office. 
 
Fax or e-mail the unique patient study number and assigned 
study arm to the participating site. 
 
Treatment must not commence until the patient has been registered 
with the Sidney Kimmel Comprehensive Cancer Center’s Clinical 
Research Office and randomization has been completed by the 
coordinating center. 
 
4.1.2 
Multicenter/Participating site registration 
Central registration for this study will take place at SKCCC, Johns Hopkins University. 
Patient registration at each study site/institution will be conducted according to the 
institution’s established policies. Before registration, patients will be asked to sign 
and date an Institutional Review Board (IRB)-approved consent form and a research 
authorization/HIPAA form. Patients must be registered with their local 
site/institution and also with the sponsor or Lead Site before beginning any 
treatment. 
4.1.3 
Randomization 
After written informed consent has been obtained and eligibility has been 
established, the coordinating center will enter demographic and baseline 
characteristics in an interactive web response system (IWRS). The coordinating 
center will obtain the patient’s randomization assignment from the IWRS and 
appropriately notify the study site.  Randomization to one of the two treatment 
arms will occur in a 1:1 ratio. The randomization will be stratified by: Center, 
surgical margin status (R0 vs R1), PSA prior to salvage treatment (PSA ≥0.5 vs <0.5 
ng/mL), and pathologic Gleason score (7 vs 8-10). Minimization approach37 will be 
applied to ensure balanced assignment to each treatment arm. The investigator and 
the patient will be blinded to treatment assignment. 
5. 
TREATMENT/INTERVENTION PLAN 
This study is a multi-center, double-blind, placebo controlled, randomized Phase II trial in 
patients with non-castrate PSA-recurrent prostate cancer after radical prostatectomy. 
Eligible patients will be randomized in a 1:1 ratio to one of two treatment arms: salvage 
radiation therapy (SRT) plus placebo (Arm A) or SRT plus enzalutamide (Arm B) (see 
schema below). 
The following assessments and procedures will occur during the study. A schedule of 
assessments is provided in Table 1.

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Table 1 Study Calendar  
Procedures 
Baseline 
  
Treatment
Follow‐up*
 
Off‐Study
Day 1‡ 
(Start of 
Drug) 
Day 61‡ 
(Start of 
SRT) 
Day 91‡‡ 
Day 120‡ 
(End of 
SRT) 
Day 
151‡‡ 
Day 
180‡‡ 
(End of 
Drug) 
Q3 mos⁸ 
24‐
months 
Q3 
mos8,9 
Till      
study 
ends 
PSA 
progression10 
Informed Consent 
X 
Randomization 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X¹ 
 
 
 
 
 
 
 
 
 
Concurrent medications 
X¹ 
 
X 
X 
X 
X 
X 
X 
 
X 
Height 
X¹ 
 
 
 
 
 
 
 
 
 
Physical Exam, vitals, weight, ECOG 
X¹ 
 
X 
X 
X 
X 
X 
X 
 
X 
Adverse event evaluation 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pill count/diary12 
 
X 
X 
X 
X 
X 
X 
 
 
 
CBC with diff² 
X¹ 
 
X 
X 
X 
X 
X 
X 
 
X 
Serum Chemistries³ 
X¹ 
 
X 
X 
X 
X 
X 
X 
 
X 
Total serum testosterone 
X¹ 
 
X 
X 
X 
X 
X 
X 
 
X 
PSA evaluation4 
X¹ 
 
X 
X 
X 
X 
X 
X⁴ 
X 
X 
ECG⁵ 
X¹ 
 
 
 
 
 
 
 
 
 
CT A/P (or MRI)6 
X¹ 
 
 
 
 
 
 
 
 
X⁶ 
Chest X-Ray 
 
 
 
 
 
 
 
 
 
X⁶ 
Radionuclide bone scan 
X¹ 
 
 
 
 
 
 
 
 
X⁶ 
QoL questionnaires⁷ 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Tumor Tissue banking11 
X 
 
 
 
 
 
 
 
 
 
Decipher Test  
 
 
 
 
 
 
X14  
 
 
 
Treatments 
 
 
 
 
 
 
 
 
 
 
SRT13 
 
 
X 
X 
X 
 
 
 
 
 
Placebo PO daily (Arm A) 
 
X 
X 
X 
X 
X 
X 
 
 
 
Enzalutamide 160mg PO daily (Arm 
B) 
 
X 
X 
X 
X 
X 
X 
 
 
 

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Abbreviations: CBC, complete blood count; CT, computerized tomography; EKG, electrocardiogram; MRI, magnetic resonance 
imaging; PSA, prostate-specific antigen; Mos, Month 
 
1. All evaluations should be conducted within 30 days prior to registration/randomization. The exception to this is the radiologic evaluations and 
informed consent, which can be performed within 90 days prior to day 1. 
2. CBC which includes WBC (with differential), platelets, Hgb, and Hct  
3. Chemistries include albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, creatinine, glucose, sodium, potassium, total protein, 
SGOT [AST], and SGPT [ALT]. 
4. Those patients coming off study prior to PSA progression (i.e. for toxicity, etc.) should be evaluated for PSA levels every 3 months until PSA 
progression occurs. 
5. ECGs may also be performed as clinically indicated throughout the study. 
6. Radiologic evaluations (CT/MRI and bone scan) and chest x-ray (if applicable) should be conducted at PSA progression. Scans can also be 
obtained sooner as clinically indicated. 
7. Quality-of-life (QoL) tools will include FACT-P, EORTC QLQ-C30/QLQ-PR25, and SHIM.  
8. Patients should remain on study until PSA progression. This is defined as a PSA value ≥0.2 ng/mL above nadir that is confirmed by a second 
consecutive PSA value ≥8 weeks later which is higher (and ≥0.4 ng/mL). Patients should remain on study until the confirmatory PSA. 
9. The total length of the study is 18 months for full enrollment and 24-months of follow-up for the last patient or 42 months.  Patients who have 
24-months of follow-up following treatment will continue to be followed for PSA determinations only and should remain on study until PSA 
progression or study end at month 42 whichever comes first. 
10. To be conducted 2 months after the patient comes off study. 
11. In patients who have consented, a tumor tissue block should be requested for banking, preferably from the prostatectomy specimen. If not 
available, a tissue block from the prostate biopsy should be submitted. In addition, a normal tissue block from the same patient (preferably from 
the prostatectomy) should be requested for banking.  This only applies to the lead site (JHU). 
12. Drug and diary review and dispensing may be done prior to or indicated day.  
 
 
13. SRT to start 61 days (+/- 3 weeks) after Day 1. SRT will be delivered Monday-Friday 
14. Decipher Test can be completed at any time before treatment ends on Day 180.   
‡Should occur within 7 days prior (Please note that this window does not apply to the study drug administration. The participant should take the 
study drug continuously for 180 days) 
‡‡ Should occur +/- 14 days (Please note that this window does not apply to the study drug administration. The participant should take the study 
drug continuously for 180 days) 
*Follow-up visits may be performed +/- one month from the scheduled time of visit date. In the event that the participant chooses to undergo 
follow-up evaluation elsewhere or unexpectedly cannot adhere to the follow-up timeline, QoL assessments may be completed via mail or email 
and adverse event assessments may be completed by the study team via telephone.  
Note that the study calendar is based on the ideal subject. The schedule should be followed as closely and realistically as possible, but may be modified 
due to problems such as scheduling delays, conflicts such as clinic closure or poor weather conditions, or other unforeseeable events.

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5.1 
Screening/Baseline Assessment  
Before initiating any screening activities, the scope of the study should be explained to each 
patient. Patients should be advised of any known risks inherent in the planned procedures, 
any alternative treatment options, their right to withdraw from the study at any time for 
any reason, and their right to privacy. After this explanation, patients should be asked to 
sign and date a Notice of Privacy Practice research authorization/HIPAA form and an IRB-
approved statement of informed consent that meets the requirements of the Code of 
Federal Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 50).
The screening/baseline procedures will determine patient eligibility according to the 
inclusion and exclusion criteria (Sections 3.3 Inclusion Criteria & 3.4 
Exclusion 
Criteria).  
The following evaluations/assessments will be performed at this visit within 90 days of Day 
1:  
 
Obtain informed consent and research authorization. 
 
Obtain histologic and radiologic confirmation of disease. 
 
Collect details and dates of the primary therapy (eg, pathologic stage, dose and type 
of radiation therapy) and prior hormonal and non-hormonal therapies. 
 
 Record PSA and Gleason score at the time of diagnosis 
 
Determine suitability for salvage prostate bed radiation therapy 
 
Assess  presence or absence of disease in the primary site 
 
Imaging: abdomen/pelvis by CT or magnetic resonance imaging (MRI) 
radionuclide bone scan.  Relevant information should be documented. The institutional 
registration should be finalized, and appropriate documents (ie, signed informed consent, 
research authorization/HIPAA form, signed eligibility checklist and supporting source 
documentation for eligibility questions) faxed or emailed to the lead site/sponsor.  
Information for patients who do not meet the eligibility criteria to participate in this study 
(ie, screening failures) should be captured in consortium database at the pretreatment 
assessment. 
 
