A Phase 2 Study of Apalutamide in Active Surveillance Patients
Phase: PHASE2
Conditions: Prostate Adenocarcinoma
Sponsor: University of Washington

IRO REC'D FEB 19 2020 
PI: Michael T. Schweizer, MD 
Protocol Version: 6.0; September 06, 2019 
CC Protocol Number: 9582 
Apalutamide in Active Surveillance patients 
A Phase 2 Study of Apalutamide in Active Surveillance Patients 
University of Washington / Seattle Cancer Care Alliance 
Cancer Consortium Protocol Number: 9582 
IND Number: 128562 
Protocol Version Number: 6.0 
September 06, 2019 
Sponsor-Investigator/Principal Investigator:  
Site: 
Michael T. Schweizer, MD 
University of Washington / Seattle Cancer Care 
Alliance 
Email: schweizeuw.edu 
 
Co-Investigator:  
Daniel W. Lin, MD 
University of Washington 
Email: dlina.uw.edu  
University of Washington / Seattle Cancer Care 
Alliance (Principal Investigator: Michael T. 
Schweizer, MD) 
Financial and Medication Support Provided by:  
Janssen Scientific Affairs, LLC 
Research Laboratories:  
Vessella Laboratory 
University of Washington 
1959 NE Pacific St. 
HSB-1340 
Seattle, WA 98195 
FHCRC IRB Approval 
FEB 2 6 2020 
Document Released Date 
1 
IRB Approved 
Document Release Date: 02/26/2020
Printed on 1/29/2021

CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
A Phase 2 Study of Apalutamide in Active Surveillance Patients 
Protocol Version 6.0 
September 06,2019 
Sponsor-Investigator: Michael T. Schweizer, MD 
Title: A Phase 2 Study of Apalutamide in Active Surveillance Patients 
Objective: To determine if a 90-day course of apalutamide will lead to a negative repeat prostate 
biopsy in active surveillance patients. 
Study Design: This is an open label, multi-site, Phase II study to evaluate the combination of 
apalutamide in men followed on active surveillance. 
Participating Institutions: University of Washington Medical Center 
Financial and Medication Support: Janssen Scientific Affairs, LLC 
Timeline: This study is planned to complete enrollment within one year, with all patients followed 
for a total of five years. 
Treatment Plan: This is an open label, multi-site, Phase II study designed to determine the 
negative repeat prostate biopsy rate following 90-days of treatment with apalutamide. All 
subjects must be enrolled in the active surveillance program at the University of Washington 
Medical Center. All eligible patients will initiate therapy with apalutamide, which will be 
administered at the FDA approved dose for treating non-metastatic castration-resistant prostate 
cancer (i.e., 240 mg daily by mouth). Note that apalutamide is FDA approved only for the 
treatment of patients with non-metastatic castration-resistant prostate cancer, and is under 
development as an investigational product for other types of prostate cancer. Subjects will have 
either 1) an MRI detectable cancer of PIRADS 3 or more >5mm, and pathologically documented 
by MRITTRUS fusion biopsy with coordinates of biopsy site stored for repeat biopsy; or 2) a 
systematic 12 core biopsy pathologically documenting prostate cancer with the coordinates of 
the biopsy sites stored for repeat biopsy. This biopsy may be done up to 12-months prior to 
enrollment. 
Following 90-days of treatment with apalutamide, patients will undergo a repeat prostate biopsy 
selectively targeting sites of prior positive biopsies (3 from each positive biopsy site) plus a 12 
core systematic prostate biopsy without targeting. All patients will continue on active 
surveillance per the standard practice of the treating urologist. 
The primary endpoint for this trial will be the absence of residual carcinoma (i.e., a negative 
repeat biopsy) as determined by targeted and systematic biopsies following 90-days of 
apalutamide. Secondary endpoints will include: exit from active surveillance due to pathologic 
progression or otherwise at 2 years, receipt of local treatment for prostate cancer at 2 years, 
local treatment free survival, PSA progression at 2 years, PSA PFS as defined by Prostate 
Cancer Working Group 2 (PCWG2) criteria, radiographic disappearance of MRI detectable 
2 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
nodules following treatment, quality of life changes and safety (as assessed by the revised 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], 
version 4.03).1 
Biopsy specimens, blood and plasma samples will be stored at -80°C. These specimens will be 
labeled with a subject's unique study ID, and will not have personal identifiers imprinted on 
them. Samples (i.e., prostate tissue, blood and plasma) will be obtained pre- and post-treatment 
with apalutamide. These biologic specimens will be used for additional correlative work. 
Examples of studies to be conducted may include, but are not limited to: assessment for PTEN 
loss via immunohistochemistry (INC), assessment for alteration in MYC/chromosome 8q24 via 
FISH, whole blood RNA expression panel, and tumor mRNA expression profiling/risk 
classification (e.g., Decipher [GenomeDX Biosciences, San Diego, CA], Oncotype DX Prostate 
Cancer Assay [Genomic Health, Inc., Redwood City, CA], or RNA-seq).2-6  
Subject enrollment requires a baseline systematic 12 core biopsy with pathologically 
documented prostate cancer and with the coordinates of the biopsy sites stored for repeat 
biopsy. Subjects can include men with newly diagnosed prostate cancer or those already 
enrolled in active surveillance, but baseline prostate biopsy must have occurred within 12-
months of enrolling onto this study. Subjects may have had a multiparametric MRI of the 
prostate performed at least 6 months from any prior prostate biopsy. If an MRI detectable 
cancer of PIRADS 3 or more and >5mm was pathologically documented by MRI/TRUS fusion 
biopsy with coordinates of biopsy site stored, this lesion will be targeted for repeat biopsy. 
Otherwise, coordinates should be stored using a standard sextant prostate biopsy diagram 
(Appendix A) to aid in targeted repeat biopsy. Ninety days after treatment with apalutamide, all 
subjects will undergo 1) selective biopsy targeting cancer positive sites based on stored 
coordinates (3 biopsy cores per positive site); and 2) a 12 core non targeted systematic biopsy. 
PSA will be measured at baseline (i.e., within 30 days of initiating treatment per the study) and 
again within one week of completing combination therapy. PSA progression will be determined 
based on PCWG2 criteria (i.e., confirmed rising PSA  ng/mL at least one week apart).1 
Study Schema 
Must meet one of the following criteria: 
1) Very low-risk prostate cancer 
• Stage Tic 
• PSA density <0.15 ng/mL 
• Gleason 6 
• s2 cores with s509'0 involvement of any core, 
or any percent involvement if unilateral 
disease 
2) Low risk prostate cancer: 
• Stage 5T2a 
• PSA <15 ng/mL 
• Gleason 6 
3) Low-intermediate risk prostate cancer 
• Stage Tic 
• PSA <15 ng/mL 
- Gleason 3+4 in s50% of one core 
• Gleason 6 in all other cores 
ARN-509 240 mg daily 
1) Selective site 
directed biopsy 
(3 cores per site) 
And 
2) Systematic 12 
core biopsy 
Determine negative 
repeat biopsy rate 
Treatment: 90 days 
All samples collected as part of this research study will be stored at University of Washington 
and access to these samples will be limited to the Sponsor-Investigator, Co-Investigators, 
3 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
Janssen Scientific Affairs, LLC or their designees. These biologic samples will be retained for up 
to 5 years following the last patient completing the study, and any remaining samples will be 
destroyed after that time. Likewise, data generated as part of this study will be stored on secure 
servers at University of Washington and/or Janssen Scientific Affairs, LLC and access will be 
limited to the Sponsor-Investigator, Co-Investigators, Janssen Scientific Affairs, LLC or their 
designees. The identity of enrolled subjects will remain confidential, and only the treating 
physician, research team, and/or Sponsor-Investigator will have access to this information. 
Patient identifiers will not be made available to the Janssen Scientific Affairs, LLC. 
Study Population: 
Men with very low-risk to low-intermediate risk prostate cancer (see 'risk' definitions under 
inclusion criteria) enrolled (or planning to enroll) on active surveillance. 
Number of Patients: Up to 33 patients at University of Washington Medical Center. 
Inclusion Criteria:  
1. Have signed an informed consent document. 
2. Be willing/able to adhere to the prohibitions and restrictions specified in this protocol 
3. Written authorization for use and release of health and research study information has been 
obtained (i.e., HIPAA authorization) 
4. Male aged 18 to 75 years or life expectancy 0 years (as determined by the treating 
physician) 
5. Eastern cooperative group (ECOG) performance status 51 
6. Histologically confirmed adenocarcinoma of the prostate as documented by a minimum 12 
core prostate biopsy completed within 1-year of enrollment (Note: most recent prostate 
biopsy must have demonstrated prostatic adenocarcinoma) 
7. Favorable risk prostate cancer as defined by: 
Very low-risk 
a. Clinical stage Tic disease 
b. PSA density (PSAD) <0.15 ng/mL 
c. Gleason score 6 
d. 52 core biopsies with 550% involvement of any biopsy core with cancer, or 
unilateral disease 52 core biopsies with any percentage involvement 
or 
Low risk 
a. Clinical stage 5 T2a 
b. PSA < 15 ng/mL 
c. Gleason score 6 
or 
Low-intermediate risk 
a. Clinical stage Tic 
b. PSA <15 ng/ml 
c. Gleason 3+4 present in 550% of one core/site as detected by systematic biopsy 
or MRI/TRUS fusion guided biopsy 
d. Gleason 6 disease in all other cores 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
8.  Willing and qualified for active surveillance at University of Washington 
9. Serum testosterone 150 ng/dL 
10. Able to swallow the study drugs whole as a tablet 
11. Clinical laboratory values at screening: 
a. Hemoglobin A.0 g/dL, independent of transfusion and/or growth factors within 
3 months prior to randomization 
b. Platelet count .100,000 x 109/pL independent of transfusion and/or growth 
factors within 3 months prior to registration 
c. Serum albumin  g/dL 
d. GFR  mUmin 
e. Serum potassium ?.3.5 mmol/L 
f. Serum total bilirubin  x ULN (Note: In subjects with Gilbert's syndrome, if 
total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin and if direct 
bilirubin is 51.5 x ULN, subject may be eligible) 
g. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
<2.5 x ULN 
12. Medications known to lower the seizure threshold (see list under prohibited meds) must be 
discontinued or substituted at least 4 weeks prior to study entry. 
13. 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. 
Exclusion Criteria:  
1. Prior local therapy to treat prostate cancer (e.g., radical prostatectomy, radiation therapy, 
brachytherapy) 
2. Prior use of ARN-509 (apalutamide) 
3. Have known allergies, hypersensitivity, or intolerance to ARN-509 (apalutamide) or its 
excipients 
4. Prior or ongoing systemic therapy for prostate cancer including, but not limited to: 
a. Hormonal therapy (e.g., leuprolide, goserelin, triptorelin) 
b. CYP-17 inhibitors (e.g., abiraterone, ketoconazole) 
c. Antiandrogens (e.g., bicalutamide, nilutamide) 
d. Second generation antiandrogens (e.g., enzalutamide) 
e. Immunotherapy (e.g., sipuleucel-T, ipilimumab) 
f. Chemotherapy (e.g., docetaxel, cabazitaxel) 
 
5.  Have any condition that, in the opinion of the investigator, would compromise the well-being 
of the subject or the study or prevent the subject from meeting or performing study 
requirements 
 
6.  History of any of the following: 
a. Seizure or known condition that may pre-dispose to seizure (including but not 
limited to prior stroke, transient ischemic attack, loss of consciousness within 
1 year prior to registration, brain arteriovenous malformation; or intracranial 
5 
 
