Clinical trial NCT03777982
Conditions: Prostate Cancer
Keywords: Prostate Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2020-04-20; Completion date: 2024-02-13
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is being offered to those patients who have received radiation therapy and who are receiving long-term hormonal therapy for their prostate cancer and whose PSA remains detectable despite having received at least 6, but no more than 12 months of hormonal therapy.

The name of the study drugs involved in this study is:

* LHRHA (luteinizing hormone-releasing hormone agonist or antagonist)
* Abiraterone Acetate
* Apalutamide
* Prednisone

Detailed description:
This research study is a Phase III clinical trial. Phase III clinical trials test the effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that an intervention is being studied. In this study, the investigational agents are apalutamide and abiraterone acetate. Abiraterone acetate (used in combination with prednisone) is an FDA (the U.S. Food and Drug Administration) approved drug for prostate cancer, but is approved in patients that have prostate cancer spread to other parts of their body and have been previously treated with ADT. Apalutamide has also been approved by the FDA for men whose cancer does not respond to hormone therapy but it is still investigational for this type of cancer.

In this research study, the investigators are looking at two methods of androgen deprivation therapy (ADT), also known as hormonal therapy, to determine which method is better for improving long term cure rates. ADT blocks the function of hormones, including testosterone which prostate cancer uses to grow and spread. The first method of ADT includes prednisone, apalutamide, and abiraterone acetate plus standard ADT and the second method of ADT is standard ADT alone for men with this type of prostate cancer. Currently, the best standard treatment for men with this type of prostate cancer includes standard ADT. All participants in this study will receive the main standard form of ADT called a luteinizing hormone-releasing hormone agonist or antagonist (LHRHA).

Arms: arm 1: -LHRH agonist or antagonist should be prescribed per standard of care arm 2: * LHRH agonist or antagonist should be prescribed per standard of care
* Abiraterone acetate will be taken once daily
* Prednisone will be taken twice daily
* Apalutamide will be taken once daily
Interventions: intervention 1: Prednisone intervention 2: Apalutamide intervention 3: Abiraterone Acetate intervention 4: LHRH Agonist or Antagonist
Intervention descriptions: intervention 1: Taking advantage of the anti-inflammatory properties of the medication, corticosteroids are used to decrease the swelling around tumors. intervention 2: Apalutamide also prevents the androgens from working within the prostate cancer cells, and can ultimately lead to cancer cell death. intervention 3: Abiraterone acetate interferes with an enzyme that is expressed in testicular, adrenal, and prostatic tumor tissues and is required as part of the body's androgen producing process. Because of this interference the amount of androgens produced are decreased. Abiraterone acetate, blocks androgen production at three sources; the testes, the adrenal glands, as well as from the tumor itself intervention 4: Luteinizing hormone-releasing hormone (LHRH) agonists (also called LHRH analogs or GnRH agonists) are drugs that lower the amount of testosterone made by the testicles

Protocol documents:
Prot_SAP_000.pdf: 
DF/HCC Protocol #: 18-530 
Protocol Version Date: September 7, 2022
Confidential
DF/HCC Protocol #: 18-530  
TITLE:  A randomized Phase III study – Conventional Androgen Deprivation Therapy with or 
without Abiraterone acetate + prednisone and Apalutamide following a detectable PSA After 
Radiation and Androgen Deprivation Therapy:  A randomized Clinical Trial in Men with High 
Risk Prostate Cancer.  
Coordinating Center:
Dana-Farber Cancer Institute
Principal Investigator (PI):
Anthony V. D’Amico, M.D. Ph.D. 
Dana-Farber Cancer Institute – Brigham & Women’s Hospital
Adamico@bwh.harvard.edu 
 
Other Investigators:
Co-PI, Medical Oncology Chair
Mary Ellen Taplin, MD 
Dana-Farber Cancer Institute
Mary_Taplin@dfci.harvard.edu 
Clinical Consultant Physician Assistant
Ashleigh Kowtoniuk, PA-C
Brigham and Women’s Hospital
akowtoniuk@bwh.harvard.edu
Clinical Study Coordinator:
Shana Medeiros
Brigham and Women’s Hospital
Smedeiros7@bwh.harvard.edu
BWH Research Nurse: 
Marian Loffredo, RN BS O.C.N
Brigham and Women’s Hospital
Mloffredo@bwh.harvard.edu
Rosemarie Baylies, RN BSN MHP O.C.N.
Brigham and Women’s Hospital
Rosemarie_baylies@dfci.harvard.edu
 
Statistician: 
Lucia Kwak, MS
Dana-Farber Cancer Institute
lkwak@ds.dfci.harvard.edu
                                    


DF/HCC Protocol #: 18-530 
Protocol Version Date: September 7, 2022
Confidential
NCI-supplied agents:  N/A
Janssen Scientific Affairs, LLC to supply:
Apalutamide
Abiraterone acetate
Commercial:
LHRH Agonist or Antagonist
Prednisone
Janssen Scientific Affairs, LLC is supplying funding for this study.
IND #:  141406
IND Sponsor:  Anthony V. D’Amico, M.D. Ph.D. 
Protocol Type = amended / Version # = 10.0 / Version Date = September 7, 2022


DF/HCC Protocol #: 18-530 
Protocol Version Date: September 7, 2022
Confidential
SCHEMA
Arm 1
LHRH agonist or antagonist for the duration of hormonal therapy
Arm 2
LHRH agonist or antagonist for the duration of hormonal therapy
Abiraterone acetate by mouth once/day for the duration of ADT
Prednisone by mouth twice per day for the duration of ADT
Apalutamide by mouth once/day for the duration of ADT
                                                                                                   
High Risk or 
any N1M0 
Prostate 
Cancer,  
n=1000
Registration:
Detectable 
PSA after RT 
and 6-12 
months ADT
Stratify
-Entry PSA > 0.5 vs ≤ 0.5 
ng/ml
-Planned Total Duration of 
ADT ( 12 vs. > 12 months)
-USA vs Canada
Randomize
(n=400, 1:1 
ratio)
Arm 1 
LHRH agonist or 
antagonist for the 
duration of ADT
Arm 2 
LHRH agonist or 
antagonist plus 
abiraterone acetate, 
prednisone, and 
apalutamide for the 
duration of ADT


DF/HCC Protocol #: 18-530 
Protocol Version Date: September 7, 2022
Page 1
TABLE OF CONTENTS
Schema.............................................................................................................................................3
1.
OBJECTIVES......................................................................................................................5
1.1
Study Design............................................................................................................5
1.2
Primary Objective....................................................................................................5
1.3
Secondary Objectives...............................................................................................5
2.
Background..........................................................................................................................5
2.1
Study Disease and Rationale....................................................................................5
2.2
IND Agents..............................................................................................................7
2.3
Other Agents............................................................................................................8
3.
PARTICIPANT SELECTION.............................................................................................8
3.1
Eligibility Criteria....................................................................................................8
3.2
Exclusion Criteria ..................................................................................................10
3.3
Inclusion of Women and Minorities ......................................................................11
4.
REGISTRATION PROCEDURES ...................................................................................11
4.1
General Guidelines for DF/HCC Institutions ........................................................11
4.2
Registration Process for DF/HCC Institutions.......................................................12
4.3
General Guidelines for Other Investigative Sites ..................................................12
4.4
Registration Process for Other Investigative Sites.................................................12
4.5
Randomization.......................................................................................................13
4.6
Stratification Factors..............................................................................................13
5.
TREATMENT PLAN........................................................................................................13
5.1
Treatment Regimen................................................................................................13
5.2
Pre-Treatment criteria............................................................................................14
5.3
Agent Administration.............................................................................................14
5.4
Concomitant Medications......................................................................................15
5.5
Supportive Care .....................................................................................................20
5.6
Criteria for Taking a Participant Off Protocol Therapy.........................................20
5.7
Duration of Follow Up...........................................................................................20
5.8
Criteria for Taking a Participant Off Study ...........................................................21
5.9
Replacement...........................................................................................................21
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................21
6.1
Dose Modifications for Toxicity Attributed to Apalutamide ................................21
6.2
Dose Modifications for LFT Abnormalities Attributed to Abiraterone 
Acetate ...................................................................................................................23
6.3
Dose Modifications for Hypokalemia Attributed to Abiraterone Acetate.............24
6.4
Dose Modifications for Hypertension and Edema/Fluid Retention 
Attributed to Abiraterone Acetate..........................................................................25
6.5
Dose Modifications for Toxicity Attributed to LHRH agonist..............................25


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7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................26
7.1
Adverse Events ......................................................................................................26
7.2
Overview................................................................................................................26
7.3
Management of Safety Data...................................................................................26
7.4
Definitions..............................................................................................................27
7.5
Unlisted (Unexpected) Adverse Event/Reference Safety Information..................29
7.6
Special Reporting Situations..................................................................................30
7.7
Pregnancy...............................................................................................................30
7.8
Maintenance of Safety Information .......................................................................30
7.9
Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Janssen Medicinal Products to Janssen...............................................31
7.10
Reporting Procedures for Reporting Safety Data and Product Quality 
Complaints (PQCs) for Non-Janssen Medicinal Products.....................................32
7.11
Transmission Methods...........................................................................................32
7.12
Reconciliation of SAEs..........................................................................................33
7.13
Dissemination of Safety Information from Janssen to Principal 
Investigators...........................................................................................................33
7.14
Contacting Janssen Regarding Safety....................................................................33
7.15
Final Study Report.................................................................................................33
7.16
Reporting................................................................................................................33
7.17
IND Safety Reports Unrelated to this Trial ...........................................................34
7.18
Expedited Adverse Event Reporting......................................................................34
7.19
Expedited Reporting to the Food and Drug Administration (FDA) ......................35
7.20
Expedited Reporting to Hospital Risk Management .............................................35
7.21
Routine Adverse Event Reporting .........................................................................35
8.
PHARMACEUTICAL INFORMATION..........................................................................35
8.1
Abiraterone Acetate (AA)......................................................................................35
8.2
Apalutamide (ARN-509, JNJ-56021927)..............................................................37
8.3
Prednisone..............................................................................................................38
8.4
LHRH Agonist or Antagonist................................................................................39
9.
Study calendar....................................................................................................................41
9.1
Arm 1 Calendar & Evaluations..............................................................................41
9.2
Arm 2 Calendar and Evaluations (cycle = 28 days) Number of months left 
of ADT at time of registration = number of cycles on study (i.e. if patient 
has 12 more months of ADT left, he will have 12 cycles on study)......................43
10.
MEASUREMENT OF EFFECT .......................................................................................46
10.1
Progression Free Survival......................................................................................46
11.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................46
11.1
Data Reporting.......................................................................................................46
11.2
Data Safety Monitoring..........................................................................................47
11.3
Multicenter Guidelines...........................................................................................47
11.4
Collaborative Agreements Language.....................................................................47


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12.
STATISTICAL CONSIDERATIONS...............................................................................48
12.1
Study Design and Primary Endpoint......................................................................48
12.2
Endpoints ...............................................................................................................48
12.3
Sample Size, Accrual Rate and Study Duration ....................................................49
12.4
Interim Monitoring Plan ........................................................................................50
12.5
Analysis of Primary Endpoints..............................................................................50
12.6
Analysis of Secondary Endpoints..........................................................................50
12.7
Reporting and Exclusions ......................................................................................51
13.
ETHICS..............................................................................................................................51
13.1
Institutional Review Board (IRB) Approval..........................................................51
13.2
Ethics Conduct of the Study ..................................................................................52
13.3
Informed Consent Procedures................................................................................52
14.
PUBLICATION PLAN .....................................................................................................52
15.
REFERENCES: .................................................................................................................52
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................55
16.
INTRODUCTION .............................................................................................................61
1.1.
Purpose...................................................................................................................61
17.
GENERAL ROLES AND RESPONSIBILITIES .............................................................61
2.1.
Coordinating Center...............................................................................................61
2.2.
External Site...........................................................................................................61
18.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................62
3.1.
Protocol Revisions and Closures ...........................................................................62
3.2.
Informed Consent Requirements ...........................................................................63
3.3.
IRB Re-Approval...................................................................................................63
3.4.
DF/HCC Multi-Center Protocol Confidentiality ...................................................63
3.5.
Participant Registration and Randomization .........................................................64
3.6.
Initiation of Therapy ..............................................................................................64
3.7.
Eligibility Exceptions.............................................................................................65
3.8.
Data Management..................................................................................................65
3.9.
Protocol Reporting Requirements..........................................................................65
4.
MONITORING: QUALITY CONTROL..........................................................................66
4.1.
Ongoing Monitoring of Protocol Compliance.......................................................66
4.2.
Monitoring Reports................................................................................................66
4.3.
Accrual Monitoring................................................................................................67
5.
AUDITING: QUALITY ASSURANCE ...........................................................................67
5.1.
DF/HCC Internal Audits........................................................................................67
5.2.
Audit Notifications.................................................................................................67
5.3.
Audit Reports.........................................................................................................67
5.4.
External Site Performance .....................................................................................67


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APPENDIX C: Drug Diary............................................................................................................69


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1. OBJECTIVES
1.1 Study Design
The goal of this study is to assess whether metastasis free survival is prolonged after completing 
novel androgen deprivation therapy (ADT) in men with high risk prostate cancer whose PSA 
remains detectable (defined as, at or above the minimum level defined as measurable by the 
assay. For example, 0.02 would be eligible on an assay which defines undetectable PSA as 
<0.02) following radiation and 6-12 months of conventional ADT.  This is a randomized phase 
III study involving the use of 2 novel hormonal therapy agents (apalutamide and abiraterone 
acetate with prednisone) in addition to conventional ADT with a LHRH agonist or antagonist as 
compared to conventional ADT alone for the duration of treatment with ADT.
1.2 Primary Objective
The primary objective is to evaluate whether metastasis free survival is prolonged in men 
undergoing novel ADT (LHRH agonist or antagonist, apalutamide, and abiraterone acetate with 
prednisone) as compared to conventional ADT with a LHRH agonist or antagonist alone in men 
whose PSA remains detectable after radiation therapy and 6-12 months of ADT for high risk 
prostate cancer.   
1.3 Secondary Objectives

To evaluate the PSA nadir following randomization

To evaluate castrate resistant PSA failure

To evaluate prostate cancer -specific survival

To evaluate overall survival

To evaluate disease free survival
2. BACKGROUND
2.1 Study Disease and Rationale
Prostate cancer is the most commonly diagnosed non-cutaneous cancer in the U.S. male
population and the second leading cause of cancer death.  While many men who present with 
high risk prostate cancer are curable, some will die from castrate resistant disease.  Accumulating 
evidence suggests that a PSA that remains detectable following radiation therapy and at least 6 
months of ADT is associated with an increased risk of prostate cancer-specific and all-cause 
mortality (PCSM, ACM).9,10 Following initiation of this treatment, the median level and time to 
PSAn has been observed to be 0.1 ng/mL and 6 months, respectively.9,10 Moreover, a PSAn > 0.5 
ng/ml has been shown to be a surrogate for all-cause mortality (ACM)6 and the median time to 
death from PC shortens as the PSAn increases.9,10  The clinical implication of these observations 
is that men whose PSA level is detectable at the end of RT and 6-12 months of ADT, which 