The following assessments must occur within 30 days of registration/randomization: 
 
Physical exam (vital signs, height/weight, EKG, etc) 
 
Laboratory tests (CBC w/diff, PSA, testosterone, comprehensive chemistry panel, 
including bilirubin, creatinine, SGOT[AST], SGPT[ALT]) 
 
ECOG performance status (Appendix A) 
Review of concurrent medications (see Appendix B for a listing of medications with the 
potential for drug interactions) 

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5.2 
Treatment Period  
The following procedures are to be conducted each study visit on visit on Day 1, 61, 91, 120, 
151 and 180 days while on study. Day 1, 61, 120 procedures should be done within seven 
days prior; day 91,151 and 180 procedures should be done +/- 14 days (see Table 1): 
 
Review  concurrent medications (see Appendix B for a listing of medications 
with the potential for drug interactions) 
 
Physical  exam (vital signs, weight) 
 
ECOG performance status (Appendix A) 
 
Adverse  events evaluation 
 
Review pill diary 
 
Laboratory  tests  (CBC w/diff, PSA, testosterone, comprehensive chemistry 
panel, including bilirubin, creatinine, SGOT[AST], SGPT[ALT] 
 
QoL questionnaires 
 
The following procedures are to be conducted at each follow-up visit every 3 months ±1 
month up to 24 months (see Table 1). If participants are unable to return for follow-up, 
outside records may be obtained and assessments may be conducted via phone, email, or 
mail when possible: 
 
Review concurrent medications (see Appendix B for a listing of medications 
with the potential for drug interactions)  
 
Physical exam (vital signs, weight) 
 
ECOG performance status (Appendix A) 
 
Adverse events evaluation 
 
Laboratory tests  (CBC w/diff, PSA, testosterone, comprehensive chemistry 
panel, including bilirubin, creatinine, SGOT[AST], SGPT[ALT] 
 
QoL questionnaires 
 
The following procedure is to be conducted at each follow-up visit every 3 months ±1 
month past the first 24 months and up to 42 months (see Table 1): 
 
Laboratory test (PSA) 
 
 
 
 
 
 
 

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5.2.1 
Treatment schema 
 
Figure 2 – Treatment Schema. 
Treatment Arms and Study Procedures 
Patients will be randomized equally (1:1) to one of two arms – 
 
Arm A (control): Salvage radiation therapy (3D-CRT/IMRT) 66.6-70.2 Gy 
given 1.8 Gy M-F for 37 -39 fx 
PLUS Placebo PO once daily for 6 months (2 months prior to SRT, 2 months 
during SRT and 2 months following SRT) 
 
Arm B (experimental): Salvage radiation therapy (3D-CRT/IMRT) 66.6-70.2 
Gy as 1.8 Gy M-F for 37-39 fx 
PLUS Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months 
prior to SRT, 2 months during SRT and 2 months following SRT) 
 
Continue treatment until disease progression, unacceptable toxicity, or any criteria 
in Section 6.5 ‐ Removing Patients from the Protocol. 
For a maximum period of 6 months. 
Placebo:  
PO once daily for 6 months (2 months prior to SRT, 2 months during 
SRT and 2 months following SRT) for Arm A. 
Enzalutamide:  160 mg PO once daily for 6 months (2 months prior to SRT, 2 months 
during SRT and 2 months following SRT) for Arm B. 
5.2.2 
Clinical and laboratory assessments 
On day 1, 61, 91, 120, 151 and 180 visits while on study (Day 1, 61, 120 procedures should 
be done within seven days prior, day 91,151, 180 procedures should be done +/- 14 days, 
see Table 1) patients will have non-fasting blood drawn for the following values:  

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 
CBC w/diff 
 
Comprehensive chemistry panel 
 
PSA 
 
Testosterone 
5.2.3 
Safety assessments 
Adverse events (AEs) will be monitored at each scheduled visit and throughout the 
study. Toxicity will be assessed using the most recent National Cancer Institute 
(NCI) guidance: the most recent version of Common Terminology Criteria for 
Adverse Events (CTCAE). 
 
All nonserious AEs and SAEs, regardless of relationship to study treatment, will be 
collected from registration through the post-treatment visit and will be recorded in 
the subject’s medical record and on the CRF. Following the post-treatment visit, only 
new treatment-related AEs and SAEs will be recorded. Seizures (regardless of 
causality) will be recorded throughout the study. 
5.2.3.1 Seizures 
Seizures that occur at any time during the study, regardless of causality, 
severity, or outcome, will be recorded in the subject’s medical record and on 
the CRF. 
5.3 
Treatment‐Limiting Adverse Event 
A treatment-limiting adverse event is any AE related to protocol therapy experienced 
during the study resulting in treatment termination. 
5.4 
Dose Modifications 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in 
Section 6. The most recent NCI CTCAE will be used to grade adverse events. 
At each study visit for the duration of their participation in the study, patients will be 
evaluated for adverse events (all grades), serious adverse events (SAEs), and adverse events 
that require study drug interruption or discontinuation. Patients discontinued from the 
treatment phase of the study for any reason will be evaluated approximately 30 days after 
the last dose of the study drug. 
If patients either require that the study drug be discontinued because of an adverse event 
(as described below) or have a treatment interruption of greater than 2 weeks for 
enzalutamide or placebo, at the investigator’s discretion, they may continue on SRT until 
completion of the SRT. 
Dose reduction for enzalutamide or placebo will be allowed. If a patient experiences a ≥ 
Grade 3 toxicity or an intolerable side effect, withhold dosing for one week or until 
symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 
mg). 
 
Any toxicity requiring enzalutamide discontinuation will be recorded as an AE in the 
subject’s medical record and on the CRF. 

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5.4.1 
Seizures 
Seizures that occur at any time during the study, regardless of causality, severity, or 
outcome, will result in enzalutamide discontinuation and be recorded in the 
subject’s medical record and on the CRF. 
 
5.5 
End of Treatment/Treatment Discontinuation Visit (+/‐ 30 days from last dose) 
The following procedures are to be conducted every 3 months ±1 month up to 24 months 
(see Table 1): 
 
Review concurrent medications (see Appendix B for a listing of medications 
with the potential for drug interactions) 
 
Physical exam (vital signs, weight) 
 
ECOG performance status (Appendix A) 
 
Adverse events evaluation 
 
Laboratory tests  (CBC w/diff, PSA, testosterone, comprehensive chemistry 
panel, including bilirubin, creatinine, SGOT[AST], SGPT[ALT] 
 
QoL questionnaires 
 
Decipher Test (Will only be completed once before treatment ends on Day 180. 
This test will not be repeated.)  
5.6 
Follow‐up (Every 3 months for >24 months or until death) 
Patients will be followed for >2 years (and up to 42 months total) after removal from 
treatment or until death. Patients withdrawn from the study because of AEs will be followed 
until the adverse event has either resolved or stabilized. Reasons for premature withdrawal 
should be determined and noted. 
Freedom-from-PSA-progression (FFPP) is the primary objective and is defined as the time 
from randomization to the date of PSA progression. A subject who does not have PSA 
progression at the time of the analysis will be censored at the last date of PSA measurement. 
In patients who achieve an undetectable PSA value (defined as ≤0.1 ng/mL), PSA 
progression is defined as a detectable PSA value (≥0.2 ng/mL) that is confirmed by a second 
consecutive PSA value obtained ≥8 weeks later which is higher (and ≥0.4 ng/mL).  In 
patients who do not achieve an undetectable PSA, PSA progression is defined as a 0.2 ng/mL 
increase from nadir that is confirmed by a second consecutive PSA value obtained ≥8 weeks 
later which is higher. 
5.7 
Concomitant Medications 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, 
over-the-counter medications, or alternative therapies must be documented on the case 
report form (CRF). The principal investigator should be alerted if the patient is taking any 
agent found in Appendix B (a listing of medications with the potential for drug-drug 
interactions). 

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5.7.1 
Supportive Care Medications 
Subjects should receive full supportive care, including transfusions of blood and 
blood products, antibiotics, antiemetics, or other therapies, in accordance with 
standard practice at the clinical trial site. 
All concomitant medications administered from screening through the post-
treatment visit, including indication, dose, route, frequency and treatment dates, 
will be recorded in the subject’s medical record and on the CRF. After the post-
treatment visit, only anticancer therapies will be recorded. 
5.7.2. 
Prohibited before enrollment and during administration of study treatment 
 Any therapy for prostate cancer except for that radical prostatectomy and those 
administered in this protocol. 
 Strong inducers or inhibitors of CYP2C8 (gemfibrozil, rifampin [see examples in 
Appendix B]). 
 Medications that are metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a 
narrow therapeutic index (see examples in Appendix B). 
  Strong inducers or inhibitors of CYP3A4 (including but not limited to phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, and phenobarbital [see examples 
in Appendix B]).  
 Medications that may lower seizure threshold as determined by the investigator. 
5.7.3 
Drugs that may affect exposure to Enzalutamide 
The principal investigator should be alerted if the patient is taking any agent found 
in Appendix B (a listing of medications with the potential for drug-drug 
interactions). 
Refer to the following links for updated lists of CYP inhibitors, inducers, and 
substrates: 
•http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/Druglnteractionslabeling/ucm093664.htm#potency   
• http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
Drugs That Inhibit or Induce CYP2C8 
Co-administration of a strong CYP2C8 inhibitor (e.g., gemfibrozil) increased the 
composite AUC0-∞ of enzalutamide plus its active metabolite in healthy volunteers 
(Section 7.2.2); therefore, co-administration of enzalutamide with strong CYP2C8 
inhibitors should be avoided if possible. If co-administration of enzalutamide with 
strong CYP2C8 inhibitors cannot be avoided, reduce the enzalutamide dose to 80 mg 
once daily. If co-administration of the strong inhibitor is discontinued, the 
enzalutamide dose should be returned to the dose used prior to initiation of the 
strong CYP2C8 inhibitor. 
 
The effects of CYP2C8 inducers on the PK 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. 
 
 

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Drugs That Induce CYPJA4 
The effects of CYP3A4 inducers on the PK 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. 
 
6. 
THERAPEUTIC AGENTS 
 
6.1 
Enzalutamide 
Compound Number: MDV3100 
Proposed International 
Nonproprietary Name: enzalutamide 
Molecular Formula: C21H16F4N4O2S 
Chemical Name: 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- 
sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide 
 
 
Figure 3 Chemical Structure of Enzalutamide 
Molecular Weight: 464.44 
Appearance: White crystals 
Solubility: Practically insoluble in water 
Hygroscopicity: Not hygroscopic 
Enzalutamide (MDV3100) is an orally-available synthetic small molecule being developed 
as a potential treatment for prostate, breast and potentially other cancers. Enzalutamide is 
presented in a soft gelatin capsule filled with a formulation containing 40 mg of the active 
pharmaceutical ingredient. The therapeutic dose under phase 3 clinical investigation is 160 
mg once daily (4 capsules, each 40 mg). 

