A Salvage Trial of AR Inhibition With ADT and Apalutamide With Radiation Therapy Followed by Docetaxel in Men With PSA Recurrent Prostate Cancer After Radical Prostatectomy (STARTAR)
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Andrew J. Armstrong, MD

CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and 
regulations.  Written authorization from the coordinating site and sponsor is required for disclosure otherwise. 
 
A Salvage Trial of AR Inhibition with ADT and Apalutamide 
with Radiation therapy followed by Docetaxel in Men with 
PSA Recurrent Prostate Cancer after Radical Prostatectomy 
(STARTAR) 
NCT03311555 
 
 
 
 
 
 
 
Sponsor: 
PI – Duke Cancer Institute 
 
 
Funding Source: 
Study Drug Source: 
Janssen Scientific Affairs, LLC 
Janssen Scientific Affairs, LLC 
 
 
Protocol Source: 
PI – Duke Cancer Institute 
 
 
Duke IRB#: 
Duke IND#: 
Pro00080868 
136725 
 
 
 
 
 
 
Principal Investigator 
Andrew Armstrong, MD 
DUMC 103861 
Durham NC 27710 
andrew.armstrong@duke.edu  
Phone (919) 668-8797 
Fax (919) 660-0178 
 
 
 
Sub-Investigators 
Daniel George, MD 
Michael Harrison, MD 
Bridget Koontz, MD 
W. Robert Lee, MD 
William Berry, MD 
Christopher Hoimes, DO 
 
 
Statistician 
Yuan Wu, PhD 
yuan.wu@duke.edu    
 
 
 
 
 
 
 
 
 
 
ver 01   February 10, 2017 
ver 02   August 03, 2017 
ver 03   August 23, 2017  
ver 04   September 25, 2017 
ver 05   October 4, 2017 
ver 06   February 12, 2018 
ver 07   April 10, 2018 
 
ver 08   June 28, 2018 
ver 09   Aug 22, 2018 
ver 10   Oct 19, 2018 
ver 11   Feb 25, 2019 
ver 12   May 25, 2019 
ver 13   Sep 25, 2019 
ver 14   Aug 07, 2020 
ver 15   July 15, 2021 
 

 
 
 

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Responsible Study Personnel 
 
 
 
 
Principal Investigator 
 
 
Multi Site Management 
 
Andrew Armstrong, MD 
andrew.armstrong@duke.edu 
 
Carol Winters, RN, OCN, CCRC  
 
 
2424 Erwin Rd, Hock Plaza 7045  
Durham, NC  27705 
 
 
 
Tel: (919)668-8577, (919)668-3018  
Fax:  (919)668-7117 
 
 
 
Data Manager 
GU-multisite@duke.edu  
 
Monika Anand, PhD, CCRP 
2424 Erwin Rd, Hock Plaza 7052 
Durham, NC 27705 
Tel: (919)681-8838   
Fax: (919)668-0639 
monika.anand@duke.edu  
 
 
Regulatory Coordinator 
 
Steven Gray, PhD, RAC 
2424 Erwin Rd, Hock 7046 
Durham, NC 27705 
 
 
Tel:  (919)668-5176   
Fax: (919)668-0639 
 
GURegs@duke.edu  
 
 
 
 
 
 
 
 
 
External Sites Participating in This Study 
Wake Forest University 
Site PI : Rhonda Bitting, MD 
rbitting@wakehealth.edu 
 
Cornell University 
Site PI: Scott Tagawa 
stt2007@med.cornell.edu 
 
GU Research Network/Urology Cancer Center 
Site PI: Luke Nordquist, MD 
drnordquist@gucancer.com  
 

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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS ............................................................................................................... 4 
2 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY ....................................................................... 5 
3 
STUDY SCHEMA ........................................................................................................................... 13 
4 
BACKGROUND AND SIGNIFICANCE ............................................................................................. 13 
5 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 17 
6 
INVESTIGATIONAL PLAN ............................................................................................................. 19 
7 
RADIATION THERAPY .................................................................................................................. 25 
8 
STUDY DRUG ............................................................................................................................... 29 
9 
SUBJECT ELIGIBILITY .................................................................................................................... 32 
10 
SCHEDULE OF EVENTS ................................................................................................................. 33 
11 
SAFETY MONITORING AND REPORTING ..................................................................................... 40 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................................................... 50 
13 
STATISTICAL METHODS AND DATA ANALYSIS ............................................................................ 52 
14 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS .................................................................... 55 
15 
REFERENCES ................................................................................................................................ 59 
APPENDIX A:  ECOG and Karnofsky Performance Status Criteria ......................................................... 61 
APPENDIX B:  VAS Pain and Fatigue Score Criteria ............................................................................... 62 
APPENDIX C:  Concomitant medications to be avoided ....................................................................... 64 
APPENDIX D:  Lymph node locations .................................................................................................... 65 
 
 
 
 
 

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1 LIST OF ABBREVIATIONS 
Use this list as a starting point for abbreviations used in this protocol. 
 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
GnRH 
Gonadotropic Releasing Hormone 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IMRT 
Intensity-Modulated Radiation Therapy 
IV (or iv) 
Intravenously 
LHRH  
Luteinizing Hormone Releasing Hormone 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
p.o. 
per os/by mouth/orally 
PORT 
Post-Operative Radiotherapy 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 

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2 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
2.1 Purpose 
 
Primary Objective: 
 
To describe the rate of 36-month (3-year) progression free survival (composite definition, please 
see section 5.2) in men with recurrent PSA-only disease after prostatectomy, who receive combined 
apalutamide (ARN-509 or JNJ-56021927) and standard ADT with salvage radiation therapy followed 
by docetaxel, ADT, and apalutamide, AND who have had testosterone recovery to >100 ng/dl at 36 
months. 
 
Secondary Objectives: 
1. To determine the proportion of men at 12, 24, and 36 months with PSA <0.1ng/mL and 
testosterone recovery to >100 ng/dl 
2. To describe the biochemical (PSA) progression free survival over time. 
3. To describe the PSA nadir (10%, 50% and 90% PSA decline as maximum response) 
4. To describe the time to testosterone recovery 
5. To describe the safety profile of combination apalutamide, ADT, and radiation therapy followed 
by apalutamide, ADT, and docetaxel 
6. To describe the percentage of patients completing all treatments including salvage radiation 
therapy and 6 cycles of docetaxel 
 
Exploratory Objectives: 
 
1. To describe the quality of life in patients receiving the combination of apalutamide , ADT, and 
salvage radiation therapy, as well as the combination of apalutamide, ADT, and docetaxel 
2. Archived prostatectomy specimens will be collected and stored for up to 15 years, for 
eventual analysis of the correlation of outcomes with pre-treatment genomic risk scores 
(Decipher assay if available), androgen receptor (AR) target genes, AR splice variants, markers 
of DNA repair, and epithelial-plasticity (EP) biomarkers.  
3. Plasma samples will be collected and stored for eventual analysis of circulating proteins and 
circulating tumor DNA. 
 
Hypothesis: 
 
Recent data supports an interaction between androgen receptor (AR) activity and DNA repair and 
radiation sensitivity in prostate cancer.  Based on our previous clinical trial experience of treating 
men with  recurrent disease after radical prostatectomy and high risk features, the 3-year rate of 
progression free survival for men receiving salvage radiation therapy alone is 50% [1].   We 
hypothesize that AR inhibition with apalutamide added to standard salvage external beam 
radiation with androgen deprivation therapy, as well as the addition of 6 cycles of docetaxel, will 
further prolong progression free survival. 
 

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2.2 Background and Significance 
 
The treatment of men with PSA recurrence following radical prostatectomy has generally been 
unsatisfying, given the high rates of persistent or recurrent disease despite salvage radiotherapy.  In 
most large series, the rate of development of metastatic disease following salvage radiation therapy 
for PSA-only disease is approximately 60-70%.  This suggests that, in high risk individuals, only 30-
40% of PSA-only disease is truly localized and thus curable with radiotherapy.  While radiotherapy 
alone in the salvage setting may reduce the risk of local recurrence in prostate cancer, it has an 
unclear benefit on reduction of metastatic disease and overall survival.  Systemic therapeutic options 
for these men are thus needed to improve systemic control and eliminate potential micrometastatic 
deposits.    
 
Androgen deprivation therapy (ADT) added to radiation therapy for the primary treatment of 
prostate cancer has a demonstrated survival benefit [2], and the benefit of ADT for salvage radiation 
setting has been shown by two randomized trials, particularly with significant pre-treatment PSA.  
RTOG 9601 randomized 761 patients with pT3 or pT3R1 with post-resection PSA between 0.2-4 
ng/ml to PORT versus PORT with 2 years of bicalutamide 150mg daily. At 12 years of follow up, OS 
was improved with bicalutamide (76.3% vs. 71.3%, HR 0.77, 95% CI 0.59-0.99, p=0.04) [3]. In 
addition, the prostate cancer specific incidence of death at 12 years was improved with 
bicalutamide (5.8% vs. 13.4%, HR 0.49, 95% CI 0.32-0.74, p<0.001). The 12-year incidence of 
metastatic prostate cancer was also improved with bicalutamide (14.5% vs. 23%, HR 0.63, 95% CI 
0.46-0.87, p=0.05). There were no increases in grade 3-4 toxicities [3]. The Phase III GETUG trial 
randomizing the use of 6 months LHRH agonist with standard salvage PORT provides additional 
evidence for the currently most common PORT-ADT regimen, finding a biochemical and clinical 
progression free benefit at 5 years (80 vs 62%, HR 0.5) [4]. Other data also support a multimodal 
approach - a retrospective case series identified 441 patients who were treated with salvage XRT; of 
these, 24% also received ADT. Multivariate analysis of concurrent ADT was shown to improve 
progression-free survival (HR 0.65, p=0.046) in high risk patients [5].  
 
The androgen receptor (AR) has also been shown to control the transcription of key DNA repair 
genes important in mediating radioresistance in prostate cancer. Indeed, AR inhibition increases 
DNA damage in tumors, improving radiosensitivity and decreasing survival of prostate cancer cells  
[6]. This suggests that ADT and potent AR inhibition may act synergistically with radiation. Clinically, 
high-risk patients with biochemical recurrence after surgery are often managed with the 
combination of ADT and radiation therapy.   
 
Enzalutamide is an androgen receptor antagonist that not only blocks androgen binding to its 
receptor but also inhibits nuclear translocation and DNA binding. The Phase I/II clinical trial of 
enzalutamide showed significant anti-tumor response in patients with progressive metastatic CPRC, 
with median time to progression of 47 weeks [7]. The phase 3 AFFIRM trial of enzalutamide revealed 
an improvement in survival of 4.8 months over placebo alone in men with metastatic CRPC who had 
received docetaxel [8]. Subsequently, the Phase 3 PREVAIL trial of enzalutamide revealed an 
improvement in both progression free survival and overall survival over placebo alone in men with 
metastatic CRPC who had not received chemotherapy [9]. Therefore, enzalutamide is an effective 
therapy for patients with progressive, metastatic CRPC before and after treatment with 
chemotherapy. Even earlier treatment with enzalutamide, in pre-metastatic and/or castrate-
sensitive disease, may be beneficial and is an active area of investigation.   
 

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Similar to enzalutamide, apalutamide is a competitive AR inhibitor that is fully antagonistic to AR 
overexpression, lacking significant agonist activity, or inducing activity for AR nuclear localization or 
DNA binding [10]. In Phase I testing apalutamide was dosed between 30 mg and 480 mg once daily, 
resulting at all dose levels and a median 50% decline from baseline PSA at 12 weeks of 47% [11].  The 
most frequently reported adverse event was grade 1/2 fatigue (47%). A Phase II multicenter study 
evaluated the clinical efficacy of apalutamide at 240 mg daily in non-metastatic (nm) CRPC patients. 
In 47 evaluable patients, 89% had ≥50% PSA decline at 12 weeks. Median time to PSA progression 
was 24.0 mo (95% confidence interval [CI], 16.3 months - not reached [NR]); median metastasis-free 
survival was NR (95% CI, 33.4 months - NR). The most common AE was fatigue (any grade, n=31 
[61%]) [12]. A Phase III Study of apalutamide versus placebo in men with non-metastatic CRPC 
showed that apalutamide prolonged metastasis-free survival and time to symptomatic 
progression[13].    
 
The Phase II multicenter study, “Salvage therapeutic radiation with Enzalutamide and ADT in men 
with recurrent prostate cancer” (STREAM) was recently conducted at Duke and 2 other centers and 
enrolled 38 patients. The analysis from this trial is pending. Accrual was complete in January 2016 
and to date, no patients have progressed with about a 12-month median follow up. Our early data 
suggest the safety of concurrent ADT/enzalutamide with salvage PORT based on the lack of additive 
or severe toxicities to date, and based on the high proportion of men with undetectable PSA values 
early in their treatment course, this regimen appears quite effective at suppressing AR activity and 
controlling disease. Apalutamide is a second-generation AR antagonist similar to enzalutamide and 
would likely have similar activity in this patient population. 
 
Docetaxel has been shown to have clinical benefit when used with ADT as first-line for newly-
diagnosed metastatic CSPC. The CHAARTED study randomized patients to ADT alone versus ADT and 
docetaxel 75mg/m2 every 3 weeks for 6 cycles. The combination of ADT and docetaxel increased 
median overall survival by 13 months (57.6 vs. 44.0 months, HR 0.61, 95% CI 0.47-0.80, p<0.001) 
[14]. This survival benefit was supported in the STAMPEDE study, which was a multi-arm study 
including patients with non-metastatic but locally advanced disease, with ADT versus ADT and 
docetaxel as one of the comparisons. In men with M0 prostate cancer, the addition of docetaxel 
improved median OS by 10 months (77 versus 67 months, HR 0.76, 95% CI 0.63-0.91, p = 0.003) [15]. 
There was an increased risk (12%) of febrile neutropenia in patients treated with both docetaxel and 
ADT. Finally, the RTOG 0521 trial also studied the addition of 6 cycles of docetaxel to ADT and 
radiation early on for patients with high risk prostate cancer (defined as Gleason 9 or 10 with 
PSA<150, Gleason 7 or 8 with PSA 20-150, or pT2, Gleason 8 and PSA <20). The 4-year overall 
survival was 93% with docetaxel and 89% without docetaxel, HR 0.70, 90% CI: 0.51-0.98, with one-
sided p=0.04) [16]. Concerns surrounding the RTOG 0521 trial include the one-sided p-value and the 
deaths from protocol treatment or unknown cause was slightly higher in patients treated with 
docetaxel (6 out of 43 deaths in docetaxel arm [2 from protocol treatment and 4 from unknown 
cause] vs. 0 out of 59 in ADT/radiation arm) [16]. 
 
Based on these data, there is a role for docetaxel in combination with first-line ADT, and there is 
evidence to support the early use of docetaxel in men with non-metastatic CSPC who are treated 
with primary radiotherapy and ADT.  
 
The goal of this study is therefore to determine the feasibility and efficacy of treatment with 
apalutamide and androgen-deprivation in the setting of standard salvage external beam radiation 

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therapy, followed by the combination of apalutamide and ADT with 6 cycles of docetaxel, in men 
with high risk prostate cancer and rising PSA after prostatectomy.  
 
Based on the above data, we hypothesize that potent AR inhibition with ADT will result in 
radiosensitivity in the PSA recurrent setting and defective DNA repair, as well as effective systemic 
control. In addition, we hypothesize that the addition of docetaxel will provide greater systemic 
control over ADT/apalutamide and RT alone. In order to investigate the early use of combination 
docetaxel and ADT/apalutamide still further, we propose a Phase IB/II clinical trial of ADT, 
apalutamide, and docetaxel with salvage radiation therapy for biochemical recurrent prostate 
cancer. 
 