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Document Release Date: 02/26/2020
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
masses such as schwannomas and meningiomas that are causing edema or mass 
effect) 
b. Severe or unstable angina, myocardial infarction, symptomatic congestive heart 
failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, 
cerebrovascular accident including transient ischemic attacks), or clinically 
significant ventricular arrhythmias within 6 months prior to registration. 
c. Any condition that in the opinion of the investigator, would preclude participation in 
this study 
7.  Current evidence of any of the following: 
a. Uncontrolled hypertension 
b. Gastrointestinal disorder affecting absorption 
c. Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) or 
other medical condition that would make prednisone/prednisolone (corticosteroid) 
use contraindicated 
d. 
Any condition that in the opinion of the investigator, would preclude participation in 
this study 
8. The use of drugs known to lower the seizure threshold, including: atypical antipsychotics 
(e.g., clozapine, olanzapine, risperidone, ziprasidone), bupropion, lithium, meperedine, 
pethidine, phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine), 
and tricyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, 
maprotiline, mirtazapine) (see Appendix C for a more complete list of prohibited concomitant 
medications). 
9. The use of strong CYP3A4 inhibitors, including: itraconazole, clarithromycin, erythromycin, 
diltiazem, verapamil, delavirdine, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, voriconazole, grapefruit juice (or grapefruits) (see Appendix C for a 
more complete list of prohibited concomitant medications). Note: If a patient is on a strong 
CYP3A4 inhibitor, they can be reconsidered for enrollment if they can safely stop said 
medication. A two week or 5 half-lives, whichever is longer, washout will be required prior to 
enrolling on study. Subject may not resume medication while receiving apalutamide. 
10. Strong CYP3A4 inducers, including: phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, efavirenz, tipranivir, St. John's wort (see Appendix C for a more complete list 
of prohibited concomitant medications). Note: If a patient is on a strong CYP3A4 inducer, 
they can be reconsidered for enrollment if they can safely stop said medication. A two week 
or 5 half-lives, whichever is longer, washout will be required prior to enrolling on study. 
Subject may not resume medication while receiving apalutamide. 
11. Any psychological, familial, sociological, or geographical condition that could potentially 
interfere with compliance with the study protocol and follow-up schedule. 
Primary Obiective: Determine the negative repeat biopsy rate by site directed and systematic 
prostate biopsy after 90-days of apalutamide. 
Secondary Obiectives:  
1. Determine the rate of exit at 2 years from active surveillance due to pathologic 
reclassification. 
2. Determine the overall rate of exit at 2 years from active surveillance. 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
3. Determine the rate of local treatment (e.g., radical prostatectomy, radiation therapy, 
brachytherapy) at 2 years and the local treatment free survival. 
4. Determine PSA progression rates and PSA progression free survival (PFS), as defined by 
the Prostate Cancer Working Group 2 (PCWG2) criteria. 
5. Determine the rate of radiographic disappearance of MRI detectable prostate cancer 
following treatment (only in patients with a baseline nodule that is PIRADS 3 or more and 
>5mm). 
6. Investigate the safety of apalutamide in men undergoing active surveillance. 
a. Safety will be evaluated by the incidence, severity, duration, causality, seriousness, 
and type(s) of adverse events as assessed by the revised National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 
published 14 June 2010. 
7. Track quality of life utilizing the FACT-P and SF36 surveys for each cohort. 
8. Exploratory biomarker Assessment. Examples of these may include, but are not limited to: 
assessment for genomic PTEN loss via fluorescence in situ hybridization (FISH), PTEN 
immunohistochemistry (IHC), assessment for alteration in MYC/chromosome 8q24 via FISH 
and tumor mRNA expression profiling/risk classification (e.g., Decipher, Oncotype DX 
Prostate Cancer Assay, or RNA-seq). 
Primary Endpoint: Negative (i.e., no residual carcinoma) site directed and systematic prostate 
biopsy following 90-days of apalutamide. 
Secondary Endpoints:  
1. Exit from active surveillance due to pathologic reclassification at 2 years. 
2. Exit from active surveillance for any reason at 2 years. 
3. Local treatment (e.g., radical prostatectomy, radiation therapy, brachytherapy) at 2 years 
and the local treatment free survival. 
4. PSA progression and PSA progression free survival (PFS), as defined by the Prostate 
Cancer Working Group 2 (PCWG2) criteria [Scher et al, 2008]. 
5. Radiographic disappearance of MRI detectable prostate cancer following treatment (in 
patients with a baseline nodule that is PIRADS 3 or more and >5mm). 
6. Safety of apalutamide in men undergoing active surveillance. 
a. Safety will be evaluated by the incidence, severity, duration, causality, seriousness, 
and type(s) of adverse events as assessed by the revised National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 
published 14 June 2010. 
7. Quality of life as assessed using the FACT-P and SF36 surveys. 
8. Exploratory biomarkers assessment. Examples of these may include, but are not limited to: 
assessment for genomic PTEN loss via fluorescence in situ hybridization (FISH), PTEN 
immunohistochemistry (NC), assessment for alteration in MYC/chromosome 8q24 via FISH 
and tumor mRNA expression profiling/risk classification (e.g., Decipher, Oncotype DX 
Prostate Cancer Assay, or RNA-seq). 
7 
 
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Document Release Date: 02/26/2020
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CC Protocol Number: 9582 	
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients 	Protocol Version: 6.0; September 06, 2019 
SYNOPSIS 	
2 
Study schema 	
3 
1. INTRODUCTION 	
10 
1.1 
Overview and Rational 	
 10 
1.2 
Androgen/Androgen Receptor Directed Therapies 	
 11 
1.3 
Active Surveillance 	
 15 
1.4 
Exploratory Biomarkers 	
 23 
2. STUDY OBJECTIVES 	
 25 
2.1 
Primary Objective 	
 25 
2.2 
Secondary Objectives 	
 25 
2.2 
Primary Endpoint 	
 26 
2.2 
Secondary Endpoint 	
 26 
3. PATIENT POPULATION AND SELECTION 	
 27 
3.1 
Inclusion Criteria 	
 27 
3.2 
Exclusion Criteria 	
 29 
3.3 
Inclusion of Minorities and Women 	
 31 
4. TREATMENT PLAN 	
 32 
4.1 
Study Design 	
 32 
4.2 
Removal of Patients from Study 	
 34 
5. Treatment Assessment and Evaluation 	
 36 
5.1 
Screening Studies 	
 36 
5.2 
Treatment Phase 	
 36 
5.3 
End of Study 	
 37 
5.4 
Long Term Follow-up 	
 38 
6. STUDY CALENDAR 	
 39 
7. STUDY ASSESSMENTS 	
 40 
7.1 
Prostate Biopsy 	
 40 
7.2 
Prostatic MRI 	
 40 
8 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
7.3  Exploratory Biomarkers  
42 
7.4 Safety  
44 
8. PHARMACEUTICAL INFORMATION  
45 
8.1  APALUTAM IDE  
45 
9. DATA MONITORING AND REPORTING REQUIREMENTS  
54 
9.1  Management of Safety Data  
55 
9.2  Definitions  
55 
9.3 Pregnancy  
60 
9.4  Adverse Event Monitoring and Reporting  
60 
9.5  Company Reporting Procedures  
61 
9.6  Evaluating Adverse Events  
64 
9.7  IRB Reporting  
67 
9.8  Protocol Amendments  
68 
9.9  Informed Consent  
68 
10. STATISTICAL METHODS  
69 
10.1 Study Design and Sample Size  
69 
10.2 Data Analysis  
69 
13. REFERENCES  
71 
14. APPENDICES  
78 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
1. Introduction 
1.1. Overview and Rationale 
Prostate cancer is highly curable when caught at an early stage, with 10-year 
overall survival (OS) rates following radical prostatectomy (RP) or radiation therapy 
reported at >80%.7.9 While this data is encouraging, it is now recognized that a large 
number of men with localized, low grade prostate cancer are being over treated. Large 
population based screening programs conducted in Europe have reported that the 
number of men with prostate cancer who need to be treated in order to save one life 
may be as high as 48.9 A similar study conducted in the United States did not find that 
prostate cancer screening efforts led to any improvement in overall survival (05).19  
A logical conclusion from the aforementioned screening data is that only a subset of 
higher risk men may stand to benefit from localized prostate cancer treatment. One 
strategy to mitigate this over treatment entails the expectant management of men with 
favorable risk prostate cancer (i.e., active surveillance), where only patients with 
pathologic upstaging are referred for local therapy (e.g., prostatectomy or radiation 
therapy).11-13  Active surveillance can lead to approximately 45% to 70% of men with 
favorable risk disease avoiding local therapy, with approximately 25 to 35% leaving the 
program due to pathologic upstaging.13'14  Medical strategies to further decrease the rate 
of exit from active surveillance due to pathologic upstaging are needed given the 
morbidity associated with RP or prostatic radiation therapy. The need for intervention in 
this group is further bolstered by the fact that in spite of presenting with favorable risk 
disease, a subset of these patients will still go on to die from metastatic prostate 
cancer.1415  
Androgen/androgen receptor (AR) targeted therapies remain the backbone of 
advanced prostate cancer therapy.16  The initial treatment paradigm typically involves 
driving testosterone levels down to the castrate range (i.e., <50 ng/dL), most often 
through chemical castration with an LHRH agonist or antagonist. This approach is 
successful in controlling the disease in upwards of 85% of men; however, responses 
are typically transient and at the time of progression men are labeled as having castrate 
resistant prostate cancer (CRPC).17'18  The observation that even in a castration-
resistant state AR regulated genes (e.g., PSA) remain expressed has led to the further 
10 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
exploration of the AR-signaling axis as a therapeutic target in men with CRPC. 
Subsequently, newer AR-directed agents like abiraterone and enzalutamide, which 
inhibit AR-signaling in men with CRPC through disrupting the ligand-AR interaction (Abi 
through ligand depletion and Enza through receptor antagonism) have been 
developed.19-23  The next-generation pure AR-antagonist apalutamide builds on the 
success of enzalutamide, with improved pharmacokinetics/pharmacodynamics 
(PK/PD), and is currently under clinical investigation.' 
Given the proven track record of targeting the androgen/AR axis in the more 
advanced setting, AR-signaling inhibitors are the logical choice to evaluate at an earlier 
stage. Indeed, twenty-four weeks of neoadjuvant abiraterone acetate in combination 
with an LHRH agonist (leuprolide) has been reported to result in a 24% total/near total 
pathologic complete response (pCR) rate as documented in prostatectomy 
specimens.25 Monotherapy with apalutamide may have the theoretical advantage of not 
causing prolonged testosterone suppression. This is in contrast to the LHRH agonists 
which have been documented to cause prolonged testosterone suppression following 
their discontinuation.26-29  
The hypothesis of this trial is that apalutamide will lead to negative repeat 
biopsies as determined through systematic and site directed biopsies in active 
surveillance patients, which should in turn lead to decreased rates of pathologic 
progression and attrition from active surveillance. 
1.2. Androgen/Androgen Receptor Directed Therapies 
The initial management of advanced prostate cancer, as well as higher risk 
localized prostate cancer being treated with radiation therapy, typically involves 
targeting the androgen/androgen receptor (AR) signaling axis through lowering serum 
testosterone levels."' This is accomplished either through surgical castration or now 
more commonly with an LHRH agonist/antagonist (i.e., hormonal therapy [HT]). 
Hormonal therapy is initially highly effective in those with metastatic prostate cancer, 
leading to objective responses in >85% of individuals.17  Unfortunately, after a variable 
period of symptom relief, androgen ablation invariably ceases to suppress prostate 
cancer growth and patients eventually succumb to their disease. This disease state 
defined by progression in spite of androgen ablation has been termed castrate resistant 
11 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
prostate cancer (CRPC).18  More recently it has come to light that CRPC is still largely 
dependent on androgen/AR axis signaling. This realization has led to the development 
of multiple newer AR directed therapies.'" Mechanistically these agents primarily 
work either through ligand depletion (e.g., abiraterone acetate) or through interference 
with AR trafficking and signaling (e.g., apalutamide, enzalutamide). 
Traditional HTs have several unwanted side effects, making their use in an 
otherwise healthy population of men somewhat disadvantageous. Specifically, these 
agents have been shown to increase one's risk of diabetes and cardiovascular disease, 
lead to weight gain, and cause serum total cholesterol levels to increase.31-34 While one 
could argue that brief periods of LHRH agonist therapy are unlikely to produce such 
unwanted effects, it has been well documented that the use of HT for even a transient 
period of time can lead to prolonged periods of testosterone suppression — potentially 
putting these men at risk for the aforementioned side effects.28-28 After approximately 8 
months of HT only —35% of men will recover their testosterone to baseline and only 70-
80% of men will recover their testosterone to within a normal range." 
1.2.1. APALUTAMIDE 
Apalutamide works through competitive AR inhibition and unlike the older 
anti-androgens (e.g., bicalutamide, nilutamide), is a pure AR antagonist. It 
additionally has the ability to prevent AR nuclear translocation and DNA binding 
to nuclear response elements.24 It is generally felt to function similarly to 
enzalutamide, another AR targeted therapy approved for men with mCRPC pre-
and post-docetaxel. In docetaxel pre-treated patients enzalutamide was shown to 
result in a 37% reduced risk of death compared to placebo (HR 0.63, 95% Cl, 
0.53-0.75; P<0.001), and in docetaxel naïve patients it led to a 29% reduction in 
the risk of death compared to placebo (HR 0.71, 95% Cl, 0.60 to 0.84; 
P<0.001).2223 Preclinical work comparing apalutamide to enzalutamide, 
however, demonstrated that apalutamide may have several theoretical 
advantages over enzalutamide.' Namely, in mouse models apalutamide was 
able to achieve a maximal therapeutic effect at 30 mg/kg/day compared to 100 
mg/kg/day of enzalutamide (Figure 1). Apalutamide is also able to achieve 
equivalent intra-tumoral concentrations at a lower plasma steady state 
concentration compared to enzalutamide. Finally, while high-dose Apalutamide 
12 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
(i.e., 3-fold higher than the Phase II dose of 240 mg/day based on dose per m2  
body surface area and standard species conversion factors) has resulted in 
tremors and seizures in dogs, apalutamide is less effective than enzalutamide at 
crossing the blood-brain barrier. This may result in decreased CNS toxicities in 
those treated with apalutamide compared to enzalutamide. For instance, while 
enzalutamide has been implicated in causing seizures in a minority of patients, 
possibly through off target inhibition of GABA-A, no seizure have occurred in 
subjects treated on the Phase I/II studies of apalutamide (see apalutamide 
Investigator's Brochure).22.37  
Individual LNCIPAR (cc) Xenografts, Day 28 
(castrate mates) 
Tumor volume  (%chango) 
 