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Table 2 Agents Studied in this Protocol 
Study Drug 
Lot # 
Batch # 
Source of Supply 
Enzalutamide 
      
      
Astellas/Medivation 
Salvage Radiation 
Therapy 
NA 
NA 
Radiation Oncology 
Department 
6.1.1 
Pharmacokinetics 
Following oral administration in animals, enzalutamide is eliminated slowly from 
plasma with a long half-life (t1/2) across species. The t1/2 does not appear to be 
affected by the dose size; but, the bioavailability in animals appears to decrease with 
increasing dose size. The 2 major human metabolites (N-desmethyl enzalutamide 
and an inactive carboxylic acid metabolite) are also produced in animals. In vitro 
studies show that enzalutamide is metabolized by human recombinant cytochrome 
P450 (CYP) isoenzymes CYP2C8 and CYP3A4/5. Enzalutamide and/or its major 
human metabolites caused direct in vitro inhibition of multiple CYP enzymes 
including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5; however, 
subsequent clinical data showed that enzalutamide is an inducer of CYP2C9, 
CYP2C19 and CYP3A4/5 and has no clinically meaningful effect on CYP2C8 in vivo. 
In vitro data show that enzalutamide and N-desmethyl enzalutamide are potential 
inhibitors, but not substrates, of the efflux transporter P‑glycoprotein (P-gp). The 
protein binding of enzalutamide in human plasma is 97% to 98% and is similar in 
mice, rats, rabbits and dogs. The protein binding of the carboxylic acid derivative 
and N-desmethyl enzalutamide in human plasma are 98% and 95%, respectively, 
and are comparable across species. The extent of binding for enzalutamide, the 
carboxylic acid derivative and N-desmethyl enzalutamide is constant over a wide 
range of concentrations. 
6.1.2. 
Dosage Selected 
6.1.2.1 Preparation, and Schedule of Administration 
 
Enzalutamide or placebo: 160 mg PO once daily for 6 months (2 months prior to 
SRT, 2 months during SRT and 2 months following SRT).  This consists of taking 
four 40-mg capsules all at one time. Enzalutamide or placebo is to taken at the 
same time daily Enzalutamide or placebo can be administered with/without food 
and needs no premedication.  Treatment will be administered on an outpatient 
basis and agent dispensed at the time of pill diary review (see Table 1 – Study 
Calendar). 
6.1.2.2 Supply, storage requirements, and special handling 
Supply and packaging: 
Enzalutamide: Fill solution: enzalutamide, caprylocaproyl macrogolglycerides, 
butylhydroxyanisole, butylhydroxytoluene. 
Capsule: gel mass (gelatin, purified water, sorbitol sorbitan solution and glycerol, 
titanium dioxide), ink (iron oxide black).  The appearance is an opaque white to off-

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white oblong liquid filled soft gelatin capsule. Capsules are packaged in polyvinyl 
chloride laminated with polychloro-trifluoroethylene/aluminum foil blisters or 
packaged in high-density polyethylene bottles with child-resistant induction seal 
closure. Each capsule is 40 mg. Patients must take four capsules all at one time, for 
a total daily dose of 160 mg. 
 
Placebo: Fill solution: Caprylocaproyl Polyoxylglycerides, NF or Caprylocaproyl 
Macrogolglycerides, EP (Labrasol®)a, Butylated Hydroxyanisole, NF or 
Butylhydroxyanisole, EP (BHA), Butylated Hydroxytoluene, NF or 
Butylhydroxytoluene, EP (BHT). 
Capsule: Soft gelatin capsule (Gelatin, NF, EPb), plasticizer (Sorbitol Special-
Glycerin Blendb, c), colorant (Titanium Dioxide USP), capsule print ink (Opacode® 
WB Black Ink d). 
 
Enzalutamide and placebo will be provided by Astellas Scientific and 
Medical Affairs, Inc. 
Storage requirements for enzalutamide or placebo: 
Store at room temperature (≤ 25C). 
Special handling:  
For more information please follow the storage instructions provided on the drug 
product label. 
6.1.3. 
Dosing Delays and Treatment Modifications for Toxicity 
Toxicity will be assessed using the most recent NCI CTCAE. 
Dose reduction for enzalutamide or placebo will be permitted. If a patient 
experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing for 
one week or until symptoms improve to ≤ Grade 2, then resume at the same or a 
reduced dose (120 mg or 80 mg). 
 
If patients either require that the study drug be discontinued because of an adverse 
event (as described below) or have a treatment interruption of greater than 2 weeks 
for enzalutamide, at the investigator’s discretion, they may continue on SRT until 
completion of the SRT. 
6.1.3.1 Dose‐limiting toxicity (DLT) 
A DLT for this study will be defined as a ≥ Grade 3 toxicity or an intolerable side 
effect.  In addition, enzalutamide should be permanently discontinued in 
patients who have a seizure while on treatment.  
6.2 
Salvage Radiation Therapy (SRT) 
Note: Intensity Modulated RT (IMRT) is allowed for this study. 
Patients will undergo salvage radiation therapy (SRT) to start 60 days (31 day window 
allowed) after Day 1 (Day 61). Research visits during radiotherapy will occur during the 
first week of SRT and within 1 week of completion of radiotherapy according to the above 
schedule of events. Weekly visits during radiotherapy may be performed locally by the 
treating radiation oncologist according to standard of care practice and should include a 

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review of systems, vital signs, and examination. Radiation therapy may be performed locally 
as standard-of-care provided it conforms to protocol-specified treatment and dosing 
specifications. Receipt of protocol specified salvage radiation will be documented including 
dose, field, and timing. 
6.2.1 
Dose specifications 
SRT will start 60 days after Day 1 (31 day window). Radiotherapy dose will be 
specified to the Planning Target Volume (PTV), as described in section 5.3.3.4. The 
total dose to the prostate bed is 66.6-70.2 Gy in 37-39 fractions.≥ 95% of the PTV 
should receive the prescribed dose. 
6.2.2 
Radiation technical factors 
Megavoltage equipment is required with effective photon energies ≥ 6 MV. 
6.2.3 
Localization, simulation and immobilization 
A urethrogram or MRI is recommended, but not required, to establish the most 
inferior portion of the prostate bed. Use of contrast, other than for the urethrogram, 
is discouraged. Simulation should be with a moderately full bladder (the patient 
should not be uncomfortable at simulation and probably will have more difficulty 
maintaining a full bladder during treatment). An overly distended rectum can 
introduce a systematic positioning error that may increase the probability of 
missing the CTV. 
 
A treatment planning CT scan will be required to define the clinical and planning 
target volumes, and the critical normal structures. The treatment planning CT will 
be acquired with the patient set up in the same position as for daily treatments. 
Each patient will be positioned in the supine position. The CT scan of the pelvis 
should start at or above the iliac crest down to below the perineum (below the 
ischial tuberosities). All tissues to be irradiated must be included in the CT scan. CT 
scan thickness should be ≤ 0.5 cm through the region that contains the target 
volumes (i.e., from the bottom of the sacroiliac joints down to the penile urethra). 
The regions above and below the target volume region may be scanned with slice 
thickness ≤ 1.0 cm 
6.2.4 
SRT target volumes 
The definition of volumes (CTV, PTV) will be in accordance with ICRU Report #50: 
Prescribing, Recording, and Reporting Photon Beam Therapy. 
CTV (Prostate Bed) 
Contrast may be used for simulation but can distort the anatomy slightly and so is 
not recommended. The bladder should be reasonably full for simulation, keeping in 
mind that patients may not be able to maintain as full a bladder during 
radiotherapy. Having a full bladder at simulation ensures that the CTV will be of 
maximal dimensions. The seminal vesicles or remnants thereof, if identified on CT 
or MRI as being present, will receive the full dose. The immediate periprostatic bed 
surgical clips should receive the full dose. The CTV will extend from the top of the 
penile bulb inferiorly, or 1.5 cm below the urethrogram peak if done, to just above 
the pubic symphysis superiorly (at least for the anterior-most portion of the 
bladder). Laterally, the CTV will extend from the medial edge of one obturator 

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internus muscle to the other. Anteriorly the CTV will include the entire bladder neck 
until the mid-pubic symphysis, where a gradual reduction off of the anterior bladder 
is made. Posteriorly, the CTV is defined by the anterior-most aspects of the anus-
rectum. The CTV may be increased (not decreased) beyond these limits based on 
pre-prostatectomy imaging information. The pelvic lymph nodes are not to be 
included in the CTV on this protocol. 
PTV 
The PTV margins should be a 0.5-1.5 in all dimensions. 95% of the PTV must receive 
the prescribed dose. Care should be taken to conform the prescribed dose as closely 
to the PTV as possible, so as to avoid including the entire width of the rectum in the 
posterior blocked margin at the bladder neck-rectum interface. The maximum dose 
heterogeneity allowable in the PTV will be 10%; a variation will be > 10% and a 
violation > 15%. 
Normal Tissues 
Normal tissues will be outlined as solid structures, including the rectum, bladder 
and femoral heads. The penile bulb may be outlined as a reference structure. No 
constraints will be placed on the penile bulb. The rectum will be outlined from the 
anterior flexion of the rectosigmoid superiorly to the ischial tuberosities inferiorly. 
The planning parameters outlined below for IMRT should be used as a guide; formal 
3D-CRT normal tissue prostate bed constraints have not been the standard in the 
past and are not specified here. It should be possible to come close to achieving the 
constraints outlined for IMRT, at least within the variation range. 
6.2.5 
Prostate bed planning for IMRT 
Planning Parameters 
The plan will be deemed acceptable under the following conditions. 
PTV: The dose marker levels for bladder and rectum have been modeled after prior 
studies in men treated definitively with IMRT for prostate cancer. At least 95% of 
the PTV should receive the prescribed dose (66 Gy); a variation will be noted if < 
95% to 90% of the PTV receives the prescribed dose, and a protocol violation will be 
noted if < 90% of the PTV receives the prescribed dose. The maximum dose 
heterogeneity allowable in the PTV will be 10%; a variation will be > 10% and a 
violation > 15%. Since the dose is prescribed to the minimum isodose line of the 
PTV, the dose variability is seen in portions of the target volume receiving higher 
than the specified dose. 
Rectum: Less than or equal to 25% and 45% of the rectum should receive ≥ 65 Gy 
and ≥ 40 Gy, respectively. A variation will be noted if up to an additional 7.5% of the 
rectal volume receives above the target doses specified. The inclusion of rectal 
volumes beyond these constraints will be considered a protocol violation. 
 
Bladder: Less than or equal to 40% and 60% of the bladder (minus prostate bed 
CTV) should receive ≥ 65 Gy and ≥ 40 Gy, respectively. The criteria for the bladder 
have been relaxed because the dosimetric relationship of volume exposed to the 
specified marker doses is much less clear and the bladder neck is included in the 
CTV. A primary variation will be noted if up to an additional 7.5% of the bladder 

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volume receives above the target doses specified. The inclusion of bladder volumes 
beyond these constraints will be considered a secondary protocol variation; it will 
not be considered a protocol violation. 
 