2.3 Design and Procedures 
 
This is a non-blinded single-arm phase II FDA IND multicenter study of approximately 42 subjects to 
assess feasibility and efficacy of combined apalutamide and androgen-deprivation (ADT) with 
salvage radiation therapy, followed by apalutamide, ADT, and docetaxel for 6 cycles. Duke is the lead 
site for this trial, involving 3 additional centers. 
Eligible men will have recurrent PSA-only prostate cancer within 4 years of prostatectomy, and a PSA 
of greater than 0.2 ng/mL and less than 4 ng/mL in the absence of metastatic disease on CT and bone 
scans. 
Week 1 Day 1 of treatment is defined as the first day a subject receives Apalutamide or ADT inclusive 
of situations where a subject may not receive the second drug until week 2 due to scheduling issues, 
and treatment would continue for approximately 8 weeks neo-adjuvant to IMRT followed by 
concurrent with salvage IMRT per standard of care, continue throughout a four-week period 
between end of radiation and initiation of docetaxel, and continue through approximately 18 weeks 
with 6 cycles of docetaxel treatment, for a total of approximately 36 weeks of systemic treatment. 
Apalutamide will be given at a dose of 240 mg by mouth daily for the duration of treatment, and ADT 
will be administered per institutional standard for approximately 36 weeks (9 months).  Standard 
external beam radiotherapy of 66 to 74 Gy will be administered to the prostate bed according to 
local standard of care, usually a period of 6-8 weeks. Intensity Modulated RT (IMRT) is allowed for 
this study. Inclusion of the pelvic nodes as part of the salvage radiation plan for patients with node 
positive disease will be performed at the discretion of the treating radiation oncologist.   
The endpoints are 36-month (3-year) progression free survival and the proportion of men at 12, 24, 
and 36 months with a PSA of <0.1 ng/mL who also have testosterone recovery to >100 ng/dl.   
 
2.4 Selection of Subjects 
 
2.4.1 Inclusion Criteria 
 
1.   Histologically-confirmed diagnosis of prostate adenocarcinoma.  Variants of prostate cancer, 
including predominantly (>50%) neuroendocrine features and small cell carcinoma of the 
prostate, are not permitted. 

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2. Gleason sum of 7 (with pT3 disease or positive margins or positive nodes [4 or fewer]), 8, 9, or 
10 based on the radical prostatectomy specimen 
3. PSA relapse within 4 years of prostatectomy defined by persistently detectable or rising PSA after 
surgery.   
4. Evidence of disease recurrence or progression as evidenced by a PSA > 0.20 ng/ml.  This requires 
2 consecutive rises in PSA, at least 1 week apart, over the post-prostatectomy nadir or one PSA 
value above 0.20 ng/mL if the patient failed to achieve a post-prostatectomy nadir of < 0.2 
ng/mL.    
5. Age ≥ 18 years 
6. Karnofsky performance status ≥ 80% 
7. Adequate laboratory parameters 
• 
Adequate bone marrow function:  ANC ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hb >9g/dL 
• 
AST/SGOT and ALT/SGPT ≤ 2.5 x Institutional Upper Limit of Normal (ULN)  
• 
Serum bilirubin ≤ 1.5 x Institutional ULN (In subjects with Gilbert’s syndrome, if total 
bilirubin is > 1.5xULN, measure direct and indirect bilirubin and patient is eligible if direct 
bilirubin ≤ 1.5xULN). 
• 
Glomerular filtration rate (either estimated or calculated from 24-hour urine collection) 
≥ 45 mL/min 
• 
  Serum potassium ≥3.5 mmol/L 
8.   A minimum of 4 weeks from any major surgery prior to Cycle 1 Day 1.   
9.   Ability to swallow, retain, and absorb oral medication. 
10. Ability to understand and the willingness to sign a written informed consent document. 
11. Must use a condom if having sex with a pregnant woman. 
12. Male patient and his female partner who is of childbearing potential must use 2 acceptable 
methods of birth control (one of which must include a condom as a barrier method of 
contraception) starting at screening and continuing throughout the study period and for 3 
months after final study drug administration. 
 
2.4.2 Exclusion Criteria 
 
1.  Radiographic evidence of metastatic disease by standard CT and bone scan.  Patients with node-
positive disease (≤4 positive nodes) at the time of radical prostatectomy are eligible.  Patients 
with pelvic nodes less than 1.5 cm by short axis at the time of screening are eligible.  Patients 
with any enlarged lymph nodes in the retroperitoneum or above the aortic bifurcation or with 
pelvic nodes ≥ 1.5 cm must be excluded. 
2.  PSA ≥ 4.0 ng/mL. 
3. Testosterone level ≤ 100 ng/dL. 
4.   More than 1 month of prior hormone exposure or hormone exposure within 30 days of 
enrollment (up to 1 month of prior LHRH agonist and/or anti-androgen therapy as neoadjuvant 
therapy prior to prostatectomy is allowed).  Prior enzalutamide, apalutamide, darolutamide, 
ketoconazole, abiraterone, or TAK700 for prostate cancer are prohibited.  Prior first-generation 
antiandrogen therapy (including but not limited to bicalutamide, flutamide, nilutamide) and 
prior estrogen therapy (including estrogen patch) are not allowed within 30 days of enrollment. 
All investigational agents are prohibited within 30 days of enrollment. 
5. The following medications are prohibited within 2 weeks of enrollment and while on study 
drug:  

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• 5 α-reductase inhibitors (finasteride, dutasteride);  
• Biologic or other agents with anti-tumor activity against prostate cancer (excluding 
herbal supplements);  
 
• Androgens (testosterone, dehydroepiandrosterone [DHEA], etc.)  
6.  Prior immunotherapy for prostate cancer including sipuleucel-T. 
7.   Prior systemic chemotherapy (docetaxel, cabazitaxel, estramustine, other cytotoxic agents) 
8.  History of solid organ or stem cell transplantation. 
9.  History of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, prior 
head or traumatic brain injury with loss of consciousness, prior or current space-occupying 
lesion in the brain).  Also, history of loss of consciousness or transient ischemic attack within 6 
months of enrollment. 
10.   Known or suspected brain metastasis or active leptomeningeal disease. 
11. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or 
uncontrolled infection) that could cause unacceptable safety risks or compromise compliance 
with the protocol. 
12. Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial 
or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident 
including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 
months prior to enrollment 
13. Sustained uncontrolled hypertension (>150/90 average over 1 week) despite optimal medical 
management 
14.  Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of apalutamide or increase the risk of radiation (e.g., uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndromes, prior small bowel resection, or inflammatory bowel 
disease). 
15. Patients who have received prior prostate or pelvic radiotherapy, including external beam or 
brachytherapy. 
16. Patients who have not recovered from side effects of prior systemic therapy prior to Cycle 1 
Day 1. 
17. Use of medications known to lower the seizure threshold within 4 weeks prior to study entry. 
18. Patients unable or unwilling to abide by the study protocol or cooperate fully with the 
investigator. 
2.5 Subject Recruitment and Compensation 
 
This study will be open to members of all demographic groups who meet the eligibility criteria. A 
caregiver known to the patient will introduce the study and if the patient is interested, a member of 
the study team will approach him for enrollment. Patients will not be enrolled without prior approval 
of their physician (if not a member of the study team).   
2.6 Consent Process 
 
The prospective participant will have as much time as he may need to make an informed decision 
about the study and all treatment related questions will be answered.  Prospective participants will 
be consented in an exam room where it is just the research staff, the patient and his family, if so 
desired by the patient.  Before, during, and after the consent is signed, the research team and 

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investigators will be available in person and by phone to answer any questions the participants may 
have.  Any and all other available treatment options are offered to the patient in order to avoid 
undue influence.  Participants are not offered compensation for this study in order to avoid any 
monetary coercion/influence other than the provision of parking passes.  
 
2.7 Subject’s Capacity to Give Legally Effective Consent 
 
Subjects who do not have capacity to give legally effective consent will not be enrolled. 
2.8 Study Interventions 
 
After consent and enrollment, each subject will receive a GnRH agonist or antagonist depot injection 
(selection at the discretion of the care provider), and this treatment will be repeated at necessary 
intervals for a total of about 36 weeks of androgen deprivation therapy.  Subjects will receive 
education about how to take apalutamide, including avoidance of contraindicated concurrent 
medications, safe handling, and side effects.  Subjects will then receive apalutamide 240mg PO daily 
from the investigational pharmacy and will take apalutamide daily for approximately 36 weeks.  On 
week 9 (+/- 14 days), subjects will begin salvage radiation therapy to the prostate bed.  Radiation 
will be given per institutional standard of care, concurrent with ADT and daily apalutamide. About 4 
weeks (+/- 7 days, pending recovery of adverse events from radiation to Grade 2 or less) after 
completing radiation, patients will start docetaxel 75mg/m2 intravenously, every 3 weeks for 6 
cycles. Patients will continue their ADT and daily apalutamide during chemotherapy with docetaxel. 
Subjects will return to a clinic for a safety follow-up visit approximately 4 weeks after completion of 
all therapy.  Every 3 months from the SFU visit , subjects will return to clinic  for symptoms, 
laboratory, and prostate cancer monitoring, including PSA and testosterone. Study termination for 
each subject is 36 months (3 years) after Cycle 1 Day 1.  Cycle 1 Day 1 is defined as the first day of 
treatment (ADT and/or apalutamide) 
2.9 Risk/Benefit Assessment 
 
Potential risks of this study include the potential for apalutamide toxicity, including gastrointestinal 
disorders (abdominal pain, constipation, diarrhea, nausea/vomiting), fatigue, dizziness, taste 
changes, rashes, decreased appetite, hot flashes, insomnia, hypothyroidism, itching, fractures, 
increase in falls, increase in blood cholesterol or triglycerides, and very rarely seizure activity. During 
the chemotherapy portion of the study, patients may develop side effects of docetaxel 
chemotherapy, including peripheral neuropathy, alopecia, rashes, onycholysis, stomatitis, diarrhea, 
nausea/vomiting, myelosuppression, anemia, thrombocytopenia, and rare infusion reactions. There 
is potential that taking apalutamide during radiation therapy and during chemotherapy may make 
side effects of either one worse; however, there is also the potential benefit that the addition of 
apalutamide may improve cancer outcomes. Additional risks of study inclusion include potential loss 
of confidentiality, although all steps will be taken to protect the patient’s privacy and confidentiality. 
 
2.10 Costs to the Subject 
 
Patients and their insurers will be expected to pay costs of routine care, including routine clinic visits, 
radiation therapy and androgen-deprivation therapy with a GnRH agonist/antagonist.  Any visit or 

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procedure solely for research purposes, as well as the cost of both apalutamide and docetaxel, will 
be covered by research funds.  
2.11 Data Analysis and Statistical Considerations 
 
The primary objective of this single arm, open-label, one stage Phase II study is to estimate the 36 
month progression-free survival rate of men with recurrent, PSA-only disease after prostatectomy 
receiving combined apalutamide and standard androgen-deprivation therapy with salvage radiation 
therapy, followed by apalutamide and ADT with docetaxel.  The target sample size is 42.  It is 
primarily hypothesized that the 36-months (3-year) PFS rate will be improved with the combined 
therapy compared to the historical control data in a similar patient setting. Based on our prior 
experience conducting a trial of docetaxel and salvage RT in a similar group of men, and based on a 
model and nomogram by Stephenson et al for men with recurrent disease after radical 
prostatectomy [1], the PFS rate at 36-months among prostate cancer patients is 40-50%.  This trial 
is designed to have more than 85% power to reject the null hypothesis of 36-month PFS rate of 
40% when the true PFS rate at 36 months is 65%, with a two-sided alpha of 0.05. The sample size 
needed will be 38, and factoring in a 10% drop out rate, the final sample size is 42 patients.  A one 
sample one-sided binomial test will be used to test whether the 36-month PFS rate is larger than the 
hypothesized value from the historical controls.  
 
The Kaplan-Meier product-limit estimator will be used to estimate the distribution of PFS, 
biochemical progression free survival, time to PSA nadir, and time to testosterone recovery. The 
median survival times and 95% confidence intervals will be reported. The frequency and proportion 
(and 95% confidence interval) of men at 12, 24, and 36 months with a PSA of <0.1 ng/ml and 
testosterone recovery will be reported. In addition, descriptive statistics with 95% confidence 
intervals will be calculated for secondary endpoints of safety profile and quality-of-life (QOL) 
endpoints, the continuous safety and QOL endpoints will be summarized as the patient counts, 
mean, standard deviation, median, 25thand 75th percentiles, minimum and maximum.  The 
categorical safety and QOL endpoints will be categorized using frequencies and percentages.  
2.12 Data and Safety Monitoring 
 
This protocol is being conducted at additional sites external to Duke University. The Sponsor- 
Investigator is responsible for monitoring these sites to assure the safety and protection of all subjects 
and to assure that the study is conducted, recorded, and reported in accordance with the protocol and 
applicable regulations.  Data for safety and severe adverse events will be monitored on an ongoing 
basis through monthly investigator and staff meetings, including data from all centers involved.   
 
To assure that the investigator obligations are fulfilled and all applicable regulations and guidelines 
are being followed, the Sponsor-Investigator will designate the DCI Monitoring Team to assure that 
the external site facilities are acceptable, the protocol and investigational plan are being followed, the 
IRB/IEC has been notified of approved protocol changes as required, complete records are being 
maintained, appropriate and timely reports have been made to the Sponsor-Investigator and the 
IRB/IEC, study drug and study drug inventory are controlled and the Investigator is carrying out all 
agreed activities. Monitoring also includes review regulatory and eligibility, conduct, data quality and 
adverse event reporting for select cases. 

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2.13 Privacy, Data Storage, and Confidentiality 
 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data 
will be maintained.   
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during 
the course of the study.  All research-related interactions with the participant will be conducted by 
qualified research staff who are directly involved in the conduct of the research study. 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock 
and key accessible only by the research staff.  Electronic records of subject data will be maintained 
using a dedicated web-access secure database, which is housed in an encrypted and password-
protected server behind the Duke firewall. Access to electronic databases will be limited to delegated 
personnel.  The security and viability of the IT infrastructure will be managed by the DCI and/or Duke 
Medicine.   
Upon completion of the study, research records will be archived and handled per institutional policy.     
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals. 
 
3 STUDY SCHEMA 
 
 
 
 
 
4 BACKGROUND AND SIGNIFICANCE 
4.1 Study Disease: Prostate cancer 
 

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Worldwide, prostate cancer is the second most common cancer in men.  The current lifetime risk of 
prostate cancer for men in the United States is approximately 1 in 6 [17].  Hormonal therapies include 
surgical castration or medical therapy with gonadotropin-releasing hormone analogues, AR 
antagonists, testosterone synthesis inhibitors, ketoconazole and/or estrogenic compounds.  Tumors 
that progress despite castrate levels of testosterone in the blood are considered castration-resistant.  
Despite the early sensitivity of these tumors to hormonal strategies, castration-resistant progression 
generally represents a transition to the lethal variant of the illness.  The median survival of metastatic 
castration-resistant disease is approximately 1 to 2 years [18].  Results of clinical investigations and 
studies on the molecular profiles of these progressing prostate tumors show that the AR remains 
functional and that the tumors should respond to strategies directed at the AR signaling axis. 
Overexpression of the AR has been documented in upwards of 50% of CRPC specimens and is 
believed to contribute to tumor progression [19, 20]. 
 
