A Randomized, Phase II Study of Apalutamide +/- Stereotactic Body Radiotherapy (SBRT) in Castration-Resistant Prostate Cancer Patients With Oligometastatic Disease on PSMA-PET Imaging
Phase: PHASE2
Conditions: Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, PSA Progression, Stage IV Prostate Adenocarcinoma AJCC v7
Sponsor: University of California, San Francisco

Phase II – Apalutamide
Page 1 of 65
PILLAR
(PSMA Imaging Leveraged for Local/Regional Therapy 
and Androgen Receptor Targeted Therapy)
A Randomized, Phase II Study of Apalutamide +/- 
Stereotactic Body Radiotherapy (SBRT) in Castration-
Resistant Prostate Cancer Patients with Oligometastatic 
Disease on PSMA-PET Imaging 
Protocol Number:  CC # 175519
Study Drug:  Apalutamide
Version Number: 10.0
Version Date:  12-08-2023
IND Number:  137942
Principal Investigator (Sponsor-Investigator)
Rahul Aggarwal, MD
University of California San Francisco
 
Statistician
Li Zhang, PhD
Revision History
Version 1.0 
03-21-2017
Version 2.0 
09-06-2017
Version 3.0
10-19-2017
Version 4.0
11-15-2017
Version 5.0
01-17-2018
Version 6.0
02-12-2020
Version 7.0
06-10-2021
Version 8.0
04-11-2023
Version 9.0
06-20-2023
Version 10.0
12-08-2023

Phase II – Apalutamide
Page 2 of 65
Protocol Signature Page
Protocol No.: 175519
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review 
Committee (PRC), Institutional Review Board (IRB), and Data Safety Monitoring 
Committee (DSMC). 
2.
I will conduct the study in accordance with applicable IRB requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and 
welfare of study participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or 
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to 
conduct the protocol in accordance with Good Clinical Practices (ICH-GCP), the 
applicable ethical principles, the Statement of Investigator (Form FDA 1572), and 
with local regulatory requirements. In accordance with the FDA Modernization Act, I 
will ensure the registration of the trial on the www.clinicaltrials.gov website. 
5.
I agree to maintain adequate and accurate records in accordance with IRB policies, 
Federal, state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date

Phase II – Apalutamide
Page 3 of 65
Protocol Signature Page – Participating Sites
Protocol No.:     175519 
Participating Site(s)
Principal Investigator Name: 
 
Institution Name:
Address:  
Telephone:  
E-mail:  
Principal Investigator Name: 
 
Institution Name:
Address:  
Telephone:  
E-mail:  
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator (Form 
FDA 1572), Institutional Review Board regulations, and all national, state and local laws 
and/or requirements of the pertinent regulatory requirements. 
Principal Investigator
Site
Printed Name
Institution Name
Signature
Date

Phase II – Apalutamide
Page 4 of 65
Abstract
Title
A Randomized, Phase II Study of Apalutamide +/- Stereotactic Body 
Radiotherapy (SBRT) in Castration-Resistant Prostate Cancer 
Patients with Oligometastatic Disease on PSMA-PET Imaging
Patient population
The study population includes men 18 years of age or older with 
CRPC. Key eligibility criteria include:

Histologically confirmed prostate adenocarcinoma.

Progressive, castration-resistant prostate cancer with ongoing 
castration therapy during the course of study treatment.

At least one but no more than 5 discrete PSMA-avid radiation 
fields on baseline PSMA-PET scan amenable to SBRT in 
judgment of treating clinician.

No prior abiraterone acetate, enzalutamide, apalutamide, or 
docetaxel initiated in CRPC setting.
Rationale for Study
Apalutamide is a next-generation anti-androgen that binds directly to 
the ligand-binding domain of AR, impairing nuclear translocation and 
DNA binding. Apalutamide binds AR with 5-fold greater affinity than 
bicalutamide, and induces partial or complete tumor regression in 
both castration-sensitive and castration-resistant prostate cancer.
The efficacy of AR targeting agents in conventionally defined non-
metastatic disease has been demonstrated in several phase 2 trials. 
In the non-metastatic castration resistant prostate cancer (NM-
CRPC) subset (n =51) of the phase 2 study of apalutamide, the 12-
week PSA response (≥ 50% decline from baseline) was 91%. While 
phase 3 trials are still maturing (e.g. ARN-509-003) it is assumed that 
these trials are very likely to establish the utility of agents like 
apalutamide in prolonging the metastasis-free interval in patients with 
NM-CRPC.
There has been considerable erosion in the size of the population of 
patients with NM-CRPC. In part, this reflects more frequent 
conventional imaging driven by PSA testing. However, the impact 
seen to date on the proportion of patients with NM-CRPC is dwarfed 
by the anticipated exponential growth of targeted imaging.
Prostate Specific Membrane Antigen (PSMA) PET is the most 
sensitive imaging modality available. The significant increase of 
PSMA PET scanning in other parts of the world provides insight to 
the anticipated uptake of PSMA scanning in the US. It is anticipated 
that the US will have tremendous market penetration by PSMA PET 
scanning. Although PSMA PET has largely been evaluated in early 
stage hormone-sensitive disease, at UCSF we have begun to 
evaluate PSMA PET scanning in patients with CRPC who have 
progressive disease by PSA criteria, but who do not have evidence 
of metastatic disease on conventional (bone scan and CT 

Phase II – Apalutamide
Page 5 of 65
abdomen/pelvis) imaging - the SPARTAN population. In our first 
group of roughly 25 "SPARTAN eligible" patients with undergoing 
PSMA PET scanning, approximately 50% were found to have 
oligometastatic disease (defined by convention as 5 or fewer 
lesions), whereas 25% were found to have widely metastatic disease 
(> 5 lesions), and 25% did not have detectable lesions (unpublished 
data). Thus, it is conceivable that had SPARTAN patients undergone 
targeted imaging with PSMA PET, approximately 75% of patients 
would have been ineligible and would have been found to have 
metastatic disease by PSMA PET. 
Despite this anticipated dramatic stage migration, there is no 
consensus regarding the appropriate treatment for patients with 
oligometastatic CRPC. Reasonable options that are being tested in 
these patients include stereotactic body radiotherapy (SBRT), 
surgical resection of limited nodal disease, and systemic therapy with 
androgen receptor targeted therapy, including AR inhibitors such as 
apalutamide.
SBRT is an advancing treatment approach made possible by recent 
advancements in radiation delivery, which allow for precise treatment 
within any anatomical region of the body. As a result, the capacity to 
deliver tumor killing radiation doses in a single or few outpatient 
radiation treatments is now possible. In addition, by minimizing the 
irradiation of surrounding healthy tissue, it should also be possible to 
decrease the rate of complications. Intracranial stereotactic body 
radiation therapy (SBRT) has been shown to be a highly effective 
treatment for brain lesions13. Data suggests SBRT provides high 
rates of local progression-free survival (92-93% at 3 to 5 years post-
SBRT) in metastatic hormone-sensitive prostate cancer, as well as 
high rates of local control (90-100%) in other cancers as well.   
Toxicity has been minimal in multiple U.S., European and Japanese 
trials of extracranial stereotactic radiotherapy to the lung, liver, spine, 
pelvis and abdomen despite the use of very high biological 
equivalent doses for patients with both organ confined and metastatic 
cancer.
The impending dramatic stage migration from PSMA PET imaging 
and the current lack of consensus regarding appropriate therapies 
represents an opportunity to establish the role of apalutamide in the 
treatment of what is likely to become the fastest growing population 
of prostate cancer patients. It is clear that PSMA PET imaging will be 
utilized much more frequently in the future, and likely become a 
standard of care with respect to imaging. The increased usage of 
PSMA PET will inevitably result in a significant increase in the 
number of patients with "oligometastatic" castration-resistant prostate 
cancer. The goal of this study is to assess the efficacy of 
apalutamide in this patient population, and determine if the addition 
of stereotactic body radiotherapy can improve outcomes. The 
proposed treatment represents a logical combination of the current 
state-of-the-art systemic targeting of AR, the current state-of-the-art 
radiation therapy, and the current state-of-the-art imaging for prostate 
cancer lesions.  The study schema is shown on the following page.
Primary Objective
To demonstrate whether the proportion of patients with an 