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comprises 40% of men with high risk PC10, harbor residual prostate cancer that is likely castrate 
resistant with a concomitant increase in the biological aggressiveness of the residual disease with 
increasing PSA level.  
With the advent of agents11,12,13 that have been shown to prolong survival in men with castrate 
resistant metastatic PC and prolong the time to metastasis and any cause of death in men with 
non-metastatic PC,7 the opportunity exists to evaluate in the setting of prospective randomized 
controlled trial (RCT ) whether the time to metastasis and any cause of death can be prolonged 
with the addition of these agents to the standard of care (ADT using an LHRH agonist or 
antagonist) in men with high-risk PC whose PSA level remains detectable following RT and 6-
12 months of ADT.
We propose a randomized Phase III study in order to assess the impact on metastasis free 
survival and overall survival that novel ADT vs LHRH agonist or antagonist alone 
provides in men with high risk prostate cancer whose PSA level remains detectable 
following RT and 6-12 months of conventional ADT.
This study is open to patients who underwent radiation and hormone therapy after presenting 
with localized, high risk, and pelvic node positive or negative prostate cancer, and now have a 
detectable PSA 6-12 months after ADT initiation, and a planned total ADT duration of at least 
12 months based on the results of the ASCENDE RT trial.1  Pelvic node positive disease is 
defined as disease including pelvic lymph nodes that are clinically suspicious on CT, MRI or 
PET imaging up to and including the bifurcation of the common iliac vessels. Radiation therapy 
will be completed prior to the patient being randomized. It will be treatment to the prostate and 
seminal vesicles that could include dose escalated conventionally fractionated (75.6 to 79.2 Gray 
(Gy) in 1.8  to 2.0 Gy fractions) or hypofractionated (60.0 Gy in 3 .0 Gy fractions) treatment, or 
45 to 50.4 Gy RT and a brachytherapy boost as that these are all accepted standards of care.1,4-5  
Pelvic radiation would be permitted.  
Abiraterone acetate is a CYP17 inhibitor blocks mineralocorticoid synthesis in the adrenal gland 
(see section 2.2.2).  Given that apalutamide (section 2.2.1) may be effective in a subset of 
prostate cancer patients with acquired resistance to abiraterone acetate3 we propose combining 
these two drugs in addition to conventional ADT (defined in this protocol as LHRH agonist or 
antagonist) in the experimental arm.  The control arm of this study is the current standard of care, 
a 12- to 36-month course of conventional ADT. Eighteen months of ADT will be commonly 
used based on recent results showing that 18 months of ADT appears to provide similar cancer 
control compared to 36 months of ADT with respect to all-cause mortality (ACM) given the 
upper limit of the 95% confidence interval on the point estimate (1.02) for the hazard ratio for 
ACM of 1.29 (p = 0.84) after a median follow up of 9.4 years and absolute survival rates at 10 
years differing by 0.4%.2 Twelve months of ADT with brachy boost following EBRT is also 
considered standard of care based on the ASCENDE RT trial.1 Men will be stratified by the 
planned total duration of ADT ( 12 vs. > 12 months).
A stratification by the PSAn level following RT and 6-12 months of ADT, which has been 
shown to be a potential surrogate for ACM (> vs ≤ 0.5 ng/ml) during an era before agents 


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capable of treating castrate resistant disease were discovered, would be prudent in order to 
ensure that this potential surrogate endpoint for ACM6 is balanced between the two randomized 
treatment arms. 
In addition, in order to adjust for the potential uptake in the use of PET at the time of castrate 
resistant PSA failure (defined as PSA nadir + 2 ng/ml and serum testosterone < 50) and at the q6 
months following documentation of castrate resistant PSA failure, we are including a pre-
randomization stratification by country (USA vs Canada) since PET usage will track with 
country given national guidelines for its use and reimbursement by insurers. In men scanned for 
recurrence following PSA failure in the castrate sensitive post-operative setting, a > 90% positive 
predictive value for PET has been observed when the PSA level is > 2 ng/ml and the testosterone 
level is normal (NCT # 03515577). Therefore, it is expected that the positive predictive value of 
PET in men who have castrate resistant PSA failure (defined as PSA nadir + 2 ng/ml and serum 
testosterone < 50) will be at least > 90%.
2.2 IND Agents
2.2.1
Apalutamide 
Apalutamide is FDA approved for the treatment of non-metastatic castration resistant prostate 
cancer and for metastatic castration sensitive prostate cancer, however apalutamide is still 
considered investigational in this trial setting.  Apalutamide is a novel androgen receptor (AR) 
antagonist that lacks partial agonist activity. Apalutamide impairs nuclear translocation and DNA 
binding of AR, preventing transcriptional activation of AR target genes.8 Anticipated AEs from 
apalutamide clinical trials include fatigue,   diarrhea,  weight loss,  taste alterations, joint pain or 
muscle spasms, increased blood pressure, rash, itching, hot flashes,  falls, fractures, seizures, 
reduced or blocked blood flow to the heart and brain including heart attack and stroke, changes 
in thyroid function, increase in triglycerides, increase in blood cholesterol, and decreased 
appetite.  Subjects will be closely monitored for seizures in human clinical trials of apalutamide 
and medications that potentially lower the seizure threshold will be prohibited (see section 5.4.4). 
Further details about the ongoing and completed clinical studies with apalutamide may be found 
in the Investigator’s Brochure. 
2.2.2
Abiraterone Acetate
Abiraterone acetate inhibits CYP17 (17a-hydrolase / 17,20-lyase), an adrenal enzyme important 
in the synthesis of testosterone (T) and dihydrotestosterone (DHT). In pre-clinical and early-
phase clinical studies, abiraterone acetate was found to impair synthesis of adrenal androgens 
and corticosteroids. Consequently, abiraterone acetate is administered in combination with low-
dose steroid supplementation (e.g., prednisone). Abiraterone acetate given with a low dose of 
prednisone is FDA approved for the treatment of patients with metastatic CRPC who 
experienced disease progression after docetaxel chemotherapy, and also for metastatic high risk 
castration sensitive prostate cancer patients. The approved dose of abiraterone acetate is 1000 
mg/day in combination with prednisone 5 mg twice daily. A randomized Phase III study of 
patients with docetaxel-refractory metastatic CRPC demonstrated a statistically significant 
increase in overall survival (14.8 vs. 10.9 months; HR 0.65; P < 0.0001) and time to tumor 


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progression, as well as increased radiographic progression-free survival and rate of PSA 
response in patients treated with the combination of abiraterone acetate + prednisone compared 
to placebo + prednisone. The combination of abiraterone acetate and prednisone was well-
tolerated. The most frequent adverse events were hypertension, hypokalemia, and fluid retention. 
Abiraterone acetate is currently approved and marketed for the treatment of patients with 
metastatic CRPC and metastatic high-risk castration sensitive prostate cancer in combination 
with prednisone.
2.3 Other Agents
2.3.1
Prednisone
Prednisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally 
occurring and synthetic, which are readily absorbed from the gastrointestinal tract.  Prednisone is 
used with abiraterone to reduce the mineralocorticoid-related adverse events that arise because of 
CYP17A1 inhibition with abiraterone.  Coadministration with the recommended dose of 
glucocorticoid compensates for abiraterone-induced reductions in serum cortisol and blocks the 
compensatory increase in adrenocorticotropic hormone seen with abiraterone.
2.3.2
LHRH Agonists or Antagonists  
Gonadotropin-releasing hormone agonists or antagonists when chronically administered, result in 
marked reductions in blood levels of testosterone and estrogen.  The most frequent side effects 
are loss of muscle mass, hot flashes, loss of libido and erectile dysfunction.
3. PARTICIPANT SELECTION
3.1 Eligibility Criteria 
A bone scan and/or PET (of any kind) will be used to ensure M0 high risk prostate cancer. A 
bone scan and/or PET is to be done up to 6 months prior to the start of initial ADT therapy or up 
to one month after initiation of ADT to rule out bony metastatic disease. Subjects must meet all 
of the following applicable inclusion criteria to participate in this study:  
3.1.1
Histologically confirmed prostate cancer 
3.1.2
PSA> undetectable (any value at or above the lower limit of detection for the 
assay used) after radiation and at least 6, but not more than 12 months of 
conventional ADT (LHRH agonist or antagonist with or without oral anti-
androgens, excluding abiraterone acetate and apalutamide) in patients with non-
metastatic high risk or N1 prostate cancer8

High risk is defined per the NCCN guidelines – clinical, radiographic, 
or pathological (biopsy proven) T3 or higher, Gleason 8-10, PSA > 20 
ng/mL, the presence of intraductal, ductal, or cribriform features with 
any Gleason score, and can be N0 or N1

A month is defined as 28 days


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3.1.3
Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included 
in the informed consent or obtained separately.  Subject must have the ability to 
understand and willingness to sign the written informed consent document.
3.1.4
Age ≥18 at the time of consent
3.1.5
ECOG Performance Status ≤ 2 (Appendix A)
3.1.6
Demonstrate adequate organ function as defined in the table below. All screening 
labs to be obtained within 3 months of registration. 
System
Laboratory Value
Hematological:
   Platelet count (plt)1
≥ 100,000/ µL
   Hemoglobin (Hgb)1
≥ 9 g/dL
   Absolute neutrophil count (ANC)
≥ 1000 cells/µL
Renal:
   CrCl2
≥ 45 mL/min 
Hepatic and Other:
   Bilirubin3
≤ 1.5 × upper limit of normal (ULN)
   Aspartate aminotransferase (AST)
< 2.5 × ULN
   Alanine aminotransferase (ALT)
< 2.5 × ULN
   Serum Albumin
> 3.0 g/dL
   Serum potassium
≥ 3.5 mmol/L
Coagulation:
   International Normalized Ratio (INR)
      or Prothrombin Time (PT) 
   Activated Partial Thromboplastin Time
      (aPTT)
≤ 1.5 × ULN (unless on prophylactic or 
therapeutic dosing with low molecular 
weight heparin)
1 Independent of transfusion and/or growth factors within 3 months prior to 
randomization
2 Cockcroft-Gault formula will be used to calculate creatinine clearance
3 In subjects with Gilbert’s syndrome, if total bilirubin is >1.5 × ULN, measure direct 
and indirect bilirubin; if direct bilirubin is ≤1.5 × ULN, subject may be eligible


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3.1.7
Agrees to use a condom (even men with vasectomies) and another effective 
method of birth control if he is having sex with a woman of childbearing potential 
OR agrees to use a condom if he is having sex with a woman who is pregnant 
while on study drug and for 3 months following the last dose of study drug. Must 
also agree not to donate sperm during the study and for 3 months after receiving 
the last dose of study drug.
3.1.8
Ability to understand and comply with study procedures for the entire length of 
the study as determined by the site investigator or protocol designee
3.1.9
Medications known to lower the seizure threshold (section 5.4.4) must be 
discontinued or substituted prior to C1D1 of study treatment for patients on Arm 
2
3.1.10 Able to swallow pills.
3.2 Exclusion Criteria
Subjects meeting any of the criteria below may not participate in the study:
3.2.1
Prior radical prostatectomy (excluding TURP and simple prostatectomy)
3.2.2
History of any of the following:

Seizure or known condition that may predispose to seizure (e.g., prior 
stroke within 1 year of randomization, brain arteriovenous malformation, 
Schwannoma, meningioma, or other benign CNS or meningeal disease 
which may require treatment with surgery or radiation therapy)

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 
randomization
3.2.3
Known current evidence of any of the following:

Uncontrolled hypertension. Participants with a history of hypertension are 
allowed provided blood pressure is controlled by anti-hypertensive therapy

Gastrointestinal disorder affecting absorption

Known history of testing positive for human immunodeficiency virus 
(HIV) or known acquired immunodeficiency syndrome.

Known active or chronic hepatitis B infection (defined as having a 
positive hepatitis B surface antigen (HBsAg) test at screening). Subject 
with past or resolved hepatitis B infection (defined as having a negative 
HBsAg test and positive antibody to hepatitis B core antigen test) are 
eligible. Hepatitis B viral DNA must be obtained in subjects with positive 
hepatitis B core antibody prior to first treatment start. 


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
Active hepatitis C infection. Subjects positive hepatitis C antibody test are 
eligible if PCR is negative for hepatitis C viral DNA. 

Pre-existing condition that warrants long-term corticosteroid use
greater than the equivalent of 10 mg prednisone daily. Physiologic
replacement is permitted. Topical, intra-articular steroids or inhaled
corticosteroids are permitted.

Any condition that, in the opinion of the site investigator, would preclude 
participation in this study

Baseline moderate or severe hepatic impairment (ChildPugh Class B or C)
3.2.4
Patients who are currently receiving treatment with a prohibited medication 
according to Section 5.4 (Tables 2 and 3),  must discontinue that medication prior 
to starting treatment and must not restart for the duration of the study if 
randomized to ARM 2.
3.2.5
Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have 
a narrow therapeutic index. If an alternative treatment cannot be used, exercise 
caution and consider a dose reduction of the concomitant CYP2D6 substrate
3.2.6
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to study drugs
3.2.7
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, psychiatric illness or social situations that would limit compliance with 
study requirements
3.2.8
Individuals with a history of another malignancy are not eligible if the cancer is 
under active treatment or the cancer can be seen on radiology scans or if they are 
off cancer treatment but in the opinion of their oncologist have a high risk of 
relapse within 5 years.
3.3 Inclusion of Women and Minorities
Every effort will be made to include men from minority populations. The enrollment of minority 
men will reflect the proportion of minority subjects at the sites participating in the trial.  Women 
by birth are not affected by prostate cancer and therefore are not eligible.
4. REGISTRATION PROCEDURES
4.1 General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the DF/HCC Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. Any 
participant not registered to the protocol before protocol therapy begins will be considered 


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ineligible and registration will be denied. 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
The eligibility checklist(s) and all pages of the consent form(s) will be faxed to the ODQ at 617-
632-2295. The ODQ will (a) review the eligibility checklist, (b) register the participant on the 
protocol, and (c) randomize the participant.
Randomization can only occur during ODQ business hours (8:30am - 5pm Eastern Time, 
Monday through Friday excluding holidays).
An email confirmation of the registration and/or randomization will be sent to the Overall PI, 
study coordinator(s) from the Lead Site, treating investigator and registering person immediately 
following the registration and/or randomization.
Following DF/HCC registration, participants may begin protocol therapy. Following registration, 
participants should begin protocol therapy within 21 days. Start of protocol therapy for patients 
on Arm 2 is defined as the start of the experimental drugs (apalutamide and abiraterone acetate). 
Since Arm 1 is a continuation of the treatment they are currently receiving, they will be 
considered on protocol therapy once they are randomized. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2 Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101A) must be followed. 
4.3 General Guidelines for Other Investigative Sites 
Eligible participants will be entered on study centrally at DF/HCC.   The required forms will be 
provided to sites by the study coordinator. Following registration, participants should begin 
protocol therapy within 21 days. Start of protocol therapy for patients on Arm 2 is defined as the 
start of the experimental drugs (apalutamide and abiraterone acetate). Since Arm 1 is a 
continuation of the treatment they are currently receiving, they will be considered on protocol 
therapy once they are randomized. Issues that would cause treatment delays should be discussed 
with the Overall PI. 
4.4 Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the research nurse or 
data manager and e-mailed to the Coordinating Center:

Copy of screening test results, including imaging and pathology results 

Signed participant consent form


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13

HIPAA authorization form

Eligibility checklist

Clinic note, covering screening requirements and baseline AEs

Additional screening assessments 
The research nurse or data manager at the participating site will send the registration packet via 
email to the project manager at DFCI CTO.  To complete the registration process, the 
coordinator will follow DF/HCC Standard Operating Procedure for Human Subject Research 
Titled Subject Protocol Registration (SOP #: REGIST-101A) and register the participant on the 
protocol.  The coordinator will e-mail the participant study number and treatment assignment to 
the participating site. 
 