ARN409 
 MDV311/0  
I F 
30 mg/kg  100 mpg  30 mg/kg  104 milike 
Figure 1: Apalutamide comparative efficacy to enzalutamide (MDV-3100) in 
mouse xenograft models. Apalutamide is able to achieve maximal therapeutic 
effect at 30 mg/kg/day compared to 100 mg/kg/day of enzalutamide. 
1.2.1.1. APALUTAMIDE Clinical Trial Experience 
The first in human Phase I/II study of apalutamide is currently 
ongoing [Clinicaltrials.gov, NCT01171898]. This study is evaluating men 
with mCRPC. Results from the Phase I portion of this study (N=30) 
demonstrated that apalutamide is generally safe and well tolerated. At 
the maximum tested dose of 300 mg daily by mouth only 1/4 subjects 
experienced a grade 3 adverse event (AE) (abdominal pain). The other 
three individuals receiving a dose of 300 mg daily did not experience 
dose limiting toxicities (DLT) (see apalutamide Investigator's Brochure); 
[Rathkopf, ASCO GU 2012]. Common grade 1-2 AEs observed in the 
Phase I study included: fatigue (47%), nausea (30%), abdominal pain 
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(20%), arthralgias (13%), diarrhea (17%), dyspnea (13%) and peripheral 
sensory neuropathy (13%). Five patients experienced serious adverse 
events and one patient discontinued the study due to an adverse event 
(atrial fibrillation) deemed unrelated to study treatment. PSA declines 
50% were observed in 12 (55%) patients. 18F-166-fluoro-5a-
dihydrotestosterone (FDHT) PET evaluation demonstrated AR blockade 
at four weeks across multiple doses. Given promising activity observed 
across all doses in conjunction with no appreciable difference in FDHT-
PET uptake at 240 mg compared to 300 mg of apalutamide, a dose of 
240 mg has been selected for Phase ll testing.22,24 
The Phase II portion of this study is ongoing and will evaluate 
three expansion cohorts with a total enrollment of 97 patients ( see 
apalutamide Investigator's Brochure).22 The primary endpoint of the 
Phase II study is PSA response at 12 weeks according to Prostate 
Cancer Working Group 2 (PCWG2) Criteria.' All cohorts will consist of 
men who are chemotherapy naïve and have CRPC. Specific cohorts are: 
1) non-metastatic CRPC, 2) mCRPC pre-abiraterone acetate and 3) 
mCRPC post-abiraterone acetate. Preliminary results for the non-
metastatic CRPC cohort, mCRPC pre-abiraterone acetate cohort and the 
mCRPC post-abiraterone acetate cohort demonstrated 50% PSA 
declines at 12-weeks in 91% (41/45), 88% (22/25) and 29% (4/14) 
subjects, respectively (see apalutamide Investigator's Brochure).38 The 
most frequent, treatment-emergent, all causality, adverse events 
observed in > 10% of patients were fatigue (43%), diarrhea (32%), 
abdominal pain (25%), and nausea (23%). Table 6 in the apalutamide 
Investigator's Brochure lists all Phase ll AEs reported in more than 3 
patients by cohort. In Phase II, as of 20 August 2012, there were three 
Grade 3 treatment-related AEs: diarrhea, abdominal pain, and rash. Both 
diarrhea and rash occurred in NM-CRPC patients, with start dates 
approximately one month after the start of treatment and both were 
ongoing at the time of the data cut. The third Grade 3 AE (abdominal 
pain) occurred in a metastatic treatment-naïve CRPC patient, starting 29 
days after the start of treatment. It resolved after eight days of study 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
treatment interruption with no further recurrence or sequelae. Table 7 in 
the apalutamide Investigator's Brochure lists all Phase ll treatment-
related Grades 3 AEs. 
Apalutamide was recently approved by the FDA for use in men 
with non-metastatic CRPC on the basis of Phase III data showing that it 
significantly prolonged the time to development of metastatic disease39. In 
the pivotal Phase III study, patients with a PSA doubling time  months 
were randomized 2:1 between apalutamide or placebo. Men in the 
apalutamide group had a median metastasis-free survival of 40.5 months 
vs. 16.2 months in the placebo group (HR = 0.28; 95% CI 0.23 to 0.35; 
P<0.001). Several additional studies evaluating apalutamide are ongoing, 
including a Phase I trial evaluating it in combination with abiraterone 
acetate in a mCRPC population [clinicaltrials.gov, NCT01792687]. 
1.3. Active Surveillance 
While watchful waiting is primarily focused on avoiding treatment in those with 
advanced prostate cancer and a minimal life expectancy, active surveillance is geared 
towards individualizing management in those with favorable risk disease who are 
otherwise fit for local therapy — the intent being to not sacrifice overall cure rates while 
minimizing overtreatment." Those individuals felt most appropriate for this strategy 
have traditionally had low to very low-risk localized prostate cancer, usually as defined 
by the criteria proposed by Epstein or D'Amico; however, several cohorts now allow 
men with favorable-intermediate risk disease (i.e., low-volume Gleason 3+4 
disease).14,40-42 By focusing on those with favorable risk disease, active surveillance has 
been able to achieve comparable survival rates compared to those receiving immediate 
treatment while allowing approximately 45% to 70% of men to avoid local therapy 
(Table 2).1314 Furthermore, given that upward of 45% of men may qualify for active 
surveillance (i.e., have at least low risk disease), if management of patients per this 
paradigm becomes more widely accepted, the number of men avoiding unnecessary 
local therapy could reach nearly 50,000 per year in the United States alone.43,44  
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Apalutamide in Active Surveillance patients 	
Protocol Version: 6.0; September 06, 2019 
Inclusion Criteria 
Center 
Total 
number 
enrolled 
Number 
meeting 
all 
inclusion 
criteria (%) 
Median 
age 
(years) 
Median 
follow-up 
(months) 
Gleason 
PSA criteria 
CT 
Total 
positive 
cores 
Any 
given 
core 
positivity 
(%) 
Number 
receiving 
local therapy 
(%) 
OS 
Prostati 
Cancer 
Specific 
OS % 
Johns 
Hopkins' 
769 
633 (82) 
66 
32 
Gleason 53+3 
PSA density 50.15 
ng/ml/m1 
1 
<2 
550% 
255 (33.2) 
98 
100 
University of 
Miami' 
230 
230 (100) 
64 
32 
Gleason 56 
PSA 510 ng/ml 
<2 
52 
520% 
32 (14) 
100 
100 
University of 
California San 
Francisco' 
640 
376 (59) 
62 
47 
Gleason 53+3 
PSA 510 ng/ml 
52 
533% 
550% 
Low-risk 
(n=376): 
104 (28) 
Intermediate 
risk (n=90): 
27 (28) 
97 
100 
University of 
Toronto" 
993 
993 (100) 
68 
77 
Gleason 56 
Gleason <3+4 
(select 
patients only) 
Before year 2000: 
- 
- 
- 
267 (27) 
85 
98.5 
Men 570 years-old: 
PSA 510 ng/ml 
Men >70 years-old: 
PSA 515 ng/ml 
After year 2000: 
PSA 510 ng/ml 
Life expectancy <10 
years/significant 
comorbidities: PSA 
10-20 ng/ml 
Memorial- 
Sloan 
Kettering' 
238 
238 (100) 
64 
22 
53+3 
PSA 510 ng/ml 
52a 
53 
550% 
- 
- 
"able 2: Key North American active surveillance cohorts. Abbreviations: OS, overall survival; cT clinical tumor stage. 
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Enrollment criteria vary across active surveillance cohorts, but in general enrollment 
is offered only to those with favorable risk prostate cancer, which can be defined as 
very low-risk to low-intermediate risk disease (i.e., low-volume Gleason 3+4 
disease).40,41,48 In general, local intervention is recommended upon pathologic 
reclassification (i.e., increased tumor volume or Gleason score), with some also 
recommending intervention following a change in PSA kinetics.13,14,46 The reported 
reasons men leave active surveillance in pursuit of treatment include: Gleason grade 
change (8% to 38%), PSA increase (14% to 26%) and anxiety (3% to 9%).49  
As conducted at Johns Hopkins, active surveillance focuses on men with very low-
risk disease as defined per the Epstein criteria (i.e., Tic stage, PSA density <0.15 
ng/mL, PSA <10 ng/mL, Gleason 56, 52 cores involved and 550% cancer in any given 
core).11,13,41 Approximately 80% of men enrolled in the active surveillance program at 
Johns Hopkins met all criteria for very low-risk disease, with the other 20% failing to 
meet the PSA <10 ng/mL requirement only. Surveillance has entailed semiannual PSA 
measurements with digital rectal exam (DRE) and an annual 12 to 14 core biopsy. 
Curative local therapy is in turn only recommended upon pathologic upgrade from the 
enrollment criteria. To date, 1,134 men have enrolled in active surveillance, with 508 
(45%) men exiting the program. Out of those who have exited, 298 (26%) were 
secondary to pathologic upstaging, 99 (9%) elected to undergo treatment in spite of 
stable pathology and 113 (10%) electively withdrew from the program (Figure 2). Out of 
the 113 that electively withdrew from active surveillance, 66 (58.4%) were lost to follow-
up. In regard to those who exited active surveillance due to pathologic upstaging, 130 
(44%) exited due to Gleason score upgrading, 168 (56%) exited due to an increase in 
disease volume (i.e. total number of effected cores >2 or >50% involvement in any 
given core). Within two years 143 (12.6%) exited; 65 (45%) due to Gleason score 
upgrading and 78 (55%) due to an increase in disease volume. Only one of the 
subjects on active surveillance at Johns Hopkins has died as a result of prostate cancer 
Unpublished data)." 
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Tx 
Exits (508) 
298 pathologic, Tx at JHMI 
99 elective, Tx at JHMI 
L"3 Withdrawals 
(737) 
[ 
45 deaths 
other causes, 
1 PCa death 
Very low risk 
Prostate Cancer 
CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
Figure 2: Johns Hopkins active surveillance schematic. AS, active surveillance; Tx, 
local treatment (e.g. prostatectomy, radiation therapy); JHMI, Johns Hopkins 
Medical Institution; PCa, prostate cancer. 
In contrast to the Johns Hopkins active surveillance cohort, the University of 
Toronto cohort allows select patients with intermediate-risk prostate cancer to enroll.' 
Prior to the year 2000, patients >70 years-old who had a PSA up to 15 ng/ml or a 
Gleason score 53+4 were allowed to enroll. After 2000, any patient could enroll if they 
had a PSA of 10-20 ng/ml and/or a Gleason score 53+4 as long as they had a life 
expectancy of <10 years and significant comorbidities. Gleason 7 patients with primary 
pattern 4 disease were excluded given that these patients have been shown to have 
poorer outcomes compared to primary pattern 3 patients." Out of 993 men enrolled 
onto this cohort, 25% fulfilled the D'Amico criteria for intermediate risk." After a median 
follow up of 6.4 years, 27% of men have received intervention for their prostate cancer. 
Reasons for leaving the program include: short PSA doubling time (11.7%), grade 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
progression (9.5%), patient preference (1.6%), stage progression (0.8%) and biopsy 
volume progression (0.6%). Prostate cancer-specific mortality remains low, with only 
6% of patients having died from metastatic prostate cancer at 15-years. There does, 
however, appear to be an increased risk of death for those with intermediate risk 
disease compared to those with low-risk disease (15 year OS: 50.3% vs. 68.8%, 
P<0.0001; 15 year prostate cancer-specific survival: 88.5% vs. 96.3%, P<0.01).15  
One area in need of further study is how to best manage minority patients with 
prostate cancer. For instance, African American men have been reported to have a 1.6 
fold increased age-adjusted incidence of prostate cancer and a 2.4 fold increased age-
adjusted prostate cancer mortality." While some of the observed disparities in 
outcomes can be attributed to socioeconomic factors, a difference in tumor biology 
cannot be excluded, with some data pointing to African Americans harboring faster 
growing tumors compared to Caucasians.50.51 It has recently been reported that 
amongst a cohort of men with very low-risk prostate cancer being followed with active 
surveillance, African Americans were more likely to experience pathologic upgrading 
post-prostatectomy compared to Caucasians (27.3% vs. 14.4%; P<0.001).52 This data 
indicates that current means of risk stratifying based on clinical parameters alone may 
not be sufficient for certain patient populations interested in enrolling in active 
surveillance programs. Incorporating additional variables into pre-operative predictive 
models, such as prostatic MRI data, may help to overcome some of these limitations. 
1.3.1. Androgen-directed Therapy in Active Surveillance 
Two trials have assessed the clinical effects of androgen-directed therapy 
(e.g., LHRH agonist, 5a-reductase inhibitor) in men with prostate cancer enrolled 
on active surveillance. The first trial reported by Fleshner and colleagues 
randomized men with low-risk prostate cancer on active surveillance (T1c-T2a, 
Gleason score 56, PSA 511 ng/mL and a life expectancy of >5 years) to 
dutasteride 0.5 mg PO daily (N=144) vs. placebo (N=145).53 The primary 
endpoint was time to prostate cancer progression, defined as the time to 
pathological or therapeutic (i.e., radical prostatectomy, radiation therapy or drug 
therapy) progression. The dutasteride group had significantly fewer patients with 
prostate cancer progression at 3 years compared to the placebo group (38% vs. 
48%, P=0.009) and a higher negative 12-core TRUS repeat biopsy rate (36% vs. 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
23%, P=0.024). It should be noted, however, that the rates of pathological 
progression were the same for the dutasteride and placebo groups (29% vs. 
33%, P=0.079). 
The second trial by Cussenot and colleagues evaluated combination 
leuprolide 22.5 mg SC and bicalutamide 50 mg PO daily in men enrolled on 
active surveillance.' Subjects were required to have low-risk prostate cancer 
(Gleason 5.6, PSA < 10 ng/mL, 53 positive cores and 5T2a). Ninety-eight 
subjects were enrolled and received a single 3-month depot injection of 
leuprolide plus 15 days of oral bicalutamide around the time of their injection. The 
primary endpoint was the negative 10-core TRUS biopsy rate approximately one 
year after initiation of therapy. They reported a negative re-biopsy rate of 45% 
(11-19 months post-medical therapy). The investigators noted that this was 
higher than the 36% negative biopsy rate reported in the trial by Fleshner and 
colleagues. 
Neither of the aforementioned studies documented the development of 
metastatic prostate cancer or prostate cancer related death. Both of these trials 
demonstrate the feasibility and safety of an androgen-directed medical 
intervention in men enrolled on active surveillance. While the randomized trial by 
Fleshner and colleagues does report a decreased rate for the composite 
therapeutic and pathological progression endpoint, the fact that the rate of 
pathologic progression between groups is the same may indicate that 5a-
reductase inhibitor therapy alone is inadequate to alter the natural course of low-
risk prostate cancer. The report by Cussenot and colleagues interestingly 
reported a higher negative repeat biopsy rate when men were treated with 
combined leuprolide plus bicalutamide; however, caution should be taken in 
comparing data across studies. It is notable that there were a substantial number 
of false negatives in the Fleshner study, as evidenced by the high number of men 
(23%) with a negative repeat biopsy on the placebo arm. 
1.3.2. MRI in Active Surveillance 
While most centers have not formally incorporated MRI into their active 
surveillance guidelines, it does appear that MRI may play a role in determining 
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whether higher risk prostate cancer is present — be it through guiding prostate 
biopsies or improving upon predictive nomograms. Indeed, it has been shown 
that current clinical models used to determine the probability of insignificant 
prostate cancer pre-prostatectomy can be improved upon through incorporating 
endorectal prostatic MRI data.55.56 MRI has also been shown to be useful in 
planning prostate biopsies, with the cancer detection rate in those with and 
without detectable prostate lesions being 70.1% and 13.1% respectively 
(P<0.001).57  The multiparametric MRI (mMRI) is most useful in excluding 
presence of clinically significant disease defined as tumor volume >0.5 cm3. 
Turkbey et al reported that at 3.0 T mMRI can accurately estimate the index 
tumor volume sized above 0.5 cm3 compared with prostatectomy histological 
findings. MRI could detect 127 of 135 (94%) index tumors. Mean volume of 
tumors detected on MRI was 2.02 cm3 (median 0.98, range 0 to 21). Eight tumors 
were missed by MRI, the mean tumor histological volume 0.19 cm3 (median 0.11, 
range 0.0046 to 0.58) .59 In a study by Rosenkrantz et al, it has been shown that 
mMRI can accurately (82.7-89%) detect tumor foci measuring more than 3 mm 
on prostatectomy histological exam. The median diameter of tumors detected by 
MRI was 9 mm (range, 4-20 mm). They only considered tumor foci of larger than 
3 mm on histopathology as tumor positive.59  Lee et al have also reported the 
mean diameter of tumor suspicious lesions in a subgroup of patients with lesions 
less than 1 cm on DWI (8.26±1.51mm).69  
Recent advances in mMRI employ both morphologic and functional MR 
techniques, which allow extending the obtainable imaging information beyond 
anatomical assessment. Diffusion-weighted imaging (DWI) interrogates the 
tissue microstructure at the microscopic scale of water self-diffusion and by 
measuring the Brownian motion of water molecules provides information about 
the functional environment of water in tissue and reflecting cellular status of 
normal and pathological tissue.61 Furthermore, DWI is sensitive to changes in the 
micro-diffusion of water within the intra-cellular space and extracellular space 
and cytotoxic edema due to alterations in the ATP dependent sodium-potassium 
pumps.62 The quantitative biomarker of water diffusivity is apparent diffusion 
coefficient (ADC). In general, water movement is restricted by compacted or 
proliferating cells, which enables the ADC to be a marker of tumor density or 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
cellularity, such that, a highly dense malignant region will have low ADC and an 
area with low cellular density will exhibit a high ADC value. Malignant lesions 
have a lower ADC values (about 20-40%) than benign or normal prostatic tissue. 
Preliminary results suggest that DWI-MRI has the potential to not only increase 
the specificity of PCa detection but also to support prediction of tumor 
aggressiveness.62 Dynamic contrast-enhanced MR imaging (DCE-MRI) 
dynamically captures the distribution of intravenously administered Gadolinium-
based contrast agents between tissue and blood pool, and allows characterizing 
the microvascular environment alterations resulting from tumor angiogenesis, 
reflecting changes in perfusion and capillary permeability.' DCE-MRI uses 
pharmacokinetic (PK) modeling to describe the microscopic processes leading to 
the distribution of contrast agent molecules between the vascular and 
extravascular spaces over time. Tissue enhancement therefore contains 
information about the microvascular properties, the extravascular space and the 
exchange rate between these compartments. The parameters in the PK model 
are: the leakage space (ye), efflux rate constant (kep), and the influx volume 
transfer constant (Kt).  These parameters are connected by the equation: 
ve=
Ktr
K  
ansr- p.  
e Limited data are available on the application of MRI in monitoring 
treatment response in prostate cancer, such as the study of monitoring response 
to androgen deprivation therapy.64 These investigators reported significant 
reduction in all DCE-MRI parameters in the region of tumor, while normal-
appearing tissue showed no significant change after 3-month therapy.64  
The significance of MRI detectable prostate lesions in men who have low 
to very-low risk prostate cancer as defined by standard clinical criteria (i.e. the 
Epstein criteria) is illustrated in data from men enrolled in the active surveillance 
program at Johns Hopkins (unpublished data)." In total, 98 active surveillance 
patients had follow-up data and underwent prostatic MRI (endorectal MRI in 
83.8%). Thirteen (13.3%) had MRI invisible tumors and 85 (86.7%) had MRI 
visible tumors. After a median follow-up post-MR' of 13 months (range, 1-42 
months), none of those with MRI invisible tumors had pathologic reclassification 
while 34 (40%) of those with MRI visible tumors did. Taken in total, the above 
data point to MRI detectable prostate nodules having clinical significance, with 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
their presence perhaps indicating an underlying significant cancer — even when 
otherwise classified as low to very low-risk. 
1.4. Exploratory Biomarkers 
1.4.1. PTEN 
PTEN is a tumor suppressor gene implicated in the tumorigenesis and 
progression of prostate cancer.66-69 It plays an important role in the modulation of 
phosphatidylinosito1-3-kinase (PI3K) signaling, most likely though preventing the 
activation of the protein kinase Akt.' Loss or inactivation of PTEN can in turn 
lead to the upregulation of PI3K/AKT signaling as well as downstream mTOR 
signaling!' Genomic PTEN loss as determined through Fluorescence in situ 
hybridization (FISH) as well as lost PTEN expression as determined by 
immunohistochemistry (IHC) have been associated with adverse pathological 
markers as well as increased risk of recurrence following prostatectomy.72-76  
1.4.2. MYC 
MYC is an onco-protein that functions as a transcription factor, regulating 
cell proliferation, metabolism, protein synthesis, mitochondrial function and stem 
cell renewal!' Like PTEN, its expression has been associated with prostate 
cancer initiation and progression.77-79 Indeed, MYC has been shown to be able 
to transform benign prostate cancer cells in a single step and its overexpression 
has been documented at the earliest stages of transformation in prostatic 
intraepithelial neoplasia samples.78.86 The region on chromosome 8q24 that 
encompasses the MYC locus is often altered (e.g. amplified, deleted) in more 
advanced disease.77,81-63 Interestingly, while alterations in chromosome 8q24 
have been documented in more advanced cases of prostate cancer, MYC protein 
expression seems to be higher in Gleason 3 disease compared to Gleason 4-5 
disease!' 
1.4.3. ERG 
Gene fusions between the androgen receptor regulated TMPRSS2 gene 
and members of the ETS family of nuclear transcription factors (primarily ERG) 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
are frequently recognized in prostate cancer specimens." Furthermore, these 
gene fusions may synergize with PTEN loss, leading to more aggressive prostate 
cancer behavior.72'86  
1.4.4. KI-67 
KI-67 (Ki67) is a nuclear protein complex that is present during all active 
phases of the cell cycle, but absent during the GO phase, making it a marker of 
cellular proliferation [Gerdes et al, 19841.86 In men with localized prostate cancer, 
Ki67 has been found to independently associate with the risk of developing 
progressive disease following both radiation therapy and radical 
prostatectomy.72'87  
1.4.5. AR-axis liquid biopsy assay 
Expression of a panel of RNA markers will be evaluated from whole blood 
collected in PAXgene RNA tubes. These cancerous RNA transcripts are involved 
in AR-signaling, steroidogenesis, proliferation, neuroendocrine and other 
pathways important in prostate cancer. Detection of differential expression levels 
may associate with response to drug treatment. 
1.4.6. Prostate Cancer mRNA Expression Profiling/Risk Classifier 
There are several commercially available mRNA expression assays 
designed to assess the risk of prostate cancer recurrence/progression (e.g., 
Decipher [GenomeDX Biosciences, San Diego, CA] and Oncotype DX Prostate 
Cancer Assay [Genomic Health, Inc., Redwood City, CA]).2-6 In addition, whole 
transcriptome sequencing (i.e., RNA-seq) can provide detailed assessment of the 
landscape of genes being transcribed within a population of cancer cells, and 
provide insights into potential resistance mechanisms. One or more of these 
approaches will be used on prostate core biopsy specimens obtained pre- and 
post-treatment with apalutamide. The goal will be to develop predictive 
biomarkers for response to apalutamide. 
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PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
2. Study Objectives 
2.1. Primary Objective 
Determine the negative repeat biopsy rate by site directed and systematic prostate 
biopsy after 90-days of apalutamide. 
2.2. Secondary Objectives 
1. Determine the rate of exit at 2 years from active surveillance due to pathologic 
reclassification. 
2. Determine the overall rate of exit at 2 years from active surveillance. 
3. Determine the rate of local treatment (e.g., radical prostatectomy, radiation therapy, 
brachytherapy) at 2 years and the local treatment free survival. 
4. Determine PSA progression rates and PSA progression free survival (PFS), as 
defined by the Prostate Cancer Working Group 2 (PCWG2) criteria.' 
5. Determine the rate of radiographic disappearance of MRI detectable prostate 
cancer following treatment (only in patients with a baseline nodule that is PIRADS 3 
or more and >5mm). 
6. Investigate the safety of apalutamide in men undergoing active surveillance. 
a. Safety will be evaluated by the incidence, severity, duration, causality, 
seriousness, and type(s) of adverse events as assessed by the revised 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), version 4.03 published 14 June 2010. 
7. Track quality of life utilizing the FACT-P and SF36 surveys for each cohort. 
8. Exploratory biomarker Assessment. Examples of these may include, but are not 
limited to: assessment for genomic PTEN loss via fluorescence in situ hybridization 
(FISH), PTEN immunohistochemistry (IHC), assessment for alteration in 
MYC/chromosome 8q24 via FISH and tumor mRNA expression profiling/risk 
classification (e.g., Decipher, Oncotype DX Prostate Cancer Assay, or RNA-seq). 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
2.3. Primary Endpoint 
Negative (i.e., no residual carcinoma) site directed and systematic prostate biopsy 
following 90-days of apalutamide. 
2.4. Secondary Endpoints 
1. Exit from active surveillance due to pathologic reclassification at 2 years. 
2. Exit from active surveillance for any reason at 2 years. 
3. Local treatment (e.g., radical prostatectomy, radiation therapy, brachytherapy) at 2 
years and the local treatment free survival. 
4. PSA progression and PSA progression free survival (PFS), as defined by the 
Prostate Cancer Working Group 2 (PCWG2) criteria [Scher et al, 2008]. 
5. Radiographic disappearance of MRI detectable prostate cancer following treatment 
(in patients with a baseline nodule that is PIRADS 3 or more and >5mm). 
6. Safety of apalutamide in men undergoing active surveillance. 
a. Safety will be evaluated by the incidence, severity, duration, causality, 
seriousness, and type(s) of adverse events as assessed by the revised 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), version 4.03 published 14 June 2010. 
7. Quality of life as assessed using the FACT-P and SF36 surveys. 
8. Exploratory biomarkers assessment. Examples of these may include, but are not 
limited to: assessment for genomic PTEN loss via fluorescence in situ hybridization 
(FISH), PTEN immunohistochemistry (IHC), assessment for alteration in 
MYC/chromosome 8q24 via FISH and tumor mRNA expression profiling/risk 
classification (e.g. Decipher, Oncotype DX Prostate Cancer Assay, or RNA-seq). 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
3. Patient Population and Selection 
Up to 33 patients will be enrolled at University of Washington Medical Center, in a 2-stage 
design. The target population will be men with very low-risk to low-intermediate risk prostate 
cancer (see 'risk' definitions under Inclusion Criteria) enrolled (or planning to enroll) on 
active surveillance. 
3.1. Inclusion Criteria 
1. Have signed an informed consent document. 
2. Be willing/able to adhere to the prohibitions and restrictions specified in this 
protocol 
3. Written Authorization for Use and Release of Health and Research Study 
Information has been obtained 
4. Male aged 18 to 75 years or life expectancy 0 years (as determined by the 
. treating physician) 
5. Eastern cooperative group (ECOG) performance status 51 
6. Histologically confirmed adenocarcinoma of the prostate as documented by a 
minimum 12 core prostate biopsy completed within 1-year of enrollment (Note: 
most recent prostate biopsy must have demonstrated prostatic 
adenocarcinoma) 
7. Favorable risk prostate cancer as defined by: 
Very low-risk 
a. Clinical stage Tic disease 
b. PSA density (PSAD) <0.15 ng/mL 
c. Gleason score 6 
d. 52 core biopsies with 550% involvement of any biopsy core with 
cancer, or unilateral disease 52 core biopsies with any 
percentage involvement 
Or 
Low risk 
a. Clinical stage 5 T2a 
b. PSA < 15 ng/mL 
c. Gleason score 6 
or 
27 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
Low-intermediate risk 
a. Clinical stage Tic 
b. PSA <15ng/m1 
c. Gleason 3+4 present in 550% of one core/site as detected by 
systematic biopsy or MRI/TRUS fusion guided biopsy 
d. Gleason 6 disease in all other cores/sites 
8. Willing and qualified for active surveillance at the University of Washington 
9. Serum testosterone 150 ng/dL 
10. Able to swallow the study drugs whole as a tablet 
11. Clinical laboratory values at screening: 
a. Hemoglobin A.0 g/dL, independent of transfusion and/or growth 
factors within 3 months prior to registration 
b. Platelet count 100,000 x 109/pL independent of transfusion 
and/or growth factors within 3 months prior to registration 
c. Serum albumin 3.0 g/dL 
d. GFR 45 mL/min 
e. Serum potassium 3.5 mmol/L 
f. 
Serum total bilirubin *1.5 x ULN (Note: In subjects with Gilbert's 
syndrome, if total bilirubin is >1.5 x ULN, measure direct and 
indirect bilirubin and if direct bilirubin is 51.5 x ULN, subject may 
be eligible) 
g. Aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) <2.5 x ULN 
12. Medications known to lower the seizure threshold (see list under prohibited 
meds) must be discontinued or substituted at least 4 weeks prior to study entry. 
13. 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. 
3.2. Exclusion Criteria:  
28 
 
