ARN-509+Abiraterone Acetate+Leuprolide With Stereotactic, Ultra-Hypofractionated Radiation (AASUR) in Very High Risk Prostate Cancer: A Single Arm, Phase II Study
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

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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. 
ARN-509, Abiraterone, Leuprolide, Radiation c15-164 
ARN-509 + Abiraterone acetate + Leuprolide with Stereotactic, 
Ultra-Hypofractionated Radiation (AASUR) in Very High Risk 
Prostate Cancer: A Single Arm, Phase II Study 
Prostate Cancer Clinical Trials Consortium, LLC (PCCTC) 
PCCTC #: c15-164 
IND #: 129,582 
Lead Site: Memorial Sloan Kettering Cancer Center 
Sponsor: Memorial Sloan Kettering Cancer Center 
Funding & Drug Support: Janssen Scientific Affairs, LLC 
 
Principal Investigator 
Statistician 
Sean M. McBride, MD, MPH 
Zhigang Zhang, PhD 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
 
McBrides@mskcc.org 
email: zhangz@mskcc.org 
Co-Investigators 
Dana Rathkopf, MD 
Marisa Kollmeier, MD 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
 
rathkopd@mskcc.org 
Kollmeim@mskcc.org 
 
 
 
 
Protocol Date: 17MAR2016 
Amended Version Date: 05JAN2024 
 

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APPROVAL OF PROTOCOL 
 
 
Title: ARN-509 +Abiraterone acetate +Leuprolide with Stereotactic, Ultra-Hypofractionated 
Radiation (AASUR) in Very High Risk Prostate Cancer: A Single Arm, Phase II Study 
 
 
 
 
Sponsor/Principal Investigator Signature: _______________________________________________________ 
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Date: _______________________________________________________ 
 
Principal Statistician Signature: _______________________________________________________ 
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Date: _______________________________________________________ 
 
PCCTC Signature: _______________________________________________________ 
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PROTOCOL AGREEMENT 
 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing Memorial 
Sloan Kettering Cancer Center with complete and timely information, as outlined in the protocol. It 
is understood that all information pertaining to the study will be held strictly confidential and that 
this confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the 
study staff and myself, I agree to maintain the procedures required to carry out the study in 
accordance with accepted GCP principles and to abide by the terms of this protocol. 
 
 
 
 
 
 
 
 
 
Principal Investigator Signature: _______________________________________________________ 
Principal Investigator Print: _______________________________________________________ 
Date: _______________________________________________________ 

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TABLE OF CONTENTS 
1. 
INTRODUCTION ..........................................................................................................................................................................6 
1.1 
Disease Background .......................................................................................................................................................................... 6 
1.2 
Treatment Background and Rationale ..................................................................................................................................... 6 
2. 
OBJECTI VES .............................................................................................................................................................................. 16 
2.1 
Primary Objective ............................................................................................................................................................................ 16 
2.2 
Secondary Objectives ..................................................................................................................................................................... 16 
3. 
PATIENT SELECTION ............................................................................................................................................................. 17 
3.1 
Inclusion Criteria ............................................................................................................................................................................. 17 
3.2 
Exclusion Criteria............................................................................................................................................................................. 18 
4. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION ................................................................................................. 19 
4.1 
Enrollment Plan................................................................................................................................................................................ 19 
4.2 
Registration Procedure................................................................................................................................................................. 20 
5. 
TREATMENT/INTERVENTION PLAN .............................................................................................................................. 21 
5.1 
Screening Assessment (Withi n 28 days prior to registration) ................................................................................. 25 
5.2 
Treatment/Intervention Period (Cycle 1 Day 1 – Cycle 6 Day 28) ........................................................................ 26 
5.3 
Follow-up (Every 3 months (±2 weeks) for 1st year; every 4 months (±2 weeks) 
for 2nd year; every 6 months (±2 weeks) for 3rd year) ................................................................................................ 27 
5.4 
Dose Modifications .......................................................................................................................................................................... 28 
5.5 
Concomitant Medications and Supportive Care .............................................................................................................. 32 
5.6 
Removing Subjects from the Protocol................................................................................................................................... 33 
6. 
THERAPEUTIC/DIAGNOSTIC AGENTS/MODALI TY ................................................................................................. 35 
6.1 
Description of Treatments ........................................................................................................................................................... 35 
6.2 
Stereotactic, Ultra-Fractionated Radiotherapy ................................................................................................................. 35 
7. 
SAFETY EVALUATION ............................................................................................................................................................ 37 
7.1 
Definitions ........................................................................................................................................................................................... 37 
7.2 
Recording and Grading of Adverse Events ......................................................................................................................... 41 
7.3 
Reporting Serious Adverse Events ......................................................................................................................................... 42 
7.4 
Janssen Scientific Affairs, LLC Requirements .................................................................................................................... 44 
7.5 
Safety Reports ................................................................................................................................................................................... 45 
8. 
CRITERIA FOR OU TCOME ASSESSMENT/THERAPEUTI C RESPONSE ................................................................ 46 
8.1 
Outcome Assessment ..................................................................................................................................................................... 46 
8.2 
Therapeutic Response................................................................................................................................................................... 47 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS ........................................................................................ 47 
9.1 
Data Collection and Management ............................................................................................................................................ 47 
9.2 
Study Monitoring and Quality Assurance ............................................................................................................................ 49 
10. 
STATISTICAL CONSIDERATIONS....................................................................................................................................... 51 
10.1 Study Endpoints ............................................................................................................................................................................... 51 
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS ....................................................................................... 53 
11.1 Roles and Responsibilities ........................................................................................................................................................... 53 
11.2 Ethical Considerations ................................................................................................................................................................... 54 
11.3 Regulatory Documentation ......................................................................................................................................................... 54 
11.4 Protocol Amendments ................................................................................................................................................................... 55 
11.5 Additional IRB Correspondence ............................................................................................................................................... 55 
11.6 Document Maintenance ................................................................................................................................................................ 56 
11.7 Written Informed Consent .......................................................................................................................................................... 57 
11.8 Protection of Privacy ...................................................................................................................................................................... 57 
11.9 Terminating or Modifying the Study ..................................................................................................................................... 58 
11.10 
Unanticipated Problems (UPs) .............................................................................................................................................. 58 
11.11 Noncompliance .................................................................................................................................................................................. 58 
11.12 Return of Genomic Data ............................................................................................................................................................... 58 

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12. 
REFERENCES ............................................................................................................................................................................. 60 
APPENDIX A: PERFORMANCE STATUS CRITERIA .................................................................................................................. 63 
APPENDIX B: MEDICATIONS WITH THE POTENTIAL FOR DRUG-DRUG INTERACTIONS ..................................... 64 
APPENDIX C: LABOR ATORY MANUAL ........................................................................................................................................ 66 
APPENDIX D: EPIC-26 ....................................................................................................................................................................... 67 
APPENDIX E: IPSS ............................................................................................................................................................................... 68 
APPENDIX F: GLOSS ARY OF ABBREVIATIONS AND ACRONYMS ..................................................................................... 69 
APPENDIX G. PILL DIARY ................................................................................................................................................................. 75 

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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 2015 as many as 220,800 American men will be diagnosed with 
prostate cancer, and nearly 27,540 will die of the disease (1). Yet, localized prostate 
carcinoma is often curable, and even metastatic disease frequently responds to treatment. 
The course of prostate cancer from diagnosis to death is best categorized as a series of clinical 
states (Figure 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. 
Figure 1. Clinical states of prostate cancer 
 
 
1.2 
Treatment Background and Rationale 
Over the past two decades, the Radiation Therapy Oncology Group (RTOG) has conducted two 
pivotal phase III trials which have established the combination of radiotherapy and androgen 
deprivation therapy (ADT) as a standard of care for patients with high-risk prostate cancer. 
In the 226 high risk patients enrolled on RTOG 94-08, 4 months of neoadjuvant and 
concurrent combined androgen blockade (Flutamide and Lupron) led to a 19% absolute 
decrease in biochemical failure and an 8% absolute improvement in overall survival (OS) at 
8 years (2). Furthermore, RTOG 92-02 showed that, compared to four months of combined 
androgen blockade, an additional 28 months of post-radiotherapy treatment with an LHRH 
agonist further decreased biochemical failures and improved OS in the group of patients with 
Gleason 8-10 disease (3). 
Despite the additional benefit that standard ADT afforded, biochemical failure in the phase III 
trials remained frequent (5-year biochemical recurrence free survival of only 55% in RTOG 
92-02). However, in the aforementioned RTOG trials, dose given to the prostate was less than 
70 Gy. Both Kuban, et al and Zelefsky, et al have shown that in high risk patients, dose beyond 
70 Gy leads to significant improvements in biochemical control with acceptable toxicities (4, 
5). Modern series have confirmed lower rates of biochemical failure using these higher 
radiation doses in high risk patients (6). But there is a sub-stratum of 

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high risk patient, variably defined, that continues to have substantial short term risk of PSA 
recurrence. Shilkrut, et al reported a 5-year biochemical recurrence free survival in this very 
high risk (defined as patients with >1 high risk feature) group after dose-escalated EBRT and 
long-term ADT of 60% (7). Narang, et al defined very high risk prostate cancer as patients 
having >1 high risk feature, or > 4 cores of Gleason 8-10 disease, or primary pattern 5 
disease; in this cohort 10-year biochemical recurrence free survival was 38.1% 
(8). Epstein, et al have reported similarly poor results for Gleason Group 5 patients: defined 
as those with any Gleason Score 9 or 10 disease. 
In order to achieve even these modest results in the very high risk cohort, the length of 
therapy and extent of toxicity, especially substantial cardiovascular sequelae secondary to 
ADT, is substantial (9, 10). In the EORTC study of short course versus long course ADT, only 
70% of patients completed the prescribed 2 years of adjuvant LHRH agonist therapy (11). 
And for those who did complete the protracted therapy, it took upwards of two-years for 
testosterone to return to baseline with all the attendant side effects that came along with such 
lengthy suppression (12). 
The future of definitive radiotherapy trials in the treatment of very high risk prostate cancer 
should thus focus on two goals: 1) further decreasing the rates of biochemical failure and 2) 
limiting the length of ADT in order to reduce the negative impact on quality-of-life. These two 
goals will likely require a combination of further radiation dose escalation and more complete 
androgen suppression. 
One method of dose escalation is the combination of brachytherapy and external beam 
radiation (13), however widespread utilization of this technique has been limited by the 
technical complexity required to implement the treatment thus restricting its use to a few 
high-volume centers. Because of the putative low alpha-beta ratio of prostate cancer, 
stereotactic, hypofractionated radiation therapy has the advantage of being able to deliver 
substantial increases of dose to intra-prostatic disease (14). In addition, because the technical 
requirements are more manageable, it is a treatment that both academic medical centers and 
community practices can implement safely and effectively. It has the added benefit of a total 
delivery time (approximately 1.5 weeks) that is greatly decreased compared to the current 
radiotherapy standard of care that requires 9 weeks or more of daily treatment. 
The use of LHRH agonists in the RTOG trials likely failed to completely inhibit androgen 
responsive gene expression (15), produce levels of testosterone below 20 ng/dL (16), or 
eradicate prostate cancer clonogens capable of surviving in low-androgen environments 
(17). It is in overcoming these resistance mechanisms that the second-generation anti- 
androgens have had their greatest impact: Abiraterone has demonstrated its capacity to 
dramatically reduce circulating levels of testosterone and thus more effectively suppress the 
androgen axis (18). Because of its ability to improve OS in the metastatic, castrate- resistant 
prostate cancer (CRPC) patients, abiraterone is now approved by the FDA for use in that 
setting (19). Enzalutamide is an oral androgen receptor (AR) antagonist with a binding 
affinity five to eight times that of bicalutamide. Enzalutamide’s binding to the C- terminal 
portion of the AR inhibits nuclear translocation, DNA binding, and coactivator peptide 
recruitment (20). This potent antagonism of AR led to a phase III trial demonstrating that 
enzalutamide conferred an OS benefit on post-docetaxel treated patients (21). The most 
recently designed AR antagonist, apalutamide, demonstrated in vitro potency superior to 
even enzalutamide, a potential property that can only increase its therapeutic index (22). 
Indeed, in a recently reported phase I trial, apalutamide 

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demonstrated maximal AR inhibition at doses well below the maximum tolerated dose 
(MTD); no patients on trial experienced seizures, a potentially limiting toxicity of 
enzalutamide (23). 
Our central hypothesis is that stereotactic, hypofractionated radiotherapy delivered with a total 
of 6 months of apalutamide, abiraterone, and leuprolide will result in a superior 3 -year rate of 
biochemical control compared to the historical control of conventionally fractionated radiation 
therapy (42-48 treatments) and long term ADT (28-36 months) in patients with very high risk 
prostate cancer. 
1.2.1 
Ultra-Hypofractionated, Stereotactic, Image Guided, Intensity Modulated Radiotherapy 
Although several randomized controlled trials have demonstrated improvements in 
biochemical failure-free survival using conventionally fractionated (1.8 Gy- 2.0 Gy 
per day) regimens, these schedules do not permit further escalation beyond doses 
currently used because of the unacceptably high rates of acute and late toxicities 
that could occur. These dose-limiting toxicities with conventional fractionation have 
led to the investigation of new approaches with hypofractionated regimens that 
would increase tumor cell killing while maintaining or decreasing normal tissue 
toxicities. These outcomes are conceivable because of the potentially unique 
radiobiologic properties of prostate cancer as explained below. 
1.2.1.1 
Radiobiology of Prostate Cancer 
The linear-quadratic (LQ) model of cell survival has long been used to predict 
and understand the effects of fractionated external beam radiation therapy on 
tumors and surrounding normal tissue. In addition, the LQ model provides us 
with a means to compare the biologic effect of different dosing regimens on 
tumors and the variety of surrounding normal tissues. 
In the LQ model, the surviving fraction (S) of a homogenous population of cells 
is assumed to be proportional to two variables: one variable proportional to 
the dose administrated (alpha) and one proportional to the square of the 
administered dose (called beta). The LQ equation for a fractionated regimen 
of radiation is thusly described S=exp[−D(α+βD/n)], wherein S is the 
proportion of cells surviving in the irradiated volume, D is the total dose, and 
n is the number of fractions used to deliver D. Alpha purportedly represents 
the intrinsic radiosensitivity of the cellular population caused by non- 
repairable injury; it is the initial slope of the cell survival curve and is linearly 
dependent with dose. Beta represents cell injury that is repairable over time 
and is responsible for changes in cell survival when the dose-per-fraction or 
dose-rate is altered. Beta increases with long cell cycle times due to repair 
processes, is responsible for the curvature of the cell survival cure, and is 
proportional to the square of the administered dose (24). 
The ratio of alpha to beta (alpha-beta ratio) describes a cell population’s ratio 
of intrinsic radiosensitivity to its repair capacity. It also predicts the 
sensitivity of a cellular population to changes in fraction size. Cells with high 
alpha/beta ratios are relatively insensitive to changes in fraction size, 
whereas cells with low alpha/beta ratios are very sensitive to changes in 
fraction size. 

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Most tumors have rapidly proliferating cell populations with high alpha/beta 
ratios of approximately 10, making them relatively insensitive to changes in 
fraction size. Normal tissues are divided into acutely reacting and late 
reacting tissues, with the former having alpha/beta ratios of 9-12 and the 
latter 2-5. Normal tissues with low alpha/beta ratios are more sensitive to 
dose per fraction. 
The LQ model allows for the calculation of a biologically effective dose (BED). 
The BED provides a quantitative indication of biologic effect that takes into 
account changes in dose-per-fraction, total dose, and overall treatment time; 
any two regimens with the same BED will kill the same proportion of cells in 
a given tissue (tumor or normal). Another value that can be calculated based 
upon the LQ model is a biologically equivalent dose (EQD); this is the total 
dose in 1.8 Gy or 2 Gy fractions that would be equivalent to the proposed 
treatment schedule. 
To maximize the therapeutic ratio, a fractionation schedule of radiotherapy 
should optimize the dose per fraction sensitivity of the tumor relative to that 
of the nearby critical normal tissues (e.g., bladder, rectum, small bowel, etc.). 
In most other cancers treated definitively with radiotherapy, adjacent normal 
late-responding tissues are more sensitive to increase in dose per fraction 
than the tumor itself; for this reason, small daily doses of radiation typically 
maximize the long-term therapeutic ratio. 
An emerging body of literature suggests that prostate cancer cells are 
radiobiologically unique compared to most tumors because they have an 
alpha/beta ratio much lower than 10. A recent comprehensive literature 
review of 17 such studies found a calculated alpha/beta ratio of 1.5 to 1.8 
(25). As such, prostate cancers have a usually high sensitivity to larger doses 
per fraction. With adjacent normal tissue having a higher alpha/beta ratio 
(the alpha-beta for late rectal toxicity has been calculated at 4.8, albeit with 
wide confidence intervals (26)), it should be possible to improve the 
therapeutic ratio by delivering hypofractionated (more dose per fraction over 
fewer fractions) regimens of radiation. This should improve biochemical 
control while maintaining a constant rate of acute and late toxicities (27). The 
below Table 1 illustrates the associated BED values for prostate cancer, acute 
responding normal tissue (i.e., tissue with high alpha/beta ratios that express 
injury during or within 2-3 weeks of radiation), and late responding normal 
tissue (i.e., tissues with low alpha/beta ratios that express injury several 
months to years after radiation) comparing the stereotactic, hypofractionated 
regimen to the Memorial Sloan Kettering Cancer Center (MSK) conventional 
regimen. 
 
Table 1. Associated BED values for prostate cancer, acute responding normal tissue, and late 
responding normal tissue 

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Scheme 
Dose/Fraction 
(Gy) 
Fractions 
Absolute 
Dose (Gy) 
BED Tumor 
(α/β=1.5) 
BED Acute 
(α/β=10) 
BED Late Rectal 
(α/β=3)* 
Prostate 
7.5-8 
5 
37.5-40 
225-253.33 
65.6-72.0 
131.3-146.7 
Pelvis 
5 
5 
25 
108.3 
37.5 
66.7 
MSK 
Standard 
Prostate 
1.8 
48 
86.4 
190.1 
101.95 
138.2 
MSK 
Standard 
Pelvis 
1.8 
25 
45 
99.00 
53.10 
72.0 
*Marzi, et al Modeling of alpha/beta for late rectal toxicity from arandomized phase II study: conventional versus hypofractionated 
scheme for localized prostate cancer. J Exp Clin Cancer Res. 2009;28:117. 
 