4.5 Randomization  
Subjects will be randomized by DF/HCC Office of Data Quality (ODQ) in a 1:1 ratio to either 
ARM 1 or ARM 2.  Cycle 1 Day 1 is considered the first day of treatment.  Following 
registration and randomization, subjects may begin protocol treatment.  Issues that would cause 
treatment delays should be discussed with the sponsor-investigator.
4.6 Stratification Factors
Stratification will be done prior to the randomization process and will include the following 
factors to ensure they are balanced between the treatment arms: 

PSAn level following RT and 6-12 months of ADT (> vs ≤ 0.5 ng/ml)

Planned total duration of ADT (12 vs. > 12 months)

USA vs. Canada
5. TREATMENT PLAN
5.1 Treatment Regimen
Subjects randomized to Arm 1 (control group) will continue to receive an LHRH agonist or 
antagonist for the duration of planned ADT. Treatment with an anti-androgen (bicalutamide) as 
well is at the discretion of the physician. 
Subjects randomized to Arm 2 (investigational treatment arm) will continue to receive an LHRH 
agonist or antagonist and apalutamide, abiraterone acetate (Zytiga), and prednisone for the 
duration of planned ADT. If patient is taking an anti-androgen at the time of randomization (i.e. 
bicalutamide), the patient is to discontinue use at least 24 hours prior to start of study drugs.
Table 1: 
Arm
Treatment
Dose
Frequency of 
administration
Route of 
administration
1
LHRH Agonist or 
Antagonist 
As prescribed


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Abiraterone 
Acetate 
1000 mg
Daily
Orally
Prednisone
5 mg
Twice Daily
Orally
Apalutamide
240 mg
Daily
Orally
2
LHRH Agonist or 
Antagonist
As prescribed
5.2 Pre-Treatment criteria
See eligibility criteria (Section 3.1).
5.3 Agent Administration
5.3.1
Arm 1
Guidelines for each medication are provided below and site investigator’s discretion may be 
used.  Subjects on ARM 1 will not be asked to record actual dosing of all medications in a drug 
diary.
5.3.1.1 LHRH Agonist or Antagonist
In both Arms, LHRH agonist or antagonist should be prescribed per standard of care and 
according to the product information. Permitted LHRH agonists or antagonists include but are 
not limited to leuprolide, goserelin, triptorelin, histrelin, and degarelix.
5.3.2
Arm 2
Guidelines for each medication are provided below and site investigator’s discretion may be 
used.  There is no specified order of administration of the study drugs (abiraterone acetate and 
apalutamide) prescribed in this protocol.  Subjects on ARM 2 will be asked to record actual 
dosing of all medications in a drug diary (Appendix C).  This diary should be brought to each 
clinic visit and reviewed by research staff. At the start of each cycle, patients should start new 30 
day bottle. Once a new cycle starts, patients are to review drug accountability of previous cycle 
with study team member (MD/NP/PA/RN) and leave any unused drug from that cycle in the 
respected bottles. At their next in person visit, patient will return all drug bottles, any unused 
drug, and drug diaries.
5.3.2.1 Abiraterone Acetate (AA)
Abiraterone acetate 1000 mg orally (four 250-mg tablets) will be taken daily.  Each bottle 
contains a 30-day supply (120 tablets).  Abiraterone acetate should be taken at the same time 
every day on an empty stomach.  No food should be consumed for at least two hours before the 
dose and for at least one hour after the dose. The tablets should be swallowed whole with water.  
Do not crush or chew tablets.  If a dose is skipped or missed, it should only be taken if within 12 


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15
hours of schedule dosing time.  If vomited, do not retake.  Subjects will be asked to return 
unused drug and empty drug containers at each clinic visit.  Women who are pregnant or who 
may be pregnant should wear gloves if they need to touch AA tablets. Study staff and caregivers 
should be notified of this information, to ensure that appropriate precautions are taken.
5.3.2.2 Prednisone
Prednisone 5 mg orally will be taken twice daily. Prednisone will be provided as a prescription 
(30, 60, or 90-day supply with refills) at the subject’s local pharmacy.  It is recommended that 
prednisone is taken with food.  If a dose is skipped or missed, it should only be taken if within 12 
hours of scheduled dosing time.  Prednisone is given in conjunction with abiraterone acetate to 
decrease the risk of mineralocorticoid excess caused by abiraterone acetate.  
5.3.2.3 Apalutamide
Apalutamide 240 mg orally (four 60-mg tablets) will be taken daily.  Each bottle contains a 30-
day supply (120 tablets).  Apalutamide can be taken with or without food at the same time every 
day.  If a dose is skipped or missed, it should only be taken if within 12 hours of scheduled 
dosing time.  If vomited, do not retake.  Subjects will be asked to return unused drug and empty 
drug containers at each clinic visit.  
5.3.2.4 LHRH Agonist or Antagonist 
LHRH agonist or antagonist should be prescribed per standard of care and according to the 
product information. Permitted LHRH agonists or antagonists include but are not limited to 
leuprolide, goserelin, triptorelin, histrelin, and degarelix. LHRH agonist or antagonist will be 
administered in clinic. Receipt of LHRH agonist or antagonist does not need to be documented in 
the drug diary.
5.4 Concomitant Medications
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a subject. All concomitant medications administered within 14 days prior to Cycle 1 Day 
1 and throughout the study until the treatment termination visit will be collected on study-
specific electronic Case-Report Forms (eCRFs). The reason(s) for treatment and dates of 
treatment should be reported to the site investigator and recorded as instructed on the study-
specific eCRFs.
5.4.1
Allowed Concomitant Medications
It is recommended that subjects take calcium carbonate (e.g., Caltrate, Tums) at a dose of at least 
500 mg orally per day every evening and Vitamin D orally at least 400 IU daily.  Calcium is best 
absorbed when taken with meals.
Treatment or prevention of osteoporosis:

Zoledronic acid

Denosumab (e.g., Prolia)

Other approved agents
5.4.2
Prohibited Concomitant Medications
Traditional herbal medicines should not be administered because the ingredients of many herbal 


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16
medicines are not fully studied and their use may result in unanticipated drug-drug interactions 
that may cause or confound assessment of toxicity.
If it is necessary for the well-being of the subject and alternative therapies are not available, 
these drugs should be used with caution and after discussion with the sponsor-investigator.
If a site investigator suspects a drug-drug interaction, the sponsor-investigator should be 
contacted.  
5.4.3
Potential Drug Interactions with Abiraterone Acetate and CYP3A4 Inducers and 
Inhibitors
Based on in vitro data, abiraterone acetate is a substrate of CYP3A4. In a dedicated drug 
interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of 
abiraterone by 55%. During the treatment phase of this trial, strong CYP3A4 inducers are 
prohibited. If a strong CYP3A4 inducer must be co-administered, the patient will be ineligible 
for this trial.  In a dedicated drug interaction trial, co-administration of ketoconazole, a strong 
inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of 
abiraterone. Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzymes 
CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of 
dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when 
dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice 
daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow 
therapeutic index (e.g., thioridazine). If an alternative treatment cannot be used, exercise caution 
and consider a dose reduction of the concomitant CYP2D6 substrate.  In a CYP2C8 drug-drug 
interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased 
by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone 
acetate. Therefore, patients should be monitored closely for signs of toxicity related to a 
CYP2C8 substrate with a narrow therapeutic index, if used.
Concomitant use of medications that may alter pharmacokinetics of abiraterone acetate or 
apalutamide will not be allowed on this study.  Specifically, strong CYP3A4 inhibitors or 
inducers that decrease the exposure of abiraterone acetate will not be allowed.  Apalutamide is 
metabolized primarily by human CYP3A4, thus co-administration with strong inhibitors or 
inducers of CYP3A4 is not allowed. The CYP3A4 inhibitors and inducers listed in Table 2 are 
prohibited concomitant medications.
Table 2   Strong CYP3A4 Inducers and Inhibitors
Strong CYP3A4 Inducers
Strong CYP3A4 Inhibitors
Aminoglutethimide
Atazanavir
Bexarotene
Clarithromycin
Bosentan
Delavirdine
Carbamazepine
Diltiazem
Dexamethasone
Erythromycin
Efavirenz
Indinavir
Fosphenytoin
Itraconazole
Griseofulvin
Nefazodone


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Modafinil
Nelfinavir
Nafcillin
Ritonavir
Nevirapine
Saquinavir
Oxcarbazepine
Telithromycin
Phenobarbital
Verapamil
Phenytoin
Voriconazole
Primidone
Grapefruit juice (or grapefruits)
Rifabutin
Rifampin
Rifapentine
Tipranivir
St. John's wort
5.4.4
Potential Drug Interactions with Apalutamide and Anti-Seizure Medications
As a class effect, AR antagonists have been associated with seizures due to an off-target 
mechanism of action (gamma amino butyric acid chloride channel [GABAA] inhibition). Drugs 
known to lower the seizure threshold or cause seizures are prohibited and a representative list is 
included below: 

Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone)

Bupropion

Lithium

Meperidine and pethidine

Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine)

Tricyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, 
maprotiline, mirtazapine
Table 3     Medications prohibited while on active treatment with Apalutamide
Generic Name
Brand Name*
aminophylline
Aminocont; Aminomal; Diaphyllin; Filotempo; Neophyllin; Norphyl; 
Phyllocontin; Syntophyllin; Tefamin; Truphylline; Xing You Shan; 
aminophylline in 
combination
Asmeton; Cha Xin Na Min; Emergent-Ez; Fufang Dan An Pian; Ke 
Zhi
amitriptyline
Amirol; Amitrip; Amixide; Deprelio; Diapatol; Elatrol; cElatrolet; 
Elavil; Endep; Enovil; Emitrip; Klotriptyl; Laroxyl; Levate; 
Limbitrol; Limbitryl; Mutabase; Mutabon; Nobritol; Novo-Triptyn; 
Pertriptyl; Redomex; Saroten; Sarotex; Sedans; Syneudon; Teperin; 
Triptizol; Triptyl; Tryptizol
amitriptyline in 
combination
PMS-Levazine
bupropion
Aplenzin; Buproban; Contrave; Elontril; Forfivo; Fortivo XL; Le Fu 
Ting; Prexaton; Quomem; Voxra; Wellbutrin; Wellbutrin XL; 
Wellbutrin SR; Yue Ting; Zyban
chlorpromazine
Aminazin; Chlorazin; Hibernal; Klorproman; Largactil; Megaphen; 


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Ormazine; Plegomazin; Solidon; Taroctyl;Thorazine; Vegetamin; 
Wintermin; Zuledin
NOTE: in Ireland also called “Clonazine” – very easy to confuse 
with clozapine.
clozapine
Azaleptin; Clopine; Closastene; Clozaril; CloZAPine; Denzapine; 
Elcrit; Fazacio ODT; Klozapol; Lanolept; Leponex; Lozapine; 
Nemea; Ozapim; Synthon, Versacloz; Zaponex
desipramine 
Deprexan; Norpramin; Nortimil; Pertofrane
doxepin
Adapin; Anten; Aponal; Deptran; Gilex; Li Ke Ning; Quitaxon; 
Silenor; Sinepin; Sinequan; Zonalon
imipramine
Impril; Melipramin; Mipralin; Norfranil; Novo-Pramine; Persamine; 
Pertofram; Pryleugan; Talendep; Tofranil; Tolerade
lithium
Arthriselect; Camcolit; Carbolith; Carbolithium; Eskolith; Hypnorex; 
Li-Liquid; Licarbium; Limas; Liskonum; Litarex; Lithane; Lithicarb; 
Lithioderm; Lithionit; Lithobid; Liticarb; Litiomal; Lito; Maniprex; 
Neurolepsin; Plenur; Priadel; Quilonorm; Quilonum; Saniquiet; 
Sedalit; Teralithe
lithium in combination
Boripharm No 23; Emser Salz; Girheulit HOM; Helidonium-Plus; 
Heweurat N; rheuma-loges; Rhus Toxicodendron Compose; Rhus-
Plus; Ricinus Compose
maprotiline
Cronmolin; Deprilept; Ludiomil; Mapromil; Melodil; Neuomil; 
Psymion
meperidine/pethidine
Alodan; Atropine and Demerol; Centralgine; Demerol; Dolantin; 
Dolantina; Dolantine; Dolargan, Dolcontral; Dolestine; Dolosal; 
Dolsin; Fada; Hospira; Liba; Mepergan; Meprozine, Mialgin; 
Opystan; Pethidine; Petigan Miro; Psyquil compositum
meperidine/pethidine 
in combination
Pamergan P100
mesoridazine
Serentil; Mesorin
mirtazapine
Arintapin; Avanza; Axit; Combar; Esprital; Mi Er Ning; Miro; Mirta 
TAD; Mirtabene; Mirtachem; Mirtadepi; Mirtagamma; Mirtalan; 
MirtaLich; Mirtamylan; Mirtaron; Mirtaz; Mirtazelon; Mirtazon; 
Mirtazonal; Mirtel; Mirtin; Mirtor; Mirzaten; Norset; Noxibel; 
Paidisheng; Psidep; Remergil; Remergon; Remeron; Remirta; Rexer; 
Yarocen; Zispin
olanzapine
Anzorin, Arenbil; Arkolamyl; Atyzyo; Bloonis; Clingozan; Egolanza; 
Lansyn; Lanzek; Lazapix; Nolian; Nykob; Olafid; Olanzaran; 
Olanzep; Olanzin; Olanzine; Olapin; Olasyn; Olazax; Olpinat; 
Olzapin; Olzin; Ou Lan Ning; Ozilormar; Parnassan; Ranofren; 
Sanza; Stygapon; Synza; Ximin; Zalasta; Zamil; Zappa; Zapris; 
Zerpi; Zolafren; Zolaxa; Zonapir; Zopridoxin; Zylap; Zypadhera; 
Zypine; Zyprexa; Zyprexa Relprew; Zydis
olanzapine in 
combination
Symbyax
risperidone
Aleptan; Apo-Risperid; Arketin; Calmapride; Diaforin; Doresol; 