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PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
1. Prior local therapy to treat prostate cancer (e.g., radical prostatectomy, radiation 
therapy, brachytherapy) 
2.  Prior use of ARN-509 (apalutamide) 
3. Have known allergies, hypersensitivity, or intolerance to ARN-509 (apalutamide) 
or its excipients 
4. Prior or ongoing systemic therapy for prostate cancer including, but not limited to: 
a. Hormonal therapy (e.g., leuprolide, goserelin, triptorelin) 
b. CYP-17 inhibitors (e.g., abiraterone, ketoconazole) 
c. Antiandrogens (e.g., bicalutamide, nilutamide) 
d. Second generation antiandrogens (e.g., enzalutamide) 
e. lmmunotherapy (e.g., sipuleucel-T, ipilimumab) 
f. Chemotherapy (e.g., docetaxel, cabazitaxel) 
5. Have any condition that, in the opinion of the investigator, would compromise the 
well-being of the subject or the study or prevent the subject from meeting or 
performing study requirements 
6.  History of any of the following: 
a. Seizure or known condition that may pre-dispose to seizure 
(including but not limited to prior stroke, transient ischemic attack, 
loss of consciousness within 1 year prior to registration, brain 
arteriovenous malformation; or intracranial masses such as 
schwannomas and meningiomas that are causing edema or mass 
effect) 
b. Severe or unstable angina, myocardial infarction, symptomatic 
congestive heart failure, arterial or venous thromboembolic events 
(e.g., pulmonary embolism, cerebrovascular accident including 
transient ischemic attacks), or clinically significant ventricular 
arrhythmias within 6 months prior to registration. 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
c.  Any condition that in the opinion of the investigator, would preclude 
participation in this study 
7. Current evidence of any of the following: 
a. Uncontrolled hypertension 
b. Gastrointestinal disorder affecting absorption 
c. Active infection (e.g., human immunodeficiency virus [HIV] or viral 
hepatitis) or other medical condition that would make 
prednisone/prednisolone (corticosteroid) use contraindicated 
d. 
Any condition that in the opinion of the investigator, would preclude 
participation in this study 
8. The use of drugs known to lower the seizure threshold, including: atypical 
antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone), bupropion, 
lithium, meperedine, pethidine, phenothiazine antipsychotics (e.g., 
chlorpromazine, mesoridazine, thioridazine), and tricyclic antidepressants (e.g., 
amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine) (see 
Appendix C for a more complete list of prohibited concomitant medications). 
9. The use of strong CYP3A4 inhibitors, including: itraconazole, clarithromycin, 
erythromycin, diltiazem, verapamil, delavirdine, atazanavir, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, 
grapefruit juice (or grapefruits) (see Appendix C for a more complete list of 
prohibited concomitant medications). 
Note: If a patient is on a strong CYP3A4 inhibitor, they can be reconsidered for 
enrollment if they can safely stop said medication. A two week or 5 half-lives, 
whichever is longer, washout will be required prior to enrolling on study. Subject 
may not resume medication while receiving apalutamide. 
10. Strong CYP3A4 inducers, including: phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentin, phenobarbital, efavirenz, tipranivir, St. John's wort (see 
Appendix C for a more complete list of prohibited concomitant medications). 
30 
 