Table 1 demonstrates the theoretical quantitative improvement in the therapeutic 
ratio using the proposed regimen: an increase in the biologically effective dose to 
tumor and a relative parity in the biologically effective dose to normal surrounding tissue, 
be they acute or late responding. The proposed dose to the prostate is equivalent to 
115.2 Gy in 1.8 Gy fractions. 
1.2.1.2 
Clinical Experience with Hypofractionated External Beam Radiation 
There are two published randomized controlled trials examining moderate 
hypofractionated regimens in the treatment of prostate cancer. Arcangeli, et 
al reported on a prospective phase III trial comparing moderate 
hypofractionation (62 Gy in 20 fractions) to conventional fractionation (80 Gy 
in 40 fractions) in the treatment of patients with high risk prostate  cancer 
(28). The equivalent dose in 1.8 Gy fractions for the hypofractionated arm was 
86.4 Gy, comparable to our current conventional standard of care at MSK. 
The authors found no difference in late GI or GU toxicities between the two 
arms; the 3-year rates of Grade 2 GI toxicity were 17% and 16% comparing 
the hypofractionated to conventionally fractionated arms, respectively; the 
rates of GU Grade 2 GU toxicity were 14% and 11% for the hypofractionated 
and conventionally fractionated arm, respectively. As predicted by the LQ 
model, these were not significant differences. More compelling, in their “very 
high risk” sub-group (initial PSA>20 ng/mL or Gleason ≥8, or T stage ≥2c), the 
3-year freedom from biochemical failure was 88% for the hypofractionated 
arm compared to 76% for the conventionally fractionated arm (p=0.014). All 
patients received 9 months of combined androgen blockade that was initiated 
2 months prior to the start of radiotherapy. 
Conversely, Pollack, et al reported a phase III trial comparing 70.2 Gy in 26 
fractions to 76 Gy in 38 fractions for favorable to high risk prostate cancer 
patients (29). They found no statistically significant differences in the 5-year 
rates of biochemical failure: 21.4% for the conventional arm versus 23.3% for 
the hypofractionated arm (p=0.745). Of note, the equivalent 1.8 Gy per 
fraction dose of 70.6 Gy in 26 fractions is 89.3 Gy. Again, rates of late toxicity 
were not significantly different. 
The largest and most robust clinical report of ultra-hypofractionation is a 
pooled analysis from a multi-institutional consortium of prospective phase II 
trials reported by King, et al (30). This included a cohort of 125 patients with 
high risk disease by D’Amico classification treated with doses ranging from 

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35 to 40 Gy in five fractions, 38% of whom received short course (median 4 
month) ADT. Although median follow-up for this group was only 23 months, 
they reported 5-year biochemical recurrence free survival of 82%. Of note, 
pelvic lymph nodes were not irradiated. 
A separate report on health-related quality of life outcomes (HR-QOL) in the 
larger cohort using the Expanded Prostate Cancer Index Composite (EPIC), 
with a median follow-up of 3 years, found a transient decline in urinary and 
bowel domains which returned to baseline by 6 months (31). One-hundred 
and ninety-four patients were evaluable at 5 years. With such extended 
follow-up, the probability of substantial late toxicities being under-reported 
due to inadequate follow-up is slight. 
None of the ultra-hypofractionated (five fractions) trials included the pelvic 
lymph nodes in the irradiated field. There is no consensus regarding the 
treatment of pelvic lymph nodes in high risk prostate cancer; as such there is 
substantial institutional variability with regards to their inclusion (32). Two 
prospective, randomized controlled trials have demonstrated no benefit to 
the expansion of the radiotherapy fields to include the nodal basins (33, 34). 
Furthermore, recent data from a trial of ultra-hypofractionated radiation in 
high risk, N0 patients revealed unacceptable toxicities with the addition of 
pelvic lymph nodes. As such, the pelvic lymph nodes will not be treated in this 
trial. 
We 
expect 
that 
the 
total 
androgen 
annihilation 
(lupron+abiraterone+apalutamide) involved in this trial will eliminate any 
micrometastatic disease in the lymph nodes. 
1.2.1.3 
Intensity-Modulated and Image-Guided Radiation Therapy 
Intensity-modulated radiation therapy (IMRT) in prostate cancer has proven 
to decrease the acute and late toxicity from definitive external beam radiation 
therapy by delivering highly conformal dose distributions (35). IMRT 
techniques have benefited from the addition of image-guided radiation (IGRT) 
techniques, where sophisticated imaging algorithms allow daily target 
localization prior to and during treatment. IGRT minimizes interfraction 
uncertainty, or variability in the target position from fraction to fraction, and 
intrafraction variability, or variability of the target position during 
administration of a fraction of radiation. Specifically, placement of localization 
markers in the prostate gland before a course of external beam radiotherapy 
allows daily target localization with in-room imaging during administration 
of a fraction of radiation. For all patients undergoing stereotactic, 
hypofractionated radiation, we have routinely placed Calypso markers into 
the prostate prior to treatment. These are radiofrequency transponders 
placed into the prostate prior to simulation. These are powered by a non- 
ionizing oscillating electromagnetic field created by an electromagnetic array 
placed anterior to the supine patient. The location of the transponders in the 
prostate is then determined by triangulating their position relative to the 
array. 
At the time of the planning CT, the three transponders as well as the treatment 
isocenter are recorded and input into the Calypso 4D tracking station. Just 
before treatment, the Calypso system directs lateral, longitudinal, and 
vertical shifts by comparing the planned and measured 

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coordinates of the three transponders. After initial localization, the Calypso 
transponders relay real-time information on any intra-fraction prostate 
motion while the treatment beam is on. Intra-fraction movement beyond 
2mm from initial set-up causes treatment to cease until the target has moved 
back into position. This level of target precision permits reduced target 
volumes, less treatment associated toxicities, and safe administration of large 
daily fractions of radiation. Successful applications of image-guided, 
hypofractionated radiation therapy have been reported in numerous sites 
other than prostate, including lung, CNS, pancreas, bones, lymph nodes, and 
soft tissue. 
1.2.2 
Abiraterone Acetate 
Abiraterone acetate is converted in vivo to abiraterone, an androgen 
biosynthesis inhibitor, that inhibits 17α‑hydroxylase/C17,20-lyase (CYP17). 
This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues 
and is required for androgen biosynthesis. CYP17 catalyzes two sequential 
reactions: 1) the conversion of pregnenolone and progesterone to their 17α 
-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent 
formation of dehydroepiandrosterone (DHEA) and androstenedione, 
respectively, by C17, 20 lyase activity. DHEA and androstenedione are 
androgens and are precursors of testosterone. Inhibition of CYP17 by 
abiraterone can also result in increased mineralocorticoid production by the 
adrenals. Androgen sensitive prostatic carcinoma responds to treatment 
that decreases androgen levels. Androgen deprivation therapies, such as 
treatment with GnRH agonists or orchiectomy, decrease androgen 
production in the testes but do not affect androgen production by the 
adrenals or in the tumor. Abiraterone acetate decreased serum testosterone 
and other androgens in patients in the placebo‑controlled Phase 3 clinical 
trial. It is not necessary to monitor the effect of abiraterone acetate on serum 
testosterone levels. Changes in serum prostate specific antigen (PSA) levels 
may be observed but have not been shown to correlate with clinical benefit 
in individual patients. 
1.2.2.1 
Pharmacokinetics and Metabolism 
The pharmacokinetics of abiraterone and abiraterone acetate have been 
studied in healthy subjects and in patients with metastatic CRPC. In vivo, 
abiraterone acetate is converted to abiraterone. In clinical studies, 
abiraterone acetate plasma concentrations were below detectable levels in 
>99% of analyzed samples. 
Following oral administration of abiraterone acetate to patients with 
metastatic CRPC, the median time to reach maximum plasma abiraterone 
concentrations was two hours. Abiraterone accumulate was observed at 
steady-state, with a 2-fold higher exposure compared to a single 1000 mg 
dose of abiraterone acetate. 
At the dose of 1000 mg daily in patients with metastatic CRCP, steady-state 
values of Cmax were 232 ±177 ng/mL and of AUC were 1060 ±681 ng.hr/mL. 
No major deviation from dose proportionality was observed in the dose 
range of 250 mg to 1000 mg. 

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Systemic exposure of abiraterone is increased when abiraterone acetate is 
administered with food. Abiraterone Cmax and AUC were approximately 7- and 
5-fold higher, respectively, when abiraterone acetate was administered with 
a low fat meal and approximately 17- and 10-fold higher, respectively, when 
abiraterone acetate was administered with high-fat meal. 
1.2.3 
Apalutamide 
Apalutamide is an orally available, potent, and selective AR antagonist that acts by 
inhibiting nuclear translocation of AR and its subsequent binding to DNA androgen 
response elements (ARE). Unlike bicalutamide, it shows no significant agonist 
properties in an in vitro model of CRPC. Gene transcription of the AR-driven genes, 
PSA and TMPRSS2, is inhibited by apalutamide and results in concentration- 
dependent reduction of these protein levels in vitro. Apalutamide was also shown to 
reduce proliferation of CRPC cells as well as increase apoptosis and necrosis in vivo. 
These effects are supported by the anti-tumor activity of apalutamide observed in 
murine tumor models of CRPC. 
In a first-in-human phase I trial of apalutamide in metastatic CRPC patients, 60% of 
patients had a ≥50% decline in PSA as compared with baseline, and of those, six (20%) 
had a ≥90% decline. More importantly for our own proposed study, in a phase II trial 
looking at the sub-group of patients with non-metastatic CRPC (n=47), at 12 weeks, 
PSA response was 91% and the median time to progression had not yet been reached 
(36). 
In a recently published, randomized phase 3 trial involving men with nonmetastatic 
castration-resistant prostate cancer, the risk of metastasis or death was 70% lower 
with apalutamide than with the placebo. The median metastasis-free survival was 
more than 2 years longer than the placebo group (37). 
1.2.3.1 
Pharmacokinetics and Metabolism 
Apalutamide is a low clearance molecule with moderate volume of 
distribution in mice, rates, and dogs. High oral bioavailabilitya was obtained 
with the lipid-based formulation used in exploratory and definitive repeat- 
dose toxicology studies in rats and dogs. Plasma exposure in rats and dogs 
increased in a dose-proportional manner over a dose range of 5-300 
mg/kg/day and 5-40 mg/kg/day, respectively. 
Four metabolites have been identified with different proportions between 
species. All four were assessed for their on-target effects against AR. 
Metabolite M1 was found to be essentially inactive as an AR antagonist, while 
metabolites M2 and M4 were approximately 30-fold less potent against AR 
than apalutamide. Metabolite M3 was the most potent AR antagonist, but was 
still 3-fold less potent than apalutamide. M3 is considered the predominant 
metabolite, with a longer elimination half-life than apalutamide. 
In humans, apalutamide was rapidly absorbed, with measurable plasma 
concentrations within 30 minutes after ingestion of a single oral dose of 1 to 
16 soft gelatin capsules (total apalutamide dose, 30mg to 480 mg). On 
average, peak plasma concentrations occurred 2 to 3 hours after 
administration in each dose group. The increases in plasma Cmax values and 

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in the AUC were linear and dose-proportional. Plasma apalutamide 
concentrations declined slowly, with a mean half-life value at steady-state of 
4 days. 
Preliminary pharmacodynamic analysis of 18-fluorodihydrotestosterone 
positron emitting tomography confirmed substantial inhibition of AR at doses 
of 120 mg/day. Combining the aforementioned data with pre-clinical studies, 
240 mg was selected as the phase II dose (RP2D). 
1.2.4 
Synergy between Leuprolide, Abiraterone, and Apalutamide 
Studies in healthy volunteers have shown that with treatment with LHRH agonists the 
levels of intraprostatic tissue androgens only decline by 30% (38). This repository of 
ligand would certainly be sufficient to stimulate the AR pathway in prostate 
adenocarcinoma. Furthermore, work by the same group revealed that, in hormone- 
sensitive prostate cancer patients, treatment with LHRH agonists, despite reductions 
in intraprostatic tissue androgens by 75%, did not suppress key androgen-dependent 
genes, such as TMPRSS2 and PSA (39). Perhaps more alarming was the finding that 
the levels of tissue testosterone in metastatic CRPC was even higher than those found 
in eugonadal prostate controls. The AR-related mechanisms that provide for 
continued tumor viability in the setting of LHRH agonist therapy (castrate resistance) 
include AR amplification, mutations leading to promiscuous AR activation by weak 
androgens, other steroid hormones, and intracrine synthesis of androgens by tumor. 
Indeed, expression of genes converting adrenal androgens or tissue precursors to 
testosterone have been seen (40). 
Because of abiraterone’s success in the metastatic CRPC setting, it is clear that 
prostate cancer remains reliant on intra-tumoral androgen production for its 
survival. Until recently, data for this same reliance in high risk, locally-advanced 
prostate cancer was lacking. However, Taplin, et al recently reported on their 
outcomes with the use of neoadjuvant abiraterone in combination with leuprolide in 
the up-front, high risk setting prior to prostatectomy (41). Patients were initially 
randomized to either leuprolide alone for 12 weeks or leuprolide in combination with 
abiraterone; all patients then received an additional 12 weeks of combination therapy 
until radical prostatectomy; biopsies were conducted at week 12 of the study. 
Compared to leuprolide alone, there were statistically significant decreases at 12 
weeks in intra-tumoral levels of DHT and DHEA in the group treated with both 
leuprolide and abiraterone (p<0.0001). Similar decreases were seen with 
androstenedione and testosterone. A PSA nadir of ≤0.2 ng/mL at 12 weeks was 
achieved in 90% of the patients in the combination arm versus only 4% in the 
leuprolide alone arm (p<0.0001). At the time of prostatectomy, those who had 
undergone 24 weeks of combined therapy versus those who had undergone only 12 
weeks had a nearly significantly higher rate of near pathological complete response 
(CR) or total CR, 34% versus 15%, respectively (p=0.09). Importantly, toxicity was 
similar to that seen on the prior phase III trials. Grade 3 adverse events (AEs) included 
LFT elevation in 9% and hypokalemia in 5%; no Grade 4 AEs were reported (42). 
The data from Taplin, et al makes clear that, even in the high-risk, locally advanced 
setting, there are clonogens capable of escaping chemical castration with LHRH 
agonists. This cohort of patients may thus benefit from combined ADT. 

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Although the report by Taplin, et al of near-complete or complete responses in high- 
risk patients after prostatectomy is encouraging, the data beg the question of whether 
more complete androgen-axis blockade may improve still further on the rate of tumor 
cell kill. As mentioned, while intra-tumoral production of androgens via adrenal 
precursors is present as an acutely activated response to medical castration, and 
likely suppressed by abiraterone, additional escape mechanisms exist, most notably 
increases in AR ligand promiscuity, AR copy number alterations and missense 
mutations in the AR ligand-binding domain (LBD) leading to enhanced ligand binding. 
These three strategies represent conceivable mechanisms by which prostate cancer 
cells could escape death even in the face of the dramatic reductions in intra-tumor 
androgens seen with abiraterone in combination with leuprolide. And it is the 
potential presence of these clonogens in higher risk prostate cancers that provides us 
the principal rationale for the combination of a highly-selective androgen antagonist 
with leuprolide and abirateroner. Indeed, in phase III clinical trials of metastatic 
CRPC, enzalutamide has demonstrated an impressive ability to improve OS. Indeed, 
this strategy is being actively pursued in the Alliance for Clinical Trials in Oncology 
(Alliance) Trial A031201 in the metastatic CRPC setting (NCT01949337). 
A recent phase I/II reported a favorable toxicity profile for bone metastatic CRPC 
patients treated with a combination of abiraterone and enzalutamide (43). In our own 
trial, because of the biochemical similarity between enzalutamide and apalutamide, 
we imagine that a similarly small proportion of patients will experience substantial 
Grade 2 or Grade 3 toxicities. Indeed, a recently reported Phase Ib trial by Posadas, et 
al involving 29 patients demonstrated a favorable toxicity profile, with only 14% of 
patients experiencing a Grade3/4 reaction (44). The majority of patients in the 
aforementioned trial were continued on an LHRH antagonist/agonist during their 
therapy. 
1.2.5 
Synergy between Androgen Deprivation and Radiation 
Multiple clinical trials have shown that, for patients with intermediate and high risk 
prostate cancer, the addition of both short and long course ADT provides significant 
improvements in biochemical recurrence-free survival, disease-free survival, and OS. 
One putative mechanism responsible for this achievement may be an increase in local 
control as evidenced by the reduction in the proportion of patients with positive 
biopsies two years after radiation; in those patients who received short course 
neoadjuvant anti-androgen therapy, the rate of positive biopsies at a median of 38 
months post-treatment was 16% compared to 42% in those patients who had not 
(45). Recent in vitro data provides a compelling biological explanation for the synergy 
between anti-androgen therapy and radiation. Polkinghorn, et al found that AR 
activity up-regulates flux through a host of DNA repair pathways in response to 
ionizing radiation (46). Inhibition of these pathways with AR antagonists, in their 
case, apalutamide, decreased tumor cell survival in response to ionizing radiation. 
These data, in addition to the results of the aforementioned RTOG clinical trials, which 
have definitively shown that ADT (using LHRH agonists) improves OS when 
compared with radiation alone, lead us to hypothesize that the combination of ADT, 
using leuprolide and abiraterone, and AR blockade, using apalutamide, will further 
improve local and thus biochemical disease control in our cohort of high risk patients. 