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Hunperdal; Jing Ping; Ke Tong; Leptinorm; Lergitec; Orizon; Ozidal; 
Perdox; Ranperidon; Resdone; Ridal; Ridonex; Rileptid; Ripedon; 
Risepro; Rispa; Rispaksole; Rispefar; Rispemylan; Rispen; Rispera; 
Risperanne; Risperdal; Risperdalconsta; Risperdaloro; 
Risperigamma; Risperon; Rispolept; Rispolux; Rispond; Rispons; 
Risset; Rixadone; Rorendo; Ryspolit; Si Li Shu; Sizodon; Speridan; 
Suo Le; Torendo; Zhuo Fei; Zhuo Fu; Ziperid; Zoridal
theophylline
Aerolate; Afonilum; Aminomal; An Fei Lin; Apnecut; Apo-Theo; 
Asmalix; Asmalon; Bi Chuan; Bronchoparat; Bronchoretard; Cylmin; 
Diffumal; Elixifilin; Elixophyllin; Etipramid; Euphyllin; Euphyllina; 
Euphylline; Euphylong; Frivent; Gan Fei Lin; Nuelin; Protheo; 
Pulmophylline; Quelesu; ratio-Theo-Bronc; Respicur; Retafyllin; Shi 
Er Ping; Slo-Bid; Slo-Phyllin; Telbans; Teotard; Terdan; Teromol; 
Theo-24; Theo-Dur; Theo; Theochron; Theodur; Theofol; Theolair; 
Theoplus; Theospirex; Theostat ;  Theotard; Theotrim; Theovent; 
Tromphyllin; Unicon; Unicontin; Unifyl; Uniphyl; Uniphyllin 
Continus; Uniphyllin; UniXan; Xanthium; Xi Fu Li; Yan Er
theophylline in 
combination
Antong; Baladex; Bi Chuan; Binfolipase; Broncho-Euphyllin; 
Broncomar; Do-Do ChestEze; Elixophyllin-GG; Elixophyllin-KI; 
Insanovin; Marax ; Neoasma; Theofol Comp; Theophedrinum-N; Xu 
Hong; Yi Xi Qing
thioridazine
Detril; Elperil; Melleril; Ridazin; Ridazine; Thiodazine; Thioril; 
Sonapa
ziprasidone
Geodon; Li Fu Jun An; Pramaxima; Si Bei Ge; Ypsila; Zeldox; 
Zipwell; Zypsila; Zypsilan
** NOTE:  this document is intended as an aid in identifying prohibited meds, but due to the 
global scope of the apalutamide studies it may not be all inclusive. 
5.4.5
Potential Drug Interactions with Apalutamide and Anti-Coagulation Medications 
The potential for drug-drug interaction between apalutamide and warfarin (eg, Coumadin), as 
well as other anti-coagulation medications, 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.
5.4.6
Effect of apalutamide on abiraterone acetate and prednisone
The potential for drug-drug interactions between abiraterone acetate and prednisone with 
apalutamide to assess whether combined intake of abiraterone acetate and prednisone with 
apalutamide may lead to reduced abiraterone and prednisone exposure levels because of 
induction caused by apalutamide was assessed in a Phase 1b open label study conducted in 
subjects with mCRPC. Exposure to abiraterone decreased by 24% and 14% for Cmax and AUC0-24 
, respectively, and exposure to prednisone decreased by 51% and 61% for Cmax and AUC0-24, 
respectively when co-administered with apalutamide. Based on these data, the recommended 
dose of prednisone is 5 mg two times per day when abiraterone is co-administered with 
apalutamide. No change to the usual clinical dose of abiraterone acetate is recommended


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5.5 Supportive Care
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, anti-emetics, etc., when appropriate. 
5.6 Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on subject response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
the duration of hormonal therapy or until one of the following criteria applies, whichever comes 
first:

Disease progression 

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Subject demonstrates an inability or unwillingness to comply with the oral medication 
regimen and/or documentation requirements

Subject decides to withdraw from the protocol therapy

General or specific changes in the subject's condition render the subject unacceptable for 
further treatment in the judgment of the site investigator

Protocol therapy is interrupted for ≥ 21 days

Requirement of 2 dose reductions
Subjects will be removed from the protocol therapy when any of these criteria apply.  The reason 
for removal from protocol therapy, and the date the subject was removed, must be documented in 
the case report form (CRF). Alternative care options will be discussed with the subject.
When a participant is removed from protocol therapy and/or is off the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore. 
5.7 Duration of Follow Up
Patients will be on treatment for the duration of their originally planned ADT, which would be 
anywhere between at least 6 months to 30 months. After completion of study drug, active follow 
up will be every 6 months until study completion, being when we reach the required number of 
observed metastasis to do the final study analysis. At baseline and at each follow up, a PSA and 
total serum testosterone level will be obtained in addition to physician assessed toxicity using the 
National Cancer Institute Common Terminology Criteria for Adverse Events. CT or MRI of the 
chest, abdomen and pelvis, and bone scan or any type of PET CT are to be done once; at the time 
of initial PSA failure, defined as PSA at nadir + 2 ng/ml and testosterone level above 50 ng/dl. 
After results of protocol required scans at sign of PSA failure, investigator should initiate salvage 
therapy at their discretion. Then, if the PSA is still + 2 ng/ml above nadir and the testosterone is 
lower than 50 ng/dl while still on salvage ADT, also known as castrate resistant PSA failure, 
imaging is to be done every 6 months or sooner if the investigator chooses, until distant 
metastasis defined as bone, lymph node or visceral metastasis is documented. Survival status can 
be assessed using public records.


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Note:  If the treating physician decides to initiate salvage therapy prior to the patient’s PSA 
reaching nadir +2 ng/ml, and the testosterone level is < 50 ng/ml, then this would also be 
considered castrate resistant PSA failure and the imaging should be done then and every 6 
months thereafter.
5.8 Criteria for Taking a Participant Off Study
Subjects will be removed from the study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a subject off study, and the date the subject was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101.
5.9 Replacement
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been assigned to treatment or administered at least one dose 
of the study drug.  Subjects who have dropped out will not be replaced.
6. DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following tables. The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5 should be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5 can be downloaded from the CTEP website:
 https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm .
All adverse events experienced by subjects will be collected from the time of the first dose of 
study treatment, throughout the study, until the end-of-treatment visit.  Subjects continuing to 
experience toxicities at the end-of-treatment visit may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible.
If study medications are held for more than a total of 21 days, the subject should be discontinued 
from protocol treatment.  Treatment interruption and re-initiation not covered in the following 
guidelines should be discussed with the sponsor-investigator.  
6.1 Dose Modifications for Toxicity Attributed to Apalutamide
Dose modifications are provided as guidance and should not replace the site investigator’s 


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clinical judgment.
Toxicity
Dose of
Abiraterone Acetate
Dose of 
Prednisone
Dose of 
Apalutamide
Grade 1 or 2
No change
No change
No change
Grade ≥ 3 
No change
No change
Hold until Grade 1 or baseline, 
resume at full dose
First Recurrence
Grade ≥ 3
No change
No change
Hold until Grade 1 or baseline, 
resume at 180 mg (3 tablets)
Second Recurrence
Grade ≥ 3
No change
No change
Hold until Grade 1 or baseline, 
resume at 120 mg (2 tablets)
Third Recurrence
Grade ≥ 3
No change
No change
Discontinue
First occurrence of 
seizure (any grade) or 
Grade 4 neurotoxicity
No change
No change
Discontinue
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 21 days

Initiate dermatological treatmenta
o
Topical steroid cream AND
o
Oral Antihistamines

Monitor for change in severitya


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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 21 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 21 days, rash has not resolved to Grade ≤ 1, contact 
PI who will contact Janssen to discuss further 
management and possible discontinuation of study drug. 
Note: Rash may be graded differently according to the type of rash and associated symptoms. 
For example, maculo-papular rash is graded by body surface area covered and not severity of the 
rash. Please consult NCI-CTCAE Version 5 for specific grading criteria for other types of rash.
a Obtain bacterial/viral cultures if infection is suspected
b Subject presents with other rash related symptoms such as pruritus, stinging, or burning
c 1 dose level reduction = 60mg (1 apalutamide tablet)
d If there is blistering or mucosal involvement, stop apalutamide dosing immediately and 
contact PI who will 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 PI who will contact Janssen.
6.2 Dose Modifications for LFT Abnormalities Attributed to Abiraterone Acetate
Dose modifications are provided as guidance and should not replace the site investigator’s 
clinical judgment.
Toxicity
Dose of Abiraterone Acetate
Dose of Apalutamide Dose of Prednisone
Grade 1 or 2
No change
No change
No change


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Grade 3
Hold until return to baseline 
or until AST or ALT
≤ 2.5 x ULN and 
total bilirubin ≤ 1.5 x ULN, 
RESUME at 750 mg (3 
tablets) only after discussion
 and agreement with 
sponsor-investigator
Hold until return to 
baseline
No change
Recurrence
Grade 3
Hold until return to baseline 
or to AST or ALT
≤ 2.5 x ULN and 
total bilirubin ≤1.5 x ULN, 
RESUME at 500 mg (2 tablets) 
only after discussion and 
agreement with sponsor-
investigator
Hold until return to 
baseline
No change
Grade 4
Discontinue 
abiraterone acetate treatment
Hold until return to 
baseline
No change 
or consider 
tapering if 
abiraterone 
acetate 
discontinued
Concurrent elevation 
of AST/ALT > 3x 
ULN with bilirubin 
>2x ULN (unless the 
concurrent elevation is 
related to biliary 
obstruction or other 
causes unrelated to 
study treatment)
Discontinue abiraterone acetate 
treatment
No change or 
consider tapering 
if abiraterone 
acetate 
discontinued
ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function tests; ULN=upper 
limit of normal
Permanently discontinue abiraterone acetate for subjects who develop a concurrent 
elevation of ALT greater than 3 X ULN and total bilirubin greater than 2 X ULN in the 
absence of biliary obstruction or other causes responsible for the concurrent elevation.
6.3 Dose Modifications for Hypokalemia Attributed to Abiraterone Acetate 
Dose modifications are provided as guidance and should not replace the site investigator’s 
clinical judgment.
Toxicity
Dose of Abiraterone 
Acetate
Dose of Apalutamide
Dose of 
Prednisone


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Grade 1 or 2
Initiate oral potassium 
supplementation,
titrate to
≥ 3.5 to ≤ 5.0 mmol/L, 
maintenance at ≥ 4.0 mmol/L 
recommended
No change
No change
Grade ≥ 3
Hold abiraterone acetate 
and initiate IV potassium 
and cardiac monitoring, 
resume only after discussion 
and approval
by the sponsor-investigator
No change
No change 
or consider tapering 
if abiraterone acetate
 is discontinued
6.4 Dose Modifications for Hypertension and Edema/Fluid Retention Attributed to 
Abiraterone Acetate 
Dose modifications are provided as guidance and should not replace the investigator’s own 
clinical judgment.
Toxicity
Dose of Abiraterone Acetate
Dose of Apalutamide
Dose of Prednisone
Grade 1 or 2
No change
No change
No change
Grade ≥ 3
Hold until Grade 1 or baseline, 
resume at full dose
No change
No change
First
Recurrence
Grade ≥ 3
Hold until Grade 1 or baseline, 
resume at 750 mg (3 tablets)
No change
No change
Second
Recurrence
Grade ≥ 3
Hold until Grade 1 or baseline, 
resume at 500 mg (2 tablets)
No change
No change
Third
Recurrence
Grade ≥ 3
Discontinue
No change
No change or consider 
tapering if 
abiraterone acetate 
is discontinued
6.5 Dose Modifications for Toxicity Attributed to LHRH agonist
There are no dose modifications for LHRH agonist or antagonist.


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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
7.1 Adverse Events
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. A list of 
anticipated adverse events can be found in Section 8 of this protocol. The following list of 
reported and/or potential AEs and the characteristics of an observed AE will determine whether 
the event requires expedited reporting in addition to routine reporting.

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5 should be utilized for dose delays and dose modifications. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5. A copy of the CTCAE 
version 5 can be downloaded from the CTEP website:
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.
7.2 Overview
As the Sponsor of the study, Anthony V. D’Amico, M.D. Ph.D. shall be solely responsible for 
complying, within the required timelines, with any safety reporting obligation to competent 
Health Authorities, IRB/ECs and any participating (co- or sub-) investigators, as defined in 
applicable laws and regulations.  Safety data includes adverse events, product quality complaints 
(PQCs), and special situations including partner pregnancies.
Anthony D’Amico, M.D. Ph.D. will provide safety information to Janssen on adverse events, 
special situations including partner pregnancies and product quality complaints (PQC).
7.3 Management of Safety Data
This study has been designated as an interventional study.  As such, all adverse events regardless 
of causality and special situations excluding those from subjects not exposed to a Janssen 
Medicinal Product and PQCs with or without an adverse event will be reported from the time a 
subject has signed and dated an Informed Consent Form (ICF) until completion of the subject’s 
last study-related procedure (which may include contact for follow-up safety).  Serious adverse 
events will be reported for 30 days after the last dose of study drug.
For the purposes of this study, the Janssen medicinal products are:
Abiraterone acetate
Apalutamide (JNJ-56021927)


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7.4 Definitions
7.4.1
Adverse Event (AE)
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 Harmonisation [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.
7.4.2
Adverse Events of Special Interest (AESI)
Adverse events of special interest are events that Janssen is actively monitoring as a result of a 
previously identified signal (even if non-serious).

There are currently no adverse of special interest identified for apalutamide or abiraterone 
acetate.
7.4.3
Individual Case Safety Report (ICSR)
ICSRs are documentation required by Janssen for AE reporting.  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

adverse event detail (AE verbatim in English), onset date, relatedness, causality, action 
taken, outcome, (if available)

Janssen protocol ID
7.4.4
Product Quality Complaint (PQC)
A product quality compliant is defined as any suspicion of a product defect related to a potential 


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28
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product, or delivery system.  Not all PQCs involve a 
subject.  Lot and batch numbers are of high significance and need to be collected whenever 
available.
Examples of PQC include but not limited to:

Functional Problem: e.g., altered delivery rate in a controlled release product

Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules

Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe

Suspected Contamination

Suspected Counterfeit
7.4.5
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.
7.4.5.1 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.
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 


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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.]
7.4.5.2 Life Threatening Conditions
The cause of death of a subject in a study within 30-days of the last dose of apalutamide or 
abiraterone acetate, whether or not the event is expected or associated with the study drug, is 
considered a serious adverse event.
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI.
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.
7.4.6
Unexpected Adverse Event
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.  Please refer to section 8 for a partial list of expected AEs for 
each drug.  
7.4.7
Relatedness
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms: 
Unrelated
Adverse Event is not related to the study drug(s) 
Unlikely
Adverse Event is doubtfully related to the study drug(s) 
Possible
Adverse Event may be related to the study drug(s) 
Probable
Adverse Event is likely related to the study drug(s) 
Definite
Adverse Event is clearly related to the study drug(s) 
7.5 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 link to the package insert is:
http://www.janssenlabels.com/package-insert/product-monograph/prescribing-
information/ERLEADA-pi.pdf 


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For abiraterone acetate, the link to the package insert is:
http://www.janssenlabels.com/package-insert/product-monograph/prescribing-
information/ZYTIGA-pi.pdf
7.6 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 

Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen 
medicinal product, such as lack of any decline in PSA after 3 months.