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CC Protocol Number: 9582 	
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients 	Protocol Version: 6.0; September 06, 2019 
Note: If a patient is on a strong CYP3A4 inducers, they can be reconsidered for 
enrollment if they can safely stop said medication. A two week or 5 half-lives, 
whichever is longer, washout will be required prior to enrolling on study. Subject may 
not resume medication while receiving apalutamide 
11. Any psychological, familial, sociological, or geographical condition that could 
potentially interfere with compliance with the study protocol and follow-up 
schedule. 
3.3. Inclusion of Women and Minorities 
This study is focused on prostate cancer; therefore the treatment cohort is only 
applicable to men. Men from all ethnic and race groups are eligible for this study. 
31 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
4. Treatment Plan 
4.1. Study Design 
This is an open label, multi-site, Phase II study designed to determine the 
negative repeat prostate biopsy rate following 90-days of treatment with apalutamide. 
All subjects must be enrolled in the active surveillance program at the University of 
Washington Medical Center. All eligible patients will initiate therapy with apalutamide, 
which will be administered at the FDA approved dose for treating non-metastatic 
castration-resistant prostate cancer (i.e., 240 mg daily by mouth). Note that 
apalutamide is FDA approved only for the treatment of patients with non-metastatic 
castration-resistant prostate cancer, and is under development as an investigational 
product for other types of prostate cancer. Subjects will have either 1) an MRI 
detectable cancer of PIRADS 3 or more >5mm, and pathologically documented by 
MRI/TRUS fusion biopsy with coordinates of biopsy site stored for repeat biopsy; or 2) a 
systematic 12 core biopsy pathologically documenting prostate cancer with the 
coordinates of the biopsy sites stored for repeat biopsy. This biopsy may be done up to 
12-months prior to enrollment. 
Following 90-days of treatment with apalutamide, patients will undergo a repeat 
prostate biopsy selectively targeting sites of prior positive biopsies (3 from each positive 
biopsy site) plus a 12 core systematic prostate biopsy without targeting. All patients will 
continue on active surveillance per the standard practice of the treating urologist. 
Must meet one of the following criteria: 
1) Very low-risk prostate cancer: 
• Stage Tlc 
• PSA density <0.15 ng/mL 
• Gleason 6 
• 52 cores with 550% involvement of any core, 
or any percent involvement if unilateral 
disease 
1) Selective site 
directed biopsy 
(3 cores per site) 
2) Low risk prostate cancer: 
ARN-509 240 mg daily  ). 
And 
Determine negative 
repeat biopsy rate 
Treatment: 90 days 
• Stage sT2a 
• PSA <15 ng/mL 
• Gleason 6 
2) Systematic 12 
core biopsy 
3) Low-intermediate risk prostate cancer 
• Stage Tlc 
• PSA <15 ng/mL 
• Gleason 3+4 in 550% of one core 
• Gleason 6 in all other cores 
Figure 3: Study scheme. 
32 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
The primary endpoint for this trial will be the absence of residual carcinoma (i.e. a 
negative repeat biopsy) as determined by targeted and systematic biopsies following 
90-days of apalutamide. Secondary endpoints will include: exit from active surveillance 
due to pathologic progression or otherwise at 2 years, receipt of local treatment for 
prostate cancer at 2 years, local treatment free survival, PSA progression at 2 years, 
PSA PFS as defined by Prostate Cancer Working Group 2 (PCWG2) criteria, 
radiographic disappearance of MRI detectable nodules following treatment, quality of 
life changes and safety (as assessed by the revised National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE], version 4.03).1  
Biopsy specimens, blood and plasma samples will be stored at -80°C. These 
specimens will be labeled with a subjects unique study ID, and will not have personal 
identifiers imprinted on them. Samples (i.e., prostate tissue, blood, and plasma) will be 
obtained pre- and post-treatment with apalutamide. These biologic specimens will be 
used for additional correlative work. Examples of studies to be conducted may include, 
but are not limited to: assessment for PTEN loss via immunohistochemistry (IHC), 
assessment for alteration in MYC/chromosome 8q24 via FISH and tumor mRNA 
expression profiling/risk classification (e.g., Decipher [GenomeDX Biosciences, San 
Diego, CA], Oncotype DX Prostate Cancer Assay [Genomic Health, Inc., Redwood City, 
CA], or RNA-seq).2-6  
Subject enrollment requires a baseline systematic 12 core biopsy with pathologically 
documented prostate cancer and with the coordinates of the biopsy sites stored for 
repeat biopsy. Subjects can include men with newly diagnosed prostate cancer or those 
already enrolled in active surveillance, but baseline prostate biopsy must have occurred 
within 12-months of enrolling onto this study. Subjects may have had a multiparametric 
MRI of the prostate performed at least 6 months from any prior prostate biopsy. If an 
MRI detectable cancer of PIRADS 3 or more and >5mm was pathologically 
documented by MRI/TRUS fusion biopsy with coordinates of biopsy site stored, this 
lesion will be targeted for repeat biopsy. Otherwise, coordinates should be stored using 
a standard sextant prostate biopsy diagram (Appendix A) to aid in targeted repeat 
biopsy. Ninety days after treatment with apalutamide, all subjects will undergo 1) 
selective biopsy targeting cancer positive sites based on stored coordinates (3 biopsy 
cores per positive site); and 2) a 12 core non targeted systematic biopsy. PSA will be 
33 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
measured at baseline (i.e., within 30 days of initiating treatment per the study) and 
again within one week of completing apalutamide. PSA progression will be determined 
based on PCWG2 criteria (i.e., confirmed rising PSA  ng/mL at least one week 
apart).1  
All samples collected as part of this research study will be stored at University of 
Washington and access to these samples will be limited to the Sponsor-Investigator, 
Co-Investigators, Janssen Scientific Affairs, LLC or their designees. Only researchers 
associated with this study will have access to these specimens. Biologic samples will be 
retained for up to 5 years following the last patient completing the study, and any 
remaining samples will be destroyed after that time. Likewise, data generated as part of 
this study will be stored on secure servers at University of Washington and/or Janssen 
Scientific Affairs, LLC and access will be limited to the Sponsor-Investigator, Co-
Investigators, Janssen Scientific Affairs, LLC or their designees. The identity of enrolled 
subjects will remain confidential, and only the treating physician, research team and/or 
Sponsor-Investigator will have access to this information. Patient identifiers will not be 
made available to the Janssen Scientific Affairs, LLC. 
4.2. Removal of Patients from Study 
A patient may be removed from the study for a variety of reasons, including: 
1. 
Worsening symptoms that can be attributed to prostate cancer 
2. 
Unacceptable adverse event(s) 
• 
Patients develop urinary outlet obstruction requiring urinary catheterization 
and/or surgical intervention 
• 
Patients who develop grade 3 or higher liver function abnormalities: 
o Bilirubin 2 times institutional upper limit of normal (ULN) 
o AST (SCOT) or ALT (SC PT) 3 times ULN 
• 
Patients develop decreased renal function with serum creatinine ?. 2.5 times 
baseline level 
• 
Patients develop hypersensitivity or anaphylactoid reactions to apalutamide. 
3. 
Intercurrent illness that prevents further participation 
4. 
Experiencing a treatment delay of longer than 2 weeks due to drug toxicity; 
however, if the patient is receiving clinical benefit (at the discretion of the PI and/or 
34 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
local investigator), treatment may be delayed for longer than 2 weeks and then 
resumed at the discretion of the Investigator. 
5. 
Patient refuses further treatment through the study and/or withdraws consent to 
participate 
6. 
Patients is noncompliant with respect to taking drugs, keeping appointments, or 
having tests required for the evaluation of drug safety and efficacy 
7. 
General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in this study in the judgment of the PI or local 
investigator. 
8. 
Under no circumstance will care of a withdrawn patient be adversely affected by a 
decision to withdraw or be withdrawn from the study. 
35 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
5. Treatment Assessment and Evaluation 
All required treatment and end of study procedures and assessments must be done within 7 
days (+1-) of the specified study visit date unless otherwise noted. With the exception of the 
surveillance prostate biopsy, screening study procedures and assessments must be done 
within 30 days prior to enrollment. Long term follow-up procedures and assessments should 
occur two years following day 1 (+1- 30 days). After two years of follow-up, the medical 
records for study subjects will be requested and reviewed yearly through year 5 (+I- 90 
days) in order to obtain additional follow up data. 
Note: If a subject withdraws from the study prior to completing the 90-days of study drug, the 
"End of Study" procedures will be completed at the time of withdrawal. "Long Term Follow-
up" procedures will occur at the specified time regardless of whether the patient received 
90-days of study drug. 
5.1. Screening Studies (performed within 30 days before enrollment unless otherwise 
noted; i.e., Day -30 to -1) 
1. Comprehensive medical history and physical exam, including height and weight, 
medications, blood pressure, heart rate and ECOG performance status assessment 
2. Systematic 12-core prostate biopsy (within 12-months of enrollment) 
3. CBC (Complete blood count) with differential and platelet count 
4. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum 
Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline 
Phosphatase, CO2) 
5. Thyroid stimulating hormone (TSH) 
6. EKG 
7. Testosterone 
8. PSA 
36 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
5.2. Treatment Phase 
1. Comprehensive medical history and physical exam, including weight, medications, 
blood pressure, heart rate and ECOG performance status assessment (days 1, 30 
and 60) 
2. Adverse event assessment (days 1, 30 and 60) 
3. Study drug dispensation and collection of unused study drug 
4. CBC with differential (days 1, 30 and 60) 
5. CMP (days 1, 30 and 60) 
6. Serum PSA (day 1) 
7. Testosterone (days 1, 30 and 60) 
8. LH plasma level (days 1, 30 and 60) 
9. TSH (days, 30 and 60) 
10. Quality of life questionnaires (FACT-P and SF-36) (day 1) 
11. Exploratory biomarkers (see sections 1.4 and 7.3) (performed on tissue, blood and 
plasma samples) (Days 1 and 30) 
5.3. End of Study (i.e., day 91 of treatment) 
1. Comprehensive medical history and physical exam, including weight, medications, 
blood pressure, heart rate and ECOG performance status assessment 
2. Adverse event assessment 
3. Unused study drug collection 
4. Systematic 12-core prostate biopsy AND selective site directed biopsy (3-cores per 
site) 
Note: In patients with a baseline detectable nodule (PIRADS  and >5mm), 
MRITTRUS fusion guided biopsy will be used to obtain the site directed biopsies 
37 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
5. CBC with differential 
6. CMP 
7. Serum PSA 
8. Testosterone 
9. LH plasma level 
10. Exploratory biomarkers (see sections 1.4 and 7.3) (performed on tissue, blood and 
plasma samples) 
11. Quality of life questionnaires (FACT-P and SF-36) 
5.4. Long Term Follow-up 
1. Adverse event assessment (Days 180, 365, 545 and 730) 
2. Minimum 12-core prostate biopsy (Days 365 and 730) 
3. Serum PSA (Days 180, 365, 545 and 730) 
4. Quality of life questionnaires (FACT-P and SF-36) (Days 180, 365, 545 and 730) 
5.5. Long Term Record Review (at Years 3, 4 and 5, +1-90 days) 
1. Most recent PSA 
2. Prostate biopsy data (e.g. highest Gleason score, number of involved cores) 
3. Local treatment received (e.g. radiation, surgery) 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  
Protocol Version: 6.0; September 06, 2019 
6. Study Calendar: All required treatment and end of study procedures and assessments must be done within 7 days (±) of the specified 
study visit date. With the exception of the screening prostate biopsy, screening study procedures and assessments must be done 30 days 
prior to enrollment. Long-term follow-up procedures and assessments should occur two years following Day 1 (±30 days). Medical records 
will be reviewed yearly (+1- 90 days) through year five in years 3, 4 and 5. 
Screening 
Treatment phase 
End of Study 
Long-term follow-uph 
Record Review 
Day -30 to -1 
Day 1 
(±7 days) 
Day 30 
(±7 days) 
Day 60 
(±7 days) 
Day 91 
(±7 days) 
Day 180 
(±30 days) 
Day 365 
(±30 days) 
Day 545 
(±30 days) 
Day 730 
(±30 days) 
Year 3, 4, 5 
(±90 days) 
Informed Consent 
x 
History and Physicala 
x 
x 
x 
x 
x 
Adverse Event Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug dispensation 
x 
x 
x 
Unused study drug collection 
x 
x 
x 
CBCb 
x 
x 
x 
x 
x 
CMPb 
x 
x 
x 
x 
x 
EKG 
x 
Serum PSA 
x 
x 
x 
x 
x 
x 
x 
Testosterone 
x 
x 
x 
x 
x 
LH plasma levelb 
x 
x 
x 
x 
TSFIc 
x 
x 
x 
Exploratory biomarkersd 
x 
x 
x 
Quality of life questionnairese 
x 
x 
x 
x 
x 
x 
Systematic 12-core biopsy 
xf 
X 
X 
x 
Site directed biopsy (3-cores per site)g 
x 
Medical Record Review 
x 
a. History and physical assessment will include ECOG performance status and toxicity assessments. Visits will also document medications, blood pressure, height (only at screening visit) and 
weight, and heart rate. Note: nursing assessment will suffice for the physical assessment. 
b. CBC = Complete blood count with platelets and differential; CMP = Comprehensive metabolic panel (Sodium, Potassium, Chloride, BUN, Serum Creatinine, Calcium, Total Protein, Albumin, Total 
Bilirubin, AST, ALT, Alkaline Phosphatase, CO2); LH = Luteinizing hormone; TSH = thyroid stimulating hormone. 
c. If TSH is abnormal, Free T3 and T4 levels must be checked. 
d. See sections 1.4 and 7.3 for a description of exploratory biomarkers. These will be performed on tissue, blood and plasma sample. Note Samples obtained at the Day 1 visit will serve as 
baseline samples. 
e. Quality of life questionnaires include the FACT-P and SF-36 questionnaires. 
f. Screening 12-core biopsy may be performed up to 12-months prior to enrollment. 
g. In patients with a baseline detectable nodule (PIRADS  and >5mm), MRI/TRUS fusion guided biopsy will be used to obtain the site directed biopsies. Otherwise, this will be done using the 
saved coordinates of known areas of cancer as determined from the screening systematic 12-core biopsy. 
h. Patients will be required to be seen by a provider or research nurse for long-term follow-up appointments on Day 180, Day 365, Day 545 and Day 730. Long-term follow-up on Year 3, Year 4 and 
Year 5 are conducted by medical record review only to collect data on most recent PSA, highest gleason score on most recent biopsy and local treatment received (e.g. radiation, surgery). 
'X' indicates study or exam to be done on the specified day. 
39 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
7. Study Assessments 
7.1. Prostate Biopsy 
Systematic 12-core prostate biopsies will be performed using transrectal ultrasound 
(TRUS) guidance and be performed per the treating physician's discretion. Prostate 
biopsies will be interpreted through the pathology department at University of 
Washington. Gleason score, number of involved cores and percent core involvement 
will all be captured. Coordinates of the biopsy sites must be stored. These coordinates 
may be stored on either a standard sextant prostate biopsy diagram (Appendix A) or 
within the MRI/TRUS fusion software. Repeat systematic 12-core prostate biopsies will 
be performed following treatment with apalutamide. In addition, site directed biopsies 
will be performed targeting areas of known cancer using the saved coordinates from the 
screening biopsy. Site directed biopsy may be performed using either: a) TRUS 
guidance, or b) MRI/TRUS fusion guidance. MRITTRUS fusion guided biopsy will only 
occur if an MRI detectable cancer of PIRADS .3 and >5mm was pathologically 
documented at the time of screening biopsy. Note: patients are not required to have 
baseline MRI/TRUS fusion guided biopsies in order to enroll. A patient will be defined 
as having a negative biopsy if no cancer is found on systematic 12-core and site 
directed prostate biopsy as described above. The biopsy (12-core plus site directed) 
that occurs immediately following 90-days of apalutamide will be used for determining 
the primary endpoint. 
Repeat minimum 12-core TRUS guided prostate biopsy will be performed 
approximately every year following day 1 of treatment with apalutamide per standard 
active surveillance guidelines. These biopsies will be used to determine if there has 
been pathologic progression. Pathologic progression will be defined as: 1) increase in 
Gleason score, 2) increase in number of involved cores or 3) increase in maximum 
percentage of any given core's involvement. Only pathologic progression (i.e. not PSA 
progression) will trigger removal from active surveillance and recommendation for local 
prostate cancer treatment. 
7.2. Prostatic MRI 
While not required for study enrollment, we anticipate some patients will have had a 
baseline MRI and/or MRI/TRUS fusion guided biopsy prior to enrolling on active 
40 
 