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This is indeed the hypothesis of multiple on-going clinical trials. A phase II trial at 
Duke University investigating the combination of 6 months of abiraterone and 
leuprolide in combination with definitive, conventionally dose radiation (75-80Gy) to 
the prostate and seminal vesicles alone (NCT01717053). In addition, both the Dana- 
Farber Cancer Center (NCT02028988) and the University of Texas- Southwestern 
Medical Center (NCT02064582) are conducting phase II trials of enzalutamide (one 
in combination with leuprolide) with conventionally dosed radiation therapy in 
intermediate and high risk prostate cancer patients. 
Our central hypothesis is the combination of two novel anti-androgens, inhibiting two 
unique components of the androgen pathway, with leuprolide and stereotactic, 
hypofractionated radiation therapy will significantly reduce the rate of biochemical 
recurrence at 3 years in very high risk prostate cancer 
While we expect to show a substantial increase in biochemical control compared to 
historical controls, the benefit of a reduction in treatment duration cannot be 
underestimated: 1.5 weeks of radiation rather than 8-9 weeks; 6 months of ADT 
rather than 2 years. Such a regimen, if proven in a phase III setting, would both expand 
the universe of patients with high risk prostate cancer able to receive curative 
therapy, especially those in medically underserved communities distant from major 
centers, and potentially decrease the morbidity associated with extended androgen 
ablation. 
2. 
OBJECTIVES 
2.1 
Primary Objective 
• To determine the rate of biochemical failure by 36 months post treatment in high risk 
prostate cancer patients treated with leuprolide, abiraterone acetate, and apalutamide in 
conjunction with stereotactic, ultra-hypofractionated radiotherapy. 
2.2 
Secondary Objectives 
• To determine the rate of positive prostate biopsies at 24 months (required) after 
completion of anti-androgen therapy. 
• To determine the rate of undetectable PSA at 1, 2 and 3 years post-treatment for men with 
non-castrate testosterone, (where undetectable PSA is defined as ≤ 0.2 ng/ml). 
• To determine overall survival. 
• To determine the cumulative incidence of distant metastases and prostate cancer-specific 
death. 
• Evaluate acute and late toxicities, defined as any Grade 3 or greater toxicity based on the 
NCI CTCAE v 4.0 scoring scale 
• Evaluate the effects of treatment on HR-QOL outcomes, comparing baseline to subsequent 
follow-up using the EPIC-26. 
• Correlate MRI imaging with correlative and biopsy results. 
• To evaluate the predictive and prognostic capacity of the following biological correlatives: 
▪ 
MSK-IMPACT™ (Integrated Mutation Profilingof Actionable Cancer Targets) 
▪ 
Circulating tumor cells (CTCs) 
▪ 
Circulating tumor DNA (ctDNA) 

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3. 
PATIENT SELECTION 
3.1 
Inclusion Criteria 
To be included in this study, patients should meet all of the following criteria: 
• Histological or cytologic evidence of adenocarcinoma of the prostate confirmed at local 
institution. 
• At least one of the following: 
▪ 
Two or more high risk features OR 
• 
Gleason score 8-10 
• 
PSA ≥20 ng/mL within two months prior to registration 
• 
Clinical Stage ≥T3 disease, as determined by standard digital rectal 
examination (DRE) 
• 
Radiographic stage ≥T3 disease as determined by a ≥75% probability of 
extracapsular extension or seminal vesicle invasion per reading 
radiologist 
▪ 
Any Gleason 9 or 10 disease OR 
▪ 
>4 cores of Gleason 8 disease. 
• KPS ≥ 70% 
• IPSS (International Prostate Symptom Score) ≤ 20 
• Patient must be available for follow-up 
• Laboratory test findings within 28 days of study registration: 
o Adequate hepatic function: 
▪ Bilirubin ≤ 1.5 times the upper institutional limits of normal (ULN). Patients with a 
history of Gilbert’s syndrome may be enrolled if the total bilirubin is < 3 mg/dL with 
a predominance of indirect bilirubin. If the total bilirubin is >1.5 x the institutional 
ULN, direct and indirect bilirubin will be measured and if direct bilirubin is ≤ 1.5 x 
the institutional ULN, the patient will be eligible to participate 
▪ SGPT (ALT) and SGOT (AST) ≤ 2.5 x ULN 
o Adequate renal function with creatinine <2.0 x the institutional ULN 
o Adequate hematologic function: 
▪ Absolute neutrophil counts ≥ 1500 cell/mm3 
▪ Platelets ≥ 100,000 cells/mm3 (independent of blood transfusion and/or growth 
factors within 3 months prior to registration) 
o Hemoglobin value ≥9 g/dL at the Screening Visit (independent of blood transfusion 
and/or growth factors within 3 months prior to registration) 
o Albumin ≥ 3.0 g/dL 
o Potassium ≥ 3.5 mmol/L 

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• Patients with pelvic and/or retroperitoneal lymph nodes < 1.5 cm in short axis are eligible 
as they are not considered to have definitive metastases 
• 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 18 years of age and above 
• The effects of apalutamide, abiraterone, leuprolide and stereotactic, ultra- hypofractionated 
radiation on the developing human fetus at the recommended therapeutic dose are 
unknown. Men (including men with vasectomies) must agree to use adequate contraception 
(a condom and another effective method of birth control) prior to registration, for the 
duration of study participation, and for at least 3 months thereafter. Men must also agree 
not to donate sperm for the duration of study participation, and for at least 3 months 
thereafter. 
3.2 
Exclusion Criteria 
• Radiographic evidence of metastatic disease 
• Patients with one or more positive lymph nodes as determined by radiographic assessment 
of MRI or CT 
NOTE: lymph nodes noted on MRI or CT to be > 1.5 cm on the short axis will require review 
by the local reference radiologist per institutional RECIST review practices. If the lymph 
nodes are considered suspicious on repeat review, they must be confirmed negative for 
study participation 
• Prior treatment for prostate cancer; this includes any prior surgery (including 
Transurethral resection of the prostate (TURP) prostate cancer treatment), chemotherapy, 
radiation, or anti-androgen therapy/androgen deprivation therapy with the following 
exception: patients who will have been on LHRH Agonist/Antagonist Therapy for ≤1 month 
prior to registration are permitted to enroll with study PI approval 
• Prior use of steroidal antiandrogens (megestrol acetate, cyproterone acetate), AR partial 
agonists, ketoconazole, chemotherapy, immunotherapy, estrogens, radiopharmaceuticals 
within 3 months before registration 
• Prior use of non-steroidal anti-androgens (e.g., bicalutamide, flutamide, nilutamide) within 
1 month before registration 
• Prior treatment with medications known to lower the seizure threshold within 4 weeks of 
registration (see section 5.5.2 apalutamide for a list of prohibited medications) 
• History of another malignancy within the previous 3 years except for the following: 
adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, 
adequately treated Stage I or Stage II cancer currently in complete remission, or any other 
cancer that has been in complete remission for at least 3 years 
• Severe hepatic impairment (Child-Pugh Class C) 
• Concurrent treatment with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital) 
• Major surgery within 4 weeks of registration 

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• Presence of a pacemaker 
• Active infection or other medical condition that would make prednisone use 
contraindicated 
• A known hypersensitivity to abiraterone acetate, apalutamide, and prednisone and/or 
any of their excipients 
• Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, 
arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular 
accident including transient ischemic attacks), or clinically significant ventricular 
arrhythmias within 6 months prior to registration. 
• Seizure or known condition that may pre-dispose to seizure (including but not limited to 
prior stroke, transient ischemic attack, loss of consciousness within 1 year prior to 
randomization, brain arteriovenous malformation; or intracranial masses such as 
schwannomas and meningiomas that are causing edema or mass effect) 
• Any ECG changes that interfere with QT interval interpretation (e.g., left bundle branch 
block, frequent premature ventricular contractions) 
• Prolonged QTc >450ms at the Screening Visit 
• Uncontrolled diabetes, heart disease, hypertension 
• Gastrointestinal disorder that may affect absorption of study treatment 
• Activesymptomatic viral hepatitis or chronic liver disease 
• History of pituitary or adrenal dysfunction 
• Active Infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) or other 
medical condition that would make prednisone/prednisolone corticosteroid) use 
contraindicated 
• Patients with Crohn’s disease or ulcerative colitis 
• Patients that cannot tolerate MRI 
• Inability to have fiducial markers placed 
• Any condition that in the opinion of the investigator, would preclude participation in this 
study 
• Enrollment concurrently in another investigational drug study or within 4 weeks of 
registration 
• Concurrent treatment with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital) 
4. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION 
4.1 
Enrollment Plan 
4.1.1 
Participating Study Centers 
This study is anticipated to be conducted at 5-6 sites. 

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4.1.2 
Recruitment 
Potential research subjects will be identified by a member of the patient’s treatment 
team, the protocol investigator, or research team at participating centers from 
Medical Oncology, Radiation Oncology and Urology offices. Investigators will screen 
the patient’s medical records for suitable research study subjects and discuss the 
study and their potential for enrolling in the research study. Any participating sites 
that require a limited waiver must obtain it from their own site IRB/Privacy Board 
(PB) via a separate protocol addendum or request. It is the responsibility of the PCCTC 
to confirm the participating data collection sites have a limited waiver approved by 
their local IRB(s)/PB(s) if required by the site. 
4.2 
Registration Procedure 
After eligibility screening and confirmation that a patient is eligible, patients who are 
selected to participate will be registered through Medidata. A record of patients who 
fail to meet eligibility criteria (i.e., screen failures) will be maintained. Patient 
registration must be complete before beginning any treatment or study activities. A 
complete, signed study consent and HIPAA authorization are required for 
registration. 
4.2.1 
Registration 
• 
Confirm eligibility as defined in Section 3 Patient Selection. 
• 
Obtain informed consent, by following procedures in Section 11.3 Written 
Informed Consent. 
• 
Obtain completed or partially completed protocol specific Eligibility 
Checklist. 
• 
All participants will be registered through Medidata EDC. 
Central registration for this study will take place at MSK. To complete registration and 
enroll a participant, the study staff at that site must contact the designated research 
staff at the PCCTC to notify him/her of the participant registration. The following 
documents must be sent to the PCCTC (PCCTC@mskcc.org) for each enrollment 
within 24 hours of the informed consent form being signed: 
• 
The completed or partially completed MSK eligibility checklist 
• 
The signed informed consent and HIPAA Authorization form 
• 
Supporting source documentation for eligibility questions (e.g. laboratory 
results, pathology report, radiology reports, MD notes, physical exam sheets, 
medical history, prior treatment records, and EKG report). 
Note: Source documentation of eligibility is not required for MSK participants. 
Upon receipt, the research staff at the PCCTC will conduct an interim review of all 
documents for all non-MSK participants. If the eligibility checklist is not complete or 
source documentation is missing, the participant will be registered PENDING and the 
participating site is responsible for sending the completed registration documents 
within 30 days of the consent. 
If the external registration is complete, the participating site IRB has granted approval 
for the protocol, and the participating site is in good standing, the PCCTC will send the 
completed registration documents to the MSK Protocol Participant Registration Office 
for participant enrollment as stated in the protocol. 

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Once the participant is registered, the participant will be assigned a Medidata Subject 
ID. This Subject ID will be relayed back to study staff at the registering participating 
site via e-mail and will serve as the registration confirmation. This number is unique 
to the participant and must be written on all data and correspondence for the 
participant. 
Participating sites will register subjects locally per their Institutional guidelines and 
the PCCTC will register all non-MSK participants with MSK’s Clinical Trials 
Management System (CTMS) per MSK’s guidelines. MSK participants will be fully 
registered by MSK in the Clinical Trials Management System (CTMS). 
5. 
TREATMENT/INTERVENTION PLAN 
This is a single arm, phase II trial designed to determine the efficacy of a novel combination 
anti-androgen therapy with ultra-hypofractionated radiation therapy (RT) in very high risk 
prostate cancer. An interim analysis will ensure early termination of the trial should toxicities 
exceed historical controls. Eligible patients will receive a total of 6 months of leuprolide, 
abiraterone, and apalutamide to begin three months prior to RT and continuing until 
approximately 3 months post-RT. Patients will be assessed every 4 weeks (±1 week) (a cycle 
= 28 days) throughout their treatment with the study drug, and at least once during RT. 
On Cycle 1 Day 1, patients will begin abiraterone acetate (four 250 mg tablets per day; no food 
should be consumed for at least two hours before the dose of abiraterone acetate is taken and 
for at least one hour after the dose of abiraterone acetate is taken), apalutamide (four 60 mg 
tablets taken without food per day), and prednisone 5 mg twice daily (taken with food). On 
Cycle 1 Day 5 (±3 days) patients will be given a 22.5 mg 3-month depot intramuscular 
injection of leuprolide. On Cycle 4 Day 1 (+14 days) patients will receive a second and final 
22.5 mg intramuscular injection of leuprolide. On Cycle 4 Day 5 (±5 days) patients will start 
stereotactic, ultra-fractionated radiotherapy to the prostate and seminal vesicles. 
Abiraterone acetate and apalutamide will continue daily until Cycle 6 Day 28. A physician 
prescribed taper of prednisone will begin on Cycle 6 Day 28. The nature of the taper will be 
at the discretion of the treating physicians, but a recommended tapering schedule is as 
follows: 
5mg QD x 7 days, 2.5 mg QD x 7 days, 2.5 mg QOD x 7 days, then discontinue the prednisone. 
The following assessments and procedures will occur during the study. A schedule of 
assessments is provided in Table 2. 

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Protocol Schema 
 
 

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Table 2. Schedule of Assessments 
 
Assessments 
Prestudy/ 
Baseline1 
Treatment/Intervention Period (Cycle = 4 weeks) 
Follow-up* 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
1st Year 
2nd Year 
3rd Year 
Day 1 
(±7 d) 
Day 15 
(±3 d) 
Day 1 
(±7 d) 
Day 15 
(±3 d) 
Day 1 
(±7 d) 
Day 15 
(±3 d) 
Day 1 
(±7 d) 
Day 1 
(±7 d) 
Day 1 
(±7 d) 
Every 3 
months 
(±2 weeks) 
Every 4 
months 
(±2 weeks) 
Every 6 
months 
(± 2 weeks) 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Review of comorbidities 
X 
Physical exam2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Digital Rectal Examination 
X 
X 
X 
X 
Histologic and radiographic 
confirmation of disease 
X 
Pathology review3 
X 
Evaluation by Study Doctor 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
Concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X4 
X4 
X4 
Toxicity assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
X4 
X4 
Pill diary collection 
X 
X 
X 
X 
X 
X 
Imaging 
Bone scan 
X 
CT chest/abdomen 
X 
MRI prostate/pelvis 
X 
X5 
X5 
HR-QOL Questionnaires 
EPIC-26 
X 
X6 
X6 
X6 
IPSS 
X 
Laboratory tests 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, T3 & T49 
X 
X 
X 
X 
X 
Hepatitis B & C Screening 
X 

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Testosterone 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Correlatives 
Prostate biopsy 
X10 
X11 
MSK-IMPACT™ Testing12 
X 
X 
Circulating Tumor DNA (ctDNA)13 
X 
X 
X 
Circulating Tumor Cells (CTCs)14 
X 
X 
Treatment/Intervention 
Leuprolide acetate 
X15 
X15 
Apalutamide / abiraterone+pred16 
X 
 X 
Fiducial marker placement 
X17 
Radiation Therapy 
X18 
1. 
Within 28 days prior to registration; imaging can be done within 4 months of registration. 
2. 
Physical exam includes vital signs, height/weight. During Treatment/Intervention Period and Follow-up, a targeted physical exam will be completed if deemed necessary by the study doctor. 
3. 
Any time prior to registration. 
4. 
Evaluation of concomitant medications and toxicity will occur until subject begins a new therapy for prostate cancer. 
5. 
In post-treatment follow-up period, recommended MRI will only occur twice: at 6 months post anti-androgen therapy (optional, but encouraged) and 24 months post anti-androgen therapy 
(mandatory). MRIs should occur within 1 month prior (and not after) biopsy toallow for appropriate targeting. 
6. 
At 6 months, 12 months, 24 months and 36 months (±2 weeks) post anti-androgen therapy. 
7. 
CBC: White blood cells count (WBC), red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), platelet count (UNVPLT), neutrophils (NEUTP), lymphocytes (LYMP) 
8. 
Comprehensive Metabolic Panel includes calcium (CA), creatinine (CREAT), alkaline phosphatase (ALK), alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBILI) 
9. 
T3 & T4 should be done only if TSH is abnormal. 
10. Baseline prostate biopsy can be done within 4 months of registration. If the biopsywas notperformed at thesite where subject will receive treatment under thisprotocol, a repeat biopsy should be 
performed when possible. If a repeat biopsy cannot be performed, then a paraffin embedded tumor sample (block or 25 unstained FFPE slides and 1 corresponding hematoxylin and eosin (H&E) slide 
of 4-5 micron thickness) from the diagnostic biopsy should be obtained and reviewed at the treating institution. 
11. A second prostate biopsy will occur at 24 months (±2 months) post anti-androgen therapy (required, if safe and feasible). 
12. MSK-IMPACT™ evaluation will be performed on the biopsied tissue sample taken at baseline and 24 months post anti-androgen therapy, if sufficient biopsy material is available. If subject has a 
metastatic biopsy at metastaticprogression as per standard of care (notmandatoryper protocol), MSK-IMPACT™testing of the biopsied tissue sample will be completed. 
13. ctDNA at baseline, 6 months (±2 weeks) and 24 months (±2 weeks) post anti-androgen therapy, and at metastatic progression (See separate Laboratory Manual Appendix C). 
14. CTCs will be drawn only for the first 25 subjects enrolled on the study. For these patients, CTCs will be drawn at baseline, 24 months (±2 weeks) post anti-androgen therapy, and at metastatic 
progression (See separate Laboratory Manual, Appendix C). 
15. On Cycle 1 Day 5 (±3 days) and then Cycle 4 Day 1 (+14 days) patients will receive 22.5 mg injection of leuprolide. 
16. Taken in the morning, at approximately the same time everyday for 6 cycles, beginning approximately 3 cycles prior to RT start and continuing through Cycle 6 Day 28 
17. At least 5 days prior to Radiation Therapy 
18. Administered every other day beginning Cycle 4 Day 5 (±5 days) for a total of five treatments 
*Note: 1st year begins at conclusion of therapy. The 2nd year begins 12 calendar months after completion of therapy; the 3rd year begins 24 calendar months after completion of therapy. 