Phase II – Apalutamide
Page 6 of 65
undetectable serum PSA at 6 months following cessation of 
apalutamide is higher with addition of SBRT to PSMA-avid 
oligometastatic sites of disease compared to the group of patients 
receiving apalutamide monotherapy.
Secondary 
Objectives
1. To compare the time to PSA progression by PCWG 
criteria between treatment arms
2. To evaluate the safety and tolerability of apalutamide in 
combination with SBRT.
Exploratory 
Objectives
1. To evaluate the genomic factors associated with the 
presence of oligometastatic disease 
2. To evaluate the association between somatic and germline 
genomic alterations with outcomes on protocol therapy
Note: The  italicized objectives above were discontinued in 
Protocol v. 8.0. See Section 7.3 for additional information.
3. To characterize the metastatic pattern at baseline and 
atprogression in these patients and to determine whether 
features of the baseline PSMA-PET scan are associated 
with treatment outcomes. 
Study Design
This is a randomized (1:1), open-label, phase II clinical trial 
evaluating the efficacy and safety of apalutamide with or without 
SBRT to all visible lesions in men with CRPC and oligometastatic 
disease based upon PSMA-PET imaging. Patients will complete up 
to 52 weeks of treatment with apalutamide in the absence of disease 
progression, and will subsequently be followed until PSA progression 
as defined by PCWG criteria. Following development of PSA 
progression, patients may undergo repeat PSMA-PET imaging. 
Treatment at the time of progression will be at the discretion of the 
treating physician, and can include SBRT for those patients deemed 
appropriate candidates (whether or not they received prior SBRT) 
and/or any FDA approved systemic therapy.

Phase II – Apalutamide
Page 7 of 65
Number of Patients
60 (apalutamide: 30; apalutamide + SBRT: 30)
Duration of 
Therapy
Patients will continue protocol treatment until the first occurrence of 
one of the following:

Disease progression by PCWG3 criteria

Unacceptable adverse event(s) related to apalutamide 
or SBRT

Completion of treatment (52 weeks for apalutamide)

Patients decides to withdraw from the study

Significant patient non-compliance with protocol

General or specific changes in the patients’ condition 
render the patient unacceptable for further treatment 
in the judgment of the investigator.
Duration of Follow 
up
Patients will continue on study in follow up until disease 
progression by PCWG3 or withdrawal from study, whichever 
occurs first. 
Duration of Study
The anticipated study duration is approximately 36 months.  
Study Drugs/ 
Treatments

Apalutamide will be administered orally on a continuous daily 
dosing regimen, at a starting dose of 240 mg once daily (4 x 
60-mg tablets), until the completion of 12 months of 
treatment, unacceptable toxicity, or PSA progression, 
whichever occurs soonest.

SBRT will be delivered by treating radiation oncologist 
according to standard institutional practice for up to 5 PSMA-
avid radiation fields. SBRT must be initiated within 90 days 
following initiation of apalutamide therapy. 
SBRT will be delivered in 1 to 5 fractions, and the dose and 
fractionation schedule will depend on the size and location of 
the lesion/radiation field and the surrounding normal tissue 
constraints in accordance with AAPM Task Group 101 
recommendations. Typical doses include 16 – 24 Gy in 1 
fraction, 40 – 50 Gy in 4 fractions, and 40 – 60 Gy in 5 
fractions. 
Safety 
Assessments
Patients will be assessed for adverse events (AEs) at each monthly 
clinic visit while on the study treatment. Adverse events will be 
graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 
Type, incidence, severity, timing, seriousness, and relatedness of 
AEs, and laboratory abnormalities will be reported.
Efficacy 
Assessments
Disease assessments will be performed as scheduled according to 
the calendar, regardless of treatment delays resulting from toxicity. 
PSA measurements will be performed every 4 weeks until the time of 

Phase II – Apalutamide
Page 8 of 65
PSA progression by PCWG criteria. PSMA-PET imaging will be 
performed at baseline and is optional at the time of PSA progression. 
Primary Endpoint

Proportion of patients with undetectable serum PSA (< 0.2 
ng/mL) at 6 months following completion of apalutamide therapy 
(18 months from date of randomization). 
Secondary 
Endpoints
1. Time to PSA progression by PCWG criteria
2. Feasibility and Safety of apalutamide and concurrent SBRT
Exploratory
Endpoints
1. Association between genomic factors and presence of 
oligometastatic disease 
2. Association between somatic and germline genomic alterations 
with clinical outcomes
Note: The italicized objectives above were discontinued in 
Protocol v. 8.0. See Section 7.3 for additional information.
3. Association between baseline PSMA-PET scan uptake and 
distribution of lesions with treatment outcomes.
Statistical Analysis/ 
Sample Size 
Justification
The primary efficacy is based on the primary endpoint of the study, 
the proportion of patients with undetectable PSA (PSA < 0.2 ng/mL) 
6 months following completion of 12 months of apalutamide therapy 
(18 months from date of randomization). Assuming a 10% 
inevaluable/drop-out rate per treatment arm, a sample size of 60 
patients (30 patients/arm) provides 84% power to detect a difference 
in proportion of patients with undetectable PSA of 25% in the 
apalutamide + SBRT arm vs. 2.5 % in the apalutamide monotherapy 
arm, with a unidirectional level of significance of 0.10 (Fisher’s exact 
test).  Patients who discontinue apalutamide prior to completion of 12 
months of therapy for reasons other than disease progression by 
PCWG criteria will be considered inevaluable for this analysis.

Phase II – Apalutamide
Page 9 of 65
List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CT
computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTMS
Clinical Trial Management System
CTV
clinical tumor volume
DFS
disease-free survival
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
FCBP
female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBV
hepatitis B virus
HCT
hematocrit
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function test
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute

Phase II – Apalutamide
Page 10 of 65
List of Abbreviations
ORR
overall response rate
PD
disease progression
PK
pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
PTV
planning target volume
QOL
Quality of Life
RBC
red blood cell (count)
SBRT
stereotactic body radiation therapy 
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
ULN
upper limit of normal
WBC
white blood cell (count)