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CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
surveillance. In addition, select patients will undergo MRI/TRUS fusion guided site 
directed biopsies following treatment with apalutamide (see Section 7.1: Prostate 
Biopsy). In these individuals, the following MRI imaging parameters should be used 
whenever possible. 
MR Imaging techniques: Prostate MR imaging will be performed on a 3.0 Tesla magnet 
(Trio, Siemens Medical Solutions or Ingenia, Philips Healthcare) using a body torso coil. 
The patient will be imaged in supine position. MRI will be performed at least 8 weeks after 
biopsy, to minimize the influence of post-biopsy hemorrhage. Patients will receive 1 mg 
Glucagon IM injection to suppress bowel peristalsis. Imaging will consists of thin-section 
high-resolution axial, coronal and sagittal T2-weighted fast spin-echo images of the 
prostate and seminal vesicles (TRITE = 3500/101 msec, slice thickness 3 mm, interslice 
gap 0-1mm, FOV 20-28 cm), 3D isotropic T2 weighted image acquisition (TRITE = 
1600/115, slice/space 1/0 mm, FOV 35 cm), diffusion-weighted imaging (2D multislice 
single-shot echo-planar imaging, TRITE = 3300/76 msec, b values 50, 500, 800, 1000 
section thickness = 3 mm, FOV 20-28 cm), and DCE-MRI imaging sequences, consisting 
of a precontrast T1 mapping sequences using 3D VIBE (Simens) or 3D THRIVE (Philips) 
(TRITE 3.8/1.4, slice/space 3.6/0, FOV 26 cm) with the option to obtain 4 identical 
measurement parameters except different flip angles (i.e. 2, 5, 8, 15°) and NEX=4. 
Subsequent dynamic imaging will utilize intravenous power injection (Medrad) of a single-
dose (0.1 mmol/kg) of gadopentetate dimeglumine (Gd-DTPA, Magneviste) at an 
injection rate 3 mUsecond, followed by a 20-mL flush of normal saline. Axial DCE images 
of the entire prostate gland will be acquired using the TWIST T1 3D GR sequence at high 
temporal resolution of 4.2 sec (TRITE 3.8/1.4 msec, flip angle 12, matrix 160x160, FOV 
20-28 cm, NEX=1). At total of 70-post contrast phases will be acquired over 5 minutes. 
The total imaging time is 45 minutes. 
Definitions for localizing prostate carcinoma: a) focal area of discrete measurable low 
signal intensity on T2-weighted images (longest diameter 0.5 cm); b) apparent diffusion 
coefficient (ADC) reduction on DWI in reference to normal glandular tissue; d) perfusion 
abnormality on DCE-MRI in reference to normal glandular tissue. Tumors are detected 
using a combination of the T2-weighted and diffusion-weighted images. More than one 
tumor is considered to be present if the tumor noncontiguously involves the left and the 
right gland, or noncontiguously involves the same ipsilateral side (with two or more 
noncontiguous slices of "normal appearing" prostate between tumor foci). For the follow- 
41 
 