5.1 
Screening Assessment (Within 28 days prior to registration) 
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). 
During the screening period, subject eligibility will be determined according to the inclusion and 
exclusion criteria (Sections 3.1 & 3.2). The following assessments will be performed during this time: 
• Obtain informed consent and research authorization 
• Record demographics (including age) and medical history (including prior treatment forprostate 
carcinoma) 
• Review of comorbidities 
• Conduct physical exam (vital signs, height/weight) 
• Evaluation by study doctor 
• Obtain histologic and radiologic confirmation of disease 
• Performlaboratory tests 
o PSA 
o CBC 
o Comprehensive Metabolic Panel 
o Testosterone 
o TSH, T3 & T4 (T3 & T4 should be done only if TSH is abnormal) 
o Hepatitis B & C Screening 
• Digital rectal examination (DRE) 
• Assess performance status using ECOG or Karnofsky scales (per institutional preference) (Appendix 
A) 
• Determine suitability for protocol directed procedures 
• Discuss concurrent medications (see Appendix B for a listing of medications with the potential for 
drug interactions) 
• Pathology review (any time prior to registration) 
• EKG 
• Imaging (can be completed within 4 months of registration) 
o Chest/Abdomen by Computerized Tomography (CT) 
o Prostate/Pelvis by Magnetic Resonance Imaging (MRI) 
o Radionuclide bone scan 
• Biopsy of the prostate within 4 months of registration. If the biopsy was not performed at the site 
where the patient will receive treatment under this protocol, a repeat biopsy should be performed 
when possible. If a repeat biopsy cannot be performed, then a paraffin embedded tumor sample 
(block or 25 unstained FFPE slides and 1 corresponding hematoxylin and eosin (H&E) slide of 4-5 

micron thickness) from the diagnostic biopsy should be obtained and reviewed at the treating 
institution. 
• ctDNA and CTC blood draw (See separate Laboratory Manual, Appendix C) 
o Note: CTCs will be drawn only forthe first 25 subjects enrolled on the study. 
• Administration of EPIC-26 Questionnaire 
• Administration of IPSS Questionnaire 
• MSK-IMPACT™ evaluation of baseline tumor specimen if sufficient biopsy material available 
5.2 
Treatment/Intervention Period (Cycle 1 Day 1 – Cycle 6 Day 28) 
On Cycle 1 Day 1, patients will begin abiraterone acetate (four 250 mg tablets per day; taken without 
food and not within two hours of a meal), apalutamide (four 60 mg tablets) taken without food per 
day), and prednisone 5 mg twice daily (taken with food). On Cycle 1 Day 5 (±3 days) patients will be 
given a 22.5 mg 3-month depot intramuscular injection of leuprolide. On Cycle 4 Day 1 (+14 days) 
patients will receive a second and final 22.5 mg intramuscular injection of leuprolide. On Cycle 4 Day 
5 (±5 days), patients will start stereotactic, ultra-fractionated radiotherapy to the prostate and seminal 
vesicles. Abiraterone acetate and apalutamide will continue daily until Cycle 6 Day 28. A physician 
prescribed taper of prednisone will begin on Cycle 6 Day 28. 
The following assessments will be performed during this time: 
• Vital signs, height/weight; targeted physical exam if deemed necessary by study doctor 
• Toxicity assessment 
• Evaluation by study doctor 
• Pill diary collection 
• Performlaboratory tests 
o PSA 
o CBC (every 2 weeks for the first 3 months) 
o Comprehensive Metabolic Panel (every 2 weeksfor the first 3 months) 
o Testosterone 
o TSH, T3 & T4 (T3 & T4 should be done only if TSH is abnormal) (Day 1 of each cyclefor the first 
four cycles) 
 
• Assess performance status using ECOG or Karnofsky scales (per institutional preference) (Appendix 
A) 
• Discuss concurrent medications (see Appendix B for a listing of medications with the potential for 
drug interactions) 
• Administration of leuprolide acetate on Cycle 1 Day 5 (±3 days) and Cycle 4 Day 1 (+14 days) 
• Stereotactic, ultra-fractionated radiotherapy will be administered every other day(except 
weekends and holidays) beginning at Cycle 4 Day 5 for five total treatments using a intensity 
modulated treatment plan withdelivery of 7.5-8.0 Gy to the prostate and seminal vesicles. At least 
fivedays prior to CT simulation, 3 fiducial markers will be placed transrectally within the prostate 
gland to be used for target localization on each treatment day for image-guided therapy. 

• Fiducial marker placement (at least 5 days prior to simulation) 
5.3 
Follow-up (Every 3 months (±2 weeks) for 1st year; every 4 months (±2 weeks) for 2nd year; every 6 
months (±2 weeks) for 3rd year) 
The following assessments will be performed during follow-up: 
• Vital signs, height/weight; targeted physical exam if deemed necessary by study doctor 
• Toxicity assessment (will occur until patient begins a new therapy forprostate cancer) 
• Discuss concurrent medications (see Appendix B for a listing of medications with the potential for 
drug interactions) (will occur until patient begins a new therapy for prostate cancer) 
• Evaluation by study doctor 
• Performlaboratory tests 
o PSA 
o CBC 
o Comprehensive Metabolic Panel 
o Testosterone 
• Digital rectal examination (DRE) 
• Assess performance status using ECOG or Karnofsky scales (per institutional preference) (Appendix 
A) 
• Imaging 
o Prostate/pelvis by MRI. Should occur at 6 months (optional, but encouraged) and 24 months 
(mandatory) post anti-androgen therapy. Should occur within 1 month prior to (and not after) 
biopsy to allow for appropriate targeting. 
• Biopsy of the prostate at 24 months (±2 months) post anti-androgen therapy (required, if safe and 
feasible). The biopsy should be a standard template 12 core biopsy but include an MRI-fusion 
component such that any suspicious areas seen on repeat MRI prostate are specifically targeted for 
additional sampling. 
• MSK-IMPACT™ evaluation of 24-month tumor specimen if sufficient biopsy material available. 
o If subject has a metastatic biopsy at metastatic progression as per standard of care (not 
mandatory per protocol), MSK-IMPACT™ testing of the biopsied tissue sample will be 
completed. 
• ctDNA at 6 months (±2 weeks) and 24 months (±2 weeks) postanti-androgen therapy, and at 
metastatic progression (See separate Laboratory Manual, Appendix C) 
• CTCs at 24 months (±2 weeks) post anti-androgen therapy, and at metastatic progression (See 
separate Laboratory Manual, Appendix C) 
o Note: CTCs will be drawn only forthe first 25 subjects enrolled on the study. 
• Administration of EPIC-26 Questionnaire (at 6 months, 12 months, 24 months and 36 months post 
anti-androgen therapy); can be completed ± 2 weeks of times listed. 

5.4 
Dose Modifications 
Table 3. Dose modifications for toxicity attributed to apalutamide 
Toxicity 
Dose of abiraterone 
acetate 
Dose of apalutamide 
Dose of prednisone 
Grade 1 or 2 
No change 
No change 
No change 
≥ Grade 3 
No change 
Hold until Grade 1 or 
baseline, resume at full 
dose 
No change 
First Recurrence 
≥ Grade 3 
No change 
Hold until Grade 1 or 
baseline, resume at 180 
mg (3 tablets) 
No change 
Second Recurrence 
≥ Grade 3 
No change 
Hold until Grade 1 or 
baseline, resume at 120 
mg (2 tablets) 
No change 
Third Recurrence 
≥ Grade 3 
No change 
Discontinue 
No change 
First occurrence of 
seizure of any grade or 
Grade 4 neurotoxicity 
No change 
Discontinue 
No change 
 
Rash 
Dose modifications for rash are allowed only for apalutamide and are summarized in Table 4. 
If the skin rash has any component of desquamation, mucosal involvement, or pustules, stop dosing with 
apalutamide, refer to dermatologist for evaluation, and a skin biopsy is recommended (in addition to the 
interventions listed in below Table) If the skin rash is Grade 3 or higher, asking the subject to consent to 
documentation by a photograph and further evaluation by a dermatologist should also be considered. 
Table 4. Dose modifications for rash 
Severity 
Intervention 
Grade 1 
• 
Continue apalutamide at current dose 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines 
• 
Monitor for change in severitya 
Grade 2 (or 
symptomatic 
Grade 1)b 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines 
• 
Monitor for change in severitya 
o 
If rash or related symptoms improve, reinitiate apalutamide when rash is 
Grade≤1. Consider dose reduction at a 1 dose level reduction.c 
Grade ≥3e 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines AND 
o 
Consider short course of oral steroids 
• 
Reassess after 2 weeks (by site staff), and if the rash is the same or has worsened, 
initiate oral steroids (if not already done) and refer the subject to a dermatologist 
o 
Reinitiate apalutamide at a 1 dose level reductionc, d when rash is Grade≤1. 
o 
If the dose reduction will lead to a dose less than 120mg, the study drug 

 
must be stopped (discontinued) 
• 
If after 28 days, rash has not resolved to Grade≤1, contact Janssen to discuss further 
management and possible discontinuation of study drug. 
Note: Rash may be graded differently according to the type of rash and associated symptoms. For example, 
maculo-papular rash is graded by body surface area covered and not severity of the rash. Please consult NCI- 
CTCAE Version 4.03 for specific grading criteria for other types of rash. 
a. Obtain bacterial/viral cultures if infection is suspected. 
b. Subject presents with other rash related symptoms such as pruritus, stinging, or burning. 
c. 1 dose level reduction = 60 mg (1 apalutamide tablet) 
d. If a subject previously started oral corticosteroids, continue for at least 1 week after resumption of reduced dose of 
apalutamide. If the proposed total oral steroid use will exceed 28 days, contact Janssen. 
e. If there is blistering or mucosal involvement, stop apalutamide dosing immediately and contact Janssen. 
 
 
Table 5. Dose modifications for liver function test abnormalities attributed to abiraterone acetate 
Toxicity 
Dose of abiraterone acetate 
Dose of apalutamide 
Dose of prednisone 
Grade 1 or 2 
No change 
No change 
No change 
Grade 3 
Hold until return to 
baseline or to AST or ALT 
≤2.5 x ULN and total bilirubin 
≤1.5 x ULN, resume at 750 
mg (3 tablets) only after 
discussion and agreement 
with medical monitor 
Hold until return to Grade 1
No change 
Recurrence 
Grade 3 
Hold until return to 
baseline or to AST or ALT 
≤2.5 x ULN and total bilirubin 
≤1.5 x ULN, resume at 500 
mg (2 tablets) only after 
discussion and agreement 
with medical monitor 
Hold until return to baseline 
No change 
Grade 4 
Discontinue AA treatment 
Hold until return to baseline 
No change or consider 
tapering if AA is 
discontinued 
 
 
 
Table 6. Dose modifications for hypokalemia attributed to abiraterone acetate 
Toxicity 
Dose of abiraterone acetate 
Dose of apalutamide 
Dose of prednisone 
Grade 1 or 2 
Initiate oral potassium 
supplementation, titrate to 
≥3.5 to ≤5.0 mmol/L, 
maintenance at ≥4.0 
mmol/L recommended 
No 
change 
No change 

 
≥Grade 3 
Hold and initiate IV 
potassium and cardiac 
monitoring, resume only 
after discussion and 
approval by 
the medical 
monitor 
No 
change 
No change or consider 
tapering if AA is 
discontinued 
Table 7. Dose modifications for hypertension and edema/fluid retention attributed to abiraterone acetate 
Toxicity 
Dose of abiraterone acetate 
Dose of apalutamide 
Dose of prednisone 
Grade 1 or 2 
No change 
No change 
No change 
≥Grade 3 
Hold until Grade 1 or 
baseline, resume at full 
dose 
No change 
No change 
First 
Recurrence 
≥Grade 3 
Hold until Grade 1 or baseline, 
resume at 750 mg (3 tablets) 
No change 
No change 
Second 
Recurrence 
≥Grade 3 
Hold until Grade 1 or baseline, 
resume at 500 mg (2 tablets) 
No change 
No change 
Third 
Recurrence 
≥Grade 3 
Discontinue 
No change 
No change or consider 
tapering if AA is 
discontinued 
 
5.4.1 
Abiraterone 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation. The NCI CTCAEv4.0 will be used to 
grade AEs. 
At each study visit for the duration of their participation, patients will be evaluated for AEs, 
serious adverse events (SAEs), and AEs that require treatment interruption or discontinuation. 
Patients discontinued from the treatment phase of the study for any reason will be evaluated 
approximately 30 days after the last treatment. 
The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, 
hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and 
contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline 
phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, 
elevated AST, hypophosphatemia, elevated ALT and hypokalemia. (6) 
Following prolonged therapy with corticosteroids, subjects may develop Cushing’s syndrome 
characterized by central adiposity, thin skin, easy bruising, and proximal myopathy. 
Withdrawal of the corticosteroid may result in symptoms that include fever, myalgia, arthralgia, 
fatigue, and malaise. 
Hypokalemia 
For patients who develop K+ levels < 2.5 mM, abiraterone acetate must be withheld and oral 
or IV K+ repletion must be initiated along with cardiac monitoring. These patients will be taken 
off study. Those with K+ levels between 2.5 and 3.0 will have abiraterone temporarily 

withheld and K+ repeated; the abiraterone can then be reinitiated and its dose titrated so that 
K+ > 3.5 mM. 
Hypertension and Fluid Retention 
If Grade 3 or Grade 4 AEs occur, hold study medication. Adjust or add medications to mitigate 
the toxicity or consider specific mineralocorticoid receptor antagonists like eplerenone. If 
toxicity recurs and resolves, restart abiraterone at 750 mg per day. If toxicity occurs a second 
time, decrease the dose to 500 mg/day. If it recurs a third time, discontinue. 
Hepatic Impairment 
In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the 
recommended dose of abiraterone acetate to 250 mg once daily. A once daily dose of 250 mg 
in patients with moderate hepatic impairment is predicted to result in an area under the 
concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function 
receiving 1,000 mg once daily. However, there are no clinical data at the dose of 250 mg once 
daily in patients with moderate hepatic impairment and caution is advised. In patients with 
moderate hepatic impairment monitor ALT, AST, and bilirubin prior to the start of treatment, 
every week for the first month, every two weeks for the following two months of treatment and 
monthly thereafter. If elevations in ALT and/or AST greater than 5X upper limit of normal (ULN) 
or total bilirubin greater than 3X ULN occur in patients with baseline moderate hepatic 
impairment, discontinue abiraterone acetate and do not re-treat patients with abiraterone 
acetate. 
 
Hepatotoxicity 
For patients who develop hepatotoxicity during treatment with abiraterone acetate (ALT 
and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment 
with abiraterone acetate. Treatment may be restarted at a reduced dose of 750 mg once daily 
following return of liver function tests to the patient’s baseline or to AST and ALT less than or 
equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. For patients who resume 
treatment, monitor transaminases and bilirubin at a minimum of every two weeks for three 
months and monthly thereafter. If hepatotoxicity recurs at the dose of 750 mg once daily, re- 
treatment may be restarted at a reduced dose of 500 mg once daily following return of liver 
function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and 
total bilirubin less than or equal to 1.5X ULN. If hepatotoxicity recurs at the reduced dose of 500 
mg once daily, discontinue treatment with abiraterone acetate. The safety of abiraterone 
acetate re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN 
and/or bilirubin greater than or equal to 10X ULN is unknown. 
 
5.4.2 
Apalutamide 
Seizures 
Patients experiencing treatment-related seizure of any grade will have study drug 
permanently discontinued. 
Gastrointestinal Discomfort 
At any given dose level, if patients experience gastrointestinal discomfort due to the number 
of tablets, they be allowed to switch to BID regimen as needed (4 in the AM and 4 in the PM). 
All other Toxicities 
For patients experiencing Grades 1-2 treatment-related AEs, short treatment breaks can be 
instituted as per the discretion of the investigator until the severity of the toxicity decreases to 
Grade 1 or returns to baseline. If toxicity recurs, dose reductions to the next lower dose 

level will be allowed as per the discretion of the investigator. For patients experiencing Grade 
≥3 treatment-related AEs other than seizure, study drug should be held until the severity of the 
toxicity decreases to Grade 1 or returns to baseline. If toxicity recurs at Grade 3 or higher, the 
dose of apalutamide should be reduced to the next lower dose level. A maximum of 2 dose level 
reductions will be allowed. Any patient requiring > 28 day delay in treatment will have met the 
criteria for study discontinuation. 
The two lower dose levels are 180 mg (three 60mg tablets) and 120 mg (two 60 mg tablets). 
5.4.3 
Treatment Delays on Radiation Timing 
Dose reductions or treatment delays in apalutamide and/or abiraterone done prior to 
initiation of radiation therapy (i.e., within the first 3 cyclesof treatment), will not impact the 
initiation of radiation therapy at Cycle 4 Day 5 (±5 days). 
 