Femoral Heads: Less than or equal to 10% of each femoral head should receive ≥ 50 
Gy. A variation will be noted if up to an additional 5.0% of either femoral head 
receives > 50 Gy. 
 
Penile Bulb: The penile bulb may be outlined as a reference structure. No 
constraints will be placed on the penile bulb. 
 
6.2.6 
Critical structures 
The critical normal structures are the bladder, rectum, and femoral heads. The 
normal tissues will be contoured and considered as solid organs. 
 
The bladder should be contoured from its base to the dome, excluding the CTV1 
(the CTV1 includes the bladder neck). 
 
The rectum should be contoured from the anus (at the level of the ischial 
tuberosities) to the rectosigmoid flexure (this is roughly at about 10 cm) or for a 
maximum length of 15 cm if the sigmoid flexure if felt to be higher. 
 
Each femoral head should be outlined down to the interface between the greater 
and lesser trochanters. 
6.2.7 
SRT documentation requirements 
The institution will archive treatment prescription and verification images for later 
review by the study chair if requested. For conformal RT, at least one port film or 
pretreatment alignment film per field along with the digital reconstructed 
radiographs (DRRs) from the treatment planning program or, alternatively, a 
simulation verification radiograph shall be acquired and kept for evaluation if 
requested except where geometrically impractical. For IMRT, at least one port film 
from each orthogonal film along with the digital reconstructed radiographs (DRRs) 
from the treatment planning program shall be acquired and kept for evaluation. 
Note: Images are required to be taken but not submitted. 
6.2.8 
Potential SRT adverse events 
All patients will be seen weekly by their radiation oncologist during radiation 
therapy. Any observations regarding radiation reactions will be recorded and 
should include attention toward the following potential side effects: 
 
Small bowel or rectal irritation manifesting as abdominal cramping, diarrhea, 
rectal urgency, proctitis, or hematochezia; 
 
Bladder complications including urinary frequency/urgency, dysuria, 
hematuria, urinary tract infection, and incontinence; 
 
Radiation dermatitis. 
Clinical discretion may be exercised to treat side effects from radiation therapy. 
Examples of typical medications used in the management of rectal side effects, 
such as diarrhea, include diphenoxylate or loperamide. Bladder or rectal spasms 
are usually treated with anticholinergic agents or tolterodine. Bladder irritation 

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may be managed with phenazopyridine. Erectile dysfunction is often treated 
with medical management or mechanical devices.  SRT adverse event reporting. 
6.2.9 
Laboratory tests during SRT 
Standard of care practice during IMRT will be performed and includes the following 
assessments: 
 
Medical history, adverse event assessment, and medication review 
 
CBC with differential, Serum chemistries (see above) 
 
Physical examination and performance status with vital signs 
Research visits during treatment will occur at day 1, 61, 92, 120, 151 and 180 +/-14 
days according to the above schedule of events. Subjects will be referred back to 
registering institution if during the 6 weeks an AE is suspected. 
 
6.3 
Removing Patients from the Protocol 
In the absence of treatment delays because of adverse events, treatment will continue for 6 
months or until one of the following criteria applies: 
 
Patient decides to withdraw from the study 
 
Disease progression 
 
Symptomatic disease progression at any time 
 
Objective clinical disease progression 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) that may or may not be directly related to treatment 
but that, in the judgment of the treating physician, makes it dangerous for the 
patient to be retreated 
 
General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment, in the judgment of the investigator 
Because an excessive rate of withdrawals can render the study uninterpretable, 
unnecessary withdrawal of patients should be avoided. When a patient discontinues 
treatment early, the investigator should make every effort to contact the patient and to 
perform a final evaluation. The reason(s) for withdrawal should be recorded. 
6.4 
Concomitant Medications and Supportive Care 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, 
over-the-counter medications, and alternative therapies must be documented on the CRF. 
The principal investigator should be alerted if the patient is taking any agent found in 
Appendix B (a listing of medications with the potential for drug-drug interactions). Refer to 
Section 5.7 for concomitant medication guidelines. 
7. 
ADVERSE EVENTS 
7.1 
Definitions 
7.1.1 
Adverse Event (AE) 
 

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An adverse event is any untoward medical occurrence in a research patient during a 
clinical study or within 30 days post-treatment, regardless of causality. This 
includes adverse clinical or laboratory findings, any adverse drug reaction (ADR), an 
illness with onset during the study, or an exacerbation of preexisting illness or 
condition. 
 
7.1.2 
Serious Adverse Event (SAE) 
The investigator must assess each event to determine if it meets the criteria for 
classification as an SAE or serious adverse drug reaction.  
 
All SAEs that occur any time a patient is on study (ie, as soon as the informed 
consent has been signed) or within 30 days of the last dose of enzalutamide must be 
recorded, regardless of the suspected relationship to enzalutamide. Any SAE 
occurring more than 30 days after the last dose of enzalutamide must be recorded if 
a causal relationship to enzalutamide is suspected. 
 
An SAE/ADR as defined in the Code of Federal Regulations (21CFR312.32) is any 
event that: 
 
results in death 
 
is life-threatening 
 
results in inpatient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability or incapacity 
 
results in congenital anomaly or birth defect 
 
is medically significant in the opinion of the investigator 
7.1.3 
Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE, unless in the 
investigator’s opinion, study treatment resulted in an exacerbation of the patient’s 
condition. If disease progression results in death or hospitalization while on study 
or within 30 days of the last dose of enzalutamide, progressive disease will be 
considered an SAE. 
7.1.4 
Life‐threatening events 
A life-threatening event is any AE that places the patient at immediate risk of death 
from the reaction as it occurs. It is not a reaction that, had it occurred in a more 
severe form, might have caused death. 
7.1.5 
Hospitalization or prolongation of hospitalization 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) 
resulting from a precipitating, treatment-emergent adverse event. For chronic or 
long-term patients, inpatient admission also includes transfer within the hospital to 
an acute or intensive care inpatient unit. Hospitalizations for administrative reasons 
or a nonworsening preexisting condition should not be considered AEs (eg, 
admission for workup of a persistent pretreatment laboratory abnormality, yearly 
physical exam, protocol-specified admission, elective surgery). Preplanned 
treatments or surgical procedures should be noted in the baseline documentation. 
Hospitalization because of an unplanned event will be deemed an SAE. 

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Prolongation of hospitalization is any extension of an inpatient hospitalization 
beyond the stay anticipated or required for the original reason for admission. 
7.1.6 
Significant disability 
Disability is a substantial disruption of the patient’s ability to conduct normal life 
functions. 
7.1.7 
Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the 
study, the treating physician must be notified immediately. All confirmed 
pregnancies must be immediately reported to the SKCCC< Johns Hopkins and 
recorded in the consortium database. If the female partner partner becomes 
pregnant, we will seek permission to follow the pregnany until resolution and assess 
for any effects related to the study drug.  This will require the partner to sign a 
separate consent form.  
7.1.8 
Medical significance 
An event that is not fatal or life-threatening and that does not necessitate 
hospitalization may be considered serious if, in the opinion of the investigator, it 
jeopardizes the patient’s status and might lead to medical or surgical intervention to 
prevent any of the above outcomes. Such medically significant events could include 
allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or abuse. 
 
The most recent version of the NCI CTCAE handbook will be used for adverse event 
descriptions and grading. 
 
Follow-up of adverse events should continue until the event and any sequela resolve or 
stabilize at a level acceptable to the investigator and the study site/sponsor or medical 
monitor. 
Events that are not considered serious adverse events include: 
 
routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures 
 
elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
 
emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
 
respite care 
 
7.2 
Expectedness 
 
Adverse events can be considered, “expected,” or, “unexpected.” 
 
7.2.1  
Expected Adverse Events 
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. An adverse event can be considered expected 

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when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk. 
 
7.2.2 
Unexpected Adverse Events 
An adverse event can be considered unexpected when it varies in nature, intensity 
or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk. Contact the lead site, principal 
Investigator or sponsor to confirm unexpected adverse events when necessary.   
7.3 
Recording and Grading 
7.3.1 
Recording 
All observed or volunteered adverse events, regardless of treatment group, severity, 
suspected causal relationship, expectedness, or seriousness will be documented. 
A clinically significant change in a physical examination finding or an abnormal test 
result (ie, laboratory, x-ray, EKG) should be recorded as an AE, if it: 
 
is associated with accompanying symptoms 
 
requires additional diagnostic testing or medical or surgical intervention 
 
leads to a change in study dosing or discontinuation from the study 
 
requires additional concomitant drug treatment or other therapy, or 
 
is considered clinically significant by the investigator or ASMA 
An abnormal test result that is subsequently determined to be in error does not 
require recording as an adverse event, even if it originally met one or more of the 
above criteria. 
7.3.2 
Grading severity 
All adverse events will be graded for intensity on a scale of 0 to 5. Severity grades 
will be recorded and based on the most recent version of the NCI CTCAE handbook. 
7.3.3 
Attributing causality 
After grading for severity, the investigator must evaluate all clinical AEs and 
abnormal laboratory values for possible causal relationship to enzalutamide. 
Causality attribution will be decided using the criteria outlined in Table 6.  
Table 3 Relationship of Adverse Event to Study Drug 
Relationship 
Description 
Unrelated 
AE is clearly not related to enzalutamide 
Unlikely 
AE is doubtfully related to enzalutamide 
Possible 
AE may be related to enzalutamide 
Probable 
AE is likely related to enzalutamide 
Definite 
AE is clearly related to enzalutamide 

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Abnormal laboratory values of clinical significance that were present at baseline and 
did not change in severity or frequency during experimental therapy or intervention 
and those that can obviously be attributed to underlying disease will be recorded as 
unrelated and will not be considered when evaluating the AEs. 
7.4 
Reporting Adverse Events 
7.4.1 
Reporting serious adverse events 
Sponsor-Institution and Sponsor-Investigator shall be responsible for reporting any 
and all serious adverse events associated with the use of the Study Drug to the FDA 
via MedWatch (FDA Form 3500A), with a copy to Astellas via e-mail to safety-
us@us.astellas.com, or fax to 847-317-1421 and, when necessary, to the applicable 
IRB. 
Life-threatening (grade 4 or 5) SAEs, events determined to be medically significant 
by the treating Investigator, and unknown reactions or unexpected events should be 
reported to the principal investigator, site IRB and the lead site/sponsor within 
24 hours and be reported according to institutional and the following guidelines. 
SAEs that are fatal and possibly protocol related and any treatment emergent 
seizure events should be reported by phone to the Protocol Chair immediately upon 
knowledge of the event. 
The Lead Center’s Study Coordinator should be contacted when reporting an SAE or 
death. If this person cannot be reached within 24 hours, the Protocol Chair (Lead 
Center’s PI) should be contacted: Daniel Song, MD, 410-614-3880. 
The initial report for each SAE or death should include the following information: 
 
Protocol # and title 
 
Patient initials, study identification number, age 
 
Date the event occurred 
 
Description of the SAE 
 
Dose level and treatment month at the time the SAE occurred 
 
Description of the patient’s condition 
 
Relationship of SAE to study drug/treatment (see Table 6) 
 
Indication whether the patient remains on study 
Follow-up information including severity, causality, action taken, concomitant 
medications, and outcome should be communicated to the lead site/sponsor as soon 
as possible with an indication whether an amendment will need to be made to the 
protocol, the consent form, or both, as a result of this event. 
7.4.2 
Reporting SAEs at multi‐site/participating institutions  
A subject’s AEs and SAEs will be recorded and reported from the signing of the ICF 
up to at least 30 days after completing salvage radiotherapy. The investigator must 
instruct the subject to report AEs and SAEs during this time period. 