Medication error involving a Janssen medicinal product (with or without patient exposure 
to the Janssen medicinal product, e.g., name confusion)

Suspected transmission of any infectious agent via administration of a medicinal product

Unexpected therapeutic or clinical benefit from use of a Janssen 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.
7.7 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 Anthony V. D’Amico, 
M.D within 24 hours of his knowledge of the event using the Serious Adverse Event Form.  
Depending on local legislation this may require prior consent of the partner.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
7.8 Maintenance of Safety Information
All safety data should be maintained in a clinical database in a retrievable format. DF/HCC and 
Anthony V. D’Amico, MD 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 


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a reasonable timeframe at Janssen’s request.
7.9 Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Janssen Medicinal Products to Janssen
All adverse events and special situations whether serious or non-serious, related or not related, 
following exposure to a Janssen medicinal product are to be documented by the investigator and 
recorded in the CRF and in the subject’s source records. Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to a Janssen medicinal product. 
All (serious and non-serious) adverse events reported for a Janssen medicinal product should be 
followed-up in accordance with clinical practice.
7.9.1
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)
DF/HCC and Dr. Anthony D’Amico will transmit all SAEs and special situations following 
exposure to a Janssen product under study in a form provided by Janssen in accordance with 
Section 7.11, Transmission Methods, in English within 24-hours of becoming aware of the 
event(s).
Participating investigators must report each SAE to the Sponsor Investigator (Dr. Anthony 
D’Amico) within 24 hours of learning of the occurrence. In the event a participating investigator 
is not made aware of the SAE immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it and document 
the time of his or her first awareness of the AE. 
Non-DF/HCC sites participating in this research are also expected to submit each SAE to its 
local Ethics Committee according to FDA and local IRB guidelines.
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 Dr. Anthony D’Amico, within 
24 hours becoming aware, to the Janssen using the Janssen’s Serious Adverse Event Report. 
All available clinical information relevant to the evaluation of a related SAE or special situation 
is required.


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
DF/HCC and/or the PI are responsible for ensuring that these cases are complete and 
if not are promptly followed-up. A safety report is not considered complete until all 
clinical details needed to interpret the case are received. Reporting of follow-up 
information should follow the same timeline as initial reports.

Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association 
with the Janssen Product under study, are to be provided to Janssen using a 
transmission method in Section 11 within 24 hours of such report or 
correspondence being sent to applicable health authorities.
7.9.2
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.
7.9.3
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 PI 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 PI 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.
7.10
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 PI 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.
7.11
Transmission Methods
The following methods are acceptable for transmission of safety information to Janssen:


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33

Electronically via Janssen SECURE Email service (preferred)

For business continuity purposes, if SECURE Email is non-functional:
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.
7.12
Reconciliation of SAEs
At a minimum, on a quarterly basis and at the end of the Study, Janssen will provide to the 
institution and/or PI, a listing of all SAEs reported to Janssen.  The PI will review this listing and 
provide any discrepancies to Janssen.
Upon request, the PI shall provide Janssen with a summary list of all SAEs, and AEs of Special 
Interest and Special Reporting Situation reports to date, for reconciliation purposes.
7.13
Dissemination of Safety Information from Janssen to Principal Investigators
The PI will be responsible for submitting IND safety reports for the Study Product to the 
institution’s IRB in accordance with Federal regulations 21 CFR 312.66.  The PI will provide a 
copy of each IND safety report to sub-investigators where the study design is either a multi-
center or cooperative study.
Janssen agrees to provide to the PI IND safety reports for the Janssen Medicinal 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).
7.14
Contacting Janssen Regarding Safety
The names (and corresponding contact information) of the individuals who should be contacted 
regarding safety issues will be provided separately by Janssen.
7.15
Final Study Report
The PI will prepare a final report including a complete and full summary of all adverse events, 
special situations and pregnancy reports according to the timeframe outlined in the Research 
Funding Agreement.
7.16
Reporting
7.16.1 Adverse Events 

AEs will be recorded from time of signed informed consent until completion of the last 
study-related procedure. 

AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).  


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
All AEs will be reported to the sponsor-investigator, recorded in the subject’s medical 
record, and reported to Janssen and the DF/HCC IRB according to its requirements.

Subjects who have an ongoing study treatment-related AE upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline 
grade, the event is assessed by the site investigator as stable, new anticancer treatment is 
initiated, the subject is lost to follow-up, the subject withdraws consent, or until it has 
been determined that study treatment or participation is not the cause of the AE.  
7.17
IND Safety Reports Unrelated to this Trial
Janssen will provide IND safety reports from external studies that involve the study drug(s) to 
the sponsor-investigator.  The sponsor-investigator will determine if revisions are needed to the 
protocol or consent. DF/HCC study coordinator or project manager will forward these reports to 
participating sites within 1 business day of receiving the sponsor-investigator’s review.  Based 
on the sponsor-investigator’s review, applicable changes will be made to the protocol and 
informed consent document (if required).  
Site investigators (or designees) are responsible for submitting these safety reports to their 
respective IRBs, as per their IRB policies.
7.18
Expedited Adverse Event Reporting 
7.18.1 Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days 
of the last dose of treatment on the local institutional SAE form. 
7.18.2 For multi-institution studies where a DF/HCC investigator is serving as the 
Overall Principal Investigator, each participating institution must abide by the 
reporting requirements set by the DF/HCC. This applies to any medical event 
equivalent to an unexpected grade 2 or 3 with a possible, probable or definite 
attribution, unexpected grade 4 toxicities, and grade 5 (death) regardless of study 
phase or attribution.
7.18.3 DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below.  
DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 5 AE 
Expected or 
Unexpected


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Unrelated
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event.
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events. 
7.19
Expedited Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.20
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
7.21
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8. PHARMACEUTICAL INFORMATION
8.1 Abiraterone Acetate (AA)
Refer to the package insert for detailed pharmacologic and safety information.
8.1.1
Description
The chemical nomenclature of AA is 3β-acetoxy-17-(3-pyridyl) and rosta-5,16-diene. Its 
empirical formula is C26H33NO2 and it has a molecular weight of 391.55. Once absorbed after 
oral administration, AA is rapidly deacetylated and converted to the active form abiraterone. 
Abiraterone is metabolized by CYP3A4 and is an inhibitor of CYP2D6. 
8.1.2
Form
AA 250-mg tablets are oval, white to off-white and contain abiraterone acetate and compendial 
(USP/NF/EP) grade lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and purified 


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water, in descending order of concentration (the water is removed during tableting).
8.1.3
Storage and Stability
Pharmacy Storage Requirements: The study treatment must be stored in a secure area and 
administered only to subjects entered into the clinical study in accordance with the conditions 
specified in this protocol. Bottles of study treatment should be stored at a room temperature 
between 20-25º C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 
86°F) [see USP controlled room temperature].  Bottles should be stored with the cap kept on 
tightly and should not be refrigerated. 
8.1.4
Storage Requirements for the Subject
Bottles of study treatment should be stored at room temperature with the cap kept on tightly and 
should not be refrigerated. Subjects should be advised to keep all medications out of the reach 
and out of sight of children.
8.1.5
Compatibility
We do not anticipate any excess toxicity combining ARN-509 (apalutamide), AA, prednisone 
and LHRH agonists or antagonists. 
8.1.6
Handling
Study treatment must only be dispensed by a Pharmacist or medically qualified staff. Study 
treatment is to be dispensed only to subjects enrolled in this study. Once the study treatment is 
prepared for a subject, it can only be administered to that subject. Based on its mechanism of 
action, abiraterone acetate may harm a developing fetus.  Women who are pregnant or who may 
be pregnant should wear gloves if they need to touch AA tablets. Study staff and caregivers 
should be notified of this information, to ensure the appropriate precautions are taken.
8.1.7
Availability
Drug will be supplied by Janssen Scientific Affairs.  Subjects will be provided with either a 30, 
60, or 90 day supply. Information presented on the labels for the investigative product will 
comply with applicable local regulations. Site pharmacist will dispense the study treatment to 
each subject in accordance with this protocol under the guidelines of the site’s dispensation 
standard operating procedure. The agent will be provided free of charge to study subjects.
8.1.8
Ordering
Janssen does not ship product directly to individual participating study sites.  It will ship to a 
designated drug vendor who will handle the further distribution to sites.
8.1.9
Accountability
Accountability for study treatment is the responsibility of the site investigator.  The study site 
must maintain accurate records demonstrating dates and amount of study treatment (abiraterone 
acetate) received, to whom dispensed (subject), and accounts of any study treatment accidentally 
or deliberately destroyed.  Subjects will be asked to return unused drug and empty drug 
containers at each clinic visit.  At the end of the study, reconciliation must be made between the 
amount of study treatment supplied, dispensed, and subsequently destroyed.  At the time of 
delivery of study treatment to the site, the site investigator, designee, or Pharmacist (where 


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appropriate) will confirm that the supplies for the study have been received. This following 
information will be confirmed: lot numbers, quantities shipped/delivered, and date of receipt.
8.1.10  Destruction and Return
Drug should be destroyed at the site, after the sponsor– investigator approves the drug 
destruction policy at the site. Destruction will be documented in the Drug Accountability
Record Form.
8.1.11  Adverse Events
Consult the package insert for the comprehensive list of adverse events.  The most frequently 
reported AEs for abiraterone acetate include fatigue due to reduced cortisol level, resulting from 
CYP17 inhibition; hypertension; peripheral edema; and hypokalemia. Co-administration of 
prednisone 5 mg by mouth twice daily is anticipated to mitigate these anticipated AEs.  Other 
less common side effects associated with Abiraterone acetate include adrenocortical 
insufficiency (AI), hepatotoxicity, fatigue, joint swelling/discomfort, edema, hot flashes, 
diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.  The 
most common laboratory abnormalities are anemia, elevated alkaline phosphatase, 
hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, 
hypophosphatemia, elevated ALT and hypokalemia.  Consult the investigator’s brochure for the 
comprehensive list of adverse events.
8.2 Apalutamide (ARN-509, JNJ-56021927)
Refer to the package insert for detailed pharmacologic and safety information.
8.2.1
Description
Apalutamide is a potent and specific antagonist of the AR that is being developed for the 
treatment of men with prostate cancer.  The mechanism of action of ARN-509 is through 
antagonism of the androgen receptor and inhibition of AR nuclear translocation and DNA 
binding to ARs.
8.2.2
Form - Tablets
The ARN-509 drug substance is an almost white to slightly brown powder that is formulated in 
tablets at a strength of 60 mg.
8.2.3
Storage and Stability  
Tablets: ARN-509 tablets (60 mg) are packaged in 120-count, 160 cc HDPE bottles with CRC 
and include desiccant, and should at all times be kept in the original packaging.  
8.2.4
Compatibility
We do not anticipate any excess toxicity combining ARN-509, AA, prednisone and LHRH 
agonist or antagonist. 
8.2.5
Handling
There are no specific instructions for handling ARN-509. Study treatment must only be 
dispensed by a Pharmacist or medically qualified staff. Study treatment is to be dispensed only to 
subjects enrolled in this study. Once the study treatment is prepared for a subject, it can only be 


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administered to that subject. 
8.2.6
Availability
Drug will be supplied by Janssen Scientific Affairs.  Subjects will be provided with either a 30, 
60, or 90 day supply. Information presented on the labels for investigative product will comply 
with applicable local regulations. Site pharmacist will dispense the study treatment to each 
subject in accordance with this protocol under the guidelines of the site’s dispensation standard 
operating procedure. The agent will be provided free of charge to study subjects.
8.2.7
Ordering
Janssen does not ship product directly to individual participating study sites.  It will ship to a 
designated drug vendor who will handle the further distribution to sites.
8.2.8
Accountability
Accountability for study treatment is the responsibility of the site investigator.  The study site 
must maintain accurate records demonstrating dates and amount of study treatment 
(apalutamide) received, to whom dispensed (subject), and accounts of any study treatment 
accidentally or deliberately destroyed.  Subjects will be asked to return unused drug and empty 
drug containers at each clinic visit.
At the end of the study, reconciliation must be made between the amount of study treatment 
supplied, dispensed, and subsequently destroyed.  At the time of delivery of study treatment to 
the site, the site investigator, designee, or Pharmacist (where appropriate) will confirm that the 
supplies for the study have been received. This following information will be confirmed: lot 
numbers, quantities shipped/delivered, and date of receipt.
8.2.9
Destruction and Return
Drug should be destroyed at the site, after the sponsor– investigator approves the drug 
destruction policy at the site. Destruction will be documented in the Drug Accountability Record 
Form.
8.2.10 Adverse Events
Anticipated AEs from apalutamide clinical trials include fatigue, nausea, vomiting, diarrhea, 
constipation, anorexia, abdominal pain, taste alterations, rash, itching, insomnia, hot flashes, 
dizziness, falls, seizures, changes in thyroid function, increase in blood cholesterol, and 
decreased appetite. Consult the package insert for the comprehensive list of adverse events.
8.3 Prednisone
Refer to the package insert for detailed pharmacologic and safety information.
8.3.1
Description
Prednisone is a corticosteroid.
8.3.2
Form
Prednisone 5-mg tablets are small, white tablets.


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8.3.3
Storage and Stability
Prednisone will be prescribed by prescription and prescriptions may be filled at a pharmacy 
chosen by the subject.
8.3.4
Compatibility
We do not anticipate any excess toxicity combining apalutamide, abiraterone acetate, prednisone 
and LHRH agonist or antagonist. 
8.3.5
Handling
There are no specific instructions for handling prednisone.
8.3.6
Availability
Prednisone will not be provided by the study and will be prescribed by standard prescriptions.
8.3.7
Adverse Events
Prednisone may be associated with fatigue, increased appetite, insomnia, weakness, 
hyperglycemia, ecchymosis, and symptoms related to gastroesophageal reflux.  Consult the 
package insert for the comprehensive list of adverse events.  
8.4 LHRH Agonist or Antagonist
Refer to the package inserts for detailed pharmacologic and safety information.
8.4.1
Description
Leuprolide and goserelin are LHRH agonists. Degarelix is an LHRH antagonist.
8.4.2
Form
Leuprolide is a sterile solution administered as an intramuscular injection.  Goserelin implant is 
supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer 
impregnated with goserelin acetate in a disposable syringe device. Degarelix is supplied as a 
powder to be reconstituted with Sterile Water for Injection, USP (WFI).
8.4.3
Storage and Stability
Leuprolide, goserelin, and degarelix will be stored at the site pharmacy.
8.4.4
Compatibility
We do not anticipate any excess toxicity combining apalutamide, AA, prednisone and
LHRH agonist or antagonist, or with combining LHRH agonist or antagonist with Bicalutamide. 
8.4.5
Handling
There are no specific instructions for handling leuprolide, goserelin, or degarelix.
8.4.6
Availability
Leuprolide, goserelin, and degarelix will not be provided by the study and will be prescribed by 
standard prescriptions.