Phase II – Apalutamide
Page 11 of 65
Table of Contents
Protocol Signature Page ....................................................................................................2
Protocol Signature Page – Participating Sites .................................................................3
Abstract................................................................................................................................4
List of Abbreviations ........................................................................................................10
Table of Contents..............................................................................................................12
1
BACKGROUND AND OVERALL STUDY RATIONALE...........................................15
1.1
APALUTAMIDE .........................................................................................................16
1.1.1
Molecular Formula and Chemical Class..................................................................16
1.1.2
Pre-Clinical Development Overview........................................................................17
1.1.3
Overview of Clinical Studies....................................................................................19
2
STUDY OBJECTIVES ...............................................................................................21
2.1
PRIMARY OBJECTIVE..............................................................................................21
2.2
SECONDARY OBJECTIVES.....................................................................................21
2.3
EXPLORATORY OBJECTIVES ................................................................................21
3
STUDY DESIGN.........................................................................................................21
3.1
STUDY OVERVIEW AND RATIONALE ....................................................................21
3.1.1
Number of Subjects.................................................................................................22
3.2
STUDY OUTCOMES..................................................................................................23
3.2.1
Primary Endpoints ...................................................................................................23
3.2.2
Secondary Endpoints ..............................................................................................23
3.2.3
Exploratory Endpoints .............................................................................................23
4
PATIENT SELECTION...............................................................................................23
4.1
INCLUSION CRITERIA..............................................................................................23
4.2
EXCLUSION CRITERIA ............................................................................................25
4.3
DURATION OF THERAPY ........................................................................................26
4.4
DURATION OF FOLLOW UP....................................................................................26
4.5
RANDOMIZATION PROCEDURES ..........................................................................26
4.6
STUDY TIMELINE .....................................................................................................26
5
STUDY TREATMENTS..............................................................................................27
5.1
RANDOMIZATION.....................................................................................................27
5.2
BLINDING..................................................................................................................27
5.3
FORMULATION.........................................................................................................27
5.3.1
Apalutamide ............................................................................................................27
5.3.2
Packaging, Storage, and Labeling...........................................................................27
5.3.3
Drug Administration.................................................................................................27
5.3.4
Cycle Management..................................................................................................27
5.3.5
Dose Modifications ..................................................................................................27
5.4
STUDY DRUG ACCOUNTABILITY...........................................................................30
5.5
MEASURES OF TREATMENT COMPLIANCE.........................................................30
5.6
STEREOTACTIC BODY RADIATION.......................................................................30
6
CONCURRENT MEDICATIONS................................................................................31
6.1
PROHIBITED MEDICATIONS AND TREATMENTS.................................................32
6.2
RESTRICTED THERAPIES .......................................................................................32
6.3
LIFESTYLE GUIDELINES .........................................................................................32

Phase II – Apalutamide
Page 12 of 65
7
STUDY PROCEDURES AND GUIDELINES .............................................................33
7.1
CLINICAL ASSESSMENTS.......................................................................................33
7.1.1
Demographics .........................................................................................................33
7.1.2
Medical History........................................................................................................33
7.1.3
Physical Examination ..............................................................................................33
7.1.4
Vital Signs................................................................................................................33
7.1.5
Performance Status.................................................................................................33
7.1.6
Adverse Events .......................................................................................................34
7.1.7
Concomitant Medications/Therapies .......................................................................34
7.1.8
Tumor Assessments................................................................................................34
7.1.9
Tumor Biopsy (DISCONTINUED) ...........................................................................34
7.2
CLINICAL LABORATORY MEASUREMENTS.........................................................35
7.2.1
PSA .........................................................................................................................35
7.3
EXPLORATORY BIOMARKERS (DISCONTINUED)................................................35
8
STUDY ASSESSMENTS BY VISIT (APPENDIX 1) ..................................................36
8.1
SCREENING (WITHIN 42 DAYS OF RANDOMIZATION, UNLESS OTHERWISE 
SPECIFIED) ........................................................................................................................36
8.2
CYCLE 1 DAY 1.........................................................................................................36
8.3
DAY 1 OF CYCLES 2-4, THEN DAY 1 OF EVERY 2 CYCLES STARTING FROM 
CYCLE 5 THROUGH C13 (C5, C7, C9, C11, C13) (+/- 7 days) UNLESS OTHERWISE 
SPECIFIED .........................................................................................................................37
8.4
END OF TREATMENT VISIT.....................................................................................37
8.5
SAFETY FOLLOW-UP (30 DAYS FOLLOWING THE LAST DOSE OF STUDY 
DRUG) ................................................................................................................................38
8.6
POST-TREATMENT PERIOD UNTIL CONFIRMED PSA PROGRESSION BY 
PCWG CRITERIA ...............................................................................................................38
8.7
AT CONFIRMED PSA PROGRESSION (+ 28 day window)....................................38
9
ADVERSE EVENT REPORTING REQUIREMENTS.................................................38
9.1
DEFINITIONS.............................................................................................................38
9.1.1
Adverse Events (AE) ...............................................................................................38
9.1.2
Adverse Events of Special Interest .........................................................................39
9.1.3
Serious Adverse Events (SAE) ...............................................................................39
9.1.4
Expectedness..........................................................................................................40
9.1.5
Attribution ................................................................................................................40
9.1.6
Severity ...................................................................................................................40
9.1.7
Individual Case Safety Report (ICSR).....................................................................41
9.1.8
Special Reporting Situations ...................................................................................42
9.1.9
Pregnancy ...............................................................................................................42
9.2
ADVERSE EVENTS MONITORING ..........................................................................42
9.3
REPORTING REQUIREMENTS ................................................................................43
9.3.1
SAE Reporting to the Sponsor-Investigator and Janssen.......................................43
9.3.2
Non-Serious AE Reporting ......................................................................................46
9.3.3
UCSF Sponsor-Investigator Reporting Requirements to Regulatory Authorities ....46
10
END OF TREATMENT...............................................................................................47
11
PROTOCOL VIOLATIONS........................................................................................49
12
STATISTICAL METHODS AND CONSIDERATIONS...............................................49

Phase II – Apalutamide
Page 13 of 65
12.1
ANALYSIS POPULATIONS ...................................................................................49
12.2
ANALYTIC PLAN ...................................................................................................49
12.2.1 Analysis of Primary Endpoint...................................................................................49
12.2.2 Analyses of Secondary Endpoints...........................................................................49
12.2.3 Analysis of Exploratory Endpoints...........................................................................50
12.2.4 Interim Analysis .......................................................................................................50
12.2.5 Determination of Sample Size.................................................................................50
13
STUDY MANAGEMENT............................................................................................51
13.1
INVESTIGATOR RESPONSIBILITIES ...................................................................51
13.2
PRE-STUDY DOCUMENTATION...........................................................................51
13.3
INSTITUTIONAL REVIEW BOARD APPROVAL...................................................51
13.4
INFORMED CONSENT...........................................................................................52
13.5
CHANGES IN THE PROTOCOL ............................................................................52
13.6
HANDLING AND DOCUMENTATION OF CLINICAL SUPPLIES .........................52
13.7
CASE REPORT FORMS (CRFs)............................................................................52
13.8
OVERSIGHT AND MONITORING PLAN ...............................................................53
13.9
MULTICENTER COMMUNICATION ......................................................................53
13.10 RECORD KEEPING AND RECORD RETENTION ................................................54
13.11 REGULATORY DOCUMENTATION ......................................................................54
14
PROTECTION OF HUMAN SUBJECTS ...................................................................55
14.1
PROTECTION FROM UNNECESSARY HARM.....................................................55
14.2
PROTECTION OF PRIVACY..................................................................................55
15
REFERENCES...........................................................................................................56
APPENDIX 1:
SCHEDULE OF ACTIVITIES..................................................................58
APPENDIX 2:
REQUIRED LABORATORY TESTS ......................................................61
APPENDIX 3:
ECOG PERFORMANCE STATUS GRADES.........................................62
APPENDIX 4:
NATIONAL CANCER INSTITUTE (NCI) COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (CTCAE) ........................................................63
APPENDIX 5:
PROHIBITED OR RESTRICTED MEDICATIONS OR SUPPLEMENTS 
WHILE ON STUDY ....................................................................................................64
APPENDIX 6: DATA AND SAFETY MONITORING PLAN ...............................................65