Anti-androgens are most commonly used in combination with gonadotropin-releasing hormone 
analogues in earlier stage disease resulting in medical castration and the accompanying side effects 
of fatigue, erectile dysfunction, decreased libido, hot flashes, weight gain, osteoporosis, anemia and 
acceleration of the metabolic syndrome and potentially cardiovascular disease.  Enzalutamide and 
apalutamide are currently being studied in patients with earlier stage disease. 
The treatment of men with PSA recurrence following radical prostatectomy has generally been 
unsatisfying, given the high rates of persistent or recurrent disease despite salvage radiotherapy.  In 
most large series, the rate of distant or biochemical disease recurrence is approximately 60 to 70% 
following salvage radiotherapy, indicating that in these high risk individuals, only 30-40% of disease 
is purely localized and thus curable with salvage radiotherapy [1, 21].  Risk factors for PSA recurrence 
and progression despite salvage radiation therapy include increasing PSA, fast PSA kinetics, lower 
dose of radiation used, high Gleason sum, advanced tumor stage, and negative surgical margins [1, 
22]. Additional therapeutic options for these men are needed to improve systemic control and 
eliminate potential micrometastatic deposits.   
While radiotherapy alone in the adjuvant or salvage setting may reduce the risk of PSA and local 
recurrence in prostate cancer, it has an unclear benefit on the reduction of metastatic disease and 
improvement of overall survival [23, 24]].  However, recent retrospective series suggest that a 
survival benefit may be seen particularly in those men with rapid PSA doubling times or positive 
surgical margins, although benefits have been seen across nearly all subgroups [21, 25, 26].  Recent 
data suggests an important role for the androgen receptor in DNA repair during radiation therapy, 
and that blocking androgen receptor action may improve radiosensitivity [6]. 
4.2 
Study Agents – Apalutamide and Docetaxel 
 
4.2.1 APALUTAMIDE  
 
Apalutamide has been approved by the US Food and Drug Administration (FDA) for the treatment of 
non-metastatic castration resistant prostate cancer and metastatic castration sensitive prostate 
cancer but not for the treatment of recurrent PSA-only prostate cancer.  It is a competitive AR 
inhibitor developed to optimally antagonize AR transcriptional activity and prostate cancer cell 
proliferation, pharmacokinetics, and in vivo efficacy [9]. In contrast to bicalutamide, apalutamide 
lacks significant agonist activity in preclinical models of CRPC. Moreover, apalutamide does not 
induce AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human 
CRPC, apalutamide showed greater efficacy than enzalutamide (an AR antagonist which is FDA 

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approved for treatment of mCRPC). Maximal therapeutic response in this model was achieved at 30 
mg/kg/d of apalutamide, whereas the same response required 100 mg/kg/d of enzalutamide and 
higher steady-state plasma concentrations. Thus apalutamide exhibits characteristics that predict 
for a higher therapeutic index with a greater potential to reach maximally efficacious doses in man 
than current AR antagonists. There is therefore preclinical proof of principle for apalutamide as a 
promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer. 
 
In Phase I testing, apalutamide was dosed between 30 mg and 480 mg once daily, resulting in PSA 
declines at all dose levels and a median 50% decline from baseline PSA at 12 weeks of 47% [10].  The 
most frequently reported adverse event was grade 1/2 fatigue (47%). The recommended Phase II 
dose of apalutamide was found to be 240mg daily.  
 
A Phase II multicenter study evaluated the clinical efficacy of apalutamide at 240 mg daily in non-
metastatic (nm) CRPC patients. In 47 evaluable patients, 89% had ≥50% PSA decline at 12 weeks. 
Median time to PSA progression was 24.0 months (95% confidence interval [CI], 16.3 months - not 
reached [NR]); median metastasis-free survival was NR (95% CI, 33.4 months - NR). The most 
common AE was fatigue (any grade, n=31 [61%]) [12]. An ongoing Phase III study comparing 
apalutamide versus placebo in men with non-metastatic CRPC has showed that apalutamide 
prolonged metastasis-free survival and time to symptomatic progression [13] .  
 
Full details of the preclinical and clinical testing of apalutamide conducted thus far can be found in 
the apalutamide investigator’s brochure and package insert. 
 
4.2.2 DOCETAXEL 
 
Since 2004, docetaxel has been FDA-approved for treatment of mCRPC, based primarily on the TAX-
327 study [24]. More recently, docetaxel has been shown to have clinical benefit when used with 
ADT as first-line for newly-diagnosed metastatic CSPC in two separate Phase III studies. The 
CHAARTED study randomized patients to ADT alone versus ADT and docetaxel 75mg/m2 every 3 
weeks for 6 cycles. The combination of ADT and docetaxel increased median overall survival by 13 
months (57.6 vs. 44.0 months, HR 0.61, 95% CI 0.47-0.80, p<0.001) [14]. This survival benefit was 
further supported in the STAMPEDE study, which was a multi-arm study including patients with non-
metastatic but locally advanced disease, with ADT versus ADT and docetaxel as one of the 
comparisons. In men with M0 prostate cancer, the addition of docetaxel improved median OS by 10 
months (77 versus 67 months, HR 0.76, 95% CI 0.63-0.91, p = 0.003) [15]. There was an increased 
risk (12%) of febrile neutropenia in patients treated with both docetaxel and ADT.  
 
Separately, docetaxel was studied in combination with ADT and radiation therapy in the RTOG 0521 
trial for patients with high risk, non-metastatic castration sensitive prostate cancer (defined as 
Gleason 9 or 10 with PSA<150, Gleason 7 or 8 with PSA 20-150, or pT2, Gleason 8 and PSA <20). The 
4-year overall survival was 93% with docetaxel and 89% without docetaxel, HR 0.70, 90% CI: 0.51-
0.98, with one-sided p=0.04) [15]. Patients treated with ADT, radiation and docetaxel experienced 
more grade 3 and 4 hematological adverse events (expected anemia, thrombocytopenia, and 
neutropenia) than patients treated with ADT and radiation without chemotherapy (64% vs. 22%). 
Concerns surrounding the RTOG 0521 trial include the one-sided p-value and the deaths from 
protocol treatment or unknown cause was slightly higher in patients treated with docetaxel (6 out of 
43 deaths in docetaxel arm vs. 0 out of 59 in ADT/radiation arm) [16]. 
 

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4.2.3 
Androgen Deprivation Therapy 
 
An LHRH agonist concurrent with radiation is standard-of-care for men with intermediate-high risk 
prostate cancer [27], and is being widely adopted as a new standard of care for those with 
significantly elevated post-operative PSA. ADT will consist of treatment with a GnRH agonist or 
antagonist per physician and institutional preference. Either leuprolide acetate (Lupron Depot, 22.5 
mg or 45 mg IM), triptorelin pamoate (Trelstar, 11.25 mg or 22.5 mg IM), goserelin acetate (Zoladex, 
10.8mg SC) or degarelix (Firmagon 120 mg or 240 mg SC) will be administered monthly, every 3 
months, or every 6 months, depending on institutional standards, for 36 weeks total.  The addition 
of apalutamide is hypothesized to improve PFS beyond the use of ADT alone in patients receiving 
concurrent salvage external beam radiation therapy.  ADT will be administered for the duration of 
the treatment, spanning approximately 36 weeks. 
4.2.4 
Radiation Therapy 
 
Radiation is a proven adjuvant therapy for high risk prostate cancer [28, 29]. In the salvage setting, 
radiation has improved prostate-specific survival for men with short doubling times [21]. The 
radiation dose in this study is based on benefit seen with dose escalation while recognizing 
limitations of nearby critical organs. Dose constraints are provided in Section 7 to ensure protection 
of nearby normal tissues. 
4.3 
Purpose/Rationale 
 
For patients with rising PSA after prostatectomy without evidence of metastatic disease, salvage 
radiation therapy to the prostate bed is the standard of care, and the progression-free survival at 2 
years for men receiving salvage radiation therapy is around 65% [1].  Clinically, high-risk patients 
with biochemical recurrence after surgery are often managed with the combination of ADT and 
radiation therapy.  Only approximately 15% of men in the salvage radiation study mentioned above 
also received some treatment with ADT, although a recent retrospective study suggests that ADT 
concurrent with salvage radiation improves progression-free survival in high risk men [5].  There is 
also evidence that treatment with the anti-androgen bicalutamide during radiation therapy 
improves outcomes. At 12 years of follow up, OS was improved with bicalutamide (76.3% vs. 71.3%, 
HR 0.77, 95% CI 0.59-0.99, p=0.04) [3]. In addition, the prostate cancer specific incidence of death at 
12 years was improved with bicalutamide (5.8% vs. 13.4%, HR 0.49, 95% CI 0.32-0.74, p<0.001). The 
12-year incidence of metastatic prostate cancer was also improved with bicalutamide (14.5% vs. 
23%, HR 0.63, 95% CI 0.46-0.87, p=0.05). There were no increases in grade 3-4 toxicities [3].  The 
Phase III GETUG trial randomizing the use of 6 months LHRH agonist with standard PORT for early 
salvage provides evidence for the currently most common PORT-ADT regimen, finding a biochemical 
and clinical progression free benefit at 5 years (80 vs 62%, HR 0.5) [4]. There are 2 large prospective 
studies that will likely be reported in the next few years to help further address whether giving ADT 
with salvage radiation therapy is beneficial.  The RADICALS trial is designed to address the question 
of adjuvant versus delayed radiation therapy, and one arm of the RADICALS trial will look at RT alone 
and with 6 and 24 months of hormones in the salvage setting.  RTOG 0534 is a Phase III trial of ADT 
with prostate bed only versus pelvic lymph node radiation therapy in the salvage setting. While 
awaiting the results of these studies, the use and duration of ADT or other therapies concurrent with 

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salvage radiation therapy for biochemical recurrence is clinician-dependent. However, the available 
data indicates that a substantial number of patients are not cured with radiation therapy alone and 
that therefore additional options are necessary.   
 
The Phase II multicenter study, “Salvage therapeutic radiation with Enzalutamide and ADT in men 
with recurrent prostate cancer” (STREAM) was recently conducted at Duke and 2 other centers and 
enrolled 38 patients. The analysis from this trial is pending. Accrual was complete in January 2016 
and to date, no patients have progressed with about 12 month median follow up. Our early data 
suggest the safety of concurrent ADT/enzalutamide with salvage PORT based on the lack of additive 
or severe toxicities to date, and based on the high proportion of men with undetectable PSA values 
early in their treatment course, this regimen appears quite effective at suppressing AR activity and 
controlling disease. Apalutamide is a next-generation AR antagonist similar to enzalutamide and 
would likely have similar activity in this patient population. 
 
Docetaxel, as discussed above, has been shown to provide survival advantage when given early with 
ADT in metastatic castration sensitive prostate cancer. There is therefore a role for docetaxel in 
combination with first-line ADT, and there is evidence to support the early use of docetaxel in men 
with non-metastatic CSPC who are treated with primary radiotherapy and ADT. We propose to study 
the combination of ADT and apalutamide first with radiation therapy, followed by ADT and 
apalutamide with 6 cycles of docetaxel.  
 
This is a non-blinded single-arm Phase II study of approximately 42 subjects for feasibility of 
combined apalutamide and ADT with salvage radiation followed by apalutamide and ADT with 6 
cycles of docetaxel.  Standard external beam radiotherapy will be administered to the prostate bed 
according to local standard of care, usually a period of6-8 weeks. The endpoints are 36-month 
(3-year) progression free survival and the proportion of men  at  12,  24,  and  36  months  with  a  
PSA  of  <0.1  ng/mL  who  also  have testosterone recovery.  
 
5 OBJECTIVES AND ENDPOINTS 
 
5.1 
Objectives 
 
Primary objective:  To describe the rate of 36-month (3-year) progression free survival (composite 
definition, please see section 5.2) in men with recurrent PSA-only disease after prostatectomy, who 
receive combined apalutamide and standard ADT with salvage radiation therapy followed by 
docetaxel, ADT, and apalutamide, AND who have had testosterone recovery to >100 ng/dl at 36 
months. 
 
 
Secondary objectives:   
1. To determine the proportion of men at 12, 24, and 36 months with PSA <0.1ng/mL and 
testosterone recovery to >100 ng/dl 
2. To describe the biochemical (PSA) progression free survival over time. 
3. To describe the PSA nadir (10%, 50% and 90% PSA decline as maximum response) 
4. To describe the time to testosterone recovery 

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5. To describe the safety profile of combination apalutamide, ADT, and radiation therapy 
followed by apalutamide, ADT, and docetaxel 
6. To describe the percentage of patients completing all treatments including salvage radiation 
therapy and 6 cycles of docetaxel 
Exploratory objectives: 
1. 
To describe the quality of life of patients receiving the combination of apalutamide, ADT, 
and radiation therapy.  
2. 
Archived prostatectomy specimens will be collected and stored for eventual analysis of the 
correlation of outcomes with pre-treatment androgen receptor target genes, androgen 
receptor splice variants, and epithelial-mesenchymal transition (EMT) biomarkers.   
3. 
Plasma samples will be collected and stored for eventual analysis of circulating proteins 
and circulating tumor DNA. 
 
 
 
5.2 
Endpoints 
 
Primary endpoint:   The rate of progression free survival (PFS) at 36 months, with PFS defined as the 
proportion of subjects with testosterone >100 ng/dl at 36 months post-Cycle 1 Day 1 without one or 
more of the following:  
• 
Serum PSA value of 0.2 ng/mL or more above the post-radiotherapy PSA nadir and 
confirmed (at least) 4 weeks later by a second PSA measurement higher than the first by 
any amount 
• 
Continued rise in the PSA level following study treatment if no nadir is experienced, defined 
as 2 rising values greater than the baseline PSA and separated by at least 4 weeks 
• 
Evidence of clinical progression or initiation of systemic therapy for progressive disease 
• 
Death 
 
Secondary endpoints:   
1. To determine the proportion of men at 12, 24, and 36 months with a PSA of <0.1 ng/mL and 
testosterone recovery (defined as testosterone >100 ng/dl) 
2. To describe the biochemical (PSA) progression free survival over time. bPFS is similar to PFS 
but includes only PSA-based endpoints or death.   
3. To describe the median PSA nadir 
4. To describe the time to testosterone recovery 
5. To describe the safety, feasibility and tolerability profile of combination apalutamide, ADT, 
and radiation therapy followed by apalutamide, ADT, and docetaxel as assessed by NCI 
common toxicity scales 
6. To describe the percentage of patients completing all treatments including salvage radiation 
therapy and 6 cycles of docetaxel 
Exploratory endpoints: 
1. To determine the quality of life of patients receiving the combination of apalutamide, ADT, 
and radiation therapy using the Expanded Prostate Cancer Index Composite (EPIC) short form, 

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a validated scale of prostate-cancer specific quality of life.  Surveys will be performed at 
baseline, week 13, and at 12, 24 and 36 months post C1D1 follow-up.  
 
 
6 INVESTIGATIONAL PLAN 
6.1 
Study Design 
This is a non-blinded single-arm Phase II study of approximately 42 subjects to assess feasibility and 
efficacy of combined apalutamide and androgen-deprivation (ADT) for 36 weeks concurrent with 
salvage radiation therapy and then with docetaxel.  This study will be conducted at 4centers:  Duke 
Cancer Institute and three outside study centers. 
Eligible men will have recurrent PSA-only prostate cancer within 4 years of prostatectomy, and a PSA 
of >0.2 ng/mL to <4 ng/mL in the absence of metastatic disease on CT and bone scans. APPENDIX D 
provides a list of lymph node locations for determining eligibility of patients with node-positive 
disease. 
Apalutamide and/or ADT would start at week 1, continued during radiation therapy, continued 
during docetaxel therapy, and completed at the end of 18 weeks on docetaxel (approximately 36 
weeks total).  ADT will be administered as standard of care GnRH agonist or antagonist at the treating 
physician’s discretion. Apalutamide will be given at 240mg by mouth daily for the duration of 
treatment (approximately 36 weeks) and ADT will be administered per institutional standard. 
Standard external beam radiotherapy to 66-74 Gy will be administered to the prostate bed per 
institutional standard of care.  Inclusion of the pelvic nodes as part of the salvage radiation plan will 
be per the discretion of the treating radiation oncologist.  The treating physician will assess for risk 
of osteoporosis on a case-by-case basis. Subjects will be encouraged to take calcium and vitamin D, 
and an additional appropriate regimen (e.g. bisphosphonate, denosumab or others) will be 
prescribed at the discretion of the treating physician. Docetaxel therapy will begin at least 4 weeks 
post-radiotherapy. 
The endpoints are 36-month (3-year) progression free survival and the proportion of men at 12, 24, 
and 36 months with a PSA of <0.1 ng/mL who also have testosterone recovery.   
6.1.1 Definition of Dose-Limiting Toxicity (DLT) 
       Not applicable. 
6.1.2 Dose Modification 
Patients should be carefully monitored for toxicity related to treatment. Toxicity due to apalutamide 
administration may be managed by symptomatic treatment, dose interruptions and adjustment of 
the apalutamide dose.  All toxicity will be reported using CTCAE v4.03.  Dosage modifications are not 
recommended for grade 1 or 2 events.  Therapy with apalutamide should be interrupted upon the 
occurrence of a grade 3 adverse event related to study drug.  Once the adverse event has resolved 
or decreased in intensity to grade 1 or less, then apalutamide can be restarted at one dose level 
lower OR as adjusted according to the table below.  Once the dose has been reduced it should not 
be increased at a later time.  If a grade 4 toxicity related to apalutamide occurs, therapy should be 
discontinued. Patients may remain on study for radiation and docetaxel/ADT if they have an 

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apalutamide related grade 3 or 4 AE leading to discontinuation of apalutamide. Patients who 
discontinue treatment for adverse events will be followed for progression outcomes. 
 