5.4.4 
Dose modifications for abiraterone acetate and apalutamide 
1) If both drugs are held simultaneously fora length greater than 1 cycle(28 days in total; do not 
need to be consecutive days), then patient will be removed from trial and treated per 
standard of care 
2) If any one drug is held forgreater than 56 days (2 cycles), patient will be removed from trial 
and treated per standard of care 
 
5.5 
Concomitant Medications and Supportive Care 
5.5.1 
Abiraterone acetate 
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. The principal 
investigator (PI) should be alerted if the patient is taking any prohibited agents. Concurrent 
enrollment in another therapeutic clinical investigation is prohibited. 
Supportive Care Medications are permitted with their use following institutional guidelines. 
The following supportive care medications are permissible during study: conventional multi- 
vitamins, additional glucocorticoid administration such as a stress dose is permitted if clinically 
indicated for life-threatening medical conditions, and in such cases, the use of steroids will be 
documented as concomitant drug. 
Prohibited within 30 days prior to administration to study treatment: spironolactone, 5- 
alpha-reductase inhibitors, , and other investigational drug therapies. 
Prohibited 3 months before participant registration and during administration of study 
treatment: non-steroidal anti-androgens (e.g., bicalutamide, flutamide, nilutamide), steroidal 
antiandrogens (megestrol acetate, cyproterone acetate), AR partial agonists, ketoconazole, 
chemotherapy, immunotherapy, estrogens, radiopharmaceuticals,. The following medications 
are not excluded or prohibited, but are strongly discouraged: digoxin, pomegranate juice, 
indole-3-carbinol, flaxseed oil. 
CYP3A4 Inducers: Avoid concomitant strong CYP3A4 inducers during abiraterone acetate 
treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone 
acetate dosing frequency. 

CYP2D6 Substrates: Avoidco-administration of abiraterone acetate with CYP2D6 substrates 
that have a narrow therapeutic index. If an alternative treatment cannot be used, exercise 
caution and consider a dose reduction of the concomitant CYP2D6 substrate. 
 
CYP2C8: In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone 
(CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a 
single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely 
for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used 
concomitantly with abiraterone acetate. 
5.5.2 
Apalutamide 
As a class effect, AR antagonists have been associated with seizures due to an off-target 
mechanism of action (gamma amino butyric acid chloride channel [GABAA] inhibition). Drugs 
known to lower the seizure threshold or cause seizures are prohibited and a representative list 
is included below: 
• 
Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone) 
• 
Bupropion 
• 
Lithium 
• 
Meperidine and pethidine 
• 
Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine) 
• 
Tricyclic 
antidepressants 
(e.g., 
amitriptyline, 
desipramine, doxepin, imipramine, 
maprotiline, mirtazapine) 
 
Apalutamide is metabolized primarily by human CYP3A4, thus co-administration with strong 
inhibitors or inducers of CYP3A4 should be avoided as much as possible. Apalutamide may also 
induce CYP3A4; therefore, caution should be taken when administered in conjunction with 
CYP3A4 substrates that have a narrow therapeutic index. Examples of the strong CYP3A4 
inhibitors and inducers include the following: 
• Strong CYP3A4 inhibitors: itraconazole, clarithromycin, erythromycin, diltiazem, verapamil, 
delavirdine, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, voriconazole, grapefruit juice (or grapefruits); co-administration with any of 
these agents may increase apalutamide plasma concentrations 
• Strong CYP inducers: phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 
phenobarbital, efavirenz, tipranavir, St. John'swort; co-administration with any of these 
agents may decrease apalutamide plasma concentrations. 
The potential for drug-drug interaction between apalutamide and warfarin (Coumadin) is 
unknown at present. If a patient is taking warfarin, reassess PT/INR as clinically indicated 
and adjust the dose of warfarin accordingly. 
See Appendix B. Medications with the Potential for Drug-Drug Interactions for a complete list 
of medications prohibited while on active treatment with apalutamide. 
5.6 
Removing Subjects from the Protocol 
In the absence of treatment delays because of AEs, treatment will continue for 6 months unless one of 
the following occurs: 
• subject decides to withdraw from the study 

• Intercurrent illness that prevents further administration of treatment 
• unacceptable AE(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 subject 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 
• initiation of non-study therapy forprostate cancer 
• unable to swallow study drug 
Because an excessive rate of withdrawals can render the study uninterruptable, unnecessary 
withdrawal of subjects should be avoided. When a subject discontinues treatment early, the 
investigator should make every effort to contact the subject and to perform a final evaluation. The 
reason(s) for withdrawal should be recorded. In order to account for an estimated 10% dropout rate 
during treatment, we will enroll 64 patients upfront to ensure there are 53 evaluable patients. 
5.7 
Correlative Studies 
This trial, prospectively designed to correlate clinical outcomes with molecular analysis of patient 
samples, presents an ideal platform to identify biomarkers predictive of response. 
Eachsubject will have the following specimens obtained at the study site as described below: 
a) A paraffin embedded tumor sample (block or 25 unstained FFPE slides and 1 corresponding 
hematoxylin and eosin (H&E) slide; 4-5 micron thickness) via prostate biopsy at baseline and 
at 24 months post anti-androgen therapy. Baseline and 24-month biopsies will be required if 
safe and feasible at the discretion of the investigator. Metastatic progression biopsy will be 
completed per standard of care (not mandatory per protocol). Available archival tumor is 
acceptable for baseline when new procurement is not possible. 
b) Blood for EPIC to interrogate CTC data in this high risk patient population at baseline, 24 
months post anti-androgen therapy, andat metastatic progression. The first 25 patients will 
be followed with CTCs by EPIC. 
c) Blood forctDNA data at baseline, 6 months and 24 months post anti-androgen therapy, and at 
metastatic progression 
d) Targeted tumor sequencing assay, MSK-IMPACT™ (Integrated Mutation Profiling of 
Actionable Cancer Targets),(47) to detect gene mutations and other critical genetic 
aberrations in tumor biopsies pre- and post-treatment to better delineate the mechanisms of 
sensitivity and resistance to therapy; performance of MSK-IMPACT™is dependent on 
sufficient biopsy material being available. 
Specific collection and handling procedures for the correlative studies can be found in the study 
Laboratory Manual (Appendix C). 
Table 8 below describes the planned correlative assays. 
Table 8. Schedule of biomarker studies 
 
Assay 
Timepoint & Biospecimen 
Baseline 
6 Month 
24 Month 
Met. Progression 
CTC (25 patients) 
Blood 
 N/A 
 Blood 
 
Blood 
ctDNA 
MSK-IMPACT™ 
Blood 
Biopsy 
Blood 
N/A 
Blood 
Biopsy 
Blood 
Biopsy 
 
 

6. 
THERAPEUTIC/DIAGNOSTIC AGENTS/MODALITY 
6.1 
Description of Treatments 
6.1.1 
Abiraterone acetate 
Abiraterone 
acetate 
tablet 
formulation 
(ZYTIGA®) 
in 
combination 
with 
prednisone/prednisolone has been approved for the treatment of men with metastatic 
castration-resistant prostate cancer (mCRPC). Abiraterone acetate is commercially available in 
250 mg tablets that are oval, white to off white and contain abiraterone acetate and compendial 
grade lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, 
sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and purified water, in 
descending order of concentration. For this study this drug is investigational and will be 
supplied by Janssen Scientific Affairs, LLC at no cost. Abiraterone acetate must be taken on an 
empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA 
is taken and for at least one hour after the dose of ZYTIGA is taken. 
Handling abiraterone acetate tablets 
This medicine may cause harm to the unborn child if taken by women who are pregnant. It 
should not be taken by women who are breast-feeding. Women who are pregnant or who may 
be pregnant should wear gloves if they need to touch abiraterone acetate tablets. You should 
notify any caregivers of this information, to ensure the appropriate precautions are taken. 
6.1.2 
Prednisone 
Prednisone (5 mg tablets) is commercially available and will be prescribed to patients to be 
taken orally twice daily with food. If a subject has been receiving glucocorticoids other than 
prednisone or prednisolone, it will be necessary to switch the glucocorticoids to prednisone or 
prednisolone 5 mg twice daily prior to Day 1. 
6.1.3 
Apalutamide (also referred to as ARN-509 and JNJ-56021927) 
Apalutamide is FDA approved for non-metastatic castration resistant prostate cancer, however, 
and is considered investigational in this study. The tablet formulation of apalutamide is an 
immediate release oral tablet containing 60-mg of drug substance, with a non-functional green 
film coat. Each 60-mg tablet contains the following inactive ingredients: hydroxypropyl 
methylcellulose acetate succinate (HPMC-AS), colloidal anhydrous silica, croscarmellose 
sodium, microcrystalline cellulose, silicified microcrystalline cellulose, and magnesium 
stearate. Commercially available Opadry® coating powder is used for the film coating, which is 
comprised of polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol, 
talc, and colorants iron oxide yellow and iron oxide black (E172).This is an investigational drug 
and will be supplied by Janssen Scientific Affairs, LLC at no cost. 
6.1.4 
Leuprolide 
This is a commercially available, injectable, long acting analog of the native LHRH peptide 
available in 7.5 mg (1 month) injections or 22.5 mg (3-month) injections. For this study, only 
22.5 mg (3-month) injections will be used. It is administered via intramuscular injection. The 
manufacturer’s instructions should be followed. 
6.2 
Stereotactic, Ultra-Fractionated Radiotherapy 
Intensity-modulated, image-guided, ultra-hypofractionated external beam radiotherapy will begin on 
Cycle 4 Day 5 (±5 days) after the initiation of treatment with abiraterone acetate. The prostate and 
seminal vesicles will receive 7.5-8 Gy x 5 fractions. 

Image guided, intensity-modulated, ultra-fractionated radiation therapy is considered a reimbursable 
expense by Medicare. 
6.2.1 
Prior to Simulation 
• Prior to simulation, patientswill be referred for fiducial marker placement. 
• Patientsshouldhavefiducial markers at least 5 daysprior to simulation. 
6.2.2 
Simulation 
• Patients will perform a bowel preparation the night before simulation. 
• Patientswill be supineand positioned in an appropriateimmobilizationdevice. 
• Oralcontrastwill be administered for simulation. 
• A Foley catheter can be placed for simulationonly. 
• A rectal catheter can be placed for simulationonly. 
• CT imageswill be obtained as per existingdepartment protocolsandsent to thetreatment 
planning system 
• If available, MR imageswill be obtained as per existing department protocols, theywill be sent 
to the treatment planning system as well. 
• Patientsshouldhaveacomfortablyandreproduciblyfull bladder. 
6.2.3 
Treatment Planning 
• CTV1 should includetheprostate, seminal vesicles, andany areas at risk of extra- 
capsular extension. 
• PTV1 should include a 0.5 cm expansion on CTV1 inall directions, saveforposterior; 
the posterior expansion will be 0.3 cm. 
• For PTV1, the D95% should be ≥90% of theprescribeddose of 7.5 or 8 Gy per fraction. 
6.2.4 
Contouring of Normal Tissue Structures 
Bowel: should include the small intestines and the large intestines from the duodenum to the 
peritoneal reflection (distal end of the sigmoid). If the stomach is in close proximity to the 
target, it should be contoured as part of the bowel. 
Rectal Outer: the entire rectum 1cm superior and 1 cm inferior to the PTV will be defined as 
rectal outer 
Rectal Wall: a uniform contraction of 4 mm should be applied to the rectal outer contour. The 
rind between the outer rectal contour and the contracted volume will be defined as the rectal 
wall. 
Bladder Wall: the entire bladder with urinary contents should be contoured; a uniform 
contraction of 4mm should then be applied to this contour. The rind between the outer bladder 
contour and the contracted volume will be defined as the bladder wall. 
Kidney: both the right and left kidney, excluding the renal pelvis/collecting system, should be 
contoured in their entirety (renal cortex). 
Femoral Heads: the ball of the head and socket joint should be contoured. 

Urethra: should be defined using the contrast filled foley catheter. 
 
• Beamarrangements, optimizationstructuresandoptimizationparameterswill be defined at 
the discretion ofthetreatment planner usingroutine departmental procedures. 
• Thetreatment planwill be approved andreviewed by theattendingphysician. 
• The treatment plan will go through qualityassurance procedures per departmental guidelines. 
6.2.5 
Treatment Delivery 
• Patients should be treated every other day, excluding holidays and weekends. If the 
participant must miss one or two scheduled treatments due to unexpected events, they will be 
made up and this will not be considered a deviation/violation per protocol. 
• Patients shouldusea Fleet’senemathreehoursprior to each radiationfraction. 
• Intra-fraction motion management should be utilized per treating institution protocol. 
• Bladder should be comfortably full duringtreatment delivery. 
7. 
SAFETY EVALUATION 
7.1 
Definitions 
7.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment (ICH E2A). 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product 
(investigational ornon-investigational),whether ornot related to themedicinal product. 

This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
An AE will be recorded and followed from treatment administration to 30 days post treatment 
or resolution. 
7.1.2 
Adverse Events of Special Interest 
Adverse Events of Special Interest: Adverse events of special interest are events that Janssen 
Scientific Affairs, LLC, is actively monitoring as a result of a previously identified signal (even if 
non-serious). 
For abiraterone acetate, the adverse events of special interest are: 
• 
Mineralocorticoid excess (Hypertension, Hypokalemia, Fluid retention) 
• 
Hepatotoxicity 
• 
Cardiac disorders 
• 
Osteoporosis including osteoporosis-related fractures 
• 
Increased exposure with food 
• 
Rhabdomyolysis /myopathy 
• 
Acute liver failure/hepatitis which might be fatal 
• 
Drug-drug interaction (CYP2D6) 
• 
Allergic alveolitis 
Forapalutamide, theadverseevents of special interest are: 
• 
Seizures/convulsions 
• 
Fractures 
• 
Fall 
• 
Hypothyroidism 
• 
Rashes 
Any Adverse Event of Special Interest that is to be reported to the COMPANY should be recorded on a 
Serious Adverse Event Report Form and be reported to the COMPANY within24 hours of knowledge of 
the event. 
 
7.1.3 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
• 
an identifiablesubject(but notdisclosingpersonalinformationsuch as thesubject’sname, 
initialsor address) 
• 
an identifiable reporter (investigational site) 
• 
a Janssenmedicinal product 
• 
an adverseevent, outcome, or certainspecial 
situations The minimum information required is: 
• 
suspected Janssen medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 

• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
ageat AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, action 
taken, outcome, (if available) 
• 
Janssenprotocol ID 
 
7.1.4 
Expected Adverse Events 
Expected AEs are those that have been previously identified as resulting from administration 
of the agent. An AE can be considered expected when it appears in the current AE list, the 
Investigator’s Brochure, the package insert or is included in the informed consent document as 
a potential risk. 
7.1.5 
Unexpected Adverse Events 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational medicinal 
product) (ICH E2A). For a medicinal product(s) with a marketing authorization, the 
expectedness of an adverse event will be determined by whether or not it is listed in the 
applicable product information. 
For Abiraterone acetate, the link to the package insert is: 
http://www.zytiga.com/sites/default/files/pdf/full_product_information.pdf 
For apalutamide, the link to the package insert is: 
http://www.janssenlabels.com/package-insert/product-monograph/prescribing- 
information/ERLEADA-pi.pdf 
Contact the PI or Sponsor to confirm unexpected AEs when necessary. 
 
 
7.1.6 
Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered ADRs (ICH E2A). 
The phrase response to a medicinal product means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out. Reasonable possibility means there is evidence to suggest a causal relationship 
between the drug and the AE. 
7.1.7 
Serious Adverse Event (SAE) 
An SAE/ADR as defined in the Code of Federal Regulations (21CFR312.32) is any event that: 
• 
results in death 
• 
is life-threatening 
o The subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe. 
• 
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 a suspected transmission of any infectious agent via a medicinal product 
• 
is medically significant in the opinion of the investigator 
o Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is also appropriate in other situations, such as important 
medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. These should 
usually be considered serious. 
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 
7.1.8 
Progression of malignancy 
Progression of a patient’s malignancy should not be recorded as an adverse event or serious 
adverse event term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they fulfill the serious adverse event definition. 
7.1.9 
Life-threatening 
An AE or suspected adverse reaction is considered life-threatening if, in the view of either 
Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of death. 
It does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death (FDA 21 CFR 312.32). 
 
 
7.1.10 
Hospitalization (or prolongation of hospitalization) 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) resulting 
from a precipitating, treatment-emergent AE. 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 non-worsening preexisting condition should 
not be considered AEs (e.g., 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. Signs and symptoms of 
clinical sequelae resulting from hospitalization or prolongation of hospitalization will be 
reported if they fulfill the serious adverse event definition. 
Prolongation of hospitalization is any extension of an inpatient hospitalization beyond the stay 
anticipated or required for the original reason for admission. 
7.1.11 
Persistent or Significant disability/incapacity 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
patient’s ability to conduct normal life functions. 

7.1.12 
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 MSK and Janssen Scientific Affairs, LLC. All pregnancies will be 
followed until resolution (i.e., voluntary or spontaneous termination or birth) and assessed for 
congenital anomalies and birth defects. 
7.1.13 
Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product, or delivery system. Not all PQCs involve a 
subject. Lot and batch numbers are of high significance and need to be collected whenever 
available. 
Examples of PQC include but not limited to: 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 
• 
Physical Defect: e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
7.2 
Recording and Grading of Adverse Events 
7.2.1 
Recording 
All observed or volunteered AEs, regardless of treatment group, severity, suspected causal 
relationship, expectedness, or seriousness will be recorded. 
A clinically significant change in a physical examination finding or an abnormal test result 
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 sponsor investigator 
An abnormal test result that is subsequently determined to be in error does not require 
recording as an AE, even if it originally met one or more of the above criteria. 
7.2.2 
Grading severity 
All AEs will be graded based on the NCI CTCAE version 4.0. 
7.2.3 
Attributing causality 
After assigning a grade to an AE, the investigator must evaluate all AEs for possible causal 
relationship to the investigational agent/intervention. Causality attribution will be decided 
using the criteria outlined in Table 9. 