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PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
up post-treatment studies, the baseline pretreatment MR images will be used as a 
reference to identify tumor regions. 
DCE MRI Analysis: Areas suspicious for presence of tumor will be outlined by a 
radiologist as a region of interest (ROI) on the dynamic images using the T2-weighted 
and DWI images for guidance. Pharmacokinetic analysis of the DCE MRI images will be 
carried out using syngo Tissue 4D software from Siemens or DynaCAD software from 
lnvivo. The following parameters will be recorded: the volume transfer constant (Ks), 
the rate constant (kep), and the fractional leakage space (ve). 
DWI Analysis: Generated apparent diffusion coefficient (ADC) maps will be used to 
assess areas of low signal intensity reflecting restricted diffusion. Using the T2-weighted 
images and high b-value DWI images for guidance, the mean ADCs will be calculated for 
each defined ROI for each separate focus of prostate cancer. 
MRI investigational biomarkers that will be assessed at baseline and on a post-
treatment mMRI: DCE-MRI: '<trans (mini), kep (min-1), tie ( %); 
%' ); DWI: ADC (x10-3 mm2/s) 
7.3. Exploratory biomarkers 
This study will incorporate a number of exploratory biomarkers. Given our rapidly 
evolving understanding of prostate cancer pathobiology, genetics and epigenetics, it is 
impossible to prospectively define all the relevant biomarkers for the patient population 
enrolled on this study. So as to not miss an opportunity to assess the utility of yet to be 
described biomarkers in the context of this active surveillance medical intervention trial, 
we will plan to store biopsy specimens, plasma and blood samples at -80°C. All 
samples (i.e., prostate tissue, blood and plasma) will be obtained pre- and post-
treatment with apalutamide. Specific biomarkers of interest have been described in 
section 1.4 of the protocol. Admittedly, given that we may not be able to obtain 
adequate tissue to assess all of these biomarkers, we will prioritize assessing them in 
the order that they are described below. All biopsy material will be Forrnalin-Fixed 
Paraffin Embedded (FFPE) and IHC and FISH assays will be performed on these FFPE 
samples. Please refer to the laboratory manual for more detail. 
PTEN: Loss of genomic PTEN will be determined using FISH. FISH assays will be 
conducted using the PTEN-del-TECTTm Four Color Panel FISH Probe (Cymene DX) 
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according to the manufacturer's directions. A total of 30 cells from each sample will be 
evaluated and a tumor will be considered to have PTEN loss if the percentage of cells 
showing 0 or 1 PTEN probe signal is greater than 2 standard deviations (SD) above the 
mean established from normal tissue and the PTEN probe/centromere 10 probe ratio is 
more than 2 SD below the mean established in normal tissue. PTEN protein expression 
will be determined via IHC using a rabbit monoclonal anti-PTEN antibody (clone D4.3, 
#9188, Cell Signaling Technologies). PTEN IHC and FISH assays will be conducted 
similar to the methods previously described by Lotan and colleagues.74  
MYC: Alterations in chromosome 8q24, the region that encompasses the MYC locus, 
will be assessed via FISH. FISH hybridization will be done with the multicolor probes 
(ProVysion, Vysis, Inc., Downers Grove, IL) to detect and quantify chromosome 8 
centromere probe [chromosome enumeration probe 8 (CEP8)] and with two locus-
specific probes, the lipoprotein lipase (LPL; 8p21.3) and the c-MYC8q24 probe. 
MYC/chromosome 8q24 FISH assays will be conducted similar to the methods 
previously described by Jenkins and colleagues.82  
ERG: Given that ERG protein expression has been shown to be an excellent surrogate 
of TMPRSS2-ERG fusion status, we will plan to assess ERG expression using IHC.88-99  
ERG IHC will be done using an anti-ERG mouse monoclonal antibody (clone 9FY; 
Biocare, Concord, CA). ERG IHC assays will be conducted similar to the methods 
described by Chaux and colleagues.99  
KI-67: Ki67 will be assessed via IHC using an anti-Ki67 mouse monoclonal (clone 
7B11; Zymed Laboratories, South San Francisco, Calif). The mouse PowerVisionp kit 
(Leica Microsystems, Buffalo Grove, III) will be used for these assays. Ki67 IHC assays 
will be conducted using standard lab practices and in accordance with the mouse 
PowerVisionID kit instructions. 
AR-axis liquid biopsy assay: Expression of a panel of RNA markers will be evaluated 
from whole blood collected in PAXgene RNA tubes. Extracted RNA will come from 
blood cells as well as circulating tumor cells. RNA extraction and transcriptional profiling 
will be conducted similar to the methods described by Ross and colleagues.91  
Prostate Cancer Genomic Classifier: FFPE Prostate tissue samples will be obtained 
pre- and post-treatment with apalutamide and shipped to a commercial genomic testing 
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lab (e.g. Decipher [GenomeDX Biosciences, San Diego, CA] and/or Oncotype DX 
Prostate Cancer Assay [Genomic Health, Inc., Redwood City, CA]). 
7.4. Safety 
Safety will be evaluated based on the incidence, severity, duration, causality, 
seriousness, and type of adverse events (AEs), and changes in the patient's physical 
examination, vital signs, and clinical laboratory results. Investigators will use the NCI 
CTC version 4.03 (published 14 June 2010) to assess the severity of AEs and toxicities 
(see Appendix B). For safety considerations specific to apalutamide see section 8.1 of 
the protocol. 
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8. 
 
8.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.1. 
 
 
 
 
 
8.1.2. 
 
 
 
 
 
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• 
 
 
 
 
 
 
 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.3. 
 
 
 
 
 
 
 
8.1.4. 
 
 
 
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8.1.5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.8. 
 
 
 
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Protocol Version: 6.0; September 06, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Version: 6.0; September 06, 2019 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.9. 
 
 
 
 
 
 
 
 
8.1.9.1.  
 
 
 
 
 
 
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8.1.9.2. 
 
 
 
 
8.1.9.3. 
 
 
 
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9. Data Monitoring and Adverse Event Reporting Requirements 
Institutional support of trial monitoring at the University of Washington/Seattle Cancer Care 
Alliance study site will be in accordance with the FHCRC/University of Washington Cancer 
Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of this plan, 
FHCRC Clinical Research Support coordinates data and compliance monitoring conducted 
by consultants, contract research organizations, or FHCRC employees unaffiliated with the 
conduct of the study. Independent monitoring visits occur at specified intervals determined 
by the assessed risk level of the study and the findings of previous visits per the institutional 
DSMP. 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data 
and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and 
the FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). 
The review committees evaluate accrual, adverse events, stopping rules, and adherence to 
the applicable data and safety monitoring plan for studies actively enrolling or treating 
patients. The IRB reviews the study progress and safety information to assess continued 
acceptability of the risk-benefit ratio for human subjects. Approval of committees as 
applicable is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees 
and other institutional, state and federal guidelines. 
Additionally, scheduled meetings will take place weekly and will include the protocol 
Principal Investigator (PI) (Michael Schweizer, MD), and when appropriate, the 
collaborators, sub-investigators, and biostatistician involved with the conduct of the protocol. 
During these meetings the investigators will discuss matters related to: safety of protocol 
participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential or 
real protocol violations), data completeness, and progress of data for secondary objectives. 
External monitoring of participating sites will occur at least once per year, depending on the 
rate of accrual at these sites. 
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9.1. 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 subiects not 
exposed to apalutamide and product quality complaints with or without an adverse 
event as described in this clinical protocol will be reported from the time a subject has 
signed and dated an Informed Consent Form (ICE) 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. 
9.2. Definitions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.3. 
 
 
 
 
 
 
 
 
9.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.4.1. S
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.5.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
  
9.5.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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9.5.3. 
 
 
 
 
9.6. Evaluating Adverse Events 
The grade and severity of the event will be determined using the NCI Common 
Terminology Criteria for Adverse Events, CTCAE version 4.03. A copy of the CTCAE 
version 4.03 can be downloaded from the CTEP home page (http://ctep.cancergov). All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.03. 
Adverse events must be defined using CTCAE criteria. Adverse events not included in 
the CTCAE version 4.03 should be reported and graded under the "Other" adverse 
event within the appropriate category and grade 1 to 5 according to the general grade 
definitions, mild, moderate, severe, life-threatening, fatal, as provided in the CTCAE 
version 4.03. 
9.6.1. Determining if the event is expected or unexpected 
The determination of whether an AE is expected is based on agent-specific adverse 
event information provided in Section 7and 8 Pharmaceutical Information. Unexpected 
AEs are those not listed in the agent-specific adverse event information provided in 
Section 7and 8 Pharmaceutical Information. 
9.6.2. Relationship to the medical treatment or procedure 
The Investigator should document his/her opinion of the relationship of the event to 
study medication as follows: 
• 
Unrelated- The adverse event is clearly not related to the investigational 
agent(s). 
• 
Unlikely- The adverse event is doubtfully related to the investigational 
agent(s). 
• 
Possible-The adverse event may be related to the investigational agent(s). 
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• 
Probable-The adverse event is most likely related to the investigational 
agent(s). 
• 
Definite- The adverse event is clearly related to the investigational agent(s). 
Based on this information, a decision will be made whether an adverse event should be 
reported as an expedited report (Serious Adverse Event, section 3.0) in addition to the 
routinely reported clinical data. Expedited adverse event reports that meet Institutional 
reporting criteria should be submitted to the Institutional Review Board (IRB) in 
accordance with policies of the coordinating center's IRB and local IRB where 
applicable (for the participating sites), and to the FDA in accordance with regulations 
under 21 CFR 312.32. Additionally, all SAEs should be submitted to Janssen Scientific 
Affairs, LLC within 24 hours of becoming aware of event and via secure e-mail. 
9.6.3. Documenting Adverse Events 
Each individual sign or symptom must be documented separately. Worksheets 
must be signed and dated by person conducting evaluation to be used as source 
documentation. The attribution of all adverse events must be verified by an 
investigator. Evaluation of laboratory toxicities may be documented directly on a 
printed laboratory report or CRF provided it is signed by the investigator. 
However, if an action was conducted due to this abnormality (e.g., RBC 
transfusion due to low Hgb) this would be recorded on the AE form also. 
Recording should be done in a concise manner using standard, acceptable 
medical terms. 
The adverse event recorded should not be a procedure or a clinical 
measurement (i.e., a laboratory value or vital sign) but should reflect the reason 
for the procedure or the diagnosis based on the abnormal measurement. 
Preexisting conditions that worsen in severity or frequency during the Study 
should also be recorded (a preexisting condition that does not worsen is not an 
adverse event). 
Further, a procedure or surgery is not an adverse event; rather, the event leading 
to the procedure or surgery is considered an adverse event. Any event requiring 
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in-patient hospitalization that occurs during the course of a subject's participation 
in a trial must be reported as an SAE. Hospitalizations that do not meet the 
criteria for SAE reporting are: 
A. Reasons described in the Protocol, e.g. drug administration, Protocol-
required testing 
B. Surgery or procedure planned prior to entry into the Study. 
If, in the Sponsor Investigator's judgment, a clinically significant worsening from 
baseline is observed in any laboratory or other test parameter (e.g., 
electrocardiogram [ECG], angiogram), physical exam finding, or vital sign, a 
corresponding clinical adverse event should be recorded. 
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the adverse event, whenever possible. However, a 
complete description of the signs, symptoms and investigations which led to the 
diagnosis should be provided. For example, if clinically significant elevations of 
liver function tests are known to be secondary to hepatitis, "hepatitis" and not 
"elevated liver function tests" should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an adverse event, using 
appropriate medical terminology (e.g., thrombocytopenia, peripheral edema, QT 
prolongation). 
9.6.4. Maintenance of Safety Information 
All safety data should be maintained in a research database in a retrievable 
format. The Principal Investigator shall provide all adverse events, both serious 
and non-serious, in report format. However, in certain circumstances more 
frequent provision of safety data may be necessary (e.g., to fulfill a regulatory 
request, and as such the data shall be made available within a reasonable 
timeframe at Janssen Scientific Affairs' request). 
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9.7. 
 
 
 
 
 
 
 
9.7.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.8. Protocol Amendments 
Any changes to the study protocol will be made in the form of an amendment and must 
be approved by the IRB before implementation. These changes may only be made by 
the Sponsor-Investigator (Dr. Michael Schweizer). Changes to the protocol or informed 
consent form will be reviewed and approved by Janssen Scientific Affairs, LLC prior to 
submitting to the IRB for approval. 
9.9. Informed consent 
Written informed consent will be obtained by a study investigator, or delegated Sub-
Investigator working on this study. An explanation of the nature of study, its purpose, 
procedures involved, expected duration, potential known risks and benefits will be 
provided to each participant by the investigator or the delegated Sub-Investigator. Each 
participant will be informed that participation in the study is voluntary and that they may 
withdraw from the study at any time, and that withdrawal of consent will not affect their 
subsequent medical treatment. Participants will be allowed time needed to make an 
informed decision. Participants will be encouraged to ask questions about the study and 
the consent before signing the consent form. Original signed consent forms will be filed 
in each patient's research chart, while each patient will receive a copy of the consent 
document. No patient will enter the study before the informed consent has been 
obtained. 
The Research Coordinator and the Regulatory Coordinator at the coordinating center 
will be made aware of new participants via email. The Sponsor-Investigator will be 
responsible for reviewing the informed consent forms from participating sites and 
verifying eligibility. Once it has been confirmed that a new candidate has provided 
consent and is eligible to participate in the study, the coordinating center will register the 
patient and provided him with a unique study identification number. New participants' 
study checklist and informed consent form should be emailed to: 
Zoya Bauer: zbauerseattlecca.orq 
and 
CC9582(seattlecca.orq 
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10. Statistical Methods 
This is an open label, multi-site study to evaluate apalutamide in men with very low-risk 
to low-intermediate risk prostate cancer (see 'risk' definitions under Inclusion Criteria) 
enrolled on active surveillance. The primary endpoint for this trial will be the absence of 
residual carcinoma (i.e., a negative repeat biopsy) as determined by targeted and 
systematic biopsies following 90-days of apalutamide. The primary objective will be to 
determine the negative repeat biopsy rate following 90-days of apalutamide for all men 
enrolled. The negative repeat biopsy rate will be continuously assessed throughout the 
study. Apalutamide will be dosed at the current recommended Phase II dose of 240 mg daily 
by mouth. 
 