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Subjects with evidence of enzalutamide related toxicity at the post-treatment 
follow-up visit will be followed via telephone contact or weekly visits until the drug-
related toxicity has resolved. Adverse events should be based on the signs or 
symptoms detected during the physical examination and on clinical evaluation of 
the subject. In addition to the information obtained from those sources, the subject 
should be asked the following nonspecific question: "How have you been feeling 
since your last visit?" Signs and symptoms should be recorded using standard 
medical terminology. Any unanticipated risks to the subjects must be reported 
promptly to the IRB/IEC. In the event of an adverse event the first concern will be 
for the safety of the subject. 
 
All AEs and SAEs must be recorded on source documents. All AEs and SAEs for 
subjects who meet inclusion and exclusion criteria will be recorded in the CRFs and 
submitted to the lead site. The investigator must follow up on all AEs and SAEs until 
the events have subsided, returned to baseline or, in case of permanent impairment, 
until the condition stabilizes. 
 
Additional reporting is required for SAEs as follows: 
 
SAEs that are fatal and possibly protocol related should be reported by phone to 
the Protocol Chair immediately upon knowledge of the event. 
 
Each participating site is responsible for evaluating and completing any additional 
reporting to their local IRB according to local IRB guidelines. 
8. 
CRITERIA FOR OUTCOME ASSESSMENT 
8.1 
Outcome Assessment 
All baseline evaluations will be performed as closely as possible to the beginning of 
treatment. For subsequent evaluations, the method of assessment and techniques will be 
the same as those used at baseline. 
 
Measurement of clinical lesions 
 
Chest x-ray 
Should be conducted at PSA progression. Scans can also be obtained sooner as 
clinically indicated. 
 
Conventional CT, MRI 
Should be conducted at PSA progression. Scans can also be obtained sooner as 
clinically indicated. 
 
Ultrasound 
 
Endoscopy/laparoscopy 
 
Tumor markers 
FFPP is defined as the time from randomization to the date of PSA progression. A 
subject who does not have PSA progression at the time of the analysis will be 
censored at the last date of PSA measurement. In patients who achieve an 

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undetectable PSA value (defined as ≤0.1 ng/mL), PSA progression is defined as a 
detectable PSA value (≥0.2 ng/mL) that is confirmed by a second consecutive PSA 
value obtained ≥8 weeks later which is higher (and ≥0.4 ng/mL).  In patients who do 
not achieve an undetectable PSA, PSA progression is defined as a 0.2 ng/mL increase 
from nadir that is confirmed by a second consecutive PSA value obtained ≥8 weeks 
later which is higher. 
 
Cytology/histology 
8.1.1 
Primary endpoint 
The primary objective of the study is to evaluate the efficacy of the two treatment 
regimens based on freedom-from-PSA-progression (FFPP).  Overall survival has 
been the preferred primary endpoint for most phase III trials in metastatic prostate 
cancer, as well as for most registration trials for other metastatic malignancies.  
Many of the practice-changing adjuvant trials, however, have used disease-free or 
progression-free survival as the primary endpoint 38,39.  Probably the most 
analogous adjuvant therapy is the use of endocrine therapy for early stage breast 
cancer.  The primary endpoint for many of the trials evaluating tamoxifen and the 
aromatase inhibitors has been disease-free survival 40-43.  Several of the described 
prostate cancer adjuvant trials reported a lower-than-expected event rate requiring 
re-assessment of sample size and follow-up time.  Even men with the highest risk 
prostate cancers are likely to survive beyond 12 years after prostatectomy 44.  This 
data originated in the pre-docetaxel era and does not reflect the arsenal of new 
therapeutic agents that have become available to patients with advanced prostate 
cancer. We do not yet have reported data for survival after prostatectomy that 
accounts for these new treatments, which makes estimating survival a challenge.  
Furthermore, cabazitaxel, abiraterone acetate, enzalutamide, and alpharadin were 
all tested in advanced metatstatic disease patient populations, so although we know 
the benefits of these drugs individually, the impact on survival when administered 
sequentially has not been established.  We estimate that with the approval of 
cabazitaxel, sipuleucel-T, abiraterone acetate, enzalutamide, and radium-223, men 
may live as long as 15-20 years after prostatectomy.  The size, duration, and cost of a 
trial powered to detect an overall survival benefit in the this setting for prostate 
cancer is substantial and such trials must be carefully designed to ensure 
responsible utilization of resources. Despite these challenges, it is important to 
move novel therapies earlier in the treatment of prostate cancer with the hope that 
these agents improve cure rates such that the long-term cost-benefit ratio is 
favorable.  The ultimate goal of adjuvant systemic therapy is to increase the number 
of patients cured of their cancer.  The earliest indication of prostate cancer relapse is 
a rising PSA after definitive local therapy.  For these reasons, we will use 2-year 
FFPP defined as our primary endpoint.  FFPP reflects a clinically meaningful 
endpoint for high-risk patients, yet minimizes the patients and resources necessary 
to answer this question. 
FFPP is defined as the time from randomization to the date of PSA progression. A 
subject who does not have PSA progression at the time of the analysis will be 
censored at the last date of PSA measurement. In patients who achieve an 
undetectable PSA value (defined as ≤0.1 ng/mL), PSA progression is defined as a 
detectable PSA value (≥0.2 ng/mL) that is confirmed by a second consecutive PSA 

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value obtained ≥8 weeks later which is higher (and ≥0.4 ng/mL).  In patients who do 
not achieve an undetectable PSA, PSA progression is defined as a 0.2 ng/mL increase 
from nadir that is confirmed by a second consecutive PSA value obtained ≥8 weeks 
later which is higher. 
8.1.2 
Secondary endpoints 
The first secondary endpoint is time to local recurrence within the radiation field, 
defined as the time from randomization to the date of local recurrence of disease. 
Subjects who do not have local recurrence will be censored on the date of their last 
evaluable tumor assessment for local recurrence. Subjects who start any subsequent 
anti-cancer therapy without a prior reported local recurrence will be censored at 
the last evaluable tumor assessment prior to initiation of the subsequent anti-cancer 
therapy. 
The second secondary endpoint is radiographic metastasis free survival (rMFS), 
defined as the time from randomization to the date of metastasis or death from any 
cause, whichever occurs first. A subject who does not have metastasis and is alive 
will be censored at the last date of tumor assessment. We will pay particular 
attention to the 2-year MFS rate. 
Safety and tolerability will also be evaluated as secondary objectives.

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9. 
DATA REPORTING AND REGULATORY REQUIREMENTS 
The SKCCC Lead Coordinating Center will monitor the conduct and progress of the clinical 
trial at all participating sites.  It will provide administrative, data management, regulatory, 
and organizational support in the conduct of this multi-center trial.  The Coordinating 
Center will also function as the central location for multi-center trial documents and patient 
registration.  For more information regarding reporting, regulatory requirements and 
guidelines, see Appendix D. 
 
9.1  
Multicenter Guidelines 
 
 
9.1.1. The Protocol Chair 
 
The Protocol Chair, Daniel Song, is responsible for performing the following tasks: 
 
 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
 
Coordinating, developing, submitting, and obtaining approval for the 
protocol as well as its subsequent amendments. 
 
Assuring that all participating institutions are using the correct version of 
the protocol. 
 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs). 
 
Reviewing data from all sites 
 
9.1.2. 
Lead Coordinating Center 
 
The Lead Center SKCCC, Johns Hopkins University is responsible for performing the 
following tasks: 
 
Verifying that each participating institution has a Federal Wide Assurance 
(FWA) number. 
 
Ensuring that IRB approval has been obtained at each participating site 
prior to the first patient registration at that site. 
 
Maintaining copies of IRB approvals from each site. 
 
Implementing central patient registration 
 
Prepare appropriate data as required for review by the Protocol Chair. 
 
Establishing procedures for documentation, reporting and submitting of 
AE’s and SAE’s to the Protocol Chair and all other applicable parties. 
 
Facilitating audits by securing selected source documents and research 
records from participating sites for audit, or by auditing at participating 
sites. 
 
9.1.3. 
Participating PCCTC Sites 
 
Participating sites are responsible for performing the following tasks: 
 
Following the protocol as written, and the guidelines of Good Clinical 
Practice (GCP). 

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 
Submitting data to the Lead Center. Please follow the submission schedule in 
section 9.2.1.   
 