Two dose reductions of apalutamide are allowed.  Doses below 120 mg daily are not permitted and 
require removal of the patient from the treatment phase of the study.  If apalutamide must be held 
for any reason, it must be restarted within 28 days or the subject should discontinue treatment with 
apalutamide but remain on study for study treatments (radiation, ADT, and docetaxel as planned).  
 
Dose reductions or cycle delays of docetaxel can be made at the treating physician’s discretion based 
on docetaxel-related AEs during period of treatment. Although the intention to treat is with 6 cycles 
of docetaxel, docetaxel can be stopped early in case of severe (>grade 3 related) toxicity, at the 
discretion of the treating physician. 
 
If one subject is unable to tolerate the combination of radiation therapy with apalutamide and 
requires a ≥5 day delay in radiation therapy due to toxicity, this would trigger a temporary hold in 
accrual, until a meeting of the data and safety monitoring committee at the lead site is held to 
review the AEs and to determine if the study may proceed and if changes to the protocol are 
required.   
 
 
 
Dose Level Reduction 
APALUTAMIDE Dose 
-2 
120 mg daily 
(2 tablets) 
-1 
180mg daily 
(3 tablets) 
0 
240 mg daily 
(4 tablets) 
 
Rash 
Dose modifications for rash are allowed only for apalutamide and are summarized in below table. 
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. 
 
 
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 

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• 
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 reductionc. 
Grade ≥3d 
• 
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 reductione 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 
sponsor-investigator 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 One dose level reduction = 60mg (1 apalutamide tablet) 
d If there is blistering or mucosal involvement, stop apalutamide dosing immediately and contact 
Janssen 
e 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 sponsor-investigator. 
 
6.1.2.1 Non-hematologic: 
Apalutamide is generally well-tolerated.   Because apalutamide and ADT block the effects of the male 
sex hormones, both drugs can cause infertility and impotence and may contribute to loss of muscle 
and bone and lead to hot flashes.  Fatigue is the most common side effect of apalutamide.  Other 
possible side effects include nausea with or without vomiting, constipation or diarrhea, joint or 
muscle pains, shortness of breath, dizziness, headache, flushing, leg swelling, and trouble sleeping.  
 
Docetaxel is a commonly used chemotherapeutic agent. Side effects of docetaxel include fatigue, 
alopecia, nausea, vomiting, diarrhea, nail changes, sensory neuropathy, stomatitis, changes in taste, 
peripheral edema, myalgia, and dyspnea.  
 
Radiation AEs: Acute radiation toxicity typically presents several weeks into treatment, and can 
persist for 1-2 months after completion of RT. Side effects include fatigue, increased urinary bother 
(frequency, dysuria, urgency), increased bowel irritation (frequency, tenesmus, diarrhea, cramping), 
hematuria and hematochezia. Late effects present 6 months or more after completion of treatment 
and include urinary bother (frequency, urgency, incomplete emptying/stricture, dysuria), hematuria, 

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pelvic pain, rectal pain or bleeding (“radiation proctitis”), urinary or bowel incontinence, erectile 
dysfunction, osteoradionecrosis, and secondary malignancies.   
 
Symptoms will be monitored regularly and abnormalities will be managed per CTCAE v4.03 grading 
as above.   
 
6.1.2.2 Hematologic: 
Low blood counts are rarely reported with apalutamide.  Counts will be monitored regularly and 
abnormalities will be managed per CTCAE v4.03 grading as above.   
 
Neutropenia, anemia, and thrombocytopenia are expected side effects with docetaxel therapy. 
Patients will have a CBC check on day 11 (+/- 4 days) for a nadir draw per standard of care during 
docetaxel therapy and this check may be performed locally.  If ANC < 500 at the time of a nadir draw, 
patients should be treated with granulocyte colony-stimulating factor (G-CSF) per local standard of 
care. Patients will be transfused at the discretion of the treating physician for anemia and 
thrombocytopenia at standard of care thresholds.  
 
Radiation hematologic AEs: Radiation can infrequently cause a pan-lineage decrease in blood counts, 
which are rarely symptomatic when occurring without concomitant therapies.  As long as total bone 
marrow is not irradiated, counts recover spontaneously. 
 
Blood counts will be monitored regularly and abnormalities will be managed per CTCAE v4.03 
grading. 
6.1.3 Safety Considerations 
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 (eg, chlorpromazine, mesoridazine, thioridazine) 
• 
Tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, imipramine, maprotiline, 
mirtazapine 
 
Any seizure activity while on this study will result in immediate discontinuation of apalutamide. 
Patients may remain on study to complete radiation and docetaxel, at the discretion of the treating 
physician. 
6.1.4 Missed Doses 
If 1 or 2 consecutive doses of apalutamide are missed, the patient will be instructed to take the dose 
as scheduled the following day. However, if more than two doses are missed, the patient should 
contact their study physician.  Missed doses should not be added to the end of treatment. 

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6.1.5 Concomitant Medications 
Concomitant medication will be evaluated at each study visit during apalutamide therapy.  
Concomitant medications include all vitamins, herbal remedies, over the counter, and prescription 
medications.  ADT in the form of GnRH agonists or antagonists for 36 weeks is permitted as part of 
the study as per standard of care practice. 
 
The following medications are prohibited within 2 weeks of enrollment and while on study drug, 
unless otherwise indicated below:  
• 5 α-reductase inhibitors (finasteride, dutasteride);  
• Biologic or other agents with anti-tumor activity against prostate cancer;  
• Systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone; 
 • Androgens (testosterone, dihydroepiandrosterone [DHEA], etc.);  
• All investigational agents are prohibited within 4 weeks of enrollment; 
 
         The following treatments do not require study discontinuation: 
• Blood transfusions and growth factor support per standard of care and institutional 
guidelines;  
• Steroids given at a maximum equivalent daily dose of 10 mg of prednisone;  
o Except premedication with systemic glucocorticoids greater than the equivalent 
of 10 mg per day of prednisone is permitted prior to docetaxel infusions. 
o Short term use of systemic corticosteroids are allowed for side effect 
management or non-treatment related, emergent comorbidities that arise 
during the course of treatment.  
• Pain therapy per standard of care and institutional guidelines;  
 
APPENDIX C provides a partial list of potent CYP enzyme inhibitors and inducers that have a 
theoretical concern for drug-drug interactions with apalutamide. Concomitant medications that are 
substrates of CYP3A4 should be used with caution, and relevant monitoring should be considered, 
especially for substrates known to cause seizure, because the possibility of drug-drug interactions 
cannot be fully excluded.  
6.1.5.1 Drugs that Inhibit or Induce CYP3A4 
 
Apalutamide is metabolized primarily by human CYP3A4, thus co-administration with strong 
inhibitors or inducers of CYP3A4 (changing plasma levels of apalutamide) 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 

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• 
Strong CYP3A4 inducers: phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, efavirenz, tipranivir, St. John's wort; co-administration with any of these agents 
may decrease apalutamide plasma concentrations 
6.1.5.2 
Effect of apalutamide with warfarin 
 
The potential for drug-drug interaction between apalutamide and warfarin (eg, Coumadin, 
metabolized by CYP2C9) is unknown at present. If a subject is taking warfarin, re-assess PT 
(prothrombin time)/international normalized ratio (INR) as clinically indicated and adjust the dose 
of warfarin accordingly. 
6.1.6 Study Drug Blinding 
          Not applicable, this is an open-label study.     
6.1.7 Randomization 
          Not applicable, this is a non-randomized study.   
6.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration 
 
The dosing used for the ADT is the standard-of-care dosing. Apalutamide 240mg daily has been 
studied for efficacy in a Phase II trial as well as in a Phase III trial of men with non-metastatic CRPC. 
Docetaxel 75mg/m2 for 6 cycles was studied in the CHAARTED, STAMPEDE, and RTOG 0521 trials. 
Clinically, high-risk patients with biochemical recurrence after surgery are often managed with the 
combination of ADT and radiation therapy, although the optimal duration and benefit of ADT in the 
salvage radiation setting remains unclear. The treatment duration of 36 weeks was chosen in hopes 
of providing maximal efficacy while minimizing toxicity. 
6.3 
Rationale for Correlative Studies 
 
Archived prostatectomy specimens and plasma samples will be collected and stored for eventual 
analysis of androgen receptor target genes, androgen receptor splice variants, and epithelial-
mesenchymal transition (EMT) biomarkers. If available, the pre-treatment genomic risk score (for 
example by the Decipher assay) will be used to correlate with outcomes.  The current protocol and 
funding allows only for archival prostatectomy specimens and plasma samples to be obtained and 
banked.  Please see laboratory manual for further details.    
 
6.4 
Definition of Evaluable Subjects, On Study, and End of Study 
 
Patients who consent but do not receive a dose of study drug will be replaced and will not be 
considered evaluable.   
 
All subjects enrolled onto the study who receive at least one dose of apalutamide will be included in 
the intention-to-treat analysis for the primary endpoint.   
 
The primary endpoint is the rate of PFS at 36 months, with PFS defined as the proportion of subjects 
with testosterone >100 at 36 months post Cycle 1 Day 1, without progression as defined above.  We 

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hypothesize that ~20% of patients will not have testosterone recovery at this point and therefore will 
not be evaluable for the primary endpoint.    
 
All subjects enrolled onto the study who receive at least one dose of apalutamide will be evaluable 
for the secondary and exploratory endpoints. 
 
6.5 
Early Study Termination 
 
This study can be terminated at any time for any reason by the PI-sponsor.  If this occurs, all subjects 
on study should be notified as soon as possible.  Additional procedures and/or follow up should occur 
in accordance with Section 10.8, which describes procedures and process for prematurely withdrawn 
patients. 
 
7 RADIATION THERAPY 
       Note: Intensity Modulated RT (IMRT) is allowed for this study.  
       Radiotherapy will start on week 9 +/- 14 days after Cycle 1 Day 1. 
        
Radiation therapy may be performed locally per standard-of-care, provided it conforms to protocol-
specified treatment and dosing specifications. Weekly visits during radiotherapy may be performed 
locally by the treating radiation oncologist according to standard of care practice.   Research visits 
during radiotherapy will occur at the treating institution at week 9 and week 13, according to the 
schedule of events. 
 
All study activities occurring after the completion of radiation therapy, (excluding apalutamide, ADT 
administration, EPIC questionnaires, and correlative sample collection) will have timing based on the 
end of radiation treatment. The first day of docetaxel treatment should occur at least 4 weeks, but 
no more than eight weeks, after the last radiation treatment.   
 
 
7.1 
  Dose Specifications 
Radiotherapy will start on week 9 (+/-14) days. Radiotherapy dose will be specified to the Planning 
Target Volume (PTV), as described in section 7.4. The total dose to the prostate bed must be 66-74 
Gy in 1.8-2 Gy daily fractions. A simultaneous integrated boost to any prostate bed residual mass is 
allowed as long as DVH constraints can still be met.  ≥ 95% of the PTV should receive the prescribed 
dose. Pelvic nodal coverage for pN1 patients is allowed at the discretion of the treating provider.  
7.2 
  Technical Factors  
Megavoltage equipment is required with effective photon energies ≥ 6 MV. 
7.3 
  Localization, Simulation, and Immobilization 
Simulation should be with a moderately full bladder (the patient should not be uncomfortable at 
simulation).  Moderate bowel prep is recommended to prevent an overly distended rectum, which 
can introduce a systematic positioning error that may increase the probability of missing the CTV.  
 
A treatment planning CT scan will be required to define the clinical and planning target volumes, 
and the critical normal structures. The treatment planning CT will be acquired with the patient set 

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up in the same position as for daily treatments. Each patient will be positioned in the supine 
position. The CT scan of the pelvis should start at or above the iliac crest down to below the 
perineum (below the ischial tuberosities). All tissues to be irradiated must be included in the CT 
scan. CT scan thickness should be ≤ 0.5 cm through the region that contains the target volumes (i.e., 
from the bottom of the sacroiliac joints down to the penile urethra). The regions above and below 
the target volume region may be scanned with slice thickness ≤ 1.0 cm.  A urethrogram or MRI is 
recommended, but not required, to establish the most inferior portion of the prostate bed. Use of 
contrast, other than for the urethrogram, is discouraged. 
 
Immobilization may be performed per institutional preference and image guidance is highly 
recommended. 
 
7.4 
  Treatment Planning/Target Volumes 
The definition of volumes (CTV, PTV) will be in accordance with ICRU Report #50: Prescribing, 
Recording, and Reporting Photon Beam Therapy. 
 
7.4.1 CTV (Prostate Bed) 
 
Contrast may be used for simulation but can distort the anatomy slightly and so is not 
recommended. The bladder should be reasonably full for simulation, keeping in mind that patients 
may not be able to maintain as full a bladder during radiotherapy.  The seminal vesicles or remnants 
thereof, if identified on CT or MRI as being present, must be included in entirety within the CTV. The 
immediate periprostatic bed surgical clips must also be included within the CTV. Superior nodal clips 
do not need to be targeted. The CTV will include the urogenital diaphragm inferiorly, or 1.5 cm below 
the urethrogram peak if done, and extend superiorly to include the inferior bladder neck (typically 
just at the superior pubic symphysis) and to SV remnants. Laterally, the CTV will extend from the 
medial edge of one obturator internus muscle to the other. Anteriorly the CTV will include the entire 
bladder neck until the superior pubic symphysis, where a gradual reduction off of the anterior 
bladder is made. Posteriorly, the CTV is defined by the anterior rectal border. The CTV may be 
increased (but not decreased) beyond these limits based on pre-prostatectomy imaging 
information.  
 
The pelvic lymph nodes are not to be included in the CTV except in the setting of node positive 
disease, where it may be done by physician preference.  If included, the pelvic nodal CTV should 
include external iliac nodes to the level of the superior femoral heads, internal iliac nodes to the 
superior contours of the prostate/seminal vesicle CTV, and the common iliac nodes to the L5-S1 
junction. Inclusion of presacral nodes is recommended but may be omitted at physician discretion 
to improve organ-sparing. If nodal irradiation is performed, a cone-down to the prostate bed must 
occur no later than 50.4 Gy. Alternatively, simultaneous integrated boost is allowed with maximum 
pelvic dose of 52 Gy.  
 
7.4.2 PTV 
 

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The PTV margins should be a 0.5-1.5 cm in all dimensions. 95% of the PTV must receive the 
prescribed dose. Care should be taken to conform the prescribed dose as closely to the PTV as 
possible, so as to avoid including the entire width of the rectum in the posterior blocked margin at 
the bladder neck-rectum interface. The maximum dose heterogeneity allowable in the PTV will be 
10%; a variation will be > 10% and a violation > 15%. 
7.4.3 Normal Tissues 
 
The critical normal structures are the bladder, rectum, and femoral heads. The normal tissues will 
be contoured and considered as solid organs.  The bladder should be contoured from its base to the 
dome, excluding the CTV (the CTV includes the bladder neck).  The rectum should be contoured from 
the anus (at the level of the ischial tuberosities) to the rectosigmoid flexure (this is roughly at about 
10 cm) or for a maximum length of 15 cm if the sigmoid flexure if felt to be higher.  Each femoral 
head should be outlined down to the interface between the greater and lesser trochanters.  The 
penile bulb may be outlined as a reference structure. No constraints will be placed on the penile 
bulb.  
 
The planning parameters outlined below should be used as a guide.  Both 3D-CRT and IMRT are 
acceptable planning and delivery methods.  If 3D-CRT planning is unable to achieve normal dose 
constraints described below, IMRT is recommended.  
 
7.4.4 Prostate Bed Planning for IMRT 
 
       The plan will be deemed acceptable under the following conditions. 
  