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8.4.7
Adverse Events
Class-related toxicity is generally a manifestation of the mechanism of action and due to low 
testosterone levels. The most common reported side effects of LHRH agonists and antagonists 
include hot flashes, edema, gynecomastia, bone pain, thrombosis, and gastrointestinal 
disturbances. Other side effects include impotence and loss of libido, weight gain, depression, 
dizziness, loss of bone density, anemia, increased thirst and urination, unusual taste in the mouth, 
skin redness or hives, pain at injection site, strength loss, hair changes, penile length and 
testicular volume loss, increased cholesterol, hypertension, diabetes exacerbation, emotional 
lability, nausea, vomiting, QT prolongation, and rarely allergic generalized rash and difficulty 
breathing. Consult the package insert for comprehensive toxicity information.


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9.  STUDY CALENDAR  
9.1 Arm 1 Calendar & Evaluations 
Screening
Screening
Study Visits q3 months 
during protocol treatment
End of 
Treatment
PSA 
Failure
Long Term 
Follow Up4
Study Evaluation
Within 90 days 
prior to registration
Within 42 days 
prior to registration
± 14 days
+ 7 days
+ 28 days
± 28 days
REQUIRED ASSESSMENTS
Informed Consent
X
Medical History 
X
Diagnosis and Staging Information
X
Physical Exam
X
X
Vital signs and ECOG Performance Status1
X
X
AEs & Concomitant medications
Conmeds only
X8
AEs only
LABORATORY ASSESSMENTS
Complete Blood Cell Count with diff (CBC)2
X
X
Chemistry Profile2
X
X
Liver Function Testing3
X
X
PSA
X
X
X
Testosterone
X
X
X
Thyroid function (TSH) 7
X
Coagulation Testing (INR, PT, PTT)
X
TREATMENT EXPOSURE
LHRH Agonist or Antagonist
X6
FOLLOW-UP
Metastatic Status
X
Survival Status
X
CT or MRI of the Chest, Abdomen, and Pelvis
X5
Bone Scan or any type of PET CT 
X5
Key to Footnotes 
1: Vital signs to include upright blood pressure, heart rate, respiratory rate, temperature, body weight (kg) and height (cm).  Height at SCREENING ONLY.  If 
patients are unable to come into clinic and get vitals or a physical exam during treatment, as long as it is not a danger to the patient, it will not be considered a 
violation or deviation. However, patients should have a blood pressure recording done within window of study visit or it will be considered a violation or deviation. 
The blood pressure recording can be done at home or in clinic. If done at home, the measurements should be relayed to the provider or research team member so it 
can be recorded in the patient’s medical record.
2: Hematology testing to include full CBC with WBC, ANC, hemoglobin, and platelet count and differential. Chemistry to include Na, K+, Chloride, CO2, BUN 
creatinine, calcium, glucose.


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3: Liver functions testing to include Albumin, ALT, AST, Total protein, Alk Phos, Total Bilirubin. LFTs will be monitored at every 3 months follow up during protocol 
treatment or more often at the discretion of the treating physician for the entire course of study treatment. 
4: Long term follow-up for metastasis and survival will occur every 6 months until we reach the required amount of metastasis for a total planned study duration of 
about 5 years, assuming 200 patients accrued per year.
5: CT or MRI of the chest, abdomen and pelvis, and bone scan or any type of PET CT to be done once, at the time of initial PSA failure, defined as PSA at nadir + 2 
ng/ml and testosterone level above 50 ng/dl. After results of protocol required scans at sign of PSA failure, investigator should initiate salvage therapy at their 
discretion. Then, if the PSA is still + 2 ng/ml above nadir and the testosterone is lower than 50 ng/dl while still on salvage ADT, also known as castrate resistant 
PSA failure, imaging is to be done every 6 months or sooner if the investigator chooses, until distant metastasis defined as bone, lymph node or visceral metastasis is 
documented. Survival status can be assessed using public records. Note:  If the treating physician decides to initiate salvage therapy prior to the patient’s PSA 
reaching nadir +2 ng/ml, and the testosterone level is < 50 ng/ml, then this would also be considered castrate resistant PSA failure and the imaging should be done 
then and every 6 months thereafter. 
6: Arm 1 patients: Telemedicine/virtual visits will be allowed during study treatment and follow up, per institutional policies. Only locally/institutionally approved 
systems may be used. C1D1 does not need to be done in person and can be done virtually since Arm 1 is a continuation of their current standard of care 
treatment/ADT regimen. Study visits will start when the patient’s next LHRHA injection is due. LHRHA schedules can vary but in most cases, the patient’s LHRHA 
injection will be every 3 months, therefore the first study visit will be when the next one is due. Should the patient be on monthly injections, the first study visit will 
be when the next monthly injection is due. In the instance where the patient is receiving 6-month injections, the patient’s first study visit will be within 3 months (a 
month is defined as 28 days) after registration or when the next LHRHA injection is due, whenever is sooner. Regardless of patient’s LHRHA injection schedule, 
study visits will be every 3 months after the first study visit.
7: Only patients who are participating in this trial in Canada should have TSH evaluated at screening. Patients randomized to Arm 1 do not need subsequent TSH 
tests. Free T3 and Free T4 should be done only if TSH is abnormal. Fasting not required. 
8:  If a patient is being seen virtually and not in person, AEs will still need to be followed, assessed, and documented throughout the course of the study treatment or 
until resolved.


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9.2 Arm 2 Calendar and Evaluations (cycle = 28 days)
Number of months left of ADT at time of registration = number of cycles on study (i.e. if patient has 12 more months of 
ADT left, he will have 12 cycles on study)
Screening
Screening
Treatment 
Cycle Day 1 
Treatment 
Cycle 1-3 
Day 15
End of 
Treatment
PSA 
Failure
Long 
Term 
Follow 
Up4
Study Evaluation
Within 90 
days prior to 
registration
Within 42 
days prior to 
registration
Every 28 
days ± 3
± 3 days
+ 7 days
+ 28 
days
± 28 
days
REQUIRED ASSESSMENTS
Informed Consent
X
Medical History 
X
Diagnosis and Staging Information
X
Physical Exam
X
X
Vital signs and ECOG Performance Status1
X
X
AEs & concomitant medications
Conmeds 
only
X8
AEs only
LABORATORY ASSESSMENTS
Complete Blood Cell Count with diff (CBC)2
X
X
Chemistry Profile2
X
X
Liver Function Testing3
X
X
X
PSA
X
Q3rd Cycle
X
Testosterone
X
Q3rd Cycle
X
Thyroid function (TSH) 7
X
C3D1
Coagulation Testing (INR, PT, PTT)
X
TREATMENT EXPOSURE
LHRH Agonist or Antagonist
 X6
Abiraterone acetate
X
Prednisone
X
Apalutamide 
X
FOLLOW-UP
Metastatic Status
X
Survival Status
X
CT or MRI of the Chest, Abdomen, and Pelvis
X5
Bone Scan or any type of PET CT
X5


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Key to Footnotes 
1: Vital signs to include upright blood pressure, heart rate, respiratory rate, temperature, body weight (kg) and height (cm).  Height at SCREENING ONLY.  AE 
review should include any cardiac events that may have happened since the last clinic visit. If patients are unable to come into clinic and get vitals or a physical 
exam during treatment, as long as it is not a danger to the patient, it will not be considered a violation or deviation. However, for C1D1 visits, patients should be seen 
in person by the sub-investigator to establish a baseline foundation. Study visits after C1D1 that are done virtually, those patients should still have a blood pressure 
recording done within window of study visit or it will be considered a violation or deviation. The blood pressure recording can be done at home or in clinic. If done 
at home, the measurements should be relayed to the provider or research team member so it can be recorded in the patient’s medical record.
2: Hematology testing to include full CBC with WBC, ANC, hemoglobin, and platelet count and differential.  Chemistry to include Na, K+, Chloride, CO2, BUN 
creatinine, calcium, glucose.  
3: Liver functions testing to include Albumin, ALT, AST, Total protein, Alk Phos, Total Bilirubin. LFTs will be monitored every 15 days for the first 3 months and 
then monthly during protocol treatment or more often at the discretion of the treating physician for the entire course of study treatment. 
4: Long term follow-up for metastasis and survival will occur every 6 months until we reach the required amount of metastasis for a total planned study duration of 
about 5 years, assuming 200 patients accrued per year.
5: CT or MRI of the chest, abdomen and pelvis, and bone scan or any type of PET CT to be done once, at the time of initial PSA failure, defined as PSA at nadir + 2 
ng/ml and testosterone level above 50 ng/dl. After results of protocol required scans at sign of PSA failure, investigator should initiate salvage therapy at their 
discretion. Then, if the PSA is still + 2 ng/ml above nadir and the testosterone is lower than 50 ng/dl while still on salvage ADT, also known as castrate resistant 
PSA failure, imaging is to be done every 6 months or sooner if the investigator chooses, until distant metastasis defined as bone, lymph node or visceral metastasis is 
documented. Survival status can be assessed using public records. Note:  If the treating physician decides to initiate salvage therapy prior to the patient’s PSA 
reaching nadir +2 ng/ml, and the testosterone level is < 50 ng/ml, then this would also be considered castrate resistant PSA failure and the imaging should be done 
then and every 6 months thereafter. 
6: Arm 2 patients: Telemedicine/virtual visits will be allowed during study treatment and follow up. Only locally/institutionally approved systems may be used. 
Patients must still get protocol-required bloodwork done and can be done at a local certified lab. C1D1 must be done in person, and then can be done virtually after 
the first cycle. Study visits will be monthly no matter what the LHRHA originally planned schedule is. Patients will receive their LHRHA when it is due or when 
instructed by their treating physician. 
7: Only patients who are participating in this trial in Canada should have TSH evaluated at screening and at Cycle 3 Day 1. Free T3 and Free T4 should be done only 
if TSH is abnormal. Fasting not required. 
8:  If a patient is being seen virtually and not in person, AEs will still need to be followed, assessed, and documented throughout the course of the study or until 
resolved.


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10. MEASUREMENT OF EFFECT
10.1
Progression Free Survival
10.1.1 Metastasis or Any Cause Death:  Metastasis or any cause death, defined as the 
time from randomization to documentation of metastasis or death due to any 
cause, whichever occurs first, or censored at the date of last disease assessment 
for those alive and metastasis free. Metastasis is defined as radiographic evidence 
of lymph node, bone or visceral involvement and can be evaluated using a CT or 
MRI chest, abdomen, and pelvis, and bone scan, or any type of PET 
10.1.2 Castrate Resistant PSA Failure Free Survival: Castrate resistant PSA failure is 
defined as the first PSA increase that is 2 ng/mL above the nadir, which is 
confirmed by a second value 3 or more weeks later, while the serum total 
testosterone level is < 50 ng/dl (per the PCWG2 criteria). Castrate resistant PSA 
failure free survival is the time from randomization to castrate resistant PSA 
failure or death from any cause, whichever comes first; or censored at the date of 
last disease assessment for those alive and PSA failure free.
10.1.3 Prostate Cancer Specific Survival:  Prostate cancer specific survival is defined 
as the time from randomization to death from prostate cancer where death due to 
other causes are considered as competing risk, or censored at the last date of 
follow up in living patients. 
10.1.4 Overall Survival: Overall Survival (OS) is defined as the time from 
randomization (or registration) to death due to any cause, or censored at date last 
known alive.
10.1.5 Disease Free Survival: A composite disease free survival endpoint consisting of 
castrate resistant PSA failure and/or local, regional or distant failure and death 
from any cause. Disease free survival is measured from the date of randomization 
to the first recorded disease recurrence, or censored at the date of last disease 
assessment for those alive and disease recurrence free.
11. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
11.1
Data Reporting
11.1.1 Method


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The DF/HCC ODQ will collect, manage, and perform quality checks on the data for this 
study.
11.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ.
11.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The board is chaired by a medical 
oncologist from outside of DF/HCC and has external and internal representation. Information 
that raises any questions about participant safety or protocol performance will be addressed by 
the Overall PI, statistician and study team. Should any major concerns arise, the DSMB will 
offer recommendations regarding whether or not to suspend the study.
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by category; 
summary of any deaths on study; audit results; and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
11.3
Multicenter Guidelines
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix B.

The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required.

Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.

Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from the third-party drug supplier.  A participating site may order the 
agent(s) only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center.
11.4
Collaborative Agreements Language
N/A


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12. STATISTICAL CONSIDERATIONS
12.1
Study Design and Primary Endpoint
This is a randomized phase III study to assess whether combination of LHRH agonist or 
antagonist with apalutamide, abiraterone acetate and prednisone (AAP) can prolong metastasis 
free survival (MFS) compared to LHRH agonist or antagonist alone in men whose PSA remains 
detectable after the completion of Radiation Therapy (RT) and 6-12 months of conventional 
ADT. Participants will be randomized with 1:1 allocation to receive LHRH agonist or antagonist 
alone (Arm1) versus LHRH + AAP (Arm2) using permuted blocks methods. Randomization will 
be stratified by the stratification factors described in section 4.6: (1) entry PSA level (> 0.5 vs ≤ 
0.5 ng/ml), (2) planned total duration of ADT (12 vs. > 12 months), and (3) USA vs. Canada.
The primary endpoint is MFS, measured from the date of randomization to the date of 
documented metastatic disease or death from any cause, censored at the date of last disease 
assessment for those alive and metastasis free.
12.2
Endpoints
12.2.1 Definition of Primary Endpoint 
The primary endpoint MFS is the composite of metastasis or any cause death, defined as the time 
from randomization to documentation of metastasis or death due to any cause, whichever occurs 
first, or censored at the date of last disease assessment for those alive and metastasis free. 
Metastasis is defined as radiographic evidence of lymph node, bone or visceral involvement and 
should be evaluated using a CT or MRI chest, abdomen, and pelvis, and bone scan or any type of 
PET.
12.2.2 Definition of Secondary Endpoints
12.2.2.1
PSA Nadir: PSA nadir is defined as the lowest PSA during the entire RT 
and ADT treatment. A nadir could occur prior to randomization or after 
randomization because patients will receive additional hormone therapy after 
randomization.
12.2.2.2
Castrate Resistant PSA Failure Free Survival:   Castrate resistant PSA 
failure is defined as the first PSA increase that is 2 ng/mL above the nadir, 
which is confirmed by a second value 3 or more weeks later, while the serum 
total testosterone level is < 50 ng/dl (per the PCWG2 criteria). Castrate 
resistant PSA failure free survival is the time from randomization to castrate 
resistant PSA failure or death from any cause, whichever comes first; or 
censored at the date of last disease assessment for those alive and PSA failure 
free.   