Phase II – Apalutamide
Page 14 of 65
1
BACKGROUND AND OVERALL STUDY RATIONALE
Apalutamide is a next-generation anti-androgen that binds directly to the ligand-binding 
domain of AR, impairing nuclear translocation and DNA binding1, and is FDA approved for 
the treatment of non-metastatic castration resistant prostate cancer and metastatic 
castration sensitive prostate cancer. Apalutamide binds AR with 5-fold greater affinity than 
bicalutamide, and induces partial or complete tumor regression in both castration-sensitive 
and castration-resistant human prostate cancer xenograft models.
The efficacy of AR targeting agents in conventionally defined non-metastatic disease has 
been demonstrated in several phase 2 trials as well as the phase 3 study of apalutamide 
versus placebo. In the non-metastatic castration resistant prostate cancer (NM-CRPC) 
subset (n =51) of the phase 2 study of apalutamide, the 12-week PSA response (≥ 50% 
decline from baseline) was 89%2. In the phase 3 study, the median metastasis-free survival 
with apalutamide versus placebo was (40.5 vs. 16.2 months, p < 0.001).3  
There has been considerable erosion in the size of the population of patients with NM-
CRPC. In part, this reflects more frequent conventional imaging driven by PSA testing. 
However, the impact seen to date on the proportion of patients with NM-CRPC is dwarfed 
by the anticipated exponential growth of targeted imaging.
Prostate Specific Membrane Antigen (PSMA) PET is the most sensitive imaging modality 
available4-6. The significant increase of PSMA PET scanning in other parts of the world 
provides insight to the anticipated uptake of PSMA scanning in the US. It is anticipated that 
there will be tremendous market penetration by PSMA PET scanning in the US. 
Although PSMA PET has largely been evaluated in early stage hormone-sensitive disease, 
at UCSF we have begun to evaluate PSMA PET scanning in patients with CRPC who have 
progressive disease by PSA criteria, but who do not have evidence of metastatic disease on 
conventional (bone scan and CT abdomen/pelvis) imaging - the SPARTAN population. In 
our first group of 25 "SPARTAN eligible" patients with undergoing PSMA PET scanning, 
approximately 50% were found to have oligometastatic disease (defined by convention as 5 
or fewer lesions), whereas 25% were found to have widely metastatic disease {> 5 leions), 
and 25% did not have detectable lesions (unpublished data). Thus, it is conceivable that 
had SPARTAN patients undergone targeted imaging with PSMA PET, approximately 75% 
of patients would have been ineligible and would have been found to have metastatic 
disease by PSMA PET. 
Despite this anticipated dramatic stage migration, there is no standard of care for patients 
with oligometastatic CRPC. Reasonable options that are being tested in these patients 
include SBRT, surgical resection of limited nodal disease, and systemic therapy with 
androgen receptor targeted therapy, including AR inhibitors such as apalutamide. SBRT is 
an advancing treatment approach made possible by recent advancements in radiation 
delivery, which allow for precise treatment within any anatomical region of the body7,8. As a 
result, the capacity to deliver tumor killing radiation doses in a single or few outpatient 
radiation treatments is now possible9-18. In addition, by minimizing the irradiation of 
surrounding healthy tissue, it should also be possible to decrease the rate of complications. 
Intracranial stereotactic body radiation therapy (SBRT) has been shown to be a highly 
effective treatment for brain lesions19. Data suggest SBRT provides high rates of local 
progression-free survival (92-93% at 3 to 5 years post-SBRT) in metastatic hormone-
sensitive prostate cancer, as well as high rates of local control (90-100%) in other cancers 
20,21.   Toxicity has been minimal in multiple U.S., European and Japanese trials of 
extracranial stereotactic radiotherapy to the lung, liver, spine, pelvis and abdomen despite 
the use of very high biological equivalent doses for patients with both organ confined and 
metastatic cancer.

Phase II – Apalutamide
Page 16 of 65
shown to reduce proliferation of CRPC cells as well as increase apoptosis and necrosis in 
vivo. These effects are supported by the anti-tumor activity of apalutamide observed in 
murine tumor models of CRPC. In these models, apalutamide showed dose-dependent 
tumor growth inhibition and tumor regression that were superior to bicalutamide. Figure 1 
depicts the percent change in tumor volume and plasma concentrations (filled circles above 
waterfall plot) of bicalutamide and apalutamide on Day 28.
Figure 1
Tumor Growth Inhibition in Castration-resistant LNCaP/AR-Luc 
Xenograft Model after 28 Days of Treatment with Bicalutamide or apalutamide (ARN-
509)
Apalutamide is a low clearance molecule with a moderate volume of distribution and high 
bioavailability (when dosed with a lipid-based formulation). Apalutamide was found to have 
a very low turnover when incubated for up to 120 minutes with rat, dog, and human liver S9 
fraction and liver microsomes.  The primary in vivo metabolites were formed by N-
demethylation and amide hydrolysis in the rat and dog. In vitro, CYP3A4 may be partially 
involved in the metabolism of apalutamide.
Apalutamide and its primary metabolite ARN000308 (M3) are inducers of human CYP2B6 
and CYP3A4 in hepatocytes at concentrations up to 30 µM. Apalutamide is a moderately 
potent inhibitor of human cytochrome P450 isoform CYP2C8 (IC 50=13.9 µM), but a weak 
inhibitor of the other major isoforms (IC50>25 µM); M3 is also a weak inhibitor of CYP major 
isoforms (IC50>25 µM).
Four metabolites have been identified with different proportions between species. All four 
were assessed for their on-target effects against the androgen receptor. Metabolite M1 was 
found to be essentially inactive as an AR antagonist, while metabolites M2 and M4 were 
approximately 30-fold less potent against AR than apalutamide. Metabolite M3 was the 
most potent AR antagonist, but was still 3-fold less potent than apalutamide. Metabolite M3 
is considered the predominant metabolite, with a longer elimination half-life than 
apalutamide.
In vitro and in vivo studies to assess cardiovascular, CNS, and respiratory system effects of 
apalutamide did not reveal any concerns.
Single-dose and repeat-dose toxicology studies up to 13 weeks of dosing have been 
conducted in male Sprague Dawley (SD) rats and male Beagle dogs (repeat-dose studies 
only).