PTV:  The dose marker levels for bladder and rectum have been modeled after prior studies in men 
treated definitively with IMRT for prostate cancer. At least 95% of the PTV should receive the 
prescribed dose; a variation will be noted if < 95% to 90% of the PTV receives the prescribed dose, 
and a protocol violation will be noted if < 90% of the PTV receives the prescribed dose. The maximum 
dose heterogeneity allowable in the PTV will be 10%; a variation will be > 10% and a violation > 15%. 
Since the dose is prescribed to the minimum isodose line of the PTV, the dose variability is seen in 
portions of the target volume receiving higher than the specified dose. 
 
Rectum: Less than or equal to 35% and 55% of the rectum should receive ≥ 65 Gy and ≥ 40 Gy, 
respectively. Less than 10 cc should receive 70 Gy. A variation will be noted if up to an additional 
7.5% of the rectal volume receives above the target doses specified. The inclusion of rectal volumes 
beyond these constraints will be considered a protocol violation. 
 
Bladder: Less than or equal to 50% and 70% of the bladder (minus prostate bed CTV) should receive 
≥ 65 Gy and ≥ 40 Gy, respectively. Less than 10 cc should receive 70 Gy. The criteria for the bladder 
have been relaxed because the dosimetric relationship of volume exposed to the specified marker 
doses is much less clear and the bladder neck is included in the CTV. A primary variation will be noted 
if up to an additional 7.5% of the bladder volume receives above the target doses specified. The 
inclusion of bladder volumes beyond these constraints will be considered a secondary protocol 
variation; it will not be considered a protocol violation. 
 

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Femoral Heads: Less than or equal to 10% of each femoral head should receive ≥ 50 Gy. A variation 
will be noted if up to an additional 5.0% of either femoral head receives > 50 Gy. 
 
Penile Bulb: The penile bulb may be outlined as a reference structure. No constraints will be placed 
on the penile bulb. 
 
Sigmoid colon (in setting of nodal irradiation): The sigmoid colon should be contoured from the recto-
sigmoid junction until it transitions to descending colon (or L4 level, whichever is inferior). No more 
than 10 cc of the sigmoid colon should receive more than 60 Gy, with less than 5% receiving > 54 Gy. 
 
Bowel (in setting of nodal irradiation): The entire intraperitoneal cavity from the recto-sigmoid 
junction to 1.5 cm above the PTV volume should be contoured.  No more than 1% of the small bowel 
volume outside of the PTV should receive more than 50.4 Gy.  
 
7.5 
  Treatment Localization 
Patients must have portal imaging performed at a minimum of once weekly for 3D-CRT and daily for 
IMRT.  Image guidance is not required but recommended and can take the form of KV matching to 
surgical clips or pelvic bones, or cone beam CT to the prostate bed. Other forms of treatment 
localization are accepted with approval by the lead site (Duke) Radiation Oncology.  Treatment with 
a full bladder is required.  
 
7.6 
  Documentation Requirements 
 
The institution will archive treatment prescription and verification images for later review if 
requested.  For conformal RT, at least one port film or pretreatment alignment film per field along 
with the digital reconstructed radiographs (DRRs) from the treatment planning program or, 
alternatively, a simulation verification radiograph shall be acquired and kept for evaluation if 
requested except where geometrically impractical.  For IMRT, at least pretreatment alignment 
orthogonal set along with the digital reconstructed radiographs (DRRs) from the treatment planning 
program shall be acquired and kept for evaluation.  
Note: Images are required to be taken but not submitted. 
 
Dosimetric details will be submitted after planning approval via [the AbiRT or Stream data intake 
sheet with DVH criteria].  
 
7.7 
   Radiation Adverse Events 
 
All patients will be seen weekly by their radiation oncologist during radiation therapy.  Any 
observations with respect to the following symptoms/side effects will be recorded using CTCAE 
v4.03 grading including but not limited to: 
   - Bowel/rectal irritation manifesting as cramping, diarrhea, urgency, proctitis, or hematochezia
 
- Urinary frequency, urgency, dysuria, hematuria, urinary tract infection, or incontinence 
- Radiation dermatitis 
 

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Clinical discretion may be exercised to treat side effects from radiation therapy. Examples of typical 
medications used in the management of rectal side effects, such as diarrhea, include diphenoxylate 
or loperamide. Bladder or rectal spasms are usually treated with anticholinergic agents or 
tolterodine.  Bladder irritation may be managed with phenazopyridine.  Erectile dysfunction can be 
treated with medical management or mechanical devices. 
 
See Section 11 for Adverse Events and Adverse Event Reporting Guidelines. 
 
8 STUDY DRUG 
8.1 
Names, Classification, and Mechanism of Action 
 
Apalutamide   
Apalutamide is being developed for the treatment of prostate cancer at a dose of 240 mg per day. 
Apalutamide is currently approved by the FDA for non-metastatic castration resistant prostate 
cancer and metastatic castration sensitive prostate cancer . 
Tablets: The apalutamide drug substance is an almost white to slightly brown powder that is 
formulated in tablets at a strength of 60 mg. 
 
Apalutamide is administered orally on a continuous once daily dosing schedule. Each cycle of drug 
administration consists of 28 days. Doses from 30 to 480 mg were tested in the Phase 1 portion of 
the first clinical study [9]. The therapeutic dose is 240 mg once daily. Apalutamide can be taken with 
or without food.  
 
Docetaxel 
Docetaxel is an antineoplastic agent belonging to the taxane family that acts by disrupting the 
microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel 
is FDA-approved for the treatment of metastatic castration resistant prostate cancer. For our current 
study, docetaxel is investigational in the high risk biochemical relapse setting. Docetaxel is 
administered intravenously every 3 weeks, at a dose of 75mg/m2. To prevent fluid retention and 
hypersensitivity, patients should be pre-medicated with oral corticosteroids such as oral 
dexamethasone 8 mg twice the day before and 12 mg 1 hour prior to docetaxel infusion or per 
institutional guidelines.   
 
 
Pharmacology  
The mechanism of action of apalutamide is through antagonism of the androgen receptor 
andinhibition of AR nuclear translocation and DNA binding to AREs. Unlike bicalutamide, 
apalutamide shows no significant agonist properties in a model of CRPC (e.g., AR-over-expressing 
prostate cancer cells; LNCaP/AR cells). Gene transcription of 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 observed in murine tumor 
CRPC models, where apalutamide showed dose-dependent tumor growth inhibition and tumor 
regression over a dose range of 0.1 to 10 mg/kg/day, with effects that were superior to 
bicalutamide. 
 

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Docetaxel binds free tubulin, promoting the assembly of tubulin into stable microtubules and 
inhibiting the disassembly of microtubules, thus inhibiting cell proliferation. Docetaxel’s maximum 
stoichiometry is one mole docetaxel per mole tubulin in microtubules.  
 
8.2 
Packaging and Labeling 
 
How Supplied: 
Apalutamide  
Apalutamide tablets (60 mg) are packaged in 120-count bottles, and should at all times be kept in 
the original packaging. 
 
Docetaxel 
Docetaxel concentrate solution will be obtained from a commercial supplier, but will likely be Teva 
Pharmaceuticals, Pfizer/Hospira, or Sagent Pharmaceuticals. Specifications for Docetaxel will be 
provided in the pharmacy manual. 
 
Detailed information on handling and storage conditions will accompany the clinical drug supplies 
to the clinical study site(s). The storage conditions and expiry will be indicated on the label of the 
drug product. 
 
8.3 
Supply, Receipt, and Storage 
 
Treatment will be administered on an outpatient basis.  Apalutamide will be given to the patient 
from clinic and patients will receive 240 mg/day (four 60 mg tablets) in an unblinded fashion.  
Apalutamide will be supplied by Janssen.  The product is provided as a tablet with a non-functional 
green film coat, in high density polyethylene (HDPE) bottles with child-resistant caps.   Apalutamide 
can be taken with or without food. 
 
Commercially available docetaxel (Taxotere®) will be used. Docetaxel will be given intravenously 
at a dose of 75mg/m2 in an infusion treatment room every 3 weeks, and patients will be supervised 
during treatment. Docetaxel will be prepared as described in the product package insert. Docetaxel 
will be supplied through this study given its investigational nature. Prior to receiving any dose of 
docetaxel, patients must have an absolute neutrophil count of >1500 cells/mm3 and a platelet count 
of >100,000 cells/mm3. In addition, the body surface area (BSA) should be capped at 2.2 m2 using 
the patient’s actual weight. 
 
Pre-medication with oral corticosteroids 
Docetaxel treatment has been associated with severe fluid retention and hypersensitivity 
reactions in a minority of patients. For this reason, all patients should be pre-medicated with 
oral corticosteroids such as oral dexamethasone 8 mg twice the day before and 12 mg 1 hour 
prior to docetaxel infusion or per institutional guidelines.  In the event that dexamethasone 
is not taken according to the above schedule, it can be given as an infusion prior to docetaxel 
infusion, but should be documented as a deviation to the protocol. 
 
 
Storage and Handling:  

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Apalutamide will be stored in a secure location with limited access within the following 
temperature range: 59°F to 86°F (15°C to 30°C). Bottles will be labeled with the study protocol 
number, medication or kit number, contents, directions for use, storage directions, clinical trial 
statement, and sponsor.  Patients will be instructed to store study drug at room temperature out 
of the reach of children. 
 
Docetaxel should be protected from light and stored between 36oF to 77oF. Docetaxel should be 
diluted and prepared per each institutional standards. 
8.4 
Dispensing and Preparation 
 
After receipt of prescription by the site Investigational Pharmacy Services, a secondary label will be 
applied with patient’s name, date, prescription, expiration, contact information, and indication.  
Apalutamide 240 mg daily will be dispensed by the site investigational pharmacy services on an as 
need basis to maintain adequate supply between study visits.  Apalutamide will be given for 
approximately 36 weeks x7 days = 252 days total.  Docetaxel will be prepared as described in the 
product package insert. 
8.5 
Compliance and Accountability 
Drug accounting on receipt, shipment, and dispensing will be carried out per site Investigational 
Pharmacy Services SOP. Patient compliance with prescription will be monitored by a study drug diary 
which will be reviewed with the research nurse staff monthly. 
8.6 
Disposal and Destruction 
 
Any apalutamide tablets returned unused by patients will be documented by the site Investigational 
Pharmacy Services and then incinerated according to SOP. 
 
 

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9  SUBJECT ELIGIBILITY 
Eligibility Criteria can be found in protocol section 2.4. 
 
 
 

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10 SCHEDULE OF EVENTS 
Timing anchored on 
Apalutamide start 
(Week #) 
  
Timing anchored on end of radiation treatment          
(Weeks After Radiation = WAR) 
  
Screeninga Within 60 
days 
Week 1 
Week 5 
Week 9c 
Week 13 
Week 17 
 
4 WAR,n 
5 WAR 
7 WARn 
8 WAR 
10, 13,16, 19 WARn 
11, 14, 17,20 WARn 
22 WAR End of 
treatmentd, 
Safety follow up 
(approx.  4 weeks after 
EOT)m,n  
Follow up  every 3 
months after SFUe,o,p 
window (+/-) 
n/a 
+/- 7 
days 
+/- 2 
weeks 
+/- 7 
days 
After this bar event timing is anchored to end of radiation not start of Apalutamide 
+/- 4 weeks 
+/- 7 days 
see 
footnotes,e,o 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history & AE 
assessmentl, b 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
X 
  
Prior & concomitant 
medicationsm, b 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
X 
  
Physical examinationb 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
X 
  
Karnofsky performance 
statusb 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
X 
  
Vital signs, height & 
weightb 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
X 
  
CT chest, abd, pelvisf 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone scanf 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC with differentialg,m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm,o 
Serum chemistriesg,m 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
X 
X m,o 
Serum PSAg 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
X 
Xo 
Testosterone g 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
 X  
X 
Xo 
TSHg 
X 
  
X 
X 
X 
X 
  
  
X 
  
  
  
X 
  
  
Apalutamide dispensingh 
  
X 
X 
X 
X 
X 
Xn 
  
Xn 
  
Xn 
  
  
  
  
ADT administrationi 
  
X 
  
  
X 
  
  
  
  
  
Xn 
  
  
  
  
Radiation therapy and 
weekly treatment checksc 
  
  
  
X 
X 
  
  
  
  
  
  
  
  
  
  
Docetaxel 
  
  
  
  
  
  
X 
  
X 
  
X 
  
  
  
  
EPIC quality of life 
questionnairek 
X 
  
  
  
X 
  
  
  
  
  
  
  
  
  
Xp 
Archival tumor blocksj 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Correlative sample- 
Plasmag 
Xg 
  
  
  
  
  
  
  
  
  
  
  
  
  
Xp 
 
 

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Footnotes to Study Flow Chart: 
a. Screening/baseline evaluations must be completed within 60 days prior to the first dose of study 
agent.   
b. Visits will occur every 4 weeks (+/- 7 days, except week 9 which is +/- 14 days), through week 17. 
Starting at 4 weeks after radiation (4 WAR), the visits will occur every 3 weeks  while receiving 
docetaxel. If possible, VAS pain and fatigue score will be collected with the physical exam. Blood 
pressure CTCAE grading will be done based on the blood pressure reading, not the number of blood 
pressure medications the subject is taking.   
c. Radiation therapy will begin on week 9 (+/- 14 days). Radiation therapy may be performed locally as 
standard-of-care, provided it conforms to protocol-specified treatment and dosing specifications.  
Receipt of protocol-specified salvage radiation will be documented including dose, field, and timing.  
Weekly visits during radiotherapy may be performed locally by the treating radiation oncologist 
according to standard of care practice.   Research visits during radiotherapy will occur at week 9 and 
week 13, according to the schedule of events.      
d. End-of-treatment visit will occur at 22 Weeks after radiation (22 WAR) (+/- 7 days), at which point 
all therapeutic intervention will be complete. 
e. Long-term follow-up visits will occur every 3 months from the safety follow-up visit and will have a 
+/- 28 day allowance window.  Follow up will continue until 36 months post-Cycle 1 Day 1 or until 
early withdrawal. If the full 36 weeks (9 months) of treatment is completed then the subject will 
continue to be followed for up to 27 months from end of treatment.  
f. CT scan of chest, abdomen, and pelvis (without IV contrast is permitted, but CT of abdomen and 
pelvis with contrast is preferred for patients with sufficient renal clearance as determined by the 
treating physician) and whole body Tc-99 bone scan will be performed within 60 days of initial study 
drug administration, as per standard-of-care to evaluate for metastatic disease. Chest CT may be 
omitted per current NCCN guidelines. PET CT and MRI modalities are acceptable if used instead of 
CT or bone scan but must cover skull base to mid-thigh. Subsequent imaging studies will be 
performed at the discretion of the treating physician.   
g. Standard-of-care laboratory assessments at the times indicated include:   
• 
Complete blood count (CBC) with differential:   WBC count with differential, platelet count, 
hemoglobin, and hematocrit.   During docetaxel therapy, a CBC w/diff will be drawn on 
day 11 from the docetaxel infusion (+/- 4 days) and may be performed locally.  
• 
Serum chemistries:   Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, calcium, total protein, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), albumin, total bilirubin, and 
alkaline phosphatase.   
• 
Testosterone and PSA levels 
• 
TSH: TSH will be measured per discretion of treating oncologist at screening and at the 
following visits: weeks 5, 9, 13, 17, 7 weeks after radiation (7 WAR), and 22 weeks after 
radiation (WAR 22)/End of treatment. If TSH is abnormal, obtain a T3/T4. 
• 
Correlative plasma sample: Drawn once at baseline (draw will be performed during 
screening; if draw cannot be performed at screening it may also be drawn on Day 1 prior 
to dosing) and also for follow up at 24 & 36 months post Cycle 1 Day 1. 
NOTE: Week 1 lab tests do not need to be repeated if the baseline labs were obtained within 7 
days of initial study drug administration.    
h. Apalutamide will be dispensed on an as need basis to maintain adequate supply between study visits.  
and should be taken daily for a total of 36 weeks.   Cycle 1 Day 1 is defined as the first day of 
treatment (apalutamide and/or ADT). Apalutamide treatment will stop at 36 weeks regardless of 
scheduling of other treatments. 