Registering all patients with the Lead Center by submitting patient 
registration form, and signed informed consent promptly 
 
Providing sufficient experienced clinical and administrative staff and 
adequate facilities and equipment to conduct a collaborative trial according 
to the protocol 
 
Maintaining regulatory binders on site and providing copies of all required 
documents to the Lead Center  
 
Collecting and submitting data according to the schedule specified by the 
protocol 
9.2 
Data Entry 
Data collected during this study will be entered into a secure database. Staff at the PCCTC 
coordinating center will be responsible for the initial study configuration and setup in the 
consortium database and for any future changes. 
9.2.1 
Case report forms 
Case report forms will be generated by the coordinating center for the collection of 
all study data. Investigators will be responsible for ensuring that the CRFs are kept 
up-to-date.  
The schedule for completion and submission of Case Report Forms and all 
supporting documents to the Lead Coordinating Center is as follows: 
 
Form  
Submission Timeline 
Eligibility Checklist  
Complete prior to registration  
Baseline Assessment Form 
Within 14 days of registration  
On-Treatment Forms (including drug diary) 
Within 10 days of course completion  
Adverse Event Report Form 
Within 14 days of each visit date 
Follow-up Form 
Within 14 days of visit date 
Off Study Form 
Within 14 days of being taken off study for any 
reason  
Data should also be submitted within the Johns Hopkins Oncospace Portal. 
9.2.2 
Source documents 
Study personnel will record clinical data in each patient’s source documents (ie, the 
patient’s medical record). Source documentation will be made available to support 
the patient research record. Study monitors will review entries on the CRFs at 
regular intervals, comparing the content with source documents. 
9.2.3 
Record retention 
The investigator will maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. 
After study closure, the investigator will maintain all source documents, study-
related documents, and the CRFs. Because the length of time required for retaining 
records depends upon a number of regulatory and legal factors, documents should 

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be stored until the investigator is notified that the documents may be destroyed. In 
this study, records are to be retained and securely stored for a minimum of 3 years 
after the completion of all study activities. 
9.3 
Data Management 
9.3.1 
Lead research program coordinators 
A Lead Research Program Coordinator at the Coordinating Center will be assigned 
to the study. A Lead Research Program Coordinator will manage the study activities 
at each of the participating sites. The responsibilities of the Lead Research Program 
Coordinator include project compliance, data collection, data entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of 
the activities of the protocol team. 
9.4 
Study Monitoring and Quality Assurance 
All clinical trials at SKCCC, Johns Hopkins are required to have Data and Safety Monitoring 
Plan (DSMP).  The Clinical Research Review Committee (CRC) is charged with ensuring that 
protocols meets the Center’s standards for Scientific Merit, Scientific Priority, and Adequate 
Scientific Progress.  The CRC in concurrence with the PI determines the risk level, then 
reviews and approves the study specific DSMP. 
Regularly scheduled registration reports will be generated to monitor patient accruals and 
the completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and the extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period, and 
potential problems will be brought to the attention of the principal investigator for 
discussion and action. 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team at least once a year, more frequently if indicated. Audits by the coordinating center 
may entail (1) shipping source documents and research records for selected patients from 
participating sites to the coordinating center for audit, or (2) on-site auditing of selected 
patient records at participating sites. 
All clinical work conducted under this protocol is subject to Good Clinical Practice (GCP) 
guidelines. This includes inspection of study-related records by the lead site, sponsor, its 
designee, or health authority representatives at any time. 
9.4.1 
Data and Safety Monitoring 
The SKCCC Compliance Monitoring Program will provide external monitoring for 
JHU-affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019).  The 
SMC Subcommittee will determine the level of patient safety risk and 
level/frequency of monitoring.  
 
The PI is responsible for internally monitoring the study. Data must be reviewed to 
assure the validity of data, as well as, the safety of the subjects. The PI will also 
monitor the progress of the trial, review safety reports, and clinical trial efficacy 
endpoints and to confirm that the safety outcomes favor continuation of the study 

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9.5 
Clinical Trial Agreement 
This trial is being conducted under one or more clinical trial agreements that contain, 
among other terms, the publication policy, indemnity agreements, and financial 
arrangements for the study. 
9.6 
End of Study 
This study will end and study database locked when 24 months of follow up is reached from 
the last patient being enrolled.  A final study report will be provided within 3 months of the 
end of the study. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
10.1.1 Analysis of the primary endpoint 
The study is a multi-center, double-blind, placebo controlled, randomized Phase II 
trial in patients with non-castrate PSA-recurrent prostate cancer after radical 
prostatectomy. Eligible patients will be randomized in a 1:1 ratio to one of two 
treatment arms: SRT plus placebo (Arm A) or SRT plus enzalutamide (Arm B).  
Randomization will be stratified by center, and surgical margin status (R0 vs R1), 
PSA prior to salvage treatment (PSA ≥0.5 vs <0.5 ng/mL), and pathologic Gleason 
score (7 vs 8-10). 
The primary objective of the study is to evaluate the efficacy of the two treatment 
regimens based on freedom-from-PSA-progression (FFPP). FFPP is defined as the 
time from randomization to the date of PSA progression. A subject who does not 
have PSA progression at the time of the analysis will be censored at the last date of 
PSA measurement. In patients who achieve an undetectable PSA value (defined as 
≤0.1 ng/mL), PSA progression is defined as a detectable PSA value (≥0.2 ng/mL) 
that is confirmed by a second consecutive PSA value obtained ≥8 weeks later which 
is higher (and ≥0.4 ng/mL).  In patients who do not achieve an undetectable PSA, 
PSA progression is defined as a 0.2 ng/mL increase from nadir that is confirmed by a 
second consecutive PSA value obtained ≥8 weeks later which is higher. 
It is very unlikely deaths in the time frame of this trial will be from prostate 
cancer.  Censoring the subjects that have died at the date of the last PSA 
measurement before death will be performed (as we will not know if PSA changes in 
the interval) unless there is clear evidence of death from prostate cancer per the 
treating physician and/or by autopsy. 
FFPP will be summarized using Kaplan-Meier method by treatment arms. FFPP 
probability will be estimated using the Kaplan-Meier method.  FFPP curves will also 
be displayed graphically. Differences in FFPP between treatment arms will be 
compared by the log rank test. The Cox proportional hazards regression model will 
be fitted, and the estimated hazard ratio (Arm B/Arm A) and corresponding 95% CI 
will be provided.  Additionally, Cox regression models  will be used to explore the 
potential influences of the other prognostic factors on the primary FFPP endpoints. 

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10.1.2 Analysis of secondary endpoints 
The first secondary endpoint is time to local recurrence within the radiation field, 
defined as the time from randomization to the date of local recurrence of disease. 
Subjects who do not have local recurrence will be censored on the date of their last 
evaluable tumor assessment for local recurrence. Subjects who start any subsequent 
anti-cancer therapy without a prior reported local recurrence will be censored at 
the last evaluable tumor assessment prior to initiation of the subsequent anti-cancer 
therapy. 
The second secondary endpoint is metastasis free survival (MFS), defined as the 
time from randomization to the date of metastasis or death from any cause up to 90 
days following the last response assessment, whichever occurs first. A subject who 
does not have metastasis and is alive will be censored at the last date of tumor 
assessment. 
Time-to-event endpoints (time to local recurrence and MFS) will be analyzed 
similarly as described for the primary endpoint (FFPP). 
 
Safety and tolerability will also be evaluated as secondary objectives.  For safety 
analysis, overall safety profile and toleration of Arm A and Arm B will be 
characterized by type, frequency, severity, timing and relationship of study therapy 
of adverse events and laboratory abnormalities. Adverse events will be summarized 
by the frequency of patients experiencing treatment emergent adverse events 
corresponding to body systems and by worst NCI CTCAE (version 4.0) grade. 
10.2 
Analysis Populations 
10.2.1 Intent‐to‐treat/Response‐to‐treatment/Evaluable population 
The Intent-to-Treat (ITT) Population includes all subjects who are randomized with 
study treatment assignment designated according to initial randomization. The ITT 
population will be the primary population for evaluating time-to-event efficacy 
endpoints (i.e. FFPP, time to local recurrence, MFS, and time to reinitiation of 
hormonal therapy) and patient characteristics.  
 
Per Protocol Population will include all patients who are randomized and received 
at least one dose of study medication, and do not have any major protocol violations 
(for example, incorrect treatment group allocation according to randomization, not 
meeting the major inclusion/exclusion criteria for disease status and prior 
therapies, noncompliance to treatment plan or assessment schedule; additional 
concurrent prohibited therapies). The per-protocol analysis will serve as 
supportive. 
10.2.2 Safety population 
Safety Population will include all patients who receive at least one dose of study 
medication, with treatment assignments designated according to actual study 
treatment received. The safety analyses population will be the primary population 
for evaluating treatment administration/compliance and safety. 

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10.2.3 Special populations 
10.2.3.1 Severe liver disease 
Patients with baseline severe hepatic impairment (Child-Pugh C) are 
excluded from this clinical trial. 
10.2.3.2 Lowered seizure threshold 
In clinical studies, seizure was identified as a risk associated with 
enzalutamide treatment. In the controlled clinical Study CRPC2, seizures 
occurred in 0.9% (7/800) of patients receiving enzalutamide 160 mg daily, 
whereas no seizures occurred in patients treated with placebo. Confounding 
factors may have contributed to the occurrence of seizures in several of 
these cases. Dose appears to be an important predictor of seizure, with a 
greater risk of seizure at daily doses higher than 160 mg. In a dose 
escalation study involving 140 patients, no patients experienced seizures at 
or below daily doses of 240 mg, whereas 3 seizures were reported, 1 each at 
360, 480 and 600 mg/day. Caution should be used in administering 
enzalutamide to patients with a history of seizures or other predisposing 
factors including, but not limited to, underlying brain injury, stroke, primary 
brain tumors or brain metastases or alcoholism. In addition, the risk of 
seizure may be increased in patients receiving concomitant medications that 
may lower the seizure threshold. Enzalutamide should be permanently 
discontinued in patients who have a seizure while on treatment. 
10.3 
Safety Analysis 
10.3.1 Evaluation of adverse events 
Treatment-emergent adverse events will be translated from investigator terms to 
MedDRA v6.0 terminology and summarized (number and percentage of patients) 
for all patients who receive at least 1 dose of enzalutamide. Adverse event 
summaries will be organized by body system, frequency of occurrence, intensity (ie, 
severity grade), and causality or attribution. Patients who experience an adverse 
event more than once will be counted only once. The occurrence with the maximum 
severity will be used to calculate intensity. 
10.3.2 Evaluation of serious adverse events and premature withdrawals 
Adverse events deemed serious and those resulting in treatment withdrawal or 
death will be summarized separately. Narrative paragraphs will be generated to 
describe the circumstances surrounding each SAE and death. 
10.3.3 Evaluation of laboratory parameters and assays 
Selected clinical laboratory parameters will be summarized and clinically significant 
changes from baseline will be discussed. 
10.3.4 Extent of exposure 
Treatment exposure will be summarized for all patients, including dose 
administration, number of cycles, dose modifications or delays, and duration of 
therapy. 