Phase II – Apalutamide
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Acute administration of apalutamide at 1,000 mg/kg was well tolerated in SD rats, with no 
morbidity, mortality or significant effects on body weight or serum chemistry markers.
In repeat-dose toxicology studies, apalutamide was well tolerated at doses up to
100 mg/kg/day in the 13-weeks study in SD rats and 10 mg/kg/day in Beagle dogs. In male 
SD rats, lethality was observed at doses of 150 mg/kg/day and greater. The 
morbidity/mortality observed at these doses occurred within the first 5 days of dosing; 
however, animals that did survive at these higher doses, appeared to develop a tolerance 
for the test article with extended exposure.  Clinical signs observed in the moribund animals 
were piloerection, hypothermia, breathing abnormalities, dehydration, and decreased 
activity. The cause of the morbidity/mortality in male rats could not be determined by 
pathologic examination. Key clinical pathology changes at doses of 150 mg/kg/day or 
greater included significant increases in cholesterol (greater than 200% from controls), 
decreases in erythrocytes, hemoglobin and hematocrit, and increases in reticulocytes, 
platelets, leukocytes, lymphocytes, basophils, and aPTT.  The increase in cholesterol is 
attributed to the anti-androgen activity of apalutamide and is believed to be responsible for 
the stated hematologic changes. Examination of red blood cell morphology revealed 
changes that were consistent with excess cholesterol being transferred to the outer 
membrane of the erythrocytes, resulting in a mild hemolytic anemia.  Pharmacologic effects 
were also observed in the male accessory sex organs (epididymides, prostate, seminal 
vesicles and to a lesser degree, the testes) at apalutamide doses as low as 50 mg/kg/day. 
Other target organs in the rat that were observed at apalutamide doses of 150 mg/kg/day or 
higher included adrenals (also at 50 mg/kg/day), liver, pituitary, thyroid, spleen, salivary 
glands, mammary gland, and stomach. With the exception of the salivary glands and 
stomach, the effects on those organs are also believed to be due to the anti-androgen effect 
of apalutamide and in many cases are specific to the physiology of the rat.
Once daily oral gavage dosing of apalutamide for 13 weeks was well tolerated in male rats 
up to 100 mg/kg/day, i.e. the highest dose tested. Pharmacologic changes characteristic of
anti-androgen compounds were noted in the adrenal gland, pituitary gland, spleen, 
mammary gland, seminal vesicles, testes, prostate, and epididymides, while changes in the 
spleen and bone marrow correlated with a mild regenerative anemia. The 100 mg/kg/day 
dose level was considered to be the no observed adverse effect level (NOAEL) and was 
associated with steady-state (Day 91) plasma Cmax and AUC0-24h values of 30.1 µg/mL and 
521 µg•h/mL, respectively, for the parent compound.
In male Beagle dogs, seizures necessitating humane euthanasia occurred at apalutamide 
doses of 25 mg/kg/day and greater, 7 to 14 days after dosing was initiated. Daily 
administration of 25 mg/kg/day of apalutamide resulted in tremors and seizures in 3 of 8 
animals after 1 week of dosing. The average apalutamide concentration at the time of first 
observation of central nervous system (CNS) toxicity was determined to be 30.2 μg/mL, 
which was about 4-fold higher than the mean apalutamide steady-state Cmax (7.55 μg/mL) 
at the Phase 3 dose of 240 mg/day measured during repeated dosing in subjects with 
CRPC.  It is likely that the convulsive seizures observed in dogs at very high doses are the 
result of apalutamide’s functional antagonism of the GABAA receptor. This is similar to what 
has been observed with other second generation AR antagonists. The 10 mg/kg/day dose 
was considered to be the NOAEL in the 28-day study, and was associated with an 
apalutamide
Cmax of 13.2 μg/mL and an AUC0-24 of 290 μg•h/mL. Other clinical pathology and target 
organ changes were limited to increases in cholesterol (up to 50% compared to controls) 
and effects on the epididymides, prostate and testes at all doses tested and attributed to the 
anti- androgen effect of apalutamide.

Phase II – Apalutamide
Page 18 of 65
Once daily oral capsule administration of apalutamide for 13 weeks was well tolerated in 
male dogs up to 10 mg/kg/day, i.e. the highest dose tested. Gross and microscopic 
pathology changes and organ weight changes characteristic of anti-androgen compounds 
were noted in the pituitary gland, prostate, testes, and epididymides; these changes were 
reversible and were attributable to the expected pharmacologic effect of apalutamide. 
Based upon the lower body weight performance in the group receiving 10 mg/kg/day, the 5 
mg/kg/day dose was considered to be the NOAEL. Corresponding steady-state (Day 91) 
plasma Cmax and
AUC0-24h values were 10.3 µg/mL and 202 µg•h/mL, respectively, for the parent compound.
Preclinical studies have demonstrated the absence of genotoxic, clastogenic, and 
phototoxic properties for apalutamide and its pharmacologically active metabolite 
ARN000308 (M3). ARN000066 (M4), an inactive metabolite of apalutamide, tested negative 
in an in vitro bacterial reverse mutation (Ames) assay, but was weakly positive in an in vitro 
chromosome aberration test in human peripheral blood lymphocytes. However, the totality 
of nonclinical data supports the lack of an in vivo genotoxic potential of ARN000066 (M4).
1.1.3
Overview of Clinical Studies
In addition to Study ARN-509-003, apalutamide is also being evaluated in Phase I studies in 
healthy men and Phase I/II, Phase II, and Phase III studies in patients with prostate cancer.
Study ARN-509-001 is an ongoing Phase I/II study in patients with progressive advanced 
CRPC. In the Phase I portion of the study, 30 patients with mCRPC received at least 1 dose 
of apalutamide at escalating dose levels: 3 patients each at 30, 60, 90, 120, 180, 240, 390, 
480 mg/day, and 6 patients at 300 mg/day. Three subgroups are being evaluated in the 
Phase 2 portion (Group 1: NM-CRPC; Group 2: mCRPC without previous ketoconazole, 
abiraterone acetate, enzalutamide or chemotherapy [for mCRPC]; and Group 3: mCRPC 
post abiraterone acetate, no previous chemotherapy [for mCRPC]). All patients received 
apalutamide orally once daily, except those in the 300, 390, and 480 mg cohorts who 
received a twice-daily dosing regimen due to the higher pill burden at those levels. The 
results of the Phase 1 portion of the study from 30 patients with mCRPC demonstrated that 
treatment with apalutamide resulted in PSA declines at all dose levels tested. Eighteen 
subjects (60%) had a ≥50% or higher maximum decrease in PSA from baseline and 6 
(20%) had ≥90% maximum decrease. Ten patients had measureable soft tissue disease at 
baseline; 5 (50%) subjects maintained stable disease response for more than 6 months, 1 
(10%) subject experienced disease progression, and the remaining 4 subjects had 
indeterminate responses. Apalutamide was well tolerated, with only 1 dose-limiting toxicity 
(DLT) at the 300 mg dose level (Grade 3 treatment-related abdominal pain). The event 
lasted 6 days and resolved with dose interruption and subsequent dose reduction to 240 mg 
(120 mg twice daily). Three additional subjects were treated at the 300 mg dose level with 
no reported DLTs. No seizures were reported at any dose level. The maximum tolerated 
dose (MTD) was not determined. The PK profile is linear and dose-proportional.
Sixteen subjects participated in an evaluation of AR binding in vivo using
16β-[18F] fluor-α-dihydrotestosterone (FDHT) positron emission tomography (PET)/CT 
scan. Apalutamide treatment reduced FDHT uptake across all dose levels (30 to 390 mg 
dose levels). A plateau was reached at approximately 120 mg (with FDHT uptake near 
background) indicating saturation of AR binding. The mean plasma trough levels associated 
with this dose (2.5 µg/mL) were at the lower end of the range that produced tumor 
regression in the LNCaP/AR mouse model. Steady state plasma levels at the 240 mg dose 
level (3 to 6 µg/mL) were more in the range sufficient to elicit a tumor response in the 
mouse xenograft model. Therefore, the 240 mg daily regimen was chosen for Phase 2 and 
Phase 3 dosing.