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i. 
ADT (3-month dose) will be given in clinic on day 1 and during clinic visits on week 13 and 10 weeks 
after radiation (10 WAR) for a total of 36 weeks of therapy.  Alternative SOC schedules including (but 
not limited to) 6-month dose are permitted provided total treatment duration of ADT is unchanged 
at 36 weeks. 
j. 
Archival specimen: Previously archived formalin-fixed or frozen primary prostate tumor blocks or 
cores will be collected on this study through the Duke Cancer Institute or participating site 
biorepository and linked to subject outcomes if available. Slides are also acceptable in lieu of blocks. 
This is an optional component of the study as detailed in the ICF.  At least 250 mg of tumor tissue is 
needed for the genomic correlative component of this study.  Frozen primary tumor samples will be 
collected if available.   See section 10.9.3 for details. 
k. Quality-of-life questionnaire (EPIC Short Form) will be administered at screening, at week 13, then 
during the 12, 24, and 36-month post C1D1 follow-up visits (5 per subject). 
l. 
All AEs are collected for the duration of study treatments as well as for 30 days following the last 
administration of any study treatment including chemotherapy, radiation or apalutamide. During 
follow-up, AEs definitely, probably or possibly attributed to study drug occurring during treatment 
are tracked until resolution to grade 1 or baseline, but new AEs not related to the study drug are not 
collected.  
m. During follow-up, treatments for prostate cancer will be collected (eg. ADT). PSA and testosterone 
should be measured every 3 months.  CMP and CBC to be drawn only if there are abnormalities due 
to chemo and these can be followed until resolution to grade 1. SOC laboratory assessments may be 
performed locally during long term follow-up. 
 
n. ADT and apalutamide treatment should occur as scheduled for 36 weeks no matter the length of 
radiation treatment. 
o. In follow up, EPIC questionnaires and correlative plasma draws have a window of +/- 3 months 
 
 
10.1 
Screening Examination 
 
The screening examination will take place within 60 days of initiation of therapy.  An informed 
consent form must be signed by the subject before any study-specific screening procedure takes 
place.  
 
Subject data to be collected at the Screening Examination includes:   
 
• 
Informed consent process utilizing a signed and dated IRB-approved ICF  
• 
Confirmation of inclusion/exclusion criteria 
• 
Medical history including concomitant illnesses and oncologic history.  Oncologic history must 
include specific documentation of prostate cancer histologic diagnosis. 
• 
Prior and concomitant medications and non-pharmacologic treatments taken within 4 weeks of 
screening will be recorded.  In addition, all prior treatments including surgery and radiotherapy 
for prostate cancer will be recorded, regardless of when administered. 
• 
CT of the chest, abdomen, and pelvis or PET scan for tumor assessment, standard-of-care 
• 
Whole body bone scan (99-Technetium), standard-of-care 
• 
Sample collection for the following laboratory evaluations (all standard-of-care): 
o Complete blood count (CBC) with differential:   WBC count with differential, platelet 
count, hemoglobin, and hematocrit. 

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o Serum chemistries:   Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, calcium, total protein, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total 
bilirubin, alkaline phosphatase, and thyroid stimulating hormone (TSH). 
o Testosterone and PSA levels.   
• 
Correlative plasma samples will be drawn at screening or prior to day 1 dosing 
• 
Physical examination to be conducted and height (cm), weight (kg), and vital signs (including 
temperature [°C], blood pressure [mmHg], heart rate [beats per minute],  respiratory rate 
[breaths per minute]. Height will be collected at screening only. 
• 
Karnofsky performance status 
• 
Quality-of-life questionnaire (EPIC Short Form) will be administered at screening. 
 
 
Upon study registration, tumor pathology will be collected as below: 
Previously archived formalin-fixed or frozen primary prostate tumor blocks or cores will be 
collected on this study through the Duke Prostate Center or participating site biorepository and 
linked to subject outcomes if available.  Slides are also acceptable in lieu of blocks. This is an 
optional component of the study as detailed in the ICF.  At least one frozen biopsy (250 mg) of 
tumor tissue is needed.  Frozen primary tumor samples will be collected if available.   See section 
10.9.3 for details.  
 
10.2 
Subject Registration and Enrollment 
 
10.2.1 Informed Consent 
 
Authorized study personnel should fully explain the scope of the study to each subject before 
obtaining informed consent.  Subjects should be advised of any known risks inherent in the planned 
procedures, of any alternative treatment options, of their right to withdraw from the study at any 
time for any reason, and of their right to privacy.  
 
When obtaining informed consent, study personnel should: 
First: Confirm that the subject is a potential candidate for study participation. 
Next: Obtain dated and signed informed consent. 
Finally: Confirm that the subject is eligible as defined in Section 2.4 (Inclusion/Exclusion Criteria).  
A record of subjects who fail to meet entry criteria (i.e., screening failures) will be maintained. 
 
Subjects will be entered into the Duke clinical trial subject registry per institutional policy.  
 
 
10.2.2 Registration 
Subject registration at each study site/institution will be conducted according to the institution’s 
established policies and all sites will be overseen by the Duke University Medical Center 
Genitourinary Oncology Group. Prior to registration, subjects will be asked to sign and date an 
Institutional Review Board (IRB)-approved consent form.  After obtaining informed consent, the 
consent document and any registration documents will be submitted for review and registration of 

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the subject by the lead site (Duke). All consented subjects will be registered and assigned a unique 
study ID. A record of subjects who fail to meet entry criteria (i.e., screen failures) will be maintained.   
 
Refer to Subject Registration Instructions in the Coordinator Manual for details.   
 
 
10.2.3 Enrollment 
Subjects will be enrolled only after all pre-treatment screening evaluations are completed and all 
eligibility criteria are met. Once the subject has been registered and found to meet all eligibility 
criteria, the subject will be approved for enrollment.  Study treatment must not commence until the 
subject has received his/her identification number and enrollment approval from the lead site. The 
date of enrollment is the date the subject takes the first dose of study drug. 
 
10.3 
Run-In Period 
 
       Not applicable.   
10.4 
Treatment Period 
 
Treatment will be administered on an outpatient basis. Apalutamide and/or ADT treatment will start 
on week 1 and continue throughout the study. Cycle 1 Day 1 is defined as the first day of treatment 
with apalutamide and/or ADT. On week 9 (+/-14 days), salvage radiation therapy will be started 
according to local standard of care, which is usually 6-8 weeks. There will be a radiation washout of 
at least 4 weeks, prior to starting docetaxel. Docetaxel will then be given for 6 cycles, per the 
schedule of events. Prednisone will not be given with docetaxel, per treatment in the CHAARTED 
protocol. Treatment period will last approximately 36 weeks. 
 
10.5 
Chemotherapy administration will begin at the 4 WAR visit, at least 
4 weeks, but no more than 8 weeks after the completion of radiation 
treatment. Scheduling of all post-radiation events will be based on 
the end of radiation treatment, with the exceptions of ADT 
administration, apalutamide discontinuation, EPIC questionnaires, 
and correlative plasma samples, which are based on the start of 
apalutamide treatment. End of Treatment 
 
At approximately WAR 22, in the event of disease progression, unacceptable toxicity, or withdrawal 
of consent, study treatment is to be stopped and an end-of-treatment visit is to be conducted within 
7 days.   
The following procedures are to be conducted at the end-of-treatment visit: 
• 
Concomitant medications and non-pharmacologic treatments to be reviewed and 
recorded. 
• 
Sample collection for the following laboratory evaluations (all standard-of-care): 
o CBC:  WBC with differential, platelet count, hemoglobin, and hematocrit. 

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o Chemistries:  sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, calcium, total protein, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total 
bilirubin, alkaline phosphatase, and TSH.   
o PSA and testosterone. 
• 
Physical examination to be conducted, including weight (kg) and vital signs (including 
temperature [°C], blood pressure [mmHg], heart rate [beats per minute], respiratory rate 
[breaths per minute] and if possible, VAS pain and fatigue score [scale of 1-10, subject reported]). 
• 
Karnofsky performance status 
• 
Adverse Events 
10.6 
Follow-up Period 
 
The safety follow-up visit will occur approximately 4 weeks after last administration of study 
treatment including chemotherapy, radiation, or apalutamide.  
All AEs are collected for the 
duration of study treatments as well as for 30 days following the last administration of any study 
treatment including chemotherapy, radiation or apalutamide. During follow-up, AEs definitely, 
probably or possibly attributed to study drug occurring during treatment are tracked until 
resolution to grade 1 or baseline, but new AEs not related to the study drug are not collected. 
 
Regular follow up visits will occur every 3 months from safety follow-up and continue for 36 months 
from Cycle 1 Day 1.  Follow-up visits will be scheduled every three months from the safety follow-
up visit (with a 28-day window period allowance). Correlatative plasma samples and EPIC Quality of 
life questionnaires will be collected per the Schedule of Events with a +/-3 month collection 
window.Imaging studies will be performed as per standard-of-care for those men with evidence of 
PSA recurrence or symptomatic disease or based on concerns of disease recurrence in the absence 
of PSA progression.   
 
Every three months laboratory assessments will be performed for PSA and testosterone outcomes. 
Other laboratory studies will be performed at the discretion of the treating physician.  CMP and CBC 
to be drawn only if there are abnormalities due to chemo (Docetaxel only) and these can be 
followed until resolution to grade 1. If a subject is unable to travel to the research site during long 
term follow-up, the standard of care laboratory assessments may be performed locally. Correlative 
plasma samples will be drawn at 24 & 36 months post Cycle 1 Day 1. 
 
Regular follow up visits will include medical history and review of any treatments for prostate 
cancer (eg. ADT) taken since the prior visit. Quality-of-life questionnaire (EPIC Short Form) will be 
administered at baseline, at week 13, then during the 12, 24, and 36 month post C1D1 follow-up 
visits (5 per subject). These questionnaires and review of prostate cancer treatments may also be 
administered by mail or over the phone. 
 
10.7 
End of Study 
 
Each subject will be followed every 3 months following their safety follow-up visit for a total of 36 
months (3 years) from Cycle 1 Day 1 or until early withdrawal.  The overall end of study will occur 
when the last enrolled subject has completed his last follow up visit.  If the full 36 weeks (9 months) 

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of treatment is completed then the subject will continue to be followed for up to 27 months from 
end of treatment.  
 
10.8 
Early Withdrawal of Subject(s) 
10.8.1 Criteria for Early Withdrawal 
 
Subjects may voluntarily withdraw from the study at any time.  The PI may also withdraw a subject 
from the study at any time based on his/her discretion.   
 
       Reasons for PI-initiated withdrawal may include the following: 
• 
Progression of disease defined as PSA rise 0.2 ng/ml above nadir or imaging consistent 
with metastatic disease; 
• 
Unacceptable toxicity (at the discretion of the treating physician) — Reason(s) for 
removal must be clearly documented in the physician progress note 
• 
Noncompliance with oral medication 
• 
A delay in radiotherapy > 2 weeks; 
• 
The patient may withdraw from study treatment at any time for any reason and still be 
followed per protocol. 
 
If one subject is unable to tolerate the combination of apalutamide with radiation and requires a 
≥5 day delay in radiation therapy due to toxicity, this would trigger a temporary hold in accrual, 
until a meeting of the data and safety monitoring committee at the lead site is held to review the 
AEs and to determine if the study may proceed and if changes to the protocol are required.   
10.8.2 Follow-up Requirements for Early Withdrawal 
 
Upon early withdrawal from study treatment, an end of treatment visit will be conducted within 7 
days as described above.  At withdrawal, all on-going study-related toxicities and SAEs should be 
followed until resolution, unless in the investigator’s opinion, the condition is unlikely to resolve due 
to the subject’s underlying disease.  Subjects should be followed up for new AEs for 30 calendar 
days after the last administration of study therapy including chemotherapy, radiation or 
apalutamide.  All new AEs possibly related to study treatment occurring during the follow up period 
should be collected.    
10.8.3 Replacement of Early Withdrawal(s) 
 
Patients who consent but do not receive a dose of study drug will be replaced and will not be 
considered evaluable.    Subjects who prematurely withdraw will not be replaced.   
10.9 
Study Assessments 
10.9.1 Medical History 
 
At the initial visit, the detailed medical history will include concomitant illnesses and oncologic 
history. All prior treatments including surgery and radiotherapy for prostate cancer will be recorded, 

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regardless of when administered.  This medical history will be updated at subsequent visits.  
Concomitant medications and non-pharmacologic treatments taken will be recorded at each visit.   
10.9.2 Physical Exam 
 
Physical examination should include:  height (cm – screening visit only), weight (kg), and vital signs.  
Vital signs include temperature [°C], blood pressure [mmHg], heart rate [beats per minute], 
respiratory rate [breaths per minute] and, if possible, VAS pain and fatigue score [scale of 1-10, 
subject reported].   Karnofsky performance status will be assessed and recorded at each visit.  All 
additional elements of the physical exam will be documented per the provider’s discretion.   
 
Please see APPENDIX A for ECOG and Karnofsky Performance Status Criteria and APPENDIX B for 
VAS Pain and Fatigue Score Criteria. 
10.9.3 Correlative Assessments 
 
Previously archived formalin-fixed or frozen primary prostate tumor blocks or core biopsies will be 
collected on this study through the Duke Cancer Institute or participating site biorepository and 
linked to subject outcomes if available.  This is an optional component of the study as detailed in the 
ICF.  At least 250 mg of tumor tissue is needed for the genomic correlative component of this study.  
Frozen primary tumor samples will be collected if available.  Slides are an acceptable alternative; 
twenty (20) slides, 5 microns thick (unstained and unbaked) will be collected.  
 
These archived specimens will be collected and stored for analysis of the correlation of outcomes 
with pre-treatment androgen receptor target genes, androgen receptor splice variants, and 
epithelial-mesenchymal transition (EMT) biomarkers for mechanisms of resistance to apalutamide, 
ADT, and radiation. If available, a pre-treatment genomic risk score (for example by the Decipher 
assay) will be used to correlate with outcomes.  Prior to storage, all specimens will be labeled with 
the study ID and date that specimen was obtained from patient. To maintain patient confidentiality, 
specimens will not be labeled with any patient identifier except the subject ID and date of collection.  
Specimens will be stored until either they are used according to established SOPs in the Duke 
Biospecimen Repository and Processing Core (BRPC) for up to 15 years after collection, whichever is 
shorter.   
 
A single EDTA tube will be drawn at baseline and upon follow up (24 and 36 months after Cycle 1 
Day 1), for storage of plasma and future work in evaluation of circulating proteins and cell free DNA 
analysis. Please refer to the lab manual for details. 
 
 
11 SAFETY MONITORING AND REPORTING 
 
The PI is responsible for the identification and documentation of adverse events and serious adverse 
events, as defined below.  At each study visit, the PI or designee must assess, through non-suggestive 
inquiries of the subject or evaluation of study assessments, whether an AE or SAE has occurred. 

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11.1 
Definitions 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse event 
does not necessarily have a causal relationship with the treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational or 
non- investigational) product, whether or not related to that medicinal (investigational or 
non-investigational) product. (Definition per International Conference on Harmonization 
[ICH]) 
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. 
 
Adverse Events of Special Interest  
There are no adverse events of special interest for apalutamide. 
 
 
Definition of Adverse Drug Reaction (ADR) 
 
A noxious and unintended response to any dose of the drug (or biological) product for which 
there is a reasonable possibility that the product cause the response.  ‘‘Reasonable 
possibility’’ means there is evidence to suggest a causal relationship between the drug and 
the adverse event. Suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any adverse event caused by a drug. 
 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
• an identifiable subject (but not disclosing personal information such as the subject’s 
name, initials or address) 
• an identifiable reporter (investigational site) 
• a Janssen medicinal product 
• an adverse event, outcome, or certain special 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 
• age at AE onset 
• reporter ID 

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• adverse event detail (AE verbatim in English), onset date, relatedness, causality, action 
taken, outcome, (if available) 
• Janssen protocol ID 
 
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 
 
Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
 
• Results in death 
• Is life-threatening 
(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.) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is a suspected transmission of any infectious agent via a medicinal product 
• Is medically important* 
 
*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. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE EVENT. 
 
Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 

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Any event requiring hospitalization or prolongation of hospitalization that occurs during the 
study must be reported as a serious adverse event, except hospitalizations for the following: 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
• 
Surgery or procedure planned before entry into the study. [Note: Hospitalizations that 
were planned before the start of data collection and where the underlying condition for 
which the hospitalization was planned has not worsened will not be considered serious 
adverse events.  
Any adverse event that results in a prolongation of the originally planned hospitalization is to 
be reported as a new serious adverse event.] 
 
Life-Threatening Conditions 
The cause of death of a subject in a study within 30-days of the last dose of apalutamide drug, 
whether or not the event is expected or associated with the study drug, is considered a serious 
adverse event. 
 
Disease progression 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. 
 
11.2 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
 
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. 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 apalutamide, the expectedness of an adverse event will be determined by whether or not it 
is listed in the Investigator's Brochure.   
11.3 
Special Reporting Situations 
 
Safety events of interest for a Janssen medicinal product that require expediting reporting 
and/or safety evaluation include, but are not limited to: 
• Drug exposure during pregnancy (maternal and paternal) 
• Overdose of a Janssen medicinal product  
• Exposure to a Janssen medicinal product from breastfeeding  
• Suspected abuse/misuse of a Janssen medicinal product 
• Inadvertent or accidental exposure to a Janssen medicinal product  
• Medication error involving a Janssen medicinal product (with or without patient 
exposure to the Janssen medicinal product, e.g., name confusion) 

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• Suspected transmission of any infectious agent via administration of a medicinal 
product 
 
These safety events may not meet the definition of an adverse event; however, from a 
JANSSEN perspective, they are treated in the same manner as adverse events. Special 
situations should be recorded on the Adverse Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be 
recorded on a Serious Adverse Event Report Form and be reported to JANSSEN within 
24 hours of becoming aware of the event. 
 
11.3.1 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 PRINCIPAL INVESTIGATOR 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. 
 
11.4 
Maintenance of Safety Information 
        
All safety data should be maintained in a clinical database in a retrievable format. The 
INSTITUTION and PRINCIPAL INVESTIGATOR shall provide all adverse events, both serious 
and non-serious, in report format. 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 request of JANSSEN 
Scientific Affairs, LLC. 
 
11.5 
Procedures for Reporting Adverse Events (AE), Serious Adverse 
Events (SAE), Special Reporting Situation, and Product Quality 
Complaints (PQCs) to JANSSEN SCIENTIFIC AFFAIRS 
 
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.  

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All (serious and non-serious) adverse events reported for a Janssen medicinal product 
should be followed-up in accordance with clinical practice. 
Suspected theft, loss, or misplacement of any Janssen supplied study drug from either Duke 
or the subject’s supply should also be reported to Janssen. 
The sequence and timing of reporting requirements is described in section 11.9 Reporting 
Timelines.  
11.5.1 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  
JANSSEN in English within 24-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 JANSSEN. 
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 JANSSEN using JANSSEN’s Serious 
Adverse Event Report Form. 
All available clinical information relevant to the evaluation of a related SAE 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 

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association with the Janssen Product under study, are to be provided to JANSSEN 
within 24 hours of such report or correspondence being sent to applicable health 
authorities. 
 
11.5.2 Non-Serious AEs 
 
All non-serious adverse events should be reported to JANSSEN according to the timeframe 
outlined in the Research Funding Agreement section entitled Reporting of Data. 
11.5.3 PQC Reporting 
 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and JANSSEN, and are mandated by regulatory 
agencies worldwide. JANSSEN has established procedures in conformity 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 immediately and if possible, take a 
picture. 
All initial PQCs involving a Janssen medicinal product under study must be reported to 
JANSSEN by the PRINCIPAL INVESTIGATOR within 24 hours after being made aware of the 
event. The Janssen contact will provide additional information/form to be completed. 
If the defect for a Janssen medicinal product under study is combined with either a serious 
adverse event or non-serious adverse event, the PRINCIPAL INVESTIGATOR must report the 
PQC to JANSSEN according to the serious adverse event reporting timelines.  A sample of 
the suspected product should be maintained for further investigation if requested by 
JANSSEN. 
 
11.6 
Reporting Procedures for Reporting Safety Data and Product Quality 
Complaints (PQCs) for Non-Janssen Medicinal Products  
 
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the PRINCIPAL INVESTIGATOR should notify the appropriate 
regulatory/competent authority or the manufacturer of that medicinal product (in the 
absence of appropriate local legislation) as soon as possible. 
Transmission Methods 
The following methods are acceptable for transmission of safety information to JANSSEN 
SCIENTIFIC AFFAIRS: 
• Electronically via Janssen SECURE Email service (preferred) 
• For business continuity purposes, if SECURE Email is non-functional: 

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o Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
• Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by JANSSEN 
SCIENTIFIC AFFAIRS  
 
11.7 
Management of Adverse Events, Serious Adverse Events and Special 
Reporting Situations 
 
In general, the PI or designate must immediately report to JANSSEN SCIENTIFIC AFFAIRS any 
serious adverse event and Special Reporting Situations, whether or not considered drug 
related. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the drug and the event (e.g., death as a result of anaphylactic reaction 
or fatal hepatic necrosis). In that case, the investigator must immediately report the event 
to JANSSEN. The PI must record non-serious adverse events and report them to JANSSEN 
following completion of the accrual and follow up period or to fulfill regulatory reporting 
requirements. 
 
For each subject, AEs SAEs, and Special Reporting Situations should be recorded after 
informed consent is obtained until the subject has completed participation in the study as 
follows: 
 
A Serious Adverse event or Special Reporting Situations must be reported if it occurs during 
a subject’s participation in the Study (whether receiving Study Product or not) and within 30 
days of receiving the last dose of Study Product. 
 
Any theft, loss, or misplacement of any Janssen supplied study drug from either Duke or the 
subject’s supply must be reported to Janssen starting with initial distribution of the study 
drug until the end of the study. This applies even if there is no suspicion of misuse or 
overdose on the part of the subject. 
 
11.8 
Recording of Adverse Events, Serious Adverse Events and Special 
Reporting Situations 
 
Recording should be done in a concise manner using standard, acceptable medical terms. 
 
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a 
laboratory value or vital sign) but should reflect the reason for the procedure or the 
diagnosis based on the abnormal measurement. 
 

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Preexisting conditions that worsen in severity or frequency during the Study should also be 
recorded (a preexisting condition that does not worsen is not an adverse event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading to the 
procedure or surgery is considered an adverse event. Any event requiring in-patient 
hospitalization that occurs during the course of a subject’s participation in a trial must be 
reported as an SAE. Hospitalizations that do not meet the criteria for SAE reporting are: 
A: Reasons described in the Protocol, e.g. drug administration, Protocol-required testing 
B. Surgery or procedure planned prior to entry into the Study. 
 
If, in the PRINCIPAL INVESTIGATOR’s judgment, a clinical significant worsening from baseline 
is observed in any laboratory or other test parameter (e.g. electrocardiogram (ECG), 
angiogram), physical exam finding, or vital sign, a corresponding clinical adverse event 
should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be 
recorded as the adverse event, whenever possible.  However, a complete description of the 
signs, symptoms and investigations which led to the diagnosis should be provided. For 
example, if clinically significant elevations of liver function tests are known to be secondary 
to hepatitis, “hepatitis” and not “elevated liver function tests” should be recorded. If the 
cause is not known, the abnormal test or finding should be recorded as an adverse event, 
using appropriate medical terminology (e/g/ thrombocytopenia, peripheral edema, QT 
prolongation). 
 
11.9 
Reporting Timelines 
 
Serious safety information (SAEs, Special Reporting Situations, and PQCs), whether or not 
considered drug related, should be reported to the DCI Safety Desk within 24 hours of 
becoming aware of the event(s), using the provided Janssen SAE Report Form and the DCI 
SAE Review Form (Site Assessment). These documents should be sent  via the REDCap survey 
system using the web link provided by the Duke multisite coordinators. For more 
information on and access to the REDCap system, please contact the GU multisite team:  
phone (919) 668-3018, e-mail:GU-Multisite@dm.duke.edu 
 
If Duke staff cannot be reached within 24 hours, the Sponsor/Investigator should be 
contacted: Dr. Andrew Armstrong (phone: (919) 668-4667 before 3:30pm on weekdays, for 
after 3:30, weekends, and holidays call the paging operator at (919) 684-8111 and ask to 
have Dr. Armstrong paged; fax: 919-660-0178; email: andrew.armstrong@duke.edu). 
 
The initial report for each SAE or death should include at minimum the following 
information: 
• protocol # and title 
• patient initials, study identification number, sex, age 

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• date the event occurred 
• description of the SAE 
• dose level and cycle number at the time the SAE occurred 
• description of the patient’s condition 
• indication whether the patient remains on study 
• causality/attribution 
 
Signature by physician, PI or sub-PI 
 
Follow-up information including severity, action taken, concomitant medications, and 
outcome should be communicated to Duke as soon as possible. 
 
Upon receipt of the Serious Adverse Event Reporting form by DCI Safety Desk, the PI will be 
notified and be required to complete the PI assessment of the DCI Safety SAE Report Review 
Form.  Within 24 hours of notification from the site, the DCI safety desk will, in turn, send 
the Janssen SAE Report Form to Janssen. Safety information will be sent to Janssen  by 
encrypted 
email 
using 
Cisco 
Registered 
Envelope 
Service 
to 
<IIS-BIO-VIRO-
GCO@its.jnj.com>. Delivery and read receipt of the secure email will serve as evidence of 
successful communication.  
 
All non-serious AEs should be reported according to the timeframe outlined in the Research 
Funding Agreement section entitled Reporting of Data. 
11.10 FDA Reporting Requirements 
 
The Sponsor/Investigator (Duke) is responsible for reporting serious adverse events to the 
FDA in accordance with applicable IND Safety Requirements (21 CFR 312.32).  
 
11.11 Dissemination of Safety Information from JANSSEN SCIENTIFIC 
AFFAIRS to INSTITUTION/PRINCIPAL INVESTIGATORS 
 
JANSSEN  will provide to the  INSTITUTION/PRINCIPAL INVESTIGATOR IND safety 
reports/SUSAR (Serious Unexpected Suspect Adverse Reaction) reports generated by the 
JANSSEN  for the Study Product as they become available until all subjects in the Protocol 
have completed their last Study visit according to the Protocol  (i.e. Last Subject Last Visit 
has occurred). 
 
11.12 Safety Oversight Committee (SOC) 
 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-
investigator Phase I and II, therapeutic interventional studies that do not have an independent Data 
Safety Monitoring Board (DSMB).  The primary focus of the SOC is review of safety data, toxicities 
and new information that may affect subject safety or efficacy.  Annual safety reviews includes but 
may not be limited to review of safety data, enrollment status, stopping rules if applicable, accrual, 

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toxicities, reference literature, and interim analyses as provided by the sponsor-investigator.  The 
SOC in concert with the DCI Monitoring Team oversees the conduct of DUHS cancer-related, sponsor-
investigator therapeutic intervention and prevention intervention studies that do not have an 
external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and 
reported in accordance with the protocol, standing operating procedures (SOPs), Good Clinical 
Practice (GCP), and applicable regulatory requirements. 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Monitoring 
 
This clinical research study will be monitored both internally by the PI and institutionally by the Duke 
Cancer Institute (DCI).  In terms of internal review the PI will continuously monitor and tabulate 
adverse events.  Appropriate reporting to the Duke University Medical Center IRB will be made.  If an 
unexpected frequency of Grade III or IV events occur, depending on their nature, action appropriate 
to the nature and frequency of these adverse events will be taken.  This may require a protocol 
amendment, dose de-escalation, or potentially closure of the study.  The PI of this study will also 
continuously monitor the conduct, data, and safety of this study to ensure that: 
• 
Interim analyses occur as scheduled; 
• 
Stopping rules for toxicity and/or response are met; 
• 
Risk/benefit ratio is not altered to the detriment of the subjects; 
• 
Appropriate internal monitoring of AEs and outcomes is done; 
• 
Over-accrual does not occur; 
• 
Under-accrual is addressed with appropriate amendments or actions; 
• 
Data are being appropriately collected in a reasonably timely manner. 
 
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved Data and 
Safety Monitoring Plan.  Briefly, protocol review begins with an initial review by the Cancer Protocol 
Committee (CPC), which assesses the ethics and safety of the protocol.  Documentation of these 
assessments will be maintained.  Formal, independent monitoring will be conducted by the DCI 
Monitoring Team after the first 3 subjects are enrolled, followed by annual monitoring of 1-3 subjects 
until the study is closed to enrollment and subjects are no longer receiving study interventions that 
are more than minimal risk.  DCI Monitoring Team reports and additional data/safety/toxicity reports 
submitted by the PI will be reviewed by the Safety Oversight Committee (SOC) on an annual basis.  
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns.  Monitoring visits may also be initiated upon 
request by DUHS and DCI Leadership, CPC, SOC, the Duke Office of Audit, Risk and Compliance, a 
sponsor, an investigator, or the IRB.   All study documents must be made available upon request to 
the DCI Monitoring Team and other authorized regulatory authorities, including but not limited to 
the National Institute of Health, National Cancer Institute, and the FDA.  Every reasonable effort will 
be made to maintain confidentiality during study monitoring 
 
12.2 
Safety Oversight Committee 
 

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The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-
investigator Phase I and II, therapeutic interventional studies that do not have an independent Data 
Safety Monitoring Board (DSMB).  The primary focus of the SOC is review of safety data, toxicities 
and new information that may affect subject safety or efficacy.  Annual safety reviews includes but 
may not be limited to review of safety data, enrollment status, stopping rules if applicable, accrual, 
toxicities, reference literature, and interim analyses as provided by the sponsor-investigator.  The 
SOC in concert with the DCI Monitoring Team oversees the conduct of DUHS cancer-related, sponsor-
investigator therapeutic intervention and prevention intervention studies that do not have an 
external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and 
reported in accordance with the protocol, standing operating procedures (SOPs), Good Clinical 
Practice (GCP), and applicable regulatory requirements. 
 
12.3 
Data Management and Processing 
12.3.1 Study Documentation 
 
Study documentation includes but is not limited to source documents, case report forms, monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder”, which includes but is not limited to signed protocol and amendments, approved and signed 
informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical trial.  When possible, 
the original record should be retained as the source document.  However, a photocopy is acceptable 
provided that it is a clear, legible, and an exact duplication of the original document. 
12.3.2 Case Report Forms (CRFs) 
 
The electronic CRF will be the primary data collection document for the study.  The CRFs will be 
updated in a timely manner following acquisition of new source data.  Only the key personnel 
delegated on the delegation of authority log are permitted to make entries, changes, or corrections 
in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system.  All users 
of this system will complete user training, as required or appropriate per regulations. 
12.3.3 Data Management Procedures and Data Verification 
 

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Users of the electronic CRF will have access based on their specific roles in the protocol.   
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be 
alerted to the presence of data inconsistencies.  Additionally, the data manager and project manager 
will cross-reference the data to verify accuracy.  Missing or implausible data will be highlighted for 
the PI requiring appropriate responses (i.e. confirmation of data, correction of data, completion or 
confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
12.3.4 Study Closure 
       Following completion of the studies, the PI will be responsible for ensuring the following 
activities: 
- 
Data clarification and/or resolution 
- 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
- 
Review of site study records for completeness 
- 
Shipment of all remaining laboratory samples to the designated laboratories 
 
13 STATISTICAL METHODS AND DATA ANALYSIS 
 
All statistical analysis will be performed under the direction of the statistician designated in key 
personnel.  Any data analysis carried out independently by the investigator must be approved by the 
statistician before publication or presentation. 
 