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10.4 
Statistical Procedures 
Summary statistics include the number of observations, mean, standard deviation, median, 
minimum, and maximum values. 
10.4.1 Sample size calculation 
Based on the largest multi-institutional SRT series published (n=1,540) in which 
patients received SRT followed by observation until the PSA reached ≥0.2 ng/mL 
above the post-SRT nadir, the 2-year FFPP was approximately 60% with SRT.  For 
our primary endpoint of 2-year FFPP we expect an absolute 20% improvement with 
the treatment of SRT+ enzalutamide (2-year FFPP 80%) over SRT alone (2-year 
FFPP 60%). 
We originally assumed an accrual time of 18 months, with >24 months of additional 
follow-up time. FFPP at 2 year from 60% to 80%, a 20% increase (corresponding to 
a hazard ratio of 0.44 under the assumption of exponential distribution of event 
times) corresponds to 39 events total of PSA progression (for example 26 in Arm A, 
and 13 in Arm B) with a 90% power to detect an improvement of, using a one-sided 
log-rank test at significance level 0.1. Adjusting for 15% non-evaluable or dropout 
patients, we will randomize a total of 122 patients (61 patients in each arm). 
The power of the study is driven by the number of PFS progression events.  The 
design requires 39 events when the analysis of the primary endpoint is conducted. 
Under the assumption that there are not non-evaluable patients or no dropout, 
a total of 102 patients needs to be enrolled over 18 months with >24 months of 
additional follow-up to reach 39 events. Because the study duration is as long as 3.5 
years, a fair number of patients may be lost to follow-up before that and their time 
to PSA progression will be censored at the last date of PSA measurement. So we 
assume a e non-evaluable and loss-to-follow-up rate of 15% when we estimate the 
total number of participants.  
The trial started enrolling patients in April 2015, and has enrolled 80 patients by 
April 2019. The rate of accrual is about 10 patients every 6 months. Due to slower 
than expected enrollment, we propose to extend the accrual time to the end of 
March 2020. We plan to conduct the primary analysis when 39 events occur.  
Our new efficacy assumption stays the same as to detect the difference of Freedom 
From PSA Progression (FFPP) at 2 year from 60% in SRT+placebo arm to 80% in 
SRT+enzalutamide arm, a 20% increase (corresponding to a hazard ratio of 0.44 
under the assumption of exponential distribution of event times.) The study power 
remains at 90% with one-sided type I error 0.1 using log-rank test. 
The sample size is 96 total (48 per arm) accounting for 15% loss-to-follow up before 
PSA progression events. Below represents the new enrollment target for patients 
given this revised power calculation based on number of events thus far, follow-up 
and drop out to date. 
 

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Total number 
of PSA 
progression 
events 
Sample size  
Planned 
accrual 
time 
(mons) 
Additional 
follow-up 
time (mons) 
End of 
accrual 
End of 
follow-up 
(start the 
analysis) 
Power
Original design 
 
 
 
39 
122 (61 per 
arm) 
18 
24
90% 
New design 
 
 
 
39 
96 (48 per 
arm) 
60 
21
March 
2020 
Dec. 2021 
90% 
 
 
10.4.2 Stratification factors 
Randomization will be stratified by center, and surgical margin status (R0 vs R1), 
PSA prior to salvage treatment (PSA ≥0.5 vs <0.5 ng/mL), and pathologic Gleason 
score (7 vs 8-10). 
10.4.3 Derived variables 
 
FFPP will be summarized using Kaplan-Meier method by treatment arms. FFPP 
curves will also be displayed graphically. Differences in FFPP between treatment 
arms will be compared by the log rank test. The Cox regression model will be 
fitted, and the estimated hazard ratio (Arm B/Arm A) and corresponding 95% CI 
will be provided. 
 
FFPP probability will be estimated using the Kaplan-Meier method  
 
Additionally, Cox regression models  will be used to explore the potential 
influences of the other factors on the primary FFPP endpoints. 
 
Time-to-event endpoints time to local recurrence and radiographic MFS will be 
analyzed similarly as described for the FFPP. 
 
For safety analysis, overall safety profile and toleration of Arm A and Arm B will 
be characterized by type, frequency, severity, timing and relationship of study 
therapy of adverse events and laboratory abnormalities. Adverse events will be 
summarized by the frequency of patients experiencing treatment emergent 
adverse events corresponding to body systems and by worst NCI CTCAE 
(version 4.0) grade. 
11. 
PROTECTION OF HUMAN SUBJECTS 
11.1 
Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by 
the International Conference on Harmonisation, and the ethical standards set forth in the 
Declaration of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 

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11.2 
Protocol Amendments 
Before starting the study, the protocol must be approved by each institution’s IRB or 
Independent Ethics Committee (IEC). Amendments to the protocol may be made only with 
consent of the lead site/sponsor and principal investigator and are subject to IRB approval 
before instituting. 
11.3 
Written Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the 
treatment program with the patient. The discussion will review the alternatives available 
(including hormonal therapy, chemotherapy, or supportive care as appropriate), the 
potential benefits of this program, the risks and the probability of their occurrence, and the 
procedures to minimize these risks. Should an adverse event occur, the provisions available 
to ensure medical intervention will also be reviewed. Why the risks are reasonable in 
relation to the anticipated benefits, incentives, or costs that will or may be incurred as a 
result of participating in the study, as well as the efforts to maintain confidentiality, will also 
be discussed with the patient. 
Patients will be required to sign and date (in triplicate) a statement of informed consent 
that meets the requirements of the Code of Federal Regulations (Federal Register Vol. 46, 
No. 17, January 27, 1981, part 50) and the IRB. The medical record will include a statement 
that written informed consent was obtained (and document the date that it was obtained) 
before the patient is enrolled in the study. The original signed document will become part of 
the patient’s medical record, a copy will be forwarded to the lead site/sponsor pursuant to 
sponsor registration and to the PCCTC coordinating center at MSKCC, and a copy will be 
sent home with each patient. 
The consent form will include the following: 
 
the nature and objectives, potential toxicities, and benefits of the intended study 
 
the length of therapy and likely follow-up required 
 
alternatives to the proposed therapy (including available standard and 
investigational therapies) 
 
the name of the investigator(s) responsible for the protocol 
 
the right of the patient to accept or refuse treatment and to withdraw from 
participation in this study 
 
Text regarding the consortium and the coordinating center should be added to 
all institutional informed consent documents and sections in the research 
authorization/HIPAA forms (eg, “Prostate Cancer Clinical Trial Consortium, 
Coordinating Center at Memorial Sloan-Kettering Cancer Center, New York, NY”) 
11.4 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. After this discussion, they 
will be asked to sign a Notice of Privacy Practice research authorization/HIPAA form. The 
original signed documents will become part of the patient’s medical records, and each 
patient will receive a copy of the signed documents. The use and disclosure of protected 
health information will be limited to the individuals described in the research authorization 

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form. The research authorization form must be completed by the principal investigator and 
approved by the IRB. 
11.5 
Terminating or Modifying the Study 
Adverse event and laboratory data from this trial will be assessed by the lead site or the 
sponsor’s medical monitor on an ongoing basis. At least quarterly, data from the clinical 
database will be reviewed. The results of this review will be shared with all investigators 
either in writing or as part of a teleconference. SAEs will be reviewed as they are reported 
to the lead site/sponsor, and the medical monitor will make an assessment regarding the 
safety of continuing or modifying the study. This assessment will be shared with the 
investigators either in writing or as part of a teleconference. Should the assessment of 
either the lead site/sponsor or the principal investigator be that the study should be 
terminated, the study will be closed to further accrual. Patients who are receiving 
enzalutamide will be assessed individually by the investigator to see if it is in the patients’ 
best interest to continue, which might be the case for a patient that is responding to the 
intervention. Follow-up safety assessments will be performed for all patients who are 
terminated from the study prematurely. 

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12. 
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Choo R, Hruby G, Hong J, et al. Positive resection margin and/or pathologic T3 
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Chawla AK, Thakral HK, Zietman AL, Shipley WU. Salvage radiotherapy after radical 
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Song DY, Thompson TL, Ramakrishnan V, et al. Salvage radiotherapy for rising or persistent 
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Liauw SL, Webster WS, Pistenmaa DA, Roehrborn CG. Salvage radiotherapy for biochemical 
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Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the Outcome of Salvage Radiation 
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Hayes SB, Pollack A. Parameters for treatment decisions for salvage radiation therapy. J Clin 
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Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term 
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Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation 
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Denham JW, Steigler A, Lamb DS, et al. Short-term androgen deprivation and radiotherapy 
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Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive 
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Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy oncology group (RTOG) 
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Tiguert R, Rigaud J, Lacombe L, Laverdiere J, Fradet Y. Neoadjuvant hormone therapy before 
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King CR, Presti JC, Jr., Gill H, Brooks J, Hancock SL. Radiotherapy after radical prostatectomy: 
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Morris MM, Dallow KC, Zietman AL, et al. Adjuvant and salvage irradiation following radical 
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Neulander EZ. Re: Neoadjuvant hormone therapy before salvage radiotherapy for an 
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Katz MS, Zelefsky MJ, Venkatraman ES, Fuks Z, Hummer A, Leibel SA. Predictors of 
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Shipley WU, Hunt D, Lukka H, et al. Initial Report of RTOG 9601: A Phase III Trial in Prostate 
Cancer: Anti-androgen Therapy (AAT) with Bicalutamide during and after Radiation Therapy (RT) 
Improves Freedom from Progression and Reduces the Incidence of Metastatic Disease in Patients 
following Radical Prostatectomy (RP) with pT2-3, N0 Disease, and Elevated PSA Levels. Int J Radiat 
Oncol Biol Phys 2010;78:S27. 
31. 
King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out 
there? Int J Radiat Oncol Biol Phys 2008;71:346-50. 
32. 
Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen 
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33. 
Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for 
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34. 
Kelly WK, Slovin S, Scher HI. Steroid hormone withdrawal syndromes. Pathophysiology and 
clinical significance. The Urologic clinics of North America 1997;24:421-31. 
35. 
Scher HI, Fizazi K, Saad F, et al. Effect of MDV3100, an androgen receptor signaling inhibitor 
(ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase 
III AFFIRM study. J Clin Oncol 2012;30. 
36. 
Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer 
after Chemotherapy. N Engl J Med 2012. 
37. 
Vickers AJ. How to randomize. J Soc Integr Oncol 2006;4:194-8. 