Phase II – Apalutamide
Page 19 of 65
Apalutamide was rapidly absorbed, with measurable plasma concentrations within 30 
minutes after ingestion of a single oral dose of 1 to 16 soft gelatin capsules (total 
apalutamide dose, 30 to 480 mg). On average, peak plasma concentrations occurred 2 to 3 
hours after administration in each dose group. The increases in plasma Cmax values and in 
the area under the plasma concentration curve (AUC) were linear and dose proportional.  
Plasma apalutamide concentrations declined slowly, with a mean half-life value at steady-
state of 4 days.
The percentage of patients with PSA reductions of ≥ 50% at 12 weeks in patients with NM-
CRPC was 89%2. Similar data were observed after 24 weeks. The data available to date 
indicate that apalutamide shows durable PSA responses in NM-CRPC and early mCRPC 
(before treatment with abiraterone acetate or chemotherapy). Apalutamide also has activity 
in a subgroup of patients with mCRPC that have progressed on abiraterone actetate. For 
the NM-CRPC subgroup, the median time to PSA progression was 24.0 months (16.3 – 
NR). 
In the NM-CRPC subgroup (n =51), the most frequent treatment-related adverse events 
reported in >10% are fatigue (61%), diarrhea (43%), and nausea (39%)2. No deaths were 
reported in this subgroup as of the safety cutoff.
In the phase 3 study, the median metastasis-free survival with apalutamide versus placebo 
was (40.5 vs. 16.2 months, p < 0.001).3  
1.2 STEREOTACTIC BODY RADIATION THERAPY IN OLIGOMETASTATIC 
PROSTATE CANCER
The definition of oligometastatic prostate cancer has varied across studies. 
Multiple uncontrolled and prospective studies had defined as ranging from ≤ 3 to ≤ 
5 lesions in various studies21. A recent retrospective analysis of pooled individual 
data from patients with castration-sensitive recurrent prostate cancer following 
definitive local therapy, with up to three positive lesions on baseline scan, to 
determine the efficacy of this treatment strategy. SBRT was defined as a 
radiotherapy dose of at least 5 Gy per fraction to a biologically effective dose 
(BED) of at least 80 Gy. A total of l19 patients were treated for 163 metastatic 
lesions (lymph node, n = 72; bone n = 43; visceral met n = 2). The 3-year and 5-
year local progression free survival rate was 93% and 92%, respectively. A lower 
radiotherapy dose predicted for higher local recurrence rate. The median distant 
progression-free survival time was 21 months (95% CI 15-27 months)19. A recent 
review highlighted 5 additional retrospective studies demonstrates the safety of 
SBRT to oligometastatic sites of disease, as well as the high rates of local control 
ranging from 90-100%20. 
Two major limitations of the currently available data are randomized studies with 
and without SBRT to begin to address whether addition of SBRT impacts 
intermediate- and long-term outcomes, as well as limited data available in the 
oligometastatic castration-resistant prostate cancer setting. The current study was 
designed to address these gaps and evaluate the role of SBRT in oligometastatic 
CRPC in a randomized fashion, with treatment of up to five bone and nodal 
radiation fields. 

Phase II – Apalutamide
Page 20 of 65
2
STUDY OBJECTIVES
2.1PRIMARY OBJECTIVE
To demonstrate whether the proportion of patients with an undetectable serum PSA at 6 
months following cessation of apalutamide is higher with addition of SBRT to PSMA-avid 
oligometastatic sites of disease compared to the group of patients receiving apalutamide 
monotherapy.
2.2SECONDARY OBJECTIVES
1.
To compare the time to PSA progression by PCWG criteria between treatment arms
2.
To evaluate the safety and tolerability of apalutamide in combination with SBRT.
2.3EXPLORATORY OBJECTIVES
1.
To evaluate the genomic factors associated with the presence of oligometastatic 
disease via exome sequencing.
2.
To evaluate the association between somatic and germline genomic alterations 
including but not limited to AR amplification and point mutations and alterations in 
DNA damage response pathway with outcomes on protocol therapy
Note: The italicized objectives above were discontinued in Protocol v. 8.0. See 
Section 7.3 for additional information.
3.
To characterize the metastatic pattern at baseline and at progression in these 
patients and to determine whether features of the baseline PSMA-PET scan are 
associated with treatment outcomes. 
3
STUDY DESIGN
3.1STUDY OVERVIEW AND RATIONALE
This is a randomized, open-label, phase II clinical trial evaluating the efficacy and safety of 
apalutamide with or without SBRT in patients with oligometastatic castration-resistant 
prostate cancer detected on PSMA-PET scan imaging. A randomized design was chosen to 
begin to address the clinically relevant question as to whether the addition of SBRT 
improves outcomes as compared to systemic therapy alone for men with oligometastatic 
prostate cancer. We chose to utilize PSMA-PET as opposed to conventional imaging to 
define oligometastatic disease based on the improved sensitivity of this imaging modality, 
enabling earlier detection of oligometastatic disease.  
The justification of assigned therapy by treatment arm is as follows:
(1) SBRT:  There is no standard timing for the use of SBRT for patients with oligo-
metastatic disease.  Therefore, it is appropriate to undertake SBRT either at the time of 
starting apalutamide as part of study treatment, or later, as post-study therapy. We chose to 
utilize SBRT as compared to more conventional radiation treatment schedule due to the 
higher rates of local control observed with higher doses of radiation therapy in prior studies 
of radiation in oligometastatic prostate cancer. 
(2) Apalutamide therapy:  Apalutamide is not considered SOC therapy in this group of 
patients, and consequently will be provided by the study.  Apalutamide is being used in both 
arms of the study in order to maintain equipoise with regards to PSA endpoints. The optimal 
duration of concurrent androgen pathway inhibitor treatment in conjunction with ADT 
remains undefined. The SPARTAN study has studied maintenance of apalutamide therapy 
until radiographic disease progression, and not for a fixed time period as in this study.  

Phase II – Apalutamide
Page 21 of 65
However the optimal duration of apalutamide therapy in this setting has not been 
determined.  Extrapolation from other studies evaluating the use of AR targeted therapy in 
hormone-naive prostate cancer patients with recurrent, but non-extensive disease suggests 
that the approach selected is appropriate.  Clinical trials testing AR targeted therapy in 
conjunction with “salvage” radiotherapy in men with progressive disease following 
prostatectomy have utilized AR targeted therapy from 6 months (Carrie et al, Lancet Oncol 
2016) to 24 months (Shipley et al, NEJM, 2017.)  Furthermore, in a trial of intermittent 
androgen deprivation in patients with non-metastatic disease progression following radiation 
therapy, one year of systemic therapy was used (Crook et al, NEJM, 2012). One year of 
apalutamide therapy will therefore be used in both arms.  Shorter duration is felt inadequate 
for patients with potentially metastatic disease, whereas longer duration would delay read 
out of results.
Although SBRT is an appropriate therapeutic approach in selected patients with 
oligometastatic prostate cancer, its utility has not been rigorously demonstrated. It is 
hypothesized that the addition of SBRT to apalutamide will result in clinically meaningful 
benefit, with improvement in time to subsequent metastasis, and potentially in an overall 
survival benefit.  However, before embarking on a large phase 3 trial, an intermediate signal 
of activity is required.   Only a very small proportion (2.5%) of patients with non-metastatic 
CRPC treated with apalutamide alone reach a serum PSA level of < 0.2 ng/mL.  A nadir 
PSA of < 0.2 ng/mL has previously been shown to be strongly associated with long-term 
survival, and therefore represents a reasonable intermediate endpoint for a randomized 
phase 2 study.   Positive results from the current study would form the strong justification for 
a follow-on randomized phase 3 study to investigate whether addition of SBRT impacts 
long-term treatment outcomes including radiographic progression-free and overall survival.  
3.1.1
Number of Subjects
A total of 60 subjects may participate in this study. Thirty subjects will be enrolled to the 
apalutamide monotherapy arm, and 30 patients will be enrolled to the apalutamide + SBRT 
arm.
3.2STUDY OUTCOMES
3.2.1
Primary Endpoints
Proportion of patients with undetectable serum PSA (< 0.2 ng/mL) at 6 months following 
completion of apalutamide therapy (18 months from date of randomization). 
3.2.2
Secondary Endpoints
1.
Time to PSA progression by PCWG criteria
2.
Feasibility and safety of apalutamide and concurrent SBRT
3.2.3
Exploratory Endpoints
1.
Association between genomic factors and presence of oligometastatic disease 
2.
Association between somatic and germline genomic alterations with clinical 
outcomes
Note: The italicized objectives above were discontinued in Protocol v. 8.0. See 
Section 7.3 for additional information.
3.
Association between baseline PSMA-PET scan uptake and distribution of lesions 
with treatment outcomes.