The primary objective of this single arm, open-label, one stage Phase II study is to estimate the 36 
month progression-free survival rate of men with recurrent, PSA-only disease after prostatectomy 
receiving combined apalutamide and standard androgen-deprivation therapy with salvage radiation 
therapy, followed by apalutamide and ADT with docetaxel.  The target sample size is 42.  It is 
primarily hypothesized that the 3-year PFS rate will be improved with the combined therapy 
compared to the historical control data in a similar patients setting. Based on a model and nomogram 
by Stephenson et al for men with recurrent disease after radical prostatectomy [1], the PFS rate at 
36-months among prostate cancer patients is 50%. The historical sample studied in the publication 
by Stephenson et al has fewer high risk features than the population that the current trial is studying. 
Therefore, this trial assumes a null hypothesis of 36-month PFS rate of 40%.  This trial is designed to 
have more than 85% power to reject the null hypothesis of 36-month PFS rate of 40% when the 
true PFS rate at 36 months is 65%, with a two-sided alpha of 0.05. The sample size needed will be 
38, and factoring in a 10% drop out rate, the final sample size is 42 patients.  A one sample one-sided 
binomial test will be used to test whether the 36-month PFS rate is larger than the hypothesized 
value from the historical controls.  
 
The Kaplan-Meier product-limit estimator will be used to estimate the distribution of PFS, 
biochemical progression free survival, time to PSA nadir, and time to testosterone recovery. The 
median survival times and 95% confidence intervals will be reported. The frequency and proportion 
(and 95% confidence interval) of men at 12, 24 and 36 months (1, 2, and 3 years) with a PSA of <0.1 
ng/ml and testosterone recovery will be reported. In addition, descriptive statistics with 95% 

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confidence intervals will be calculated for secondary endpoints of safety profile and quality-of-life 
(QOL) endpoints, the continuous safety and QOL endpoints will be summarized as the patient counts, 
mean, standard deviation, median, 25thand 75th percentiles, minimum and maximum.  The 
categorical safety and QOL endpoints will be categorized using frequencies and percentages.  
 
 
13.1 
Analysis Sets 
 
This is a non-blinded single-arm Phase II study of approximately 42 subjects to assess feasibility and 
efficacy of combined apalutamide and androgen-deprivation (ADT) first with salvage radiation 
therapy, followed by apalutamide and ADT with 6 cycles of docetaxel. Patients who receive at least 
one dose of apalutamide and ADT will be included in the analysis.  
13.2 
Patient Demographics and Other Baseline Characteristics 
Eligible men will have recurrent PSA-only prostate cancer within 4 years of prostatectomy, and a PSA 
of 0.2 - 4 ng/mL in the absence of metastatic disease on CT and bone scans. 
13.3 
Treatments 
Apalutamide and/or ADT treatment will be started on week 1. Cycle 1 Day 1 is defined as the first 
day of treatment with apalutamide and ADT. Apalutamide will be given 240mg by mouth daily for 
36 weeks, and ADT will be administered per institutional standard.  Standard external beam 
radiotherapy to 66-74 Gy will be administered to the prostate bed per local standard of care, which 
is usually a period of 6-8 weeks.  Inclusion of the pelvic nodes as part of the salvage radiation plan 
for patients with node positive disease will be per the discretion of the treating radiation oncologist. 
Docetaxel 75mg/m2 will be given every 3 weeks intravenously for 6 cycles. The entire treatment 
period is estimated to be 36 weeks. 
 Chemotherapy administration will begin at  4 WAR, at least 4 weeks, but no more than 8 weeks after 
the completion of radiation treatment. Scheduling of all post-radiation events, except for, ADT 
administration, apalutamide discontinuation, EPIC Questionnaires, and correlative plasma samples, 
will be based on the  last day of radiation treatment. 
 
13.4 
Primary Endpoint 
 
To describe the 36 month (3-year) progression-free survival in men with recurrent PSA only disease 
after prostatectomy receiving combined apalutamide and standard androgen-deprivation therapy 
with salvage radiation therapy and who have had testosterone recovery to >100 ng/dl. 
13.4.1 Variable 
        36-month (3-year) progression-free survival time. 
13.4.2 Statistical Hypothesis, Model, and Method of Analysis 
The null hypothesis is that the PFS rate at 36-months among prostate cancer patients is equal to 
40%. This rate was assumed to be 40% in our higher risk population, compared to the historical 

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control population with 36-month PFS rate of 50% [1]. One sample binomial test will be used to test 
whether the 36 month PFS rate is higher than the hypothesized value from the historical controls. 
13.4.3 Handling of missing values, censoring, and discontinuations 
Ineligible patients and patients who cancel registration before receiving any therapy will not be 
included in the analyses. We will follow each patient long enough to avoid censoring due to end of 
study, until 36 months (3 years) after last patient first visit. The binomial test assumes that other 
censoring than due to end of study is rare. However, we are comparing historical control with our 
data, which makes the study already limited and other assumptions for comparability of two data 
sets are necessary.  The study results are just important reference and more studies will be necessary 
for medical decision making. 
13.5 
Secondary Objectives 
 
1. To determine the proportion of men at 12, 24, and 36 months with PSA <0.1ng/mL and 
testosterone recovery to >100 ng/dl 
2. To describe the biochemical (PSA) progression free survival over time. 
3. To describe the PSA nadir (10%, 50% and 90% PSA decline as maximum response) 
4. To describe the time to testosterone recovery 
5. To describe the safety profile of combination apalutamide, ADT, and radiation therapy 
followed by apalutamide, ADT, and docetaxel 
6. To describe the percentage of patients completing all treatments including salvage 
radiation therapy and 6 cycles of docetaxel 
13.5.1 Key Secondary Objective – analysis plan 
To determine the proportion of men at 12, 24, and 36 months with a PSA of <0.1 ng/mL and 
testosterone recovery.  The frequency and proportion (and 95% confidence interval) of men 
at 12, 24, and 36 months with a PSA of <0.1 ng/ml and testosterone recovery will be reported. 
13.5.2 Other Secondary Objectives – analysis plan 
The Kaplan-Meier product-limit estimator will be used to estimate the distribution of PFS, 
biochemical progression free survival, time to PSA nadir, and time to testosterone recovery.  The 
median survival times and 95% confidence intervals will be reported. In addition, descriptive 
statistics will be calculated for secondary endpoints of safety profile and quality-of-life (QOL) 
endpoints, the continuous safety and QOL endpoints will be summarized as the patient counts, 
mean, standard deviation, median, 25thand 75th percentiles, minimum and maximum.  The 
categorical safety and QOL endpoints will be categorized using frequencies and percentages.    
13.6 
Exploratory Objectives 
1. To describe the quality of life of patients receiving the combination of apalutamide, 
ADT, and radiation therapy. 
 
2. Archived prostatectomy specimens will be collected and stored for eventual analysis of 
androgen receptor target genes, androgen receptor splice variants, and epithelial-
mesenchymal transition (EMT) biomarkers.  
 

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3. Plasma samples will be collected and stored for eventual analysis of circulating proteins 
and circulating tumor DNA. 
13.6.1 Key Exploratory Objective 
Descriptive statistics will be calculated for quality-of-life (QOL) endpoints, and the continuous QOL 
endpoints will be summarized as the patient counts, mean, standard deviation, median, 25thand 75th 
percentiles, minimum and maximum.  The categorical QOL endpoints will be categorized using 
frequencies and percentages.    
13.6.2 Other Exploratory Objectives 
Archived prostatectomy specimens will be collected and stored for eventual analysis of androgen 
receptor target genes, androgen receptor splice variants, and epithelial-mesenchymal transition 
(EMT) biomarkers.  Plasma samples will be collected and stored for eventual analysis of circulating 
proteins and circulating tumor DNA. The specific methodology and analysis plan has not been 
determined, as this will require additional funding.   
13.7 
Interim Analysis 
Not applicable.   
 
13.8 
Sample Size Calculation 
 
The target sample size is 42.  It is primarily hypothesized that the 3-year PFS rate will be improved 
with the combined therapy compared to the historical control data in a similar patients setting. 
Based on a model and nomogram by Stephenson et al for men with recurrent disease after radical 
prostatectomy [1], the PFS rate at 36-months among prostate cancer patients is 50%.  This trial is 
designed to have more than 85% power to reject the null hypothesis of 36-month PFS rate of 40% 
when the true PFS rate at 36 months is 65%, with a two-sided alpha of 0.05. The sample size needed 
will be 38, and factoring in a 10% drop out rate, the final sample size is 42 patients.  A one sample 
one-sided binomial test will be used to test whether the 36-month PFS rate is larger than the 
hypothesized value from the historical controls.  
 
 
14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
14.1 
Regulatory and Ethical Compliance 
 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
14.2 
DUHS Institutional Review Board and DCI Cancer Protocol 
Committee 
 
The protocol, informed consent form, advertising material, and additional protocol-related 
documents must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol 

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Committee (CPC) for review.  The study may be initiated only after the Principal Investigator has 
received written and dated approval from the CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any 
protocol amendments that potentially affect research design or data analysis (i.e. amendments 
affecting subject population, inclusion/exclusion criteria, agent administration, statistical analysis, 
etc.). 
 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most 
recent IRB approval.  The Principal Investigator must also obtain protocol re-approval from the CPC 
within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject 
enrollment. 
14.3 
Informed Consent 
 
The informed consent form must be written in a manner that is understandable to the subject 
population.  Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the 
purpose of the research, methods, potential risks and benefits, subject concerns, and other study-
related matters.  This discussion will occur in a location that ensures subject privacy and in a manner 
that minimizes the possibility of coercion.  Appropriate accommodations will be made available for 
potential subjects who cannot read or understand English or are visually impaired.  Potential subjects 
will have the opportunity to contact the Principal investigator or authorized key personnel with 
questions, and will be given as much time as needed to make an informed decision about 
participation in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator or designee must obtain 
written informed consent from the subject or a legally acceptable representative.  The original 
informed consent form will be stored with the subject’s study records, and a copy of the informed 
consent form will be provided to the subject.   
14.4 
Study Documentation 
 
Study documentation includes but is not limited to source documents, case report forms (CRFs), 
monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder”, which includes but is not limited to signed protocol and amendments, approved and signed 
informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 

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negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical trial.  When possible, 
the original record should be retained as the source document.  However, a photocopy is acceptable 
provided that it is a clear, legible, and an exact duplication of the original document. 
 
An electronic case report form (CRF) will be the primary data collection document for the study.  
Only the key personnel delegated on the delegation of authority log are permitted to make entries, 
changes, or corrections in the CRF.  For electronic CRFs, an audit trail will be maintained by the 
electronic CRF management system. 
14.5 
Privacy, Confidentiality, and Data Storage 
 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data 
will be maintained.   
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during 
the course of the study.  All research related interactions with the participant will be conducted by 
qualified research staff who are directly involved in the conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock 
and key accessible only by the research staff. Electronic records of subject data will be maintained 
using a dedicated web-access secure database, which is housed in an encrypted and password-
protected server behind the Duke firewall. Access to electronic databases will be limited to 
delegated personnel.  The security and viability of the IT infrastructure will be managed by the DCI 
and/or Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per institutional 
policy.     
 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals. 
 
14.6 
Data and Safety Monitoring 
 
 
Data and Safety Monitoring will be performed in accordance with the external site Data and Safety 
Monitoring Plan, provided under separate cover.   
 
14.7 
Protocol Amendments 
 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB 
prior to implementation.  IRB approval is not required for protocol changes that occur to protect 
the safety of a subject from an immediate hazard.  However, the Principal Investigator must inform 
the IRB and all other applicable regulatory agencies of such action immediately. 
 

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Though not yet required, the CPC should be informed about any protocol amendments that 
potentially affect research design or data analysis (i.e. amendments affecting subject population, 
inclusion/exclusion criteria, agent administration, etc.). 
14.8 
Records Retention 
 
The Principal Investigator will maintain study-related records for a period of at least six years after 
study completion per Duke policy.   
14.9 
Conflict of Interest 
 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and 
local regulations regarding reporting and disclosure of conflict of interest.  Conflicts of interest may 
arise from situations in which financial or other personal considerations have the potential to 
compromise or bias professional judgment and objectivity.  Conflicts of interest include but are not 
limited to royalty or consulting fees, speaking honoraria, advisory board appointments, publicly-
traded or privately-held equities, stock options, intellectual property, and gifts. 
 
The Duke University School of Medicine’s Research Integrity Office (RIO) reviews and manages 
research-related conflicts of interest.  The Principal Investigator and Sub-Investigators must report 
conflicts of interest annually and within 10 days of a change in status, and when applicable, must 
have a documented management plan that is developed in conjunction with the Duke RIO and 
approved by the IRB/IEC. 
 
 

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15 REFERENCES 
 
 
1. 
Stephenson, A.J., et al., Predicting the outcome of salvage radiation therapy for recurrent 
prostate cancer after radical prostatectomy. J Clin Oncol, 2007. 25(15): p. 2035-41. 
2. 
D'Amico, A.V., et al., 6-month androgen suppression plus radiation therapy vs radiation therapy 
alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA, 
2004. 292(7): p. 821-7. 
3. 
Shipley, W.U., et al., Radiation with or without Antiandrogen Therapy in Recurrent Prostate 
Cancer. N Engl J Med, 2017. 376(5): p. 417-428. 
4. 
Carrie, C., et al., Salvage radiotherapy with or without short-term hormone therapy for rising 
prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a 
randomised, multicentre, open-label phase 3 trial. Lancet Oncol, 2016. 17(6): p. 747-56. 
5. 
Soto, D.E., et al., Concurrent androgen deprivation therapy during salvage prostate radiotherapy 
improves treatment outcomes in high-risk patients. Int J Radiat Oncol Biol Phys, 2012. 82(3): p. 
1227-32. 
6. 
Polkinghorn, W.R., et al., Androgen receptor signaling regulates DNA repair in prostate cancers. 
Cancer Discov, 2013. 3(11): p. 1245-53. 
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APPENDICES 
APPENDIX A:  ECOG and Karnofsky 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:  VAS Pain and Fatigue Score Criteria 
15.1.1 VAS Pain Score Criteria 
 
 
 
 
 

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15.1.2 Fatigue Score Criteria 
 
 
Fatigue Scale 
Current 
Level of 
Fatigue 
Description 
0 
No Fatigue – PI has received 
information regarding fatigue 
management 
1 
Mild Fatigue – Initiate Fatigue 
Management 
2 
Mild Fatigue – Initiate Fatigue 
Management 
3 
Mild Fatigue – Initiate Fatigue 
Management 
4 
Moderate Fatigue – Initiate 
Fatigue Management 
5 
Moderate Fatigue – Initiate 
Fatigue Management 
6 
Moderate Fatigue – Initiate 
Fatigue Management 
7 
Severe Fatigue – Initiate Fatigue 
Management 
8 
Severe Fatigue – Initiate Fatigue 
Management 
9 
Severe Fatigue – Initiate Fatigue 
Management 
10 
Severe Fatigue – Initiate Fatigue 
Management 
 
 
 

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APPENDIX C:  Concomitant medications to be avoided 
Strong inhibitors or inducers of CYP2C8 
• 
Gemfibrozil 
• 
Rifampin 
 
Strong inhibitors or inducers of CYP3A4 
• 
Bosentan 
• 
Carbamazepine 
• 
Efavirenz 
• 
Etravirine 
• 
Itraconazole 
• 
Modafinil 
• 
Nafcillin 
• 
Phenobarbital 
• 
Rifabutin 
• 
Rifampin 
• 
Rifapentine 
• 
St. John’s Wort 
 
Substrates of CYP3A4, CYP2C9, CYP2C19 
• 
Alfentanil 
• 
Apixaban 
• 
Cyclosporine 
• 
Dihydroergotamine and ergotamine 
• 
Fentanyl 
• 
Midazolam  
• 
Phenytoin and S-mephenytoin  
• 
Pimozide 
• 
Quinidine 
• 
Sirolimus  
• 
Tacrolimus 
• 
Warfarin (If coadministration with warfarin cannot be avoided, must monitor INR as clinically 
indicated while on apalutamide) 
  
 
 
 
 
 
 
 
 

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APPENDIX D:  Lymph node locations 
 
Regional Lymph Nodes: 
• 
Pelvic 
• 
Hypogastric 
• 
Obturator 
• 
Iliac (external and internal) 
• 
Sacral 
 
Distant lymph nodes: 
• 
Aortic 
• 
Common iliac 
• 
Inguinal (deep) 
• 
Inguinal (superficial, femoral) 
• 
Supraclavicular 
• 
Cervical 
• 
Scalene 
• 
Retroperitoneal