Table 9. Relationship of AE to study drug 
Relationship 
Description 
Unrelated 
AE is clearly not related 
Unlikely 
AE is doubtfully related 
Possible 
AE may be related 
Probable 
AE is likely related 
Definite 
AE is clearly related 
 
7.3 
Reporting Serious Adverse Events 
7.3.1 
Reporting serious adverse events 
All SAEs, events determined to be medically significant by the treating Investigator, unknown 
reactions or unexpected events, and any special reporting situations (see 7.3.3) that meet the 
criteria of a serious adverse event, should be reported to PI, Lead Site/Sponsor, PCCTC, and 
Janssen Scientific Affairs, LLC, within 24 hours of knowledge of the event using the contact 
information below. The initial report should include the following information at a minimum: 
• protocol # and title 
• study identification number, sex, age at event 
• date the event occurred 
• description of the SAE 
• causal relationship to the study drug 
All SAEs that occur any time a patient is on study (i.e., as soon as the informed consent has been 
signed) or within 30 days of the last dose of study drug or study intervention must be recorded 
regardless of the suspected relationship to the study drug/intervention. Any SAE occurring 
more than 30 days after the last dose of study drug/intervention must be recorded if a causal 
relationship to study drug/intervention is suspected. 
The PCCTC Report Form will be used for reporting each SAE and should be submitted to the 
PCCTC within 24 hours of learning of the event. Severity, causality, action taken, concomitant 
medications, outcome, etc. should be reported to the PCCTC as soon as possible. For MSK 
subjects, the Clinical Research Database (CRDB) SAE form is acceptable. For outside sites, the 
“Serious Adverse Event Report Form for Non-MSK Sites” should be used. 
In addition, the PCCTC will report all SAE and safety events classified as special reporting 
situations to Janssen within 24 hours of knowledge of the event using the Janssen SAE Report 
Form. 
Sites must submit both the Janssen SAE form along with the MSK SAE form to PCCTC. 
All (serious and non-serious) AEs and special situations (which may or may not meet the 
definition of an adverse event), whether serious or non-serious, related or not related, 
following exposure to apalutamide and/or abiraterone acetate are to be documented by the 
Investigator and recorded in the electronic case report form (eCRF) and in the subject’s source 
records. Investigators must record in the eCRF their opinion concerning the relationship of the 
AE and/or specific situation to apalutamide and/or abiraterone acetate. 

Follow-up of AEs should continue until the event and any sequela resolve or stabilize at a level 
acceptable to the investigator. 
The PCCTC will facilitate all SAE reporting to the MSK IRB/PB and Sponsor Investigator within 
5 calendar days. 
The MSK PI is responsible for informing all participating sites about all unexpected SAEs that 
are either possibly, probably, or definitely related to the study intervention within 15 days of 
receiving the stamped SAE from the MSK IRB/PB. 
The MSK PI is responsible for informing all participating sites about any SAE report 
pertaining to a Grade 5 event as soon as possible. 
SAE contact information for the PCCTC, Lead Site/Sponsor is listed below: 
Lead Site/Sponsor: Memorial Sloan Kettering Cancer Center 
Name: Sean McBride, MD, MPH 
Address: 1275 York Avenue 
Email: mcbrides@mskcc.org 
Phone: 212-639-5717 
 
PCCTC: 
Prostate Cancer Clinical Trials Consortium 
Email: pcctc@mskcc.org 
Janssen Scientific Affairs, LLC Transmission Methods 
The following methods are acceptable for transmission of safetyinformation to Janssen: 
• 
Electronically via Janssen SECURE Email service (preferred) 
o SAE email: IISProgram@OMPUS.jnj.com 
• 
Forbusinesscontinuitypurposes, if SECURE Email is non-functional: 
▪ 
Facsimile(fax), receipt of which is evidenced in asuccessful fax transmissionreport 
▪ 
Telephone(iffax isnon-functional). 
• 
SAE fax: 1-866-651-0219 
 
7.3.2 
Pregnancy 
Because the Janssen medicinal product may have an effect on sperm, pregnancies in partners 
of male subjects exposed to a Janssen medicinal product will be reported by the PI within 24 
hours of their knowledge of the event using the Serious Adverse Event Form. Depending 
on local legislation this may require prior consent of the partner. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required. 
7.3.3 
Special Reporting Situations 
Safety events of interest that require expedited reporting and/or safety evaluation include, 
but are not limited to: 
• Drug exposure to partner during pregnancy 
• Overdose of apalutamide and/or abiraterone acetate 
• Exposure to apalutamide and/or abiraterone acetate from breastfeeding 

• Suspected abuse/misuse of apalutamide and/or abiraterone acetate 
• Inadvertent or accidental exposure to apalutamide and/or abiraterone acetate 
• For abiraterone acetate only, failure of expected pharmacological action 
• Medication error involving apalutamide and/or abiraterone acetate 
• Suspected transmission of any infectious agent via administration of a medicinal product 
• For abiraterone acetate only, unexpected therapeutic or clinical benefit from use 
7.4 
Janssen Scientific Affairs, LLC Requirements 
7.4.1 
Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. The 
INSTITUTION (Memorial Sloan Kettering Cancer Center) and PRINCIPAL INVESTIGATOR (Dr. 
McBride) shall provide all adverse events, both serious and non-serious, in report format quarterly. 
However, in certain circumstances more frequent provision of safety data may be necessary, e.g. 
to fulfill a regulatory request, and as such the data shall be made available within a reasonable 
timeframe at the COMPANY’s (Janssen) request. 
 
7.4.2 
Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Janssen 
Medicinal Products to the COMPANY 
All adverse events and special situations, whether serious or non-serious, related or not related, 
following exposure to a Janssen medicinal product are to be documented by the investigator and 
recorded in the CRF and in the subject’s source records. Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to a Janssen medicinal product. 
All (serious and non-serious) adverse events reported fora Janssen medicinal product should be 
followed up in accordance with clinical practice. 
 
7.4.2.1 SAEs and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that have 
not resolved upon discontinuation of the subject's participation in the study, must be 
followed until any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
The INSTITUTION and the PRINCIPAL INVESTIGATOR) will transmit all SAEs and special 
situations following exposure to a Janssen product under study in a form provided by the 
COMPANY in English within24-hours of becoming aware of the event(s). 
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit an unblinded SAE 
or pregnancy exposure report to COMPANY. 
All follow-up information for serious adverse events that are not resolved at the end of the 
study or by the time of patient withdrawal must be reported directly by the PRINCIPAL 
INVESTIGATOR, within 24 hours becoming aware, to the COMPANY using the COMPANY’s 
Serious Adverse Event Report 

All available clinical information relevant to the evaluation ofa related SAE, serious ADR or 
special situation is required. 
 
• 
The INSTITUTION and/or PRINCIPAL INVESTIGATOR is responsible for ensuring 
that these cases are complete and if not are promptly followed-up. A safety report 
is not considered complete until all clinical details needed to interpret the case are 
received. Reporting of follow-up information should follow the same timeline as 
initial reports. 
 
• 
Copies of any and all relevant correspondences with regulatory authorities and 
ethics committees regarding any and all serious adverse events, irrespective of 
association with the Janssen Product under study, are to be provided to the 
COMPANY within 24 hours of such report or correspondence being sent to 
applicablehealth authorities. 
 
7.4.2.2 Non-Serious AEs 
All non-serious adverseevents should be reported to COMPANY according to the 
timeframeoutlined in the Research Funding Agreement sectionentitled 
Reporting of Data. 
7.4.2.3 PQC Reporting 
A PQC may have an impact on the safety and efficacyof the product. Timely, 
accurate, andcompletereportingandanalysis of PQC informationfromstudies 
are crucial for theprotection ofpatients, investigators, and the COMPANY, and 
are mandated by regulatory agencies worldwide. The COMPANY has 
established procedures inconformity with regulatory requirements worldwide 
to ensure appropriate reporting of PQC information. Lot and/or Batch #s shall 
be collected or any reports failure of expected pharmacological action (i.e., lack 
of effect). The product should be quarantined immediatelyand if possible, take 
a picture. 
All initial PQCs involving a Janssen medicinal product under study must be 
reported to the COMPANY by the PRINCIPALINVESTIGATOR within 24 hours 
afterbeingmadeaware of theevent. The Janssencontactwillprovideadditional 
information/form to be completed. 
If thedefect for a Janssenmedicinalproductunderstudyis combinedwitheithera 
serious adverse event or non-serious adverse event, the PRINCIPAL 
INVESTIGATOR must report the PQC to the COMPANY according to the serious 
adverse event reporting timelines. A sample of the suspected product should be 
maintained for further investigation if requested by the COMPANY. 
7.4.3 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Non-Janssen Medicinal Products 
For SAEs, special reporting situationsand PQCs following exposure to anon-Janssen medicinal 
product understudy, the PRINCIPAL INVESTIGATOR should notifytheappropriate 
regulatory/competentauthorityor themanufacturer of that medicinalproduct(intheabsence of 
appropriate local legislation) as soon as possible. 
7.5 
Safety Reports 
MSK must submit outside safety reports to the MSK IRB/PB according to institutional guidelines. All 
outside safety reports will be made available to the participating sites. Outside safety reports that are 

reportable to the MSK IRB/PB will be distributed by the PCCTC to the participating sites immediately 
upon receiving a stamped copy from the MSK IRB/PB. Participating sites will receive a special alert 
for any outside safety reports that warrant a significant change to the conduct of the study. Outside 
safety reports that are not reportable to the MSK IRB/PB, will be sent by the PCCTC to the 
participating sites monthly. 
 
Participating sites are responsible for submitting safety reports to their site IRB per their local 
guidelines. All site IRB approvals/acknowledgments of safety reports must be sent to the PCCTC upon 
receipt. 
 
8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE 
8.1 
Outcome Assessment 
8.1.1 
Primary endpoint 
The primary endpoint used to power this study is the proportion of patients who have had 
biochemical failure by 36-months post completion of anti-androgen therapy as defined by the 
Phoenix or surgical progression criteria wherein PSA failure represents an increase in PSA 
above post-treatment nadir by 2 or more ng/mL or PSA value above or equal to 0.2 ng/mL, 
respectively. The date the PSA equals or exceeds 0.2 ng/mL will be the date of failure.. 
Based on historic controls, we assume that the 3-year rate of biochemical failure with 
conventionally dosed radiation and 2-years of neoadjuvant, concurrent, and adjuvant 
leuprolide is approximately 25%. With the proposed regimen, we assume a rate of biochemical 
failure at 3-years of 10%. 
Given an unacceptable 3-year rate of biochemical recurrence of 25% and a threshold rate for 
further study of 10% or below, enrolling 53 patients will give a type-1 error rate of 0.03 (3% 
probability of declaring the regimen worthy of further study if the true rate of biochemical 
failure is 25% or higher) and a power of 0.84 (16% probability of declaring the regimen 
unworthy of further study if the true rate of biochemical failure in the arm is 10% or below). 
Thus, a sample size of 53 patients will provide us with an alpha of 0.03 and a power of 0.84. 
With an expected 10% dropout during follow-up, we would aim to enroll 64 patients. 
Due to a lower attrition rate than expected, 63 patients are evaluable (among the total 64 
enrolled). Therefore, we modified the decision rule by changing the denominator to 63. The 
current decision rule now adequately specifies that if, at study conclusion, there are more than 
9 biochemical failures among 63 evaluable patients, then we shall deem the regimen ineffective. 
If there are less than or equal to 9 biochemical failures, then we shall declare the experimental 
regimen effective, i.e., having achieved the proposed improvement to 10%. This decision rule 
maintains type 1 error rate at 0.03 with a power of 0.90. 
Patients who are lost to follow-up prior to 36 months of follow-up but after treatment 
completion will be counted as biochemical failures. As such, patients who complete the 
required treatment will be evaluable for the primary end-point of biochemical recurrence. 
8.1.2 
Secondary endpoints 
Additional outcomes on this trial will include acute (defined as within 3 months of treatment 
completion) and late (toxicities arising more than 3 months after treatment completion), 
additional tumoral control metrics (negative biopsy rate, rate of undetectable PSA, rate of 
distant metastases, rate of prostate cancer specific mortality, overall survival, MR imaging 
correlation with biopsy results, circulating tumor DNA dynamics, circulating tumor cell 

enumeration and HR-QOL metrics (EPIC26)). Tumor biopsies pre and post-treatment will be 
interrogated to better delineate the mechanisms of sensitivity and resistance to therapy. A 
customized MSK-IMPACT™ sequencing panel will be derived in concert with the MSK 
computational biology group. Selected genes will be reviewed for expression and reported for 
correlative analysis with treatment outcomes. The custom panel will be created prior to 
analysis. 

The EPIC 26 is a short form version of the full Expanded Prostate Cancer Index Composite 
(EPIC). This version contains 26 items and the same 5 domains as the full version of EPIC: 
urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal. Response 
options for each EPIC item for a Likert scale, and multi-item scare scores are transported 
linearly to a 0-100 scale with higher scores representing better HRQOL. The time frame 
asked in the question relates to symptoms experienced within the prior 4 weeks. The scoring 
method for EPIC-26 is found at http://medicine.umich.edu/dept/urology/research/epic. 
8.2 
Therapeutic Response 
8.2.1 
Criteria for Primary Efficacy End-point 
Biochemical failure will be determined using both Phoenix and surgical definitions of PSA 
progression. PSA Phoenix progression is defined as an increase in PSA by more than 2 ng/mL 
above the nadir value. The date the PSA rise equals or exceeds 2 ng/mL will be the date of 
failure. PSA surgical progression is defined as a PSA value above or equal to 0.2 ng/mL. The 
date the PSA equals or exceeds 0.2 ng/mL will be the date of failure. The proportion of patients 
with biochemical failure by 36 months after completion of anti- androgen therapy will be 
determined. 
8.2.2 
Criteria for Secondary Efficacy End-points 
1. Rate of positive biopsies: A prostate biopsy will be required prior to the start of RT—the 
standard diagnostic biopsy. Additionally, two prostate biopsies post-treatment will be 
performed—at 24 months post anti-androgen therapy (required, if safe and feasible) and 
at metastatic disease progression (if collected as per standard of care). Response criteria 
are defined as complete response or treatment failure based on an either negative or 
positive biopsy results. 
2. Proportion of patients with non-castrate testosterone (>150 ng/dLd) and an undetectable 
PSA as defined as PSA ≤0.2 ng/mL will be determined at 12 months and 24 months from 
treatment completion. 
3. Cumulative incidence of prostate cancer-specific mortality will be determined at 36 months. 
4. Cumulative incidence of distant metastasis will be determined at 36 months. 
5. OS will be determined at 36 months. 
6. Correlation between MRI and biopsy findings: the absence of restricted diffusion or 
contrast enhancement, when previously present, will be correlated with the presence of 
severe treatment effect/negative biopsy results. 
7. Incidence of CTCAE v4.0 acute (during and within 3 months of treatment completion) and 
late (3 months after treatment completion) toxicities will be evaluated 
8. The presence of or absence of circulating tumor DNA at baseline, 6 months post completion 
of anti-androgen therapy, 24 months post completion of anti-androgen therapy and at 
metastatic progression will be evaluated as a binary variable. 
9. The enumeration of circulating tumor cells at baseline, 24 months post completion of anti- 
androgen therapy, and at metastatic progression will be evaluated for the first 25 patients 
enrolled. This will be reported as a continuous variable per mL of blood. 
Descriptive reports of DNA alterations found in biopsies and correlation with outcome. 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS 
9.1 
Data Collection and Management 
Data collected during this study will be entered into a secure database. 

9.1.1 
Electronic Case Report Forms (eCRFs) 
The participating site(s) will enter data remotely into eCRFs using the internet based system, Medidata 
Rave. Data entry guidelines have been generated for this study and participating site staff will receive 
database training prior to enrolling its first participant. The participating site PI is responsible for 
ensuring these forms are completed accurately and in a timely manner. A Data and Source 
Documentation Submission Timeline is shown in the table in Section 9.1.5 below. 
9.1.2 
Source documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered into eCRFs. Relevant source documentation to be submitted 
throughout the study includes: 
• Baselinemeasures to assess pre-protocol diseasestatus(e.g., CT, PSA, bonemarrow) 
• Treatment records 
• Toxicities/AEs of grades that meet study reporting requirements and have not been previously 
submitted with a SAE Report(s) 
• Response designation 
Source documentation must include a minimum of two identifiers to allow for data verification. 
MSK will maintain the confidentiality of any subject-identifiable information it may encounter. 
9.1.3 
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 and study-related documents. Records are to 
be retained and securely stored until the later of: (a) two (2) years following the date a New 
Drug Application is approved for the Study Drug that is the subject of the Clinical Trial; or (b) 
two (2) years after the Investigational New Drug Application for such Study Drug is terminated 
or withdrawn, or such longer period of time as may be required by Participant policies, 
applicable laws, rules or regulations. 
9.1.4 
Source Documentation Submission for Registration at Participating Sites 
Participating sites should email any source documentation that corresponds to data entered at 
registration into the eCRFs to the PCCTC at PCCTC@mskcc.org (see section 4.2.1 for additional 
details). 
 
9.1.5 
Data Submission Timelines 
All data should be transmitted to the PCCTC within 14 days of visit except for SAE submission (see 
section 7.3.1). 
 
Baseline 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
SAE 
Off Study 
Submission Schedule 
Source Documentation 
Within 24 hours 
(see section 
15.1.1) 
Within 14 days of visit 
Within 24 hours 
of event (see 
section 7.3.1); 
updates to be 
submitted as 
Within 14 
days of 
visit 
eCRFs 
Within 7 days of 

1 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring%20Plans.pdf 
 
 
visit 
available 
Required Forms 
Demographics 
X 
Medical History 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
Treatment 
X 
X 
X 
X 
X 
Laboratory 
X 
X 
X 
X 
X 
X 
Lesion/EOD 
X 
X 
Adverse Event* 
X 
X 
X 
X 
X 
X 
Serious Adverse Event 
X 
Off Study 
X 
 
 
9.1.6 
Data Review and Queries 
The PCCTC will review data and source documentation as it is submitted. Data will be monitored 
against source documentation as necessary and discrepancies will be sent as queries to the 
participating sites. In addition, the PCCTC will review data for logic, consistency, and obvious 
anomalies. Queries will be sent by the PCCTC to participating sites as needed. 
Participatingsitesshouldrespond to dataqueries within14 days of receipt. 
9.2 
Study Monitoring and Quality Assurance 
9.2.1 
Data and Safety Monitoring 
The Data and Safety Monitoring Plans (DSMP) at MSK1 were approved by the National Cancer 
Institute in September 2001. The plans address the new policies set forth by the NCI in the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-334 A(15) 
Approval date: 
51 of 77 
 
 
document entitled Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical 
Trials.2 The DSMPs at MSK wereestablished andare monitored by the Office of Clinical Research. 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research quality assurance) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. There are several committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for 
Phase III clinical trials, report to the MSK Research Council and Institutional Review Board. As 
a moderate risk trial, this study will be monitored by DSMC twiceper year. 
Since therapeutic efficacy is a stated primary objective, all participating sites participants’ 
responses are subject to review by MSK’s Therapeutic Response Review Committee (TRRC). 
Radiology and additional lab reports will need to be obtained from the participating sites for 
MSK TRRC review and confirmation of response assessment. These materials must be sent to 
MSK promptly upon request 
9.2.2 
Data Monitoring and Quality Assurance 
In addition to review by DSMC, PCCTC will conduct regularly scheduled monitoring visits. 
Registration reports will be generated by the PCCTC to monitor subject 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. 
Each site participating in the accrual of participants to this protocol will be monitored at a 
minimum of 10% of all subjects, but at least 2 from each site will be 100% source data 
verified by the PCCTC during interim visits (selected subjects). Monitoring will occur once 
shortly after initiation of subject recruitment at a site, annually during the study (or more 
frequently if indicated), and at the end or closeout of the trial, for protocol and regulatory 
compliance, data verification and source documentation. Monitoring visits may be 
accomplished in one of two ways: (1) sending source documents and research records for 
selected patients from participating sites to the PCCTC for review, or (2) on-site monitoring of 
selected patient records at participating sites. 
 