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12.2.2.3
Prostate Cancer Specific Survival:  Prostate cancer specific survival is 
defined the time from randomization to death from prostate cancer where 
death due to other causes are considered as competing risk, or censored at the 
last date of follow up in living patients. 
12.2.2.4
Overall Survival: Overall survival is defined as the time from 
randomization to death from any cause with men censored at time of last 
follow up if alive.
12.2.2.5
Disease Free Survival: Disease free survival is measured from the date of 
randomization to the first recorded disease recurrence consisting of castrate 
resistant PSA failure and/or local, regional or distant failure and death from 
any cause, whichever comes first, or censored at the date of last disease 
assessment for those alive and disease recurrence free.
12.2.2.6
Toxicity as measured by CTCAE v.5:  We will measure Grade 1-5 
toxicities at study visits and follow-up using the CTCAE v.5 forms and 
determine attribution. All subjects will be evaluable for toxicity from the time 
of their first treatment.
12.3
Sample Size, Accrual Rate and Study Duration
The recent findings from Intermediate Clinical Endpoints of Cancer of the Prostate (ICECaP) 
Working Group suggested MFS is a strong surrogate of OS in localized prostate cancer; the 
estimated 5-year MFS rate was 76% (95%CI: 75-77%) and 8-year OS was 66% (65-67%) from 
diagnosis in men who received RT plus ADT for high risk localized disease defined by NCCN or 
D'Amico criteria.15 For this study, we will enroll men with high-risk prostate cancer and whose 
PSA remains detectable after completing radiation and 6-12 months of ADT. Therefore, we 
assumed the 4-year MFS rate of 65% in this population.
Recent phase III studies suggested apaplutamide8 (HR=0.28 from SPARTAN study), 
enzalutamide17 (HR=0.29), and darolutamide16 (HR=0.41 from ARAMIS study) improves MFS 
in men with M0 CRPC who continued to receive ADT.  The Stampede trial had shown that 
adding abiraterone acetate improved OS for men with high risk N0M0 or N1M0 prostate cancer 
treated with RT and ADT (HR=0.75). MFS was not analyzed by the Stampede study, but we 
would expect a greater treatment effect on MFS than OS. Given our high-risk prostate cancer 
population of N0M0 or N1M0 patients but who are showing signs of castrate resistance (i.e. 
detectable PSA) despite RT and 6-12 months of ADT, MFS HR of 0.52 was assumed for this 
population
 
This study is designed to have adequate power to detect a 48% reduction in the MFS hazard rate 
(from 0.1077 to 0.0558, hazard ratio=0.52) on the LHRH plus AAP arm. This difference 
corresponds to an improvement in 4-year MFS rate from 65% to 80% under the exponential 
distribution assumption. There will be 90% power to detect this MFS difference assuming that 
400 men are enrolled over 2 years (200 patients per year) with 3 years of additional follow-up (a 


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total of study duration of 5 years) at one-sided alpha of 0.025 assuming 10% drop out rate. Full 
information under the alternative hypothesis will occur at 105MFS events. One interim analysis 
of MFS will be conducted at 65% information time. Given that 40% of men with high risk 
prostate cancer would be expected to have a detectable PSA after 6-12 months of ADT, we 
expect at least 1000 men will be screened to identify 400 eligible men for study.10
12.4
Interim Monitoring Plan
One interim analysis of MFS is planned at 65% of information (68 events, approximately at 3.3-
3.4 years after the first participant randomized). The final analysis will be conducted when 
105MFS events have been observed. 
Early stopping for efficacy will be monitored using O’Brien Fleming use function boundaries.  
The O’Brien Fleming boundary at 65% and 100% information is 2.55 and 1.99 with 
corresponding one-sided normal significance levels of 0.005 and 0.023. Monitoring for early 
stopping in favor of the null hypothesis (lack of difference in MFS) will be done using repeated 
confidence interval methodology similar to that described by Jennison and Turnbull (1989).  At 
each interim analysis a nominal (1-2*alpha) % confidence interval on the hazard ratio will be 
computed, where alpha is the nominal significance level of the O’Brien Fleming use function 
boundary at that analysis time. If the confidence interval excludes the target HR of 0.52, the 
study will be stopped early for lack of effect.
This study will be monitored by the DF/HCC Data and Safety Monitoring Board (DSMB).  The 
DSMB meets twice each year.  For each meeting, all monitored studies are reviewed for safety 
and progress toward completion. When appropriate, the DSMB will also review interim analyses 
of outcome data. Reports regarding outcome will remain blinded to the investigators until full 
information is achieved or as directed by the DSMB.
12.5
Analysis of Primary Endpoints
Final analysis of MFS will be performed after the full information (105 events) is achieved.  
MFS distribution will be estimated using the method of Kaplan-Meier; 4-year MFS rate and 95% 
two-sided confidence interval (CI) will be provided by treatment arm.  The primary analysis is a 
superiority test of MFS, performed using a stratified log-rank test, which includes the 
stratification factors defined at randomization. A one-sided p-value from the stratified log-rank 
test less than 0.023 or two-sided p-value less than 0.046 (accounting for one interim analysis 
conducted at 65% information) will indicate that the experimental arm is superior to the control 
arm. A stratified Cox proportional hazards regression model will estimate the MFS treatment 
hazard ratio with 95% 2-sided CI.
12.6
Analysis of Secondary Endpoints
Analysis of other efficacy endpoints, including OS, disease free survival and castrate resistant 
PSA failure free survival, will be similar to those described for the MFS analysis. Prostate 
cancer-specific survival will be analyzed using a competing risk model, where cumulative 


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incidence of prostate cancer mortality, cardiovascular (CV) mortality and deaths from other 
causes will be estimated and compared between treatment arms using Gray’s test with 
adjustment of stratification factors of randomization. A nominal p-value ≤ 0.05 (two-sided) is 
considered as statistically significant.
To compare MFS and OS by randomized treatment groups, we will conduct subgroup analysis 
defined by: (1) biopsy Gleason score (≤7 vs. >7), (2) baseline comorbidity groups ( “none or 
minimal” vs. “moderate or severe” comorbidity using the established Adult Comorbidity 
Metric), (3) baseline serum testosterone levels (< 50 vs. ≥ 50 ng/mL), (4) planned total duration 
of ADT (12 vs. > 12 months), (5) baseline PSA(<0.5 vs. ≥0.5 ng/mL) and (6) N0 vs. N1 at 
diagnosis. Subgroup analyses would be considered exploratory with limited statistical power 
unless large difference exists between groups regarding treatment effect on these outcomes.
For toxicity reporting, all adverse events will be graded and analyzed using CTCAE version 5. 
The worst grade will be used if any toxicity event is reported multiple times on the same 
participant. Adverse events will be summarized according to grade, overall and by treatment 
arm, as number and percentage of participants. All adverse events resulting in discontinuation, 
dose modification, and/or dosing interruption, and/or treatment delay of drug will also be 
summarized by treatment arm. 
12.7
Reporting and Exclusions
The following Analysis Populations are planned for this study: 
Full analysis set (FAS): The FAS will include all randomized patients with treatment groups 
assigned in accordance with the randomization, regardless of the treatment actually received or 
any dosing error. Patients who are randomized but do not subsequently receive treatment are 
included in the FAS. The FAS will be used for all efficacy analyses.
Safety analysis set: The safety population will include all patients who receive at least one dose 
of study treatment. Patients will be analyzed in the treatment group according to the study 
treatment they actually receive. The safety population will be used for the analysis of safety data 
in this study.
13. ETHICS
13.1
Institutional Review Board (IRB) Approval
The final study protocol and the final version of the informed consent form must be approved in 
writing by the DFCI IRB and by the IRB of record for each outside site. 
The sponsor investigator, Dr. Anthony V. D’Amico is responsible for informing the DFCI IRB 
and all external sites of any amendment to the protocol. The site investigator is responsible for 
informing the local IRB of any amendment to the protocol in accordance with local 


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requirements. In addition, the IRB must approve all advertising used to recruit subjects for the 
study. The protocol must be re-approved by the IRB, as local regulations require. 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines.
13.2
Ethics Conduct of the Study
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws.
13.3
Informed Consent Procedures
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject. 
14. PUBLICATION PLAN
The data will be collected and analyzed by the study team.  It is anticipated that the results will 
be made public within 12 months of the end of data collection.  A manuscript is planned to be 
published in a peer-reviewed journal, however initial release may be an abstract that meets the 
requirements of the International Committee of Medical Journal Editors. A full report of the 
outcomes will be made public no later than three (3) years after the end of data collection, and a 
final report will be sent to Janssen within 3 months of completion of data collection.
15. REFERENCES:
1. Morris WJ, Tyldesley S, Rodda S et al., Androgen Suppression Combined with Elective 
Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of 
Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy 
Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate 
Cancer. Int J Radiat Oncol Biol Phys 2017;98:275-85.
2. Nabid A, Garant M, Martin A et al., Duration of androgen deprivation therapy in high 


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risk prostate cancer: Final results of a randomized phase III trial. Proceedings of the 2017 
American Society of Clinical Oncology Meeting. J Clin Oncol 35, 2017 (suppl; abstr 
5008).
3. Patel JC, Maughan BL, Agarwal AM, Batten JA, Zhang TY, Agarwal N (2013). 
"Emerging molecularly targeted therapies in castration refractory prostate cancer". 
Prostate Cancer. 2013: 981684.
4. Michalski JM, Moughan J, Purdy JA et al., Initial Results of a Phase 3 Randomized 
Study of High Dose 3DCRT/IMRT versus Standard Dose 3D-CRT/IMRT in Patients 
Treated for Localized Prostate Cancer (RTOG 0126). Int J Radiat Oncol Biol Phys; 
2014:90; 1263.
5. Dearnaley D, Syndikus I, Mossop H et al., Conventional versus hypofractionated high-
dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the 
randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncology 2016;17:1047-60.
6. Royce TJ, Chen MH, Wu J et al., Surrogate End Points for All-Cause Mortality in Men 
With Localized Unfavorable-Risk Prostate Cancer Treated With Radiation Therapy vs 
Radiation Therapy Plus Androgen Deprivation Therapy: A Secondary Analysis of a 
Randomized Clinical Trial. See comment in PubMed Commons below JAMA Oncol. 
2017 May 1;3(5):652-658.
7. Klotz , O’Callaghan C, Ding K, et al. Nadir Testosterone Within First Year of Androgen-
Deprivation Therapy (ADT) Predicts for Time to Castration-Resistant Progression: A 
Secondary Analysis of the PR-7 Trial of Intermittent Versus Continuous ADT. J Clinical 
Oncology 2015; 33: 1151–1156.
8. Smith MR, Saad F, Chowdhury S, et al., Apalutamide Treatment and Metastasis-free 
Survival in Prostate Cancer. New Engl J Med. February 8, 2018. DOI: 
10.1056/NEJMoa1715546,
9. Naik M, Reddy C, Stephans K et al. Posttreatment Prostate-Specific Antigen 6 Months 
After Radiation With Androgen Deprivation Therapy Predicts for Distant Metastasis-Free 
Survival and Prostate Cancer-Specific Mortality. Int J Radiat Oncol Biol Phys. 2016 Nov 
1;96(3):617-23.
10. Bryant AK, D’Amico AV, Nguyen PL et al., Three-month post-treatment PSA as a 
biomarker of treatment response in intermediate or high-risk prostate cancer treated with 
androgen deprivation therapy and radiotherapy. JAMA Oncology (in revision).
11. Sweeney CJ, Chen YH, Carducci M et al., Chemohormonal Therapy in Metastatic 
Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015 Aug 20;373(8):737-46.
12. Ryan CJ, Smith MR, de Bono JS et al., Abiraterone in metastatic prostate cancer without 
previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48
13. Beer TM, Armstrong AJ, Rathkopf DE et al., Enzalutamide in metastatic prostate cancer 
before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33.
14. Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following 
radiotherapy with or without hormonal therapy in men with clinically localized prostate 
cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J 
Radiat Oncolo Biol Phys. 2006 Jul 15;65:965-74.
15. Xie W, Regan MM, Buyse M, Halabi S, Kantoff PW, Sartor O, et al. Metastasis-Free 
Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer. Journal 
of clinical oncology: 2017;35(27):3097-104
16. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, 


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Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. 
Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.N Engl J Med. 2019 
Feb 14. 
17. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, 
Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN, Enzalutamide in men with 
nonmetastatic, castration-resistant prostate cancer New England Journal of Medicine. 2018 
Jun 28; 378(26): 2465-2474.


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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
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).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
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.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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APPENDIX B
Dana-Farber/Harvard Cancer Center
Multi-Center Data and Safety Monitoring Plan


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TABLE OF CONTENTS
Schema.............................................................................................................................................3
1.
OBJECTIVES......................................................................................................................5
1.1
Study Design............................................................................................................5
1.2
Primary Objective....................................................................................................5
1.3
Secondary Objectives...............................................................................................5
2.
Background..........................................................................................................................5
2.1
Study Disease and Rationale....................................................................................5
2.2
IND Agents..............................................................................................................7
2.3
Other Agents............................................................................................................8
3.
PARTICIPANT SELECTION.............................................................................................8
3.1
Eligibility Criteria....................................................................................................8
3.2
Exclusion Criteria ..................................................................................................10
3.3
Inclusion of Women and Minorities ......................................................................11
4.
REGISTRATION PROCEDURES ...................................................................................11
4.1
General Guidelines for DF/HCC Institutions ........................................................11
4.2
Registration Process for DF/HCC Institutions.......................................................12
4.3
General Guidelines for Other Investigative Sites ..................................................12
4.4
Registration Process for Other Investigative Sites.................................................12
4.5
Randomization.......................................................................................................13
4.6
Stratification Factors..............................................................................................13
5.
TREATMENT PLAN........................................................................................................13
5.1
Treatment Regimen................................................................................................13
5.2
Pre-Treatment criteria............................................................................................14
5.3
Agent Administration.............................................................................................14
5.4
Concomitant Medications......................................................................................15
5.5
Supportive Care .....................................................................................................20
5.6
Criteria for Taking a Participant Off Protocol Therapy.........................................20
5.7
Duration of Follow Up...........................................................................................20
5.8
Criteria for Taking a Participant Off Study ...........................................................21
5.9
Replacement...........................................................................................................21
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................21
6.1
Dose Modifications for Toxicity Attributed to Apalutamide ................................21
6.2
Dose Modifications for LFT Abnormalities Attributed to Abiraterone 
Acetate ...................................................................................................................23
6.3
Dose Modifications for Hypokalemia Attributed to Abiraterone Acetate.............24
6.4
Dose Modifications for Hypertension and Edema/Fluid Retention 
Attributed to Abiraterone Acetate..........................................................................25
6.5
Dose Modifications for Toxicity Attributed to LHRH agonist..............................25
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................26