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38. 
Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, 
and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 
2009;27:3109-16. 
39. 
Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast 
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40. 
Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment 
for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:1135-41. 
41. 
Davies C, Godwin J, Gray R, et al. Relevance of breast cancer hormone receptors and other 
factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. 
Lancet 2011;378:771-84. 
42. 
Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials 
of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28:509-18. 
43. 
Fisher B, Redmond C, Brown A, et al. Treatment of primary breast cancer with 
chemotherapy and tamoxifen. N Engl J Med 1981;305:1-6. 
44. 
Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation 
treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic 
lymphadenectomy. Lancet Oncol 2006;7:472-9. 
 
 
 

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APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able to 
continue all predisease performance 
without restriction. 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or sedentary 
nature (eg, light housework, office 
work). 
80 
Normal activity with effort, some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time. Ambulatory 
and capable of all self-care but unable 
to carry out any work activities. Up 
and about more than 50% of waking 
hours. 
60 
Requires occasional assistance but is 
able to care for most needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time. Capable of 
only limited self-care, confined to bed 
or chair  
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled, cannot carry on any self-
care, totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 

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APPENDIX B: MEDICATIONS WITH THE POTENTIAL FOR DRUG‐DRUG INTERACTIONS 
Class 
Agents 
Class 
Agent 
Drugs that Inhibit 
CYP2C8 
gemfibrozil 
Drugs that are 
metabolized by 
CYP3A4 
alfentanil, 
cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus and 
tacrolimus 
Drugs that Induce 
CYP2C8 
rifampin 
Drugs that are 
metabolized by 
CYP2C19 
S-mephenytoin 
Drugs that Inhibit 
CYP3A4 
itraconazole) 
Drugs that are 
metabolized by 
CYP2C9 
phenytoin, warfarin 
Drugs that Induce 
CYP3A4 
carbamazepine, 
phenobarbital, 
phenytoin, rifabutin, 
rifampin, rifapentine, 
bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin 
Substrates for efflux 
transporter P-gp 
colchicine, dabigatran 
etexilate, 
digoxin 
Substrates for BCRP, 
MRP2 or OAT3 
methotrexat 
 
 
 

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APPENDIX C: GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
 
17-AAG 
17-allylamino-17-demethoxygeldanamycin 
17-DMAG 
17-dimethylaminoethylamino-17-demethoxygeldanamycin 
2-MPPA 
2-(3-mercaptopropyl) Pentanedioic acid  
AdEERS 
Adverse Event Expedited Reporting System  
ADR 
adverse drug reaction 
ADT 
androgen-deprivation therapy 
AE 
adverse event 
AGA 
androgenetic alopecia 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
APTT 
activated partial thromboplastin time 
AR 
androgen receptor 
ASAEL 
Agent Specific Adverse Event List 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC(INF) 
area under the concentration-time curve from time zero extrapolated to 
infinite time 
AUC(0-T) 
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration 
AUC(TAU) 
area under the concentration-time curve in one dosing interval 
AUMC(INF) 
area under the moment concentration time curve extrapolated to infinity 
A-V 
atrioventricular 
-HCG 
beta-human chorionic gonadotrophin 
%BE 
percent biliary excretion 
bid 
bis in die (twice a day) 
BLQ 
below limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
BSA 
Body Surface Area 
BUN 
blood urea nitrogen 
C 
Celsius 
Ca++ 
calcium 

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caBIG 
Cancer Biomedical Informatics Grid 
CAEPR 
Comprehensive Adverse Event and Potential Risks 
CALGB 
Cancer and Leukemia Group B 
CBC 
complete blood count 
CCC 
Clinical Consortium Committee 
CCD 
Central Consortium Database 
CDE 
common data element 
CDUS 
Clinical Data Update System  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cl- 
chloride 
Clcr 
creatinine clearance 
CLNR 
nonrenal clearance 
CLR 
renal clearance 
CLT 
total body clearance 
CLT/F 
apparent total body clearance 
Cm 
centimeter 
Cmax 
maximum plasma concentration 
Cmin 
trough observed concentration 
COSTART 
Coding Symbols for Thesaurus of Adverse Reaction Terms 
CNS 
central nervous system 
CR 
complete response 
CRC 
Clinical Research Center 
CRDB 
Clinical Research Database 
CRF 
case report form 
CRMIS 
Clinical Research Management Information System 
CRPC 
castration resistant prostate cancer 
CT 
computerized tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trials Monitoring Service 
CTO 
Clinical Trials Office 
CV 
coefficient of variation 
CYP 
cytochrome p-450 
DCTD 
Division of Cancer Treatment and Diagnosis 
DEV 
deviation from the nominal value 

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%DEV 
percent deviation 
dL 
deciliter 
DHEA 
dehydroepiandrosterone 
DHEA-S 
dehydroepiandrosterone sulfate 
DHT 
dihydrotestosterone 
DLT 
dose-limiting toxicity 
DSM 
data and safety monitoring 
EA 
extent of absorption 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EKG 
electrocardiogram 
EORTC 
European Organisation for Research and Treatment of Cancer 
ESF 
eligibility screening form 
ESR 
expedited safety report 
F 
bioavailability 
FDA 
Food and Drug Administration 
FDG-PET 
2-[18F]fluoro-2-deoxyglucose positron emitting tomography 
FDHT 
18-fluoro-dehydrotestosterone 
%FE 
percent fecal excretion 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
GAPDH 
glyseraldehayde-3-phophate dehydrogenase 
GC 
gas chromatography 
GCP 
good clinical practice 
GCPII 
glutamate carboxypeptidase II enzyme 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GnRH 
gonadotropin-releasing hormone  
HAT 
histone acetyltransferases 
HCO3- 
bicarbonate 
HDAC 
histone deacetylase 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HL7 
American National Standards Institute’s Health Level Seven 
HPF 
high power field 

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HPLC 
high-performance liquid chromatography 
HR 
heart rate 
HRPC 
hormone-refractory prostate cancer 
HRT 
hormone replacement therapy 
HSP90 
heat-shock protein 90 
ICD 
International Classification of Diseases 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunochemical 
IM 
intramuscular 
IMSL 
International Mathematical Statistical Library 
IND 
investigational new drug 
INR 
international normalized ratio 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
ITT 
intent-to-treat population 
IV 
intravenous 
K 
slope of the terminal phase of the log concentration-time curve 
K+ 
potassium 
K3EDTA 
potassium ethylenediaminetetraacetic acid 
KLK1 
kallikrein 1 
LBD 
ligand-binding domain 
LC 
liquid chromatography 
LCM 
laser capture microdissection 
LC-MS 
liquid chromatography/mass spectrometry 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LLQ 
lower limit of quantitation 
ln 
natural logarithm 
LOCF 
last observation carried forward 
LOI 
letter of intent 
LPF 
low power field 
MAD 
maximum administered dose 
MDS 
myelodysplasia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
MMP 
matrix metalloproteinase 

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MRI 
magnetic resonance imaging 
MRT 
mean residence time 
MRT(INF) 
mean residence time adjusted for infusion time 
MRT(PO) 
mean residence time following oral administration 
MRT(SS) 
mean residence time at steady-state 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
MS 
mass spectrometry 
MTD 
maximum tolerated dose 
N 
number of subjects or observations 
NA 
not applicable 
N/A 
not available 
NBN 
National Biospecimen Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NOAEL 
no observed adverse effect level 
NOS 
not otherwise specified 
NSAID 
nonsteroidal anti-inflammatory drug 
NTX 
N-telopeptide cross-link 
NVB 
neurovascular bundle 
OCR 
Office of Clinical Research at MSKCC 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
PCRP 
Department of Defense Prostate Cancer Research Program 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
principal investigator 
PIN 
prostatic intraepithelial neoplasia 
PK 
pharmacokinetics 
PMB 
Pharmaceutical Management Branch 
PO 
per os (by mouth) 
PR 
partial response 
PSA 
prostate-specific antigen 
PSA-DT 
prostate-specific antigen doubling time 
PSMA 
prostate specific membrane antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QC 
quality control 

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qd 
quaque die (every day) 
qRT-PCR 
quantitative reverse transcription-polymerase chain reaction 
QOL 
quality of life 
RBC 
red blood cell 
RC 
Research Council 
RDBMS 
Relational Database Management System 
RDRC 
Radioactive Drug Research Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP 
radical prostatectomy  
RPC 
eResearch Program Coordinator 
RSA 
Research Study Assistant 
RSD 
relative standard deviation 
%RSD 
percent relative standard deviation 
SAE 
serious adverse event 
SAHA 
suberoylanilide hydroxamic acid 
SC 
subcutaneous 
SD 
standard deviation 
SD 
stable disease 
Seq 
sequence 
SHBG 
sex hormone binding globulin 
SKI 
Sloan-Kettering Institute for Cancer Research 
SMD 
stable metabolic disease 
SOP 
Standard Operating Procedures 
SPORE 
Specialized Programs of Research Excellence 
STAR 
Symptom Tracking and Reporting 
SUV 
standardized uptake value 
t 
temperature 
t1/2 
terminal half-life  
T 
time 
TAUC(TAU) 
trapezoidal area under the concentration-time curve in one dosing interval 
TAUC(0-T) 
trapezoidal area under the concentration-time curve from time zero to the 
time of the last quantifiable concentration 
TDP 
time to disease progression 
TGP 
prostate-specific transglutaminase  
tid 
ter in die (3 times a day) 
TMA 
tissue microarray  
Tmax 
time of maximum observed concentration 

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TMPRSS2 
transmembrane protease, serine 2 
TNM 
tissue, lymph node, metastases 
TX 
treatment 
ULN 
upper limit of normal 
ULQ 
upper limit of quantitation 
UR 
urinary recovery 
VEGF 
vascular endothelial growth factor 
Vss 
volume of distribution at steady-state 
WBC 
white blood cell 
WHO 
World Health Organization 

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APPENDIX D: SKCCC DATA AND SAFETY MONITORING PLAN