10.1.  Study Design and Sample Size 
We will use a Simon minimax 2-stage design, which will allow early stopping for 
futility after the first stage if the response rate is low. We expect that in the absence of 
treatment, approximately 20% of patients will have a negative repeat biopsy.53 We also 
assume that a40% of treated patients must achieve a negative repeat biopsy to warrant 
further investigation of this treatment approach in active surveillance patients. Thus, 
our null and alternative hypotheses are Ho: p520% vs. H1: 1:, 40°/0. The minimax 2-stage 
design for these parameters requires a first stage enrolling 18 patients. If 54 of 18 have 
a negative repeat biopsy the trial is stopped and Ho cannot be rejected. If >4 of 18 
patients respond, enrollment in that cohort continues until 33 patients have completed 
the trial, and the response rate is calculated for all 33 patients. If 510 of 33 patients 
have a negative repeat biopsy the null hypothesis cannot be rejected. This design will 
provide 80% power to detect a response rate of 40% (one-sided a=0.05). This design 
also provides a 72% probability of early stopping if Ho is true, affording protection 
against treating more patients than necessary if the treatment is not effective.92  
 
10.2.  Data Analysis 
The primary objective is to determine the negative repeat biopsy rate following 
treatment with apalutamide in men enrolled in active surveillance. This rate will be 
presented as the percent of subjects with a negative repeat biopsy, and will be 
calculated as: (Number of patients with a negative biopsy following 90-days of 
apalutamide) I (Total number of patients enrolled on the study) x 100. For details on the 
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definition of what constitutes a negative biopsy, refer to section 7.1: Prostate Biopsy. 
Subjects who drop out of the study due to disease progression, death, or limiting toxicity 
or individual choice will be considered as failures in estimating the negative repeat 
biopsy rate. Similarly, patients not undergoing repeat biopsy (for any reason) after 
treatment with apalutamide will be considered as failures in estimating the negative 
repeat biopsy rate. Patients who have not received at least one dose of apalutamide 
will be replaced and not considered in determining the negative repeat biopsy rate. We 
will use a 1-sample chi-square test to compare the proportion with a negative repeat 
biopsy to the null hypothesis value of 20% (above). The 95% confidence interval (Cl) of 
the primary endpoint estimate will be computed. 
Secondary endpoints will include: exit from active surveillance due to pathologic 
progression or otherwise at 2 years, the receipt of local treatment for prostate cancer at 
2 years, local treatment free survival, PSA progression free survival (PFS) at 2 years, 
radiographic disappearance of MRI detectable prostate cancer following treatment (only 
in patients with baseline MRI), quality of life, safety and changes in exploratory 
biomarkers (see protocol section 1.4) pre- and post-treatment. 
For both cohorts, the exit rate (all cause and due to pathologic progression), 
percent of men undergoing local treatment and PSA progression rate will be computed 
along with its 95% Cl at the two year time point (i.e. Day 730 visit). The local treatment 
free survival and PSA PFS will be estimated using Kaplan-Meier methods and 95% Cl 
will be estimated using Greenwood's formula.93 PSA PFS will be censored at the time of 
local therapy. PSA progression will be defined by the PCWG2 criteria (i.e. confirmed 
rising PSA  ng/mL at least one week apart). 
We will characterize toxicity as percentage by type and grade. Changes in quality 
of life (as assessed by the FACT-P and SF-36 instrument scores) and changes in 
exploratory biomarkers pre- and post-treatment will be assessed using paired t-test or 
signed-rank test for continuous variables, or McNemar chi-square tests for categorical 
variables. Baseline exploratory biomarker levels/values and change in exploratory 
biomarkers pre-/post-treatment will be correlated with the primary endpoint using chi-
square tests and logistic regression, and with secondary endpoints using proportional 
hazards models, Kaplan-Meier methods and log-rank tests. 
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References: 
1. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for 
patients with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical 
oncology: official journal of the American Society of Clinical Oncology 2008;26:1148-59. 
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Karnes RJ, Bergstralh EJ, Davicioni E, et al. Validation of a genomic classifier that 
predicts metastasis following radical prostatectomy in an at risk patient population. The 
Journal of urology 2013;190:2047-53. 
3. 
Klein EA, Yousefi K, Haddad Z, et al. A genomic classifier improves prediction of 
metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer 
patients managed by radical prostatectomy without adjuvant therapy. European urology 
2015;67:778-86. 
4. 
Erho N, Crisan A, Vergara IA, et al. Discovery and validation of a prostate cancer 
genomic classifier that predicts early metastasis following radical prostatectomy. PloS one 
2013;8:e66855. 	
I 
1 
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Knezevic D, Goddard AD, Natraj N, et al. Analytical validation of the Oncotype DX 
prostate cancer assay - a clinical RT-PCR assay optimized for prostate needle biopsies. BMC 
genomics 2013;14:690. 
6. 
Cooperberg M, Simko J, Falzarano S, et al. Development and validation of the biopsy-
based genomic prostate score (GPS) as a predictor of high grade or extracapsular prostate 
cancer to improve patient selection for active surveillance. American Urological 
Association Meeting; 2013; San Diego, CA. 
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Carver BS, Bianco FJ, Jr., Scardino PT, Eastham JA. Long-term outcome following 
radical prostatectomy in men with clinical stage T3 prostate cancer. The Journal of urology 
2006;176:564-8. 
8. 
Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression and 
survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive 
patients: long-term results. The Journal of urology 2004;172:910-4. 
9. 
Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality 
in a randomized European study. The New England journal of medicine 2009;360:1320-8. 
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Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized 
prostate-cancer screening trial. The New England journal of medicine 2009;360:1310-9. 
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Carter HB. Active surveillance for prostate cancer: an underutilized opportunity for 
reducing harm. J Nat! Cancer Inst Monogr 2012;2012:175-83. 
12. 
Newcomb LF, Brooks JD, Carroll PR, et al. Canary Prostate Active Surveillance Study: 
design of a multi-institutional active surveillance cohort and biorepository. Urology 
2010;75:407-13. 
13. 
Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: 
an update of the Johns Hopkins experience. Journal of clinical oncology: official journal of 
the American Society of Clinical Oncology 2011;29:2185-90. 
14. 
Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active 
surveillance cohort of patients with prostate cancer. Journal of clinical oncology: official 
journal of the American Society of Clinical Oncology 2015;33:272-7. 
71 
 
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PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients 	Protocol Version: 6.0; September 06, 2019 
15. 
Musunuru HB, Klotz L, Vespirini D, etal. Cautionary tale of active surveillance in 
intermediate-risk patients: Overall and cause-specific survival in the Sunnybrook 
experience. 2015 Genitourinary Cancers Symposium; 2015; Orlando, FL. 
16. 
Schweizer MT, Antonarakis ES. Abiraterone and other novel androgen-directed 
strategies for the treatment of prostate cancer: a new era of hormonal therapies is born. 
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17. 
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20. 
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Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer 
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23. 
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24. 
Rathkopf D, Scher HI. Androgen receptor antagonists in castration-resistant 
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Schweizer MT, Huang P. Kattan MW, et al. Adjuvant leuprolide with or without 
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Apalutamide in Active Surveillance patients 	Protocol Version: 6.0; September 06, 2019 
States preventative task force report on screening? J Natl Cancer Inst Monogr 
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Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free 
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PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients 	Protocol Version: 6.0; September 06, 2019 
46. 
Cooperberg MR, Cowan JE, Hilton JF, et al. Outcomes of active surveillance for men 
with intermediate-risk prostate cancer. Journal of clinical oncology: official journal of the 
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Sundi D, Ross AE, Humphreys EB, et al. African American men with very low-risk 
prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: should 
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53. 
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prostate cancer by short-term androgen deprivation to select indolent tumors suitable for 
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55. 
Shukla-Dave A, Hricak H, Akin 0, et al. Preoperative nomograms incorporating 
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Shukla-Dave A, Hricak H, Kattan MW, et al. The utility of magnetic resonance 
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Turkbey B, Mani H, Aras 0, et al. Correlation of magnetic resonance imaging tumor 
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60. 
Lee DH, Koo KC, Lee SH, et al. Tumor lesion diameter on diffusion weighted 
magnetic resonance imaging could help predict insignificant prostate cancer in patients 
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PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients 	Protocol Version: 6.0; September 06, 2019 
eligible for active surveillance: preliminary analysis. The Journal of urology 
2013;190:1213-7. 
61. 
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imaging in prostate cancer: the value of apparent diffusion coefficients for identifying 
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prostate cancer. Nature clinical practice Urology 2005;2:596-607. 
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Barrett T, Gill AB, Kataoka MY, et al. DCE and DW MRI in monitoring response to 
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Mullins JK, Bonekamp D, Landis P, et al. Multiparametric magnetic resonance 
imaging findings in men with low-risk prostate cancer followed using active surveillance. 
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Antonarakis ES, Keizman D, Zhang Z, et al. An immunohistochemical signature 
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Chaux A, Peskoe SB, Gonzalez-Roibon N, et al. Loss of PTEN expression is associated 
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Lotan TL, Gurel B, Sutcliffe S, et al. PTEN protein loss by immunostaining: analytic 
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patients. Clinical cancer research : an official journal of the American Association for Cancer 
Research 2011;17:6563-73. 
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PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients 	Protocol Version: 6.0; September 06, 2019 
75. 
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR. Loss of PTEN 
expression in paraffin-embedded primary prostate cancer correlates with high Gleason 
score and advanced stage. Cancer research 1999;59:4291-6. 
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Yoshimoto M, Cunha LW, Coudry RA, et al. FISH analysis of 107 prostate cancers 
shows that PTEN genomic deletion is associated with poor clinical outcome. British journal 
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alteration in human prostate carcinogenesis. Modern pathology: an official journal of the 
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and Prostate Cancer. Genes & cancer 2010;1:617-28. 
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expression programs in prostatic neoplasia are driven by the MYC oncogene. The American 
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PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients 	Protocol Version: 6.0; September 06, 2019 
90. 
van Leenders GI, Boormans IL, Vissers CJ, et al. Antibody EPR3864 is specific for ERG 
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Base 
Mid 
Apex 
CC Protocol Number: 9582  
PI: Michael T. Schweizer, MD 
Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
Appendix A 
Sextant Prostate Biopsy Diagram 
16 Regions of Interest 
Left 
Right 
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
Appendix B 
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS, VERSION 4.03 
Version 4.03 of the NCI CTCAE, dated 14 June 2010, may be viewed and/or downloaded by 
accessing the following website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
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Apalutamide in Active Surveillance patients  Protocol Version: 6.0; September 06, 2019 
Appendix C 
Prohibited Concomitant Medications 
Generic Name 
Brand Name* 
aminophylline 
Aminocont; Aminomal; Diaphyllin; Filotempo; Neophyllin; Norphyl; 
Phyllocontin; Syntophyllin; Tefamin; Truphylline; Xing You Shan; 
aminophylline in 
combination 
Asmeton; Cha Xin Na Min; Emergent-Ez; Fufang Dan An Pian; Ke 
Zhi 
amitriptyline 
Amirol; Amitrip; Amixide; Deprelio; Diapatol; Elatrol; cElatrolet; 
Elavil; Endep; Enovil; Emitrip; Klotriptyl; Laroxyl; Levate; Limbitrol; 
Limbitryl; Mutabase; Mutabon; Nobritol; Novo-Triptyn; Pertriptyl; 
Redomex; Saroten; Sarotex; Sedans; Syneudon; Teperin; 
Triptizol; Triptyl; Tryptizol 
amitriptyline in 
combination 
PMS-Levazine 
bupropion 
Aplenzin; Buproban; Contrave; Elontril; Forfivo; Fortivo XL; Le Fu 
Ting; Prexaton; Quomem; Voxra; Wellbutrin; Wellbutrin XL; 
Wellbutrin SR; Yue Ting; Zyban 
chlorpromazine 
Aminazin; Chlorazin; Hibernal; Klorproman; Largactil; Megaphen; 
Ormazine; Plegomazin; Solidon; Taroctyl;Thorazine; Vegetamin; 
VVintermin; 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; ZonaIon 
imipramine 
Impril; Melipramin; Mipralin; Norfranil,; Novo-Pramine; Persamine; 
Pertofram; Pryleugan; Talendep; Tofranil; Tolerade 
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Apalutamide in Active Surveillance patients 
PI: Michael T. Schweizer, MD 
Protocol Version: 6.0; September 06, 2019 
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; 
Hunperdal; Jing Ping; Ke Tong; Leptinorm; Lergitec; Orizon; 
Ozidal; Perdox; Ranperidon; Resdone; Ridal; Ridonex; Rileptid; 
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Apalutamide in Active Surveillance patients 
PI: Michael T. Schweizer, MD 
Protocol Version: 6.0; September 06, 2019 
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; 
CyImin; 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 may not be all inclusive. 
82 
 
IRB Approved 
Document Release Date: 02/26/2020
Printed on 1/29/2021