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7.1
Adverse Events ......................................................................................................26
7.2
Overview................................................................................................................26
7.3
Management of Safety Data...................................................................................26
7.4
Definitions..............................................................................................................27
7.5
Unlisted (Unexpected) Adverse Event/Reference Safety Information..................29
7.6
Special Reporting Situations..................................................................................30
7.7
Pregnancy...............................................................................................................30
7.8
Maintenance of Safety Information .......................................................................30
7.9
Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Janssen Medicinal Products to Janssen...............................................31
7.10
Reporting Procedures for Reporting Safety Data and Product Quality 
Complaints (PQCs) for Non-Janssen Medicinal Products.....................................32
7.11
Transmission Methods...........................................................................................32
7.12
Reconciliation of SAEs..........................................................................................33
7.13
Dissemination of Safety Information from Janssen to Principal 
Investigators...........................................................................................................33
7.14
Contacting Janssen Regarding Safety....................................................................33
7.15
Final Study Report.................................................................................................33
7.16
Reporting................................................................................................................33
7.17
IND Safety Reports Unrelated to this Trial ...........................................................34
7.18
Expedited Adverse Event Reporting......................................................................34
7.19
Expedited Reporting to the Food and Drug Administration (FDA) ......................35
7.20
Expedited Reporting to Hospital Risk Management .............................................35
7.21
Routine Adverse Event Reporting .........................................................................35
8.
PHARMACEUTICAL INFORMATION..........................................................................35
8.1
Abiraterone Acetate (AA)......................................................................................35
8.2
Apalutamide (ARN-509, JNJ-56021927)..............................................................37
8.3
Prednisone..............................................................................................................38
8.4
LHRH Agonist or Antagonist................................................................................39
9.
Study calendar....................................................................................................................41
9.1
Arm 1 Calendar & Evaluations..............................................................................41
9.2
Arm 2 Calendar and Evaluations (cycle = 28 days) Number of months left 
of ADT at time of registration = number of cycles on study (i.e. if patient 
has 12 more months of ADT left, he will have 12 cycles on study)......................43
10.
MEASUREMENT OF EFFECT .......................................................................................46
10.1
Progression Free Survival......................................................................................46
11.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................46
11.1
Data Reporting.......................................................................................................46
11.2
Data Safety Monitoring..........................................................................................47
11.3
Multicenter Guidelines...........................................................................................47
11.4
Collaborative Agreements Language.....................................................................47
12.
STATISTICAL CONSIDERATIONS...............................................................................48


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12.1
Study Design and Primary Endpoint......................................................................48
12.2
Endpoints ...............................................................................................................48
12.3
Sample Size, Accrual Rate and Study Duration ....................................................49
12.4
Interim Monitoring Plan ........................................................................................50
12.5
Analysis of Primary Endpoints..............................................................................50
12.6
Analysis of Secondary Endpoints..........................................................................50
12.7
Reporting and Exclusions ......................................................................................51
13.
ETHICS..............................................................................................................................51
13.1
Institutional Review Board (IRB) Approval..........................................................51
13.2
Ethics Conduct of the Study ..................................................................................52
13.3
Informed Consent Procedures................................................................................52
14.
PUBLICATION PLAN .....................................................................................................52
15.
REFERENCES: .................................................................................................................52
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................55
16.
INTRODUCTION .............................................................................................................61
1.1.
Purpose...................................................................................................................61
17.
GENERAL ROLES AND RESPONSIBILITIES .............................................................61
2.1.
Coordinating Center...............................................................................................61
2.2.
External Site...........................................................................................................61
18.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .............................62
3.1.
Protocol Revisions and Closures ...........................................................................62
3.2.
Informed Consent Requirements ...........................................................................63
3.3.
IRB Re-Approval...................................................................................................63
3.4.
DF/HCC Multi-Center Protocol Confidentiality ...................................................63
3.5.
Participant Registration and Randomization .........................................................64
3.6.
Initiation of Therapy ..............................................................................................64
3.7.
Eligibility Exceptions.............................................................................................65
3.8.
Data Management..................................................................................................65
3.9.
Protocol Reporting Requirements..........................................................................65
4.
MONITORING: QUALITY CONTROL..........................................................................66
4.1.
Ongoing Monitoring of Protocol Compliance.......................................................66
4.2.
Monitoring Reports................................................................................................66
4.3.
Accrual Monitoring................................................................................................67
5.
AUDITING: QUALITY ASSURANCE ...........................................................................67
5.1.
DF/HCC Internal Audits........................................................................................67
5.2.
Audit Notifications.................................................................................................67
5.3.
Audit Reports.........................................................................................................67
5.4.
External Site Performance .....................................................................................67


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APPENDIX C: Drug Diary............................................................................................................69


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16. INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that 
are participating in a DF/HCC clinical trial. 
1.1.
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Policies and 
Operations.       
17. GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the following general responsibilities apply, in addition to those 
outlined in DF/HCC Policies for Sponsor-Investigators: 
2.1.
Coordinating Center 
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development. 

Maintain CTEP, FDA or OBA correspondence, as applicable.

Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system 
(CTMS).

Distribute protocol and informed consent document updates to External Sites as 
needed.

Oversee the data collection process from External Sites.

Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by External Sites and provide to the DF/HCC 
Sponsor for timely review and submission to the IRB of record, as necessary. 

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the reporting requirements for the IRB of record to all External Sites.

Provide External Sites with information regarding DF/HCC requirements that they 
will be expected to comply with.

Carry out plan to monitor External Sites either by on-site or remote monitoring. 

Maintain Regulatory documents of all External Sites which includes but is not 
limited to the following: local IRB approvals/notifications from all External Sites, 
confirmation of Federalwide Assurances (FWAs) for all sites, all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites

Conduct regular communications with all External Sites (conference calls, emails, 
etc) and maintain documentation all relevant communications.
2.2.
External Site


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An External Site is an institution that is outside the DF/HCC and DF/PCC consortium that 
is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC investigator.  
The External Site acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study. 
Each External Site is expected to comply with all applicable DF/HCC requirements stated 
within this Data and Safety Monitoring Plan and/or the protocol document. 
The general responsibilities for each External Site may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their IRB of record. For studies under a 
single IRB, the Coordinating Center will facilitate any study-wide submissions.

Maintain regulatory files as per ICH GCP and federal requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial 
as required.

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research 
related activities when required by the sponsor. 

Submit Serious Adverse Event (SAE) reports to sponsor, Coordinating Center, and 
IRB of record as applicable, in accordance with DF/HCC requirements. 

Submit protocol deviations and violations to the Sponsor, Coordinating Center, and 
IRB of record as applicable.

Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements.

Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings.

Notify the sponsor immediately of any regulatory authority inspection of this 
protocol at the External Site.
18. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
Certain DF/HCC Policy requirements apply to External Sites participating in DF/HCC 
research. The following section will clarify DF/HCC requirements and further detail the 
expectations for participating in a DF/HCC Multi-Center protocol. 
3.1.
Protocol Revisions and Closures
The External Sites will receive notification of protocol revisions and closures from the 
Coordinating Center.  When under a separate IRB, it is the individual External Site’s 
responsibility to notify its IRB of these revisions.


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
Protocol revisions: External Sites will receive written notification of protocol 
revisions from the Coordinating Center. All protocol revisions should be IRB 
approved and implemented within a timely manner from receipt of the notification.

Protocol closures and temporary holds: External Sites will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and 
holds will be effective immediately.  In addition, the Coordinating Center, will 
update the External Sites on an ongoing basis about protocol accrual data so that 
they will be aware of imminent protocol closures.
3.2.
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for External Sites. The External Site consent form must follow the consent 
template as closely as possible and should adhere to specifications outlined in the DF/HCC 
Guidance Document on Model Consent Language for Investigator-Sponsored Multi-Center 
Trials.  This document will be provided separately to each External Site upon request.
External Sites must send their version of the informed consent document to the Coordinating 
Center for sponsor review and approval. If the HIPAA authorization is a separate document, 
please submit to the sponsor for the study record. Once sponsor approval is obtained, the 
External site may submit to their IRB of record, as applicable. In these cases, the approved 
consent form must also be submitted to the Coordinating Center after approval by the local 
IRB for all consent versions.
The Principal Investigator (PI) at each External Site will identify the appropriate members 
of the study team who will be obtaining consent and signing the consent form for protocols. 
External Sites must follow the DF/HCC requirement that for all interventional drug, 
biologic, or device research, only attending physicians may obtain initial informed consent 
and any re-consent that requires a full revised consent form.  
3.3.
IRB Re-Approval
Verification of IRB re-approval for the External Sites is required in order to continue 
research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received 
for the External Site on or before the anniversary of the previous approval date.  
3.4.
DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned protocol case number be used for all 
participant specific documents. Participant initials may be included or retained for cross 
verification of identification. 


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3.5.
Participant Registration and Randomization 
To register a participant, the following documents should be completed by the External 
Site and faxed or e-mailed to the Coordinating Center:

Copy of screening test results, including imaging and pathology results

Signed participant consent form

HIPAA authorization form (if separate from the informed consent document)

Completed Eligibility checklist

Clinic note, covering screening requirements and baseline AEs

Additional screening assessments 
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinating Center 
will:

Register the participant on the study with the DF/HCC Clinical Trial Management 
System (CTMS).

Upon receiving confirmation of registration, the Coordinating Center will inform 
the External Site and provide the study specific participant case number, and, if 
applicable, assigned treatment and/or dose level. 
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number.  External Sites should submit all de-identified subsequent communication and 
documents to the Coordinating Center, using this case number to identify the subject.  
Subjects will be randomized by DF/HCC Office of Data Quality (ODQ) in a 1:1 ratio to 
either ARM 1 (Standard of Care) or ARM 2 (Experimental).  Cycle 1 Day 1 is considered 
the first day of treatment.  Following registration and randomization, subjects may begin 
protocol treatment.  Issues that would cause treatment delays should be discussed with the 
sponsor-investigator.
Randomization can only occur during normal business hours, Monday through Friday from 
8:00 AM to 5:00 PM Eastern Standard Time.
3.6.
 Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific interventions 
may not be initiated until the External Site receives confirmation of the participant’s 
registration from the Coordinating Center. The DF/HCC Sponsor and IRB of record must 
be notified of any violations to this policy.


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3.7.
 Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without IRB approval will be 
permitted. All External Sites are required to fully comply with this requirement. The process 
for requesting an eligibility exception is defined below.
3.8.
Data Management
DF/HCC develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC provides a web based training for all 
eCRF users.
  
3.4.1. Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, 
or designee. 
Responses to all queries should be completed and submitted within 14 calendar days.  
If study forms are not submitted on schedule, the External Sites will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms. 
3.9.
Protocol Reporting Requirements
3.9.1. Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor and to the IRB of record.
3.9.2. Reporting Procedures
Requests to deviate from the protocol require approval from the IRB of record and the 
sponsor. 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations. 


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3.9.3. Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports per DF/HCC requirements, and 
ensure that all IND Safety Reports are distributed to the External Sites as required by 
DF/HCC Policy. External Sites will review/submit to the IRB according to their 
institutional policies and procedures.
4. MONITORING: QUALITY CONTROL
The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides 
quality control oversight for the protocol.
4.1.
Ongoing Monitoring of Protocol Compliance
The External Sites may be required to submit participant source documents to the 
Coordinating Center for monitoring. External Sites may also be subject to on-site 
monitoring conducted by the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
External Sites are complying with regulatory and protocol requirements, data quality, and 
participant safety. Monitoring practices may include but are not limited to source data 
verification, and review and analysis of eligibility requirements, informed consent 
procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy records, 
response assessments, and data management. 
External Sites will be required to participate in monthly Coordinating Center initiated 
teleconferences. 
4.1.1. Remote Monitoring
DFCI CTO will virtually monitor sites throughout the study. The coordinating center will 
review 100% of participants’ consent and eligibility for registration, and the DFCI CTO 
will review consent and eligibility for about 10% of participants within approximately 60 
days of enrollment. The DF/HCC Lead Institution will request source documentation from 
External Sites as needed to complete virtual monitoring activities. External sites will be 
asked to forward de-identified copies of participants’ medical record and source 
documents to the DF/HCC Lead Institution to aid in the source documentation verification 
process. A remote closeout visit will be conducted once per site at the end of study to 
verify resolution or previous monitoring findings and reconcile collected regulatory 
documents. Pharmacy records will be reviewed approximately once per year. Study visit 
documentation and CRFs will be reviewed for 10% of participants approximately every 6 
months.
4.2.
Monitoring Reports


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The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. 
The DF/HCC Sponsor may increase the monitoring activities at External Sites that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. 
4.3.
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each External Site. Accrual will be monitored for each External 
Site by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.
As this is a Phase III trial, 3 patients per site/annually is the minimum target for each site.
However, given the additional regulatory burden and cost of overseeing each site, a 
consideration of 5 per site/annually should be a minimum target for each site..
5. AUDITING: QUALITY ASSURANCE
5.1.
DF/HCC Internal Audits
 
All External Sites are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2-day period. 
If violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. 
5.2.
Audit Notifications
It is the External Site’s responsibility to notify the Coordinating Center of all external audits 
or inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will 
forward a copy of final audit and/or re-audit reports and corrective action plans (if 
applicable) to the Coordinating Center, within 12 weeks after the audit date. 
5.3.
Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the IRB as applicable.
5.4.
External Site Performance
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.


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External Sites that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be put on hold or closed. 


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APPENDIX C: DRUG DIARY
Study Participant Self-Administration Study Drug Diary
Participant Identifier: ____________________ ARM2 - Cycle Number: _____ Protocol #: ______
Your MD______________________Phone_____________________                
Your RN______________________Phone_____________________
Treatment Plan:
Agent
Pre-medications; 
Precautions
Dose
Route
Schedule
Apalutamide**
Can be taken with or 
without food
Take _______ 
60 mg tablets
Orally 
Once daily
Take all at once
Example: 8am
Abiraterone 
Acetate*
No food at least two 
hours before the dose 
and for at least one 
hour after the dose 
Take________
250 mg 
tablets
Orally 
Once daily
Take all at once
Example: 8pm
Prednisone
Take with food, 
preferred to be taken 
in the morning
Take________
5 mg tablets
Orally 
Twice daily
-Once in AM 
-Once in PM
     *  Abiraterone acetate should NOT be taken at the same time as Apalutamide or prednisone. 
** Apalutamide may be taken with prednisone (and food).   
INSTRUCTIONS TO THE PATIENT:
1.
All medications should be taken at the same time every day.
2.
If a dose of study medication is skipped, missed or vomited, it should not be taken (or retaken if 
vomited) on the day of the missed dose but dosing should be resumed the following day. Doses 
should be taken no later than 12 hours after the scheduled time for dosing
3.
Your study medications should not be crushed, chewed, or dissolved in water.
4.
You may not consume grapefruit or grapefruit-containing products while taking the study 
medications.
5.
Please bring your pill bottle and this form to your physician when you go to your next 
appointment.
6.
Store at 68°F to 77°F. Keep out of reach of children.
Please record how many tablets you take of abiraterone acetate, apalutamide, and prednisone, 
the time you take them and any comments here below and bring the completed Diary as well 
as your study drug supply, including empty bottles, to every study visit. This will help us keep 
track of your study drug and how well you are tolerating it.
Protocol #___________Patient Name: ______________________
Patient Study ID__________


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Number of Tablets or Capsules/Time of Day 
Date 
Day
Apalutamide (All 4 
tablets unless your 
MD reduced dose)
Abiraterone 
Acetate (All 4 
tablets unless your 
MD reduced dose)
Prednisone 
(AM)
Prednisone 
(PM)
Comments
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
 Patient’s Signature: ____________________________________________ Date: ___________________________