 
 
 
 
 
 
 
 
 
2  http://www.cancer.gov/clinicaltrials/conducting/dsm -guidelines/page1 

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The monitoring visit will include a review of source documentation to evaluate compliance for: 
 
• 
Regulatory/IRB compliance (review of current protocol and amendments, Informed 
consent documents and procedures, annual continuing review reports, AEs/SAEs) 
• 
Protocol defined treatment compliance 
• 
Subject records 
1. Signed and dated informed consent form for each subject 
2. Adherence to eligibility criteria for each subject 
3. Medical history/baseline for selected subjects 
4. On study and follow-up protocol tests forselected subjects 
5. eCRF completion for each subject 
 
Monitoring visit findings will be reviewed by PI, Dr. Sean McBride, and disseminated to the Site 
PIs and staff. 
In addition, each participating site accruing participants to this protocol will be audited by MSK 
for protocol and regulatory compliance, data verification and source documentation. Audits of 
selected participant records may be conducted on-site or remotely. 
Audits will be summarized and a final report will be sent to the PI at the audited participating 
site within 30 days of the audit. The report will include a summary of findings, participant- 
specific case review, recommendations on any performance and/or shortcomings and request 
for corrective action, when necessary. When corrective action is required, the participating site 
must reply within 45 days of receipt of the audit report with their corrective action plan. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
10.1.1 
Analysis of the primary endpoints 
Data from high-dose, conventional external beam radiation in combination with LHRH agonist 
treatment in high risk patients suggests a cumulative incidence of biochemical recurrence at 3 
years of approximately 25% (conversely, a rate of continued biochemical control of 75% at 3 
years). We assume that ultra-hypofractionation in combination with leuprolide, abiraterone, 
and apalutamide will have a 3-year rate of biochemical failure of 10%. 
Given an unacceptable rate of biochemical recurrence by 3 years of 25% (Nguyen et al. Cancer 
2013, Page 3265-3271; Shilkrut et al. AJCO 2015, In Press) and a threshold rate for further study 
of 10% or below, enrolling 53 patients will give a type-1 error rate of 0.03 (3% probability of 
declaring the regimen worthy of further study if the true rate of biochemical failure is 25% or 
higher) and a power of 0.84 (16% probability of declaring the regimen unworthy of further 
study if the true rate of biochemical failure in the arm is 10% or below). The decision rulewas 
previously noted as follows: If, at study conclusion, among the first 53 evaluable patients, there 
are more than 7 biochemical failures, then we shall declare the regimen ineffective. If there are 
less than or equal to 7 biochemical failures, then we shall declare the experimental regimen 
effective, i.e., having achieved the proposed improvement to 10%. If at any point in the trial, 
more than 7 patients experience biochemical failure, the study will be stopped for futility. 

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Patients who die prior to the 36-month end-point due to any cause will be counted as 
biochemical failures. Patients who complete therapy but who are lost during study mandated 
follow-up will be regarded as biochemical failures. In order to account for an estimated 17% 
dropout rate during therapy, we will enroll 64 patients upfront to ensure there are 53 evaluable 
patients for the above decision rule. We estimate accrual of 2 patients per month onto study 
(approximately 30 months to accrue). From the time of registration of the last patient, the 
study will continue for 42 months. The total study duration we thus estimate at 72 months. 
Due to a lower attrition rate than expected, 63 patients are evaluable (among the total 64 
enrolled). Therefore, we subsequently modified the decision rule upon MSKCC’s protocol 
amendment 15 (i.e., protocol version 9 dated 05JAN2023), by changing the denominator to 63. 
The current decision rule now adequately specifies that if, at study conclusion, there are more 
than 9 biochemical failures among 63 evaluable patients, then we shall deem the regimen 
ineffective. If there are less than or equal to 9 biochemical failures, then we shall declare the 
experimental regimen effective, i.e., having achieved the proposed improvement to 10%. This 
decision rule maintains type 1 error rate approximately around 0.025 with a power of at least 
0.80. 
Due to the uncertainty of the toxicity associated with this novel combination of therapies, the 
trial will involve a sequential stopping rule. Based on data from Cahlon, et al, an acceptable rate 
of any acute, treatment-related CTCAE Grade 4 or greater toxicity is approximately 2% (48). 
We also specify that a 10% CTCAE Grade 4 treatment-related toxicity rate is unacceptable. To 
this end, the sequential stopping rule is as follows: If ≥2 patients among the first 21, or ≥3 
among the first 42, or ≥5 among the total 64 patients developed Grade 4 acute, treatment- 
related toxicities, then the trial will stop. This ensures a 0.09 probability of stopping the trial if 
the true toxicity rate is 2% and a 0.88 probability of stopping the trial if the true toxicity is 10%. 
There will be continuous monitoring of toxicities. At study conclusion, regardless of efficacy, if 
5 or more patients experience Grade 4 or greater acute, treatment-related toxicity, we would 
recommend against use of this regimen in a phase III randomized controlled trial. 
Although the primary outcome, as well as the secondary endpoints (see Section 10.1.2 below), 
is computed from the end of treatment, for future references we will also compute all clinical 
endpoint measures from the beginning of the treatment. 
10.1.2 
Analysis of the secondary endpoints 
The rates of positive prostate biopsies at 24 months after completion of anti-androgen therapy 
and at metastatic progression, and the rates of undetectable PSA at 1, 2 and 3 years post- 
treatment for men with non-castrate testosterone will all be estimated by sample proportions. 
Overall Survival will be calculated using the method of Kaplan and Meier. The cumulative 
incidence of prostate cancer-specific mortality and distance metastasis rate will be calculated 
using the competing risks cumulative incidence method. Time zero for the calculation of these 
endpoints will be the completion of all trial-related therapy; patients who die or develop 
distant metastases during treatment will be regarding as having the respective event at t=0. 
Acute and Late Toxicities will be defined using the CTCAE version 4.0. The highest grade toxicity 
experienced by each patient in the first 3 months after treatment will be defined as acute 
toxicity; the highest grade toxicity attributable to treatment after 3 months will be defined as a 
late toxicity. Such observed toxicities will be tabulated and summarized. 
For the evaluation of EPIC-26, routine summary statistics and pairwise t-tests or Wilcoxon 
signed-rank tests will be conducted to test potential differences between scores obtained from 
baseline and during the follow-up period. To incorporate baseline factors, ANCOVA may also be 
used. 

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Sensitivities, specificity, positive-predictive value, and negative predictive value will be 
calculated for MRI versus gold-standard post-treatment biopsy results. The absence of diffusion 
restriction and contrast enhancement will be categorized as “no residual tumor”; the presence 
of these factors on multi-parametric imaging will be categorized as “residual tumor”. 

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Comparisons will then be made to pathological determination of treatment response: complete 
response/severe treatment effect vs. residual disease. 
CtDNA will be reported as a binary variable (present or absent) at baseline, 6 months and 24 
months post therapy completion, and at metastatic progression. We will correlate the presence 
or absence of ctDNA with various established clinical end-points. In addition, ctDNA will be 
evaluated for the presence or absence of various AR mutations. 
The enumeration of circulating tumor cells at baseline, 24 months post completion of anti- 
androgen therapy, and at metastatic progression will be evaluated for the first 25 patients 
enrolled. This will be reported as a continuous variable and correlated with tumor control 
outcomes. 
We will describe the various DNA alterations present at the various biopsy end-points 
(baseline, 24 months post treatment completion, and metastatic progression). We will 
correlate the presence of certain mutations at baseline (if seen in sufficient number) and 
outcome. 
Additional correlative assessments of tissues collected under the protocol may be performed 
at the discretion of the study team. 
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS 
11.1 
Roles and Responsibilities 
11.1.1 
Sponsor Investigator (Sponsor Principal Investigator) 
The Sponsor Investigator is responsible for performing the followingtasks: 
• Responsibility for the overall conduct of the study at all participating sites and for 
monitoring the progress of the study 
• Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
• Reviewing data fromall participating sites 
11.1.2 
PCCTC 
The PCCTC is responsible for performing the following tasks: 
• Ensuring that IRB approval has been obtained at each participating site prior to the first 
patient registration at that site, and maintaining copies of IRB approvals and required 
regulatory documents from each site. 
• Managing subject registration 
• Developing and maintaining Clinical Data Management documents and procedures 
• CRF development, setup of study database, and subsequent design changes 
• Participating in review of content of the CRF against the protocol requirements 
• EDC system administration (user/site accounts setup, maintenance and revocation) 
• Data review, cleaning, query management and resolution 
• Establishing procedures fordocumentation, reporting and submitting of AEs and SAEs to 
the PCCTC. 

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• Reviewing SAEs 
• Training participating sites on EDC 
• Collecting and compiling data from each participating site 
• Data reviewing from all participating sites 
• Facilitating monitoring visits and audits by securing selected source documents and 
research records from participating sites for monitoring visit and/or audit, or by 
monitoring at participating sites. 
11.1.3 
Participating Sites 
Participating sites are responsible for performing the followingtasks: 
• Following the protocol as written, the guidelines of Good Clinical Practice (GCP), and 
applicable Standard Operating Procedures (SOPs). Registering all patients with the PCCTC 
by submitting the eligibility checklist, supporting source documentation, 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 PCCTC 
• Collecting and submitting data according to the schedule specified by the protocol 
• Responding to queries in a timely manner 
11.2 
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). 
11.3 
Regulatory Documentation 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA authorization 
and any other information pertaining to participants must be approved by the MSK Institutional 
Review Board/Privacy Board (IRB/PB). There will be one protocol document and each participating 
site will utilize that document. 
The following documents must be provided to the PCCTC before the participating site can be initiated 
and begin enrolling participants: 
• Participating Site IRB approval(s) for the protocol, appendices, informed consent form and HIPAA 
authorization 
• Participating Site IRB approved informed consent form and HIPAA authorization 
• Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• Participating Site 1572 
• Conflict of Interest forms forparticipating site Investigators on the 1572 
• Curriculum vitae and medical licenses foreach investigator and consenting professional 
• Documentation of Human Subject Research Certification training for investigators and key study 
personnel at the participating site 

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• Documentation of Good Clinical Practice(GCP) training for the PI and co-PI at the participating site 
• Participating site laboratory certifications and reference ranges 
Upon receipt of the required documents, the PCCTC will submit a participating site activation request 
to MSK. Once approved, MSK will formally contact the PCCTC and grant the site permission to proceed 
with participant registration. 
11.4 
Protocol Amendments 
Each change to the protocol document must be organized and documented by the PCCTC, reviewed and 
approved by Janssen Scientific Affairs, LLC, and approved by the MSK IRB/PB. Protocol amendments 
that affect MSK only (e.g. change in MSK Co-Investigator, MSK translation, etc.) do not require IRB 
review at the participating site(s). All other protocol amendments will be immediately distributed to 
each participating site upon receipt of MSK IRB/PB approval. 
Each participating site must obtain approval for all amendments from their IRB within 45 calendar 
days of MSK IRB/PB approval. If the amendment is the result of a safety issue or makes eligibility 
criteria more restrictive, participating sites will not be permitted to continue enrolling new participants 
until site IRB approval of the revised protocol document is granted and submitted to the PCCTC, who 
will in turn submit the approval documentation to MSK. 
The following documents must be provided to the PCCTC for each amendment within the stated 
timelines: 
• Participating Site IRB approval 
• Participating Site IRB approved informed consent form and HIPAA authorization 
The PCCTC is responsible for submitting all participating site local IRB approvals and/or 
acknowledgments to MSK upon receipt. 
11.5 
Additional IRB Correspondence 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to the PCCTC within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of new 
participant registration. The PCCTC is responsible for submitting all participating site local IRB 
approvals and/or acknowledgments to MSK upon receipt. 

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Deviations 
A protocol deviation on this study is defined as any incident involving non-adherence to an IRB 
approved protocol. Deviations typically do not have a significant effect on the rights, safety, or 
welfare of research participants or on the integrity of the resultant data. Deviations that represent 
unanticipated problems involving risks to participants or others, or serious adverse events should be 
reported according to sections 7.3 and 11.10 of the protocol. 
Deviations that do not adversely affect the rights and/or welfare of the participant or the scientific 
validity of the study and are related to protocol scheduling changes outside of the allowed window 
due to a holiday (e.g., New Year’s, Thanksgiving, etc.) and/or inclement weather or other natural 
event do not require reporting to the MSK IRB/PB. However, they must be clearly documented in the 
patient’s medical record. 
Prospective Deviations 
Deviations to the research protocol that involve an informed consent procedure change and/or 
treatment/pharmacy alterations that are not allowed by the protocol require prospective approval 
from the MSK IRB/PB prior to the change being carried out. Participating sites should contact the 
PCCTC who will in turn seek approval from the MSK IRB/PB. Deviations to the research protocol that 
involve patient eligibility will not be permitted. 
Retrospective Deviations 
Deviations that include a change or departure from the research protocol without prior approval 
from the MSK IRB/PB are considered retrospective deviations. Retrospective deviations should be 
reported to the PCCTC as soon as possible, who will in turn report the deviation to the MSK IRB/PB as 
per MSK guidelines. 
Participating Site IRB Reporting 
Participating sites should report all deviations to their institution’s IRB per local guidelines. 
Approvals/acknowledgments from the participating site IRB for protocol deviations should be 
submitted to the PCCTC upon receipt. The PCCTC is responsible forsubmitting all participating site 
local IRB approvals and/or acknowledgments to MSK upon receipt. 
Other Correspondence 
Participating sites should submit all other correspondence to their institution’s IRB according to local 
guidelines, and submit copies of official site IRB correspondences to the PCCTC. The PCCTC is 
responsible for submitting all participating site local IRB correspondence to MSK upon receipt 
11.6 
Document Maintenance 
The MSK PI and participating site PI will maintain adequate and accurate records to fully document 
protocol implementation and allow data to be subsequently verified. 
The participating sites will ensure that all regulatory documents and participating site IRB 
correspondence are maintained in an on-site regulatory binder and sent to the PCCTC as outlined 
within the protocol. The on-site regulatory binder will be reviewed by the designated study monitor 
at monitoring visits. A regulatory binder for each participating site will also be maintained at the 
PCCTC; this binder may be paper or electronic. 
After study closure, the participating sites must maintain all source documents, study related 
documents and eCRFs for 7 years. 

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11.7 
Written Informed Consent 
The investigators listed on the Consenting Professionals Lists at each participating site may obtain 
informed consent and care for the participants according to Good Clinical Practice and protocol 
guidelines. 
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 
AE 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 an informed consent form 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 and a copy will be sent home with each 
patient. A note will be placed in the participant’s medical record documenting that informed consent 
was obtained for this study, and that the participant acknowledges the risk of participation. 
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 forthe protocol 
• the right of the patient to accept or refuse treatment and to withdraw from participation in this study 
• text regarding the PCCTC should be added to all institutional informed consent documents and 
sections in the research authorization/HIPAA forms (e.g., “Prostate Cancer Clinical Trials 
Consortium”) 
• the purpose of banking samples for future use, their rights in relation to it, and the safeguards in place 
to protect the confidentiality of their health information 
11.8 
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 form. The research authorization form must be completed by the PI and 
approved by the IRB. 

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11.9 
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. SAEs will be reviewed as they are reported to the Lead 
Site/Sponsor and the PCCTC, and the medical monitor, Dr. Sean McBride, 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 PI be that the study should be terminated, the study will be closed to further 
accrual. Patients who are receiving an investigational agent/intervention 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. 
11.10 Unanticipated Problems (UPs) 
Unanticipated problems involving risks to participants or others (UPs) are defined as any incident, 
experience or outcome that meets all of the following criteria: 
• 
Unanticipated (in terms of nature, severity, or frequency) given (a) the research procedures that 
are describedintheprotocol-related documents, suchasthe IRB-approved researchprotocol and 
informedconsentdocument; and (b)thecharacteristics of the subject populationbeingstudied; 
and 
• 
Relatedorpossibly related to participatingintheresearch (possibly related meansthereisa 
reasonableprobabilitythat theincident, experience or outcomemay havebeencaused by 
procedures involved in the research); and 
• 
Suggeststhattheresearchplaceparticipants or others at agreaterrisk ofharm (includingphysical, 
psychological, economic, or social harm) than was previously known or recognized. 
Participating sites are responsible for reporting all UPs to MSK as soon as possible but within 3 calendar 
days of learning of the event. UPs that are SAEs should be reported to MSK via SAE Report form as per 
section 7.3 of the protocol. All other UPs should be reported to MSK in a memo signed by the site PI. 
MSKis responsible for submitting UPs to the MSKIRB/PB according to institutional guidelines. In 
addition, the PCCTC is responsible for notifying participating sites of all non-SAEUPs that may affect the 
sites. 
 