Phase II – Apalutamide
Page 22 of 65
4
PATIENT SELECTION
The following eligibility criteria are designed to select patients for whom protocol treatment 
is considered appropriate. All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular patient. It 
is expected that all patients will be treated according to local standard of care, including 
radiation therapy if needed for local disease, prior to enrolling.
No waivers will be granted for eligibility criteria deviations.
Patients considered screen failures may be subsequently rescreened. Rescreening must be 
discussed with and approved by the Principal Investigator on a case-by-case basis. Patients 
who are determined to be eligible for the study after rescreening must sign a new informed 
consent form (ICF) and be assigned a new patient number.
4.1INCLUSION CRITERIA
1. Histologically or cytologically confirmed adenocarcinoma of the prostate.
2. Progressive, castration-resistant prostate cancer demonstrated during 
continuous ADT, defined as 3 PSA rises at least 1 week apart, with a 
minimum PSA > 0.2 ng/mL obtained during Screening.
3. At least one but no more than 5 discrete PSMA-avid radiation fields on 
baseline PSMA-PET scan. All PSMA-avid lesions in radiation fields must be 
amenable to SBRT in judgment of treating radiation oncologist. There are no 
restrictions on site of lesion/radiation field (e.g. bone, lymph node, prostate, 
visceral). Equivocal lesions/radiation fields on PSMA PET scan that are not 
definitive for metastasis will not count towards the limit of 5 radiation fields 
and will not undergo SBRT. 
4. Surgically or medically castrated, with testosterone levels of <50 ng/dL during 
Screening. If the patient is medically castrated, continuous dosing with LHRH 
analogue must have been initiated at least 4 weeks prior to randomization 
and must be continued throughout the study to maintain castrate levels of 
testosterone including post-treatment follow up period.
5. No prior systemic treatment initiated for the treatment of castration resistant 
prostate cancer, including abiraterone acetate, enzalutamide, apalutamide, 
darolutamide, other novel AR or CYP17 antagonist, or docetaxel. 
6. Patients receiving bone loss prevention treatment with bone-modifying 
agents (e.g. denosumab, zoledronic acid) must be on stable doses for at 
least 4 weeks prior to randomization
7. Patients who received a first generation anti-androgen (e.g., bicalutamide, 
flutamide, nilutamide) as most recent treatment must have at least a 6-week 
washout prior to randomization and must show continuing disease (PSA) 
progression (an increase in PSA) after washout.
8. At least 4 weeks or 5 half-lives, whichever is shorter, must have elapsed from 
the use of any anti-cancer therapy, other than LHRH analog or first 
generation antiandrogen, prior to randomization
9. At least 4 weeks must have elapsed from major surgery or radiation therapy 
prior to randomization
10.Age ≥ 18 years

Phase II – Apalutamide
Page 23 of 65
11.Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 
or 1
12.Resolution of all acute toxic effects of prior therapy or surgical procedure to 
Grade 1 or baseline prior to randomization
13.Adequate organ function as defined by the following criteria:
a. Serum aspartate transaminase (AST; serum glutamic oxaloacetic 
transaminase [SGOT]) and serum alanine transaminase (ALT; serum 
glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normal 
(ULN)
b. Total serum bilirubin ≤1.5 x ULN. In subjects with known or suspected 
Gilbert’s syndrome, if total bilirubin is >1.5 × ULN, direct bilirubin is 
≤1.5 × ULN
c. Glomerular filtration rate ≥ 45 ml/min based on Cockroft-Gault 
equation
d. Absolute neutrophil count (ANC) ≥ 1500/microliter
e. Platelets ≥ 75,000/microliter 
f.
Hemoglobin ≥ 9.0 g/dL 
g. Serum albumin ≥ 3.0 g/dL
14.Signed and dated informed consent document indicating that the patient has 
been informed of all pertinent aspects of the trial prior to randomization.
15.Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory and radiographic assessments, and other study procedures, 
including ability to swallow study drug tablets and long-term follow-up.
16.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.
4.2EXCLUSION CRITERIA
1. Presence of visceral lesions (e.g. lung, liver) detectable on baseline imaging 
or bone lesions requiring focal radiation treatment at the time of study entry
2. History of seizure or condition that may pre-dispose to seizure (e.g., prior 
stroke within 1 year prior to randomization, brain arteriovenous malformation, 
Schwannoma, meningioma, or other benign CNS or meningeal disease 
which may require treatment with surgery or radiation therapy.
3. Concurrent therapy with any of the following (all must have been discontinued 
or substituted for at least 1 week prior to randomization, except for 
medications known to lower seizure threshold which must be discontinued or 
substituted at least 4 weeks prior to randomization):
a. Medications known to lower the seizure threshold (for a complete list 
please see Appendix 5)

Phase II – Apalutamide
Page 24 of 65
b. Herbal (e.g., saw palmetto) and non-herbal (e.g., pomegranate) 
products that may decrease PSA levels.
c. Systemic (oral/IV/IM) corticosteroids. Patients on chronic stable dose 
of steroids at an equivalent dose of prednisone ≤ 10 mg daily may be 
permitted to enroll at the discretion of Principal Investigator. 
d. Any other experimental treatment on another clinical trial.
4. Any of the following within 6 months prior to randomization: Severe/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
5. Uncontrolled hypertension at study entry. Patients with a history of 
uncontrolled hypertension are allowed provided blood pressure is controlled 
by anti-hypertensive treatment.
6. Gastrointestinal disorder affecting absorption.
7. Secondary malignancy requiring active treatment except for non-melanoma 
skin cancer and superficial bladder cancer. 
8. Any medical condition that would be a contra-indication to radiation therapy, 
such as inflammatory bowel disease.
9. Spinal cord compression or impending spinal cord compression
10.Any other condition that, in the opinion of the Investigator, would impair the 
patient’s ability to comply with study procedures.
4.3DURATION OF THERAPY
Protocol therapy will continue until the first occurrence of any one of the following:

Disease progression by PCWG3 criteria

Unacceptable adverse event(s) related to apalutamide or SBRT

Completion of treatment (52 weeks)

Patients decides to withdraw from the study

Significant patient non-compliance with protocol

General or specific changes in the patients’ condition render the patient 
unacceptable for further treatment in the judgment of the investigator.
4.4DURATION OF FOLLOW UP
For safety follow up, patients will be followed for adverse events until 30 days after 
completion of treatment, removal from study, or until death, whichever occurs first.  
Patients removed from study for unacceptable treatment related adverse event(s) 
will be followed until resolution or stabilization of all treatment related adverse 
events to Grade 2 or lower.
Patients will be followed on study until confirmed PSA progression by PCWG 
criteria.