11.11 
Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges may be suspended 
and/or contract payments may be withheld, until the outstanding issues have been resolved. 
11.12 
Return of Genomic Data 
In regards to the return of genomic data, the protocol consent form asks participants for permission 
for re-contact to discuss research findings that may occur during the course of next generation 
sequencing (i.e. MSK-IMPACT™ assay). These incidental findings may be critical to the patient and/or 
family’s preventative care. If an MSK participant agrees to be re-contacted, he or she will not be told 
the specific results of the research test, but will be informed that his or her samples were analyzed 
and a potential risk was uncovered. If the participant is interested in further discussion of the 
research findings, he or she will be asked to come into the MSK Clinical Genetics Service for 
counseling and specific genetic testing. If a participating site participant agrees to have tissue sent to 
MSK for our secondary objective with MSK-IMPACT™ testing and s/he wished to be re-contacted in 
the consent form, then any significant incidental findings uncovered during MSK-IMPACT™ testing 
will be relayed to the treating physician at the treating institution so they may carry out their 
institution’s policy with regard to offering the patient confirmatory testing and genetic counseling. 

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In the course of the research, a research finding may be obtained that, in the opinion of the MSK PI, 
may be critical to the preventive care of the participant or their family. When this occurs, the MSK PI 
will communicate this to the MSK IRB Genomic Advisory Panel (GAP). The finding will be reviewed by 
the GAP to determine whether the incidental finding should be discussed with the participant. In the 
event that the GAP determines that the finding should be discussed with the participant, results will 
be returned to the Site Principal Investigator via the PCCTC. If the participant has agreed to be re- 
contacted, site policies on returning these research findings to the patient should be followed. 
 
For MSK patients, after appropriate counseling and consent, the Clinical Genetics Service will request 
permission to confirmthe result in a New York DOH-approved laboratory prior to communication of 
the specific result. If the patient is not available (e.g. deceased) then the surrogate designated on the 
consent will be contacted and the above should occur. 
 
If the subject is not an MSK patient and is being treated at one of the participating institutions, the 
findings will be returned to the outside Principal Investigator and local policies on returning these 
research findings to the patient should be followed. 
Lastly, patients will be asked to consent to tumor banking such that both frozen and fixed tumor 
cores can be utilized for future investigations. 
When samples are to be analyzed, the individual investigator needs to write an IRB biospecimen 
protocol. This protocol is fast-tracked through Research Council review and is reviewed at IRB by the 
expedited review process. This protocol is only for research that will be done on biospecimens 
obtained under identified protocols and their informed consent and research authorization that 
include the institutional future use questions. The consent and research authorization for the use of 
the biospecimens will be waived as per 45 CFR 46.116(d) and 45 CFR 164.512(i)(2)(ii). 

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12. 
REFERENCES 
 
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Hurwitz MD, Halabi S, Archer L, McGinnis LS, Kuettel MR, DiBiase SJ, et al. Combination external beam 
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Clemente S, Nigro R, Oliviero C, Marchioni C, Esposito M, Giglioli FR, et al. Role of the Technical 
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Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, et al. Gene expression analysis of 
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Trachtenberg J, Gittleman M, Steidle C, Barzell W, Friedel W, Pessis D, et al. A phase 3, multicenter, 
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17. 
Kim D, Gregory CW, French FS, Smith GJ, Mohler JL. Androgen receptor expression and cellular 
proliferation during transition from androgen-dependent to recurrent growth after castration in the CWR22 
prostate cancer xenograft. Am J Pathol. 2002;160(1):219-26. 
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Attard G, Reid AH, A'Hern R, Parker C, Oommen NB, Folkerd E, et al. Selective inhibition of CYP17 
with abiraterone acetate is highly activein the treatment of castration-resistant prostate cancer. J Clin Oncol. 
2009;27(23):3742-8. 
19. 
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic 
prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-48. 
20. 
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation 
antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-90. 
21. 
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with 
enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-97. 
22. 
Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, et al. ARN-509: a novel antiandrogen for 
prostate cancer treatment. Cancer research. 2012;72(6):1494-503. 
23. 
Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, et al. Phase I study of ARN-509, a novel 
antiandrogen, in the treatment of castration-resistant prostate cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2013;31(28):3525-30. 
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Brown JM, Carlson DJ, Brenner DJ. The Tumor Radiobiology of SRS and SBRT: Are More Than the 5 Rs 
Involved? International journal of radiation oncology, biology, physics. 2014;88(2):254-62. 
25. 
Fowler JF, Toma-Dasu I, Dasu A. Is the alpha/beta ratio for prostate tumours really low and does it 
vary with the level of risk at diagnosis? Anticancer research. 2013;33(3):1009-11. 
26. 
Tucker SL, Thames HD, Michalski JM, Bosch WR, Mohan R, Winter K, et al. Estimation of alpha/beta 
for late rectal toxicity based on RTOG 94-06. International journal of radiation oncology, biology, physics. 
2011;81(2):600-5. 
27. 
Leborgne F, Fowler J, Leborgne JH, Mezzera J. Later outcomes and alpha/beta estimate from 
hypofractionated conformal three-dimensional radiotherapy versus standard fractionation for localized 
prostate cancer. International journal of radiation oncology, biology, physics. 2012;82(3):1200-7. 
28. 
Arcangeli G, Saracino B, Gomellini S, Petrongari MG, Arcangeli S, Sentinelli S, et al. A prospective 
phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk 
prostate cancer. Int J Radiat Oncol Biol Phys. 2010;78(1):11-8. 
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Pollack A, Walker G, Horwitz EM, Price R, Feigenberg S, Konski AA, et al. Randomized trial of 
hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol. 2013;31(31):3860-8. 
30. 
King CR, Freeman D, Kaplan I, Fuller D, Bolzicco G, Collins S, et al. Stereotactic body radiotherapy for 
localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials. 
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 
2013;109(2):217-21. 
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King CR, Collins S, Fuller D, Wang PC, Kupelian P, Steinberg M, et al. Health-related quality of life after 
stereotactic body radiation therapy for localized prostate cancer: results from a multi-institutional 
consortium of prospective trials. International journal of radiation oncology, biology, physics. 
2013;87(5):939-45. 
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Nguyen PL, D'Amico AV. Targeting pelvic lymph nodes in men with intermediate- and high-risk 
prostate cancer despite two negative randomized trials. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2008;26(12):2055-6; author reply 6-7. 
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Lawton CA, DeSilvio M, Roach M, 3rd, Uhl V, Kirsch R, Seider M, et al. An update of the phase III trial 
comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen 
suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation 
interactions. International journal of radiation oncology, biology, physics. 2007;69(3):646-55. 
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Pommier P, Chabaud S, Lagrange JL, Richaud P, Lesaunier F, Le Prise E, et al. Is there a role for pelvic 
irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2007;25(34):5366-73. 

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Leibel SA, Fuks Z, Zelefsky MJ, Hunt M, Burman CM, Mageras GS, et al. Technological advances in 
external-beam radiation therapy for the treatment of localized prostate cancer. Seminars in oncology. 
2003;30(5):596-615. 
36. 
Smith M, ARN-509 in men with high-risk nonmetastatic castration resistant prostate cancer (CRPC). J 
Clin Oncol 31, 2013 (suppl 6; abstr 7). 
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Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide Treatment and 
Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018;378(15):1408-18. 
38. 
Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK, et al. Persistent intraprostatic androgen 
concentrations after medical castration in healthy men. The Journal of clinical endocrinology and 
metabolism. 2006;91(10):3850-6. 
39. 
Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, et al. Intraprostatic androgens and 
androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for 
castration-resistant prostate cancer. Cancer Res. 2007;67(10):5033-41. 
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Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, et al. Increased expression of 
genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 
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Taplin ME, Montgomery B, Logothetis CJ, Bubley GJ, Richie JP, Dalkin BL, et al. Intense androgen- 
deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk 
prostate cancer: results of a randomized phase II neoadjuvant study. J Clin Oncol. 2014;32(33):3705-15. 
42. 
Taplin M-E MR, Logothetis C, et al: Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide 
acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localizedhigh-risk prostate 
cancer (LHRPC): Results of a randomized phase II study. 2012 ASCO Annual Meeting. Abstract 4521. 
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Efstathiou eaEicwaibm, castration resistant prostate cancer. J Clin Oncol 32:5s, 2014 (suppl; abstr 
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Posadas eaPbsoA-waaAapPippwmc-rpcm. 
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Zelefsky MJ, Reuter VE, Fuks Z, Scardino P, Shippy A. Influence of local tumor control on distant 
metastases and cancer related mortality after external beam radiotherapy for prostate cancer. The Journal of 
urology. 2008;179(4):1368-73; discussion 73. 
46. 
Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ, et al. Androgen receptor 
signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3(11):1245-53. 
47. 
Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, et al. Memorial Sloan Kettering- 
Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based 
Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. The Journal of molecular 
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Cahlon O, Zelefsky MJ, Shippy A, Chan H, Fuks Z, Yamada Y, et al. Ultra-high dose (86.4 Gy) IMRT for 
localized prostate cancer: toxicity and biochemical outcomes. International journal of radiation oncology, 
biology, physics. 2008;71(2):330-7. 

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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 (e.g., 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 
 
Table 9. Medications Prohibited while on active treatment with apalutamide 
Generic Name 
Brand Name* 
aminophylline 
Aminocont; Aminomal; Diaphyllin; Filotempo; Neophyllin; Norphyl; 
Phyllocontin; Syntophyllin; Tefamin; Truphylline; Xing You Shan; 
aminophylline in 
combination 
Asmeton; Cha Xin Na Min; Emergent-Ez; Fufang Dan An Pian; Ke Zhi 
amitriptyline 
Amirol; Amitrip; Amixide; Deprelio; Diapatol; Elatrol; cElatrolet; Elavil; 
Endep; Enovil; Emitrip; Klotriptyl; Laroxyl; Levate; Limbitrol; Limbitryl; 
Mutabase; Mutabon; Nobritol; Novo-Triptyn; Pertriptyl; Redomex; 
Saroten; Sarotex; Sedans; Syneudon; Teperin; Triptizol; Triptyl; Tryptizol 
amitriptyline in 
combination 
PMS-Levazine 
bupropion 
Aplenzin; Buproban; Contrave; Elontril; Forfivo; Fortivo XL; Le Fu Ting; 
Prexaton; Quomem; Voxra; Wellbutrin; Wellbutrin XL; Wellbutrin SR; Yue 
Ting; Zyban 
chlorpromazine 
Aminazin; Chlorazin; Hibernal; Klorproman; Largactil; Megaphen; 
Ormazine; Plegomazin; Solidon; Taroctyl;Thorazine; Vegetamin; 
Wintermin; Zuledin 
Note: in Ireland also called “Clonazine” – very easy to confusewith 
clozapine. 
clozapine 
Azaleptin; Clopine; Closastene; Clozaril; CloZAPine; Denzapine; Elcrit; 
Fazacio ODT; Klozapol; Lanolept; Leponex; Lozapine; Nemea; Ozapim; 
Synthon, Versacloz; Zaponex 
desipramine 
Deprexan; Norpramin; Nortimil; Pertofrane 
doxepin 
Adapin; Anten; Aponal; Deptran; Gilex; Li Ke Ning; Quitaxon; Silenor; 
Sinepin; Sinequan; Zonalon 
imipramine 
Impril; Melipramin; Mipralin; Norfranil,; Novo-Pramine; Persamine; 
Pertofram; Pryleugan; Talendep; Tofranil; Tolerade 
lithium 
Arthriselect; Camcolit; Carbolith; Carbolithium; Eskolith; Hypnorex; Li- 
Liquid; Licarbium; Limas; Liskonum; Litarex; Lithane; Lithicarb; 
Lithioderm; Lithionit; Lithobid; Liticarb; Litiomal; Lito; Maniprex; 
Neurolepsin; Plenur; Priadel; Quilonorm; Quilonum; Saniquiet; Sedalit; 
Teralithe 
lithium in 
combination 
Boripharm No 23; Emser Salz; Girheulit HOM; Helidonium-Plus; 
Heweurat N; rheuma-loges; Rhus Toxicodendron Compose; Rhus-Plus; 
Ricinus Compose 
maprotiline 
Cronmolin; Deprilept; Ludiomil; Mapromil; Melodil; Neuomil; Psymion 
meperidine/pethidine 
Alodan ; Atropine and Demerol; Centralgine ; Demerol ; Dolantin ; 
Dolantina,; Dolantine ; Dolargan,; Dolcontral,; Dolestine ; Dolosal ; Dolsin; 
Fada; Hospira; Liba; Mepergan ; Meprozine,; Mialgin,; Opystan; Pethidine ; 
Petigan Miro ; Psyquil compositum 
meperidine/pethidine 
in combination 
Pamergan P100 

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mesoridazine 
Serentil, Mesorin 
mirtazapine 
Arintapin; Avanza; Axit; Combar; Esprital; Mi Er Ning; Miro; Mirta TAD; 
Mirtabene; Mirtachem; Mirtadepi; Mirtagamma; Mirtalan; MirtaLich; 
Mirtamylan; Mirtaron; Mirtaz; Mirtazelon; Mirtazon; Mirtazonal; Mirtel; 
Mirtin; Mirtor; Mirzaten; Norset; Noxibel; Paidisheng; Psidep; Remergil; 
Remergon; Remeron; Remirta; Rexer; Yarocen; Zispin 
olanzapine 
Anzorin, Arenbil; Arkolamyl; Atyzyo; Bloonis; Clingozan; Egolanza; 
Lansyn; Lanzek; Lazapix; Nolian; Nykob; Olafid; Olanzaran; Olanzep; 
Olanzin; Olanzine; Olapin; Olasyn; Olazax; Olpinat; Olzapin; Olzin; Ou Lan 
Ning; Ozilormar; Parnassan; Ranofren; Sanza; Stygapon; Synza; Ximin; 
Zalasta; Zamil; Zappa; Zapris; Zerpi; Zolafren; Zolaxa; Zonapir; 
Zopridoxin; Zylap; Zypadhera; Zypine; Zyprexa; Zyprexa Relprew; Zydis 
olanzapine in 
combination 
Symbyax 
risperidone 
Aleptan; Apo-Risperid; Arketin; Calmapride; Diaforin; Doresol; 
Hunperdal; Jing Ping; Ke Tong; Leptinorm; Lergitec; Orizon; Ozidal; 
Perdox; Ranperidon; Resdone; Ridal; Ridonex; Rileptid; Ripedon; Risepro; 
Rispa; Rispaksole; Rispefar; Rispemylan; Rispen; Rispera; Risperanne; 
Risperdal; Risperdalconsta; Risperdaloro; Risperigamma; Risperon; 
Rispolept; Rispolux; Rispond; Rispons; Risset; Rixadone; Rorendo; 
Ryspolit; Si Li Shu; Sizodon; Speridan; Suo Le; Torendo; Zhuo Fei; Zhuo 
Fu; Ziperid; Zoridal 
theophylline 
Aerolate; Afonilum; Aminomal; An Fei Lin; Apnecut; Apo-Theo; Asmalix; 
Asmalon; Bi Chuan; Bronchoparat; Bronchoretard; Cylmin; Diffumal; Elixifilin; 
Elixophyllin; Etipramid; Euphyllin; Euphyllina; Euphylline; Euphylong; 
Frivent; Gan Fei Lin; Nuelin; Protheo; Pulmophylline; Quelesu; ratio- 
Theo-Bronc; Respicur; Retafyllin; Shi Er Ping; Slo-Bid; Slo-Phyllin; 
Telbans; Teotard; Terdan; Teromol; Theo-24; Theo-Dur; Theo; 
Theochron; Theodur; Theofol; Theolair; Theoplus; Theospirex; Theostat ; 
Theotard; Theotrim; Theovent; Tromphyllin; Unicon; Unicontin; Unifyl; 
Uniphyl; Uniphyllin Continus; Uniphyllin; UniXan; Xanthium; Xi Fu Li; Yan 
Er 
theophylline in 
combination 
Antong; Baladex; Bi Chuan; Binfolipase; Broncho-Euphyllin; Broncomar; 
Do-Do ChestEze; Elixophyllin-GG; Elixophyllin-KI; Insanovin; Marax ; 
Neoasma; Theofol Comp; Theophedrinum-N; Xu Hong; Yi Xi Qing 
thioridazine 
Detril; Elperil; Melleril; Ridazin; Ridazine; Thiodazine; Thioril; Sonapa 
ziprasidone 
Geodon; Li Fu Jun An; Pramaxima; Si Bei Ge; Ypsila; Zeldox; Zipwell; 
Zypsila; Zypsilan 

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APPENDIX C: LABORATORY MANUAL 
PLEASE SEE SEPARATELY ATTACHED APPENDIX C – LABORATORY MANUAL INCLUDING REQUISITION 
FORMS. 

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APPENDIX D: EPIC-26 
PLEASE SEE SEPARATELY ATTACHED APPENDIX D – EPIC-26 

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APPENDIX E: IPSS 
PLEASE SEE SEPARATELY ATTACHED APPENDIX E – IPSS 

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APPENDIX F: GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
17-AAG 
17-allylamino-17-demethoxygeldanamycin 
17-DMAG 
17-dimethylaminoethylamino-17-demethoxygeldanamycin 
2-MPPA 
2-(3-mercaptopropyl) Pentanedioic acid 
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 
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 

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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 Management System 
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 
%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 

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ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EKG 
electrocardiogram 
EORTC 
European Organization 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 
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 Harmonization 
IEC 
Independent Ethics Committee 
IHC 
immunochemical 
IM 
intramuscular 

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IMSL 
International Mathematical Statistical Library 
IND 
investigational new drug 
INR 
international normalized ratio 
IP 
IPSS 
Intraperitoneal 
International Prostate Symptom Score 
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 
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 
MSK 
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 

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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 MSK 
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 
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 

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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 
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 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-334 A(15) 
Approval date: 
77 of 77 
 
 
APPENDIX G. PILL DIARY 
Please see separately attached Appendix G – Pill Diary