Phase II – Apalutamide
Page 25 of 65
4.5RANDOMIZATION PROCEDURES
Once eligibility is confirmed, subjects will be randomized with equal probability to 1 of the 2 
treatment arms. Balance in treatment assignment will be achieved using a randomized 
block design. Randomization will be carried out via computer generated random 
assignment. All subjects must commence treatment within 7 calendar days after 
randomization. Study sites will email the Eligibility Checklist to the Lead site (UCSF) in order 
to obtain the subject’s treatment assignment. Once subject eligibility is confirmed by the 
lead site, an email with the treatment assignment number will be provided to the study site.
4.6STUDY TIMELINE
The estimated study duration is approximately 36 months, 18 months for accrual and 18 
months of study follow up. 
5
STUDY TREATMENTS
5.1RANDOMIZATION 
After patients have provided their written informed consent, completed all screening 
assessments and received confirmation of eligibility, they will be randomized into the study. 
All patients must commence treatment within 7 calendar days after randomization.
5.2BLINDING
There is no blinding for this study. 
5.3FORMULATION
5.3.1
Apalutamide
Refer to the Investigator's Brochure for a list of excipients. 
5.3.2
Packaging, Storage, and Labeling
The apalutamide 60-mg tablets will packaged in 120-count, 160 cc high-density 
polyethylene (HDPE) bottles with child-resistant caps. Bottles will include desiccant.
Each bottle of study drug will be labeled with the required regulatory agency warning 
statement, the protocol number, the Sponsor’s name, and directions for patient use and 
storage. The Investigator will ensure that the study drug is stored in appropriate conditions 
in a secure location with controlled access. For clinical formulation-specific and batch-
specific storage instructions, see the packaging label.
5.3.3
Drug Administration
Apalutamide tablets will be administered orally on a continuous daily dosing regimen at a 
dose of 240 mg per day (4 x 60-mg tablets) with or without food.
5.3.4
Cycle Management
For the purposes of the study, a treatment cycle will consist of 4 weeks (28 days).
It is anticipated that individual patients may occasionally forget to take a dose.  In those 
cases, missed doses should only be replaced if the patient remembers within a 12-hour 
window. After that, patients should just take the next dose the following day, without 
compensating for the missed dose (including vomited doses). In the event of dose delays 
due to transient toxicity, tumor assessments should remain on schedule independent of 
cycle length.

Phase II – Apalutamide
Page 26 of 65
5.3.5
Dose Modifications
Intra-patient dose interruptions and/or reductions will be permitted provided that study 
discontinuation criteria have not been met (please see Section 10).

Patients experiencing treatment-related seizure of any grade will have study drug 
permanently discontinued.

For patients experiencing Grades 1-2 treatment-related adverse events, short 
treatment breaks can be instituted as per the discretion of the Investigator until the 
severity of the toxicity decreases to Grade 1 or returns to baseline. If toxicity recurs, 
dose reductions to the next lower dose level will be allowed as per the discretion of 
the Investigator.

For patients experiencing Grade 3 treatment-related adverse events other than 
seizure, study drug should be held. If the severity of the toxicity decreases to Grade 
1 or returns to baseline within two weeks, study treatment may be resumed at the 
next lower dose level, except for clinically insignificant laboratory abnormalities that 
resolve within two days on optimal treatment, in which case dose reduction is not 
required. If toxicity recurs at Grade 3 or higher, the dose of apalutamide should be 
reduced to the next lower dose level. A maximum of 2 dose level reductions will be 
allowed (Table 1).

For patients experiencing Grade 4 treatment-related adverse events, except for 
clinically insignificant laboratory abnormalities that resolve within two days on 
optimal treatment, study treatment must be permanently discontinued. 

Any patient requiring > 14 days delay in treatment due to study treatment-related 
AEs should discontinue treatment of the study treatment thought to be responsible 
for the AE. 
Table 1
Apalutamide Dose Levels
Dose 
Level
Total Daily 
Dose
Number of 60-mg Tablets 
(QD)
               0
240 mg
4
-1
180 mg
3
-2
120 mg
2
Doses reduced for study treatment-related toxicities should generally not be re-escalated, 
however, re-escalation back to the previous dose level may be permitted at the discretion of 
the Principal Investigator. 
Rash
Dose modifications for rash are allowed only for apalutamide and are summarized in below 
table. If the skin rash has any component of desquamation, mucosal involvement, or 
pustules, stop dosing with apalutamide, refer to dermatologist for evaluation, and a skin 
biopsy is recommended (in addition to the interventions listed in below Table). If the skin 
rash is Grade 3 or higher, asking the subject to consent to documentation by a photograph 
and further evaluation by a dermatologist should also be considered.
Table 2
Apalutamide Dose Modification
Severity
Intervention

Phase II – Apalutamide
Page 27 of 65
Grade 1

Continue apalutamide at 
current dose

Initiate dermatological 
treatmenta:
o
Topical steroid cream AND
o
Oral Antihistamines

Monitor for change in severitya
Grade 2 (or symptomatic 
Grade 1)b

Hold apalutamide for up to 28 days

Initiate dermatological treatmenta
o Topical steroid cream AND
o Oral Antihistamines

Monitor for change in severitya
oIf rash or related symptoms 
improve, reinitiate apalutamide 
when rash is Grade≤1. Consider 
dose reduction at a 1 dose level 
reductionc.
Grade 3d

Hold apalutamide for up to 28 days

Initiate dermatological treatmenta
oTopical steroid cream AND
oOral Antihistamines AND
Consider short course of oral steroids

Reassess after 2 weeks, and if the 
rash is the same or has worsened, 
initiate oral steroids (if not already 
done) and refer the subject to a 
dermatologist
o Reinitiate apalutamide at a 1 dose 
level reductione when rash is 
Grade≤1.
o If the dose reduction will lead to a 
dose less than 120mg, the study 
drug must be stopped 
(discontinued)

If after 28 days, rash has not 
resolved to Grade≤1, discontinue 
study drug
Grade 4

Permanently discontinue 
apalutamide

Inpatient admission for IV steroids 
and dermatology consultation
 

Phase II – Apalutamide
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Note: Rash may be graded differently according to the type of rash and associated 
symptoms. For example, maculo-papular rash is graded by body surface area covered and 
not severity of the rash. Please consult NCI-CTCAE Version 4.03 for specific grading 
criteria for other types of rash.
a Obtain bacterial/viral cultures if infection is suspected
b Subject presents with other rash related symptoms such as pruritus, stinging, or burning
c 1 dose level reduction = 60mg (1 apalutamide tablet)
d If there is blistering or mucosal involvement, stop apalutamide dosing immediately
e If a subject previously started oral corticosteroids, continue for at least 1 week after 
resumption of reduced dose of apalutamide. If the proposed total oral steroid use will 
exceed 28 days, contact Principal Investigator. 
5.4STUDY DRUG ACCOUNTABILITY
The initial study drug shipment will be shipped after all required regulatory documentation 
has been received by the manufacturer and a Clinical Trial Agreement fully executed. 
The study drug will only be dispensed to patients who meet the eligibility criteria and are 
randomized to a treatment arm in the trial. An accurate and current accounting of the 
dispensing and return of study drug for each patient will be maintained on an ongoing basis 
by the Investigator or his/her designated personnel. The number of study drug dispensed 
and returned by the patient will be recorded on the Investigational Product Accountability 
Log. The study monitor will verify these documents throughout the course of the study.
The disposition of any unused study drug should be performed per institutional guidelines. 
The Investigator must ensure that all investigational product is destroyed in compliance with 
the applicable environmental regulations, institutional policy, and any other special 
instructions provided by the manufacturer. Drug destruction must be adequately 
documented.
5.5MEASURES OF TREATMENT COMPLIANCE
At each clinic visit, patients will be asked to return any remaining study drug from the 
previous dosing cycle as well as all used and unused study drug containers.
The overall treatment compliance will be defined as the total dose in mg taken during the 
study divided by the expected total dose in mg. Patients completing their last cycle on 
capsules should continue with a maximum of 8 capsules per day and patients on tablets 
should have a maximum of 4 tablets per day.
Tablets that are not returned will be considered to have been taken, unless otherwise 
specified in the case report form (CRF).
5.6STEREOTACTIC BODY RADIATION
SBRT must be initiated within 90 days following initiation of apalutamide therapy for patients 
randomized to this treatment arm. 
For the purposes of planning an SBRT treatment, CT- and/or MRI-simulation will be 
performed with fabrication of a radiation therapy immobilization device (such as a vacuum 
lock bag) which will be custom made for each patient. For tumors located in the upper 
abdomen or thorax, respiratory motion will be considered with methods including four-
dimensional CT study or respiratory control to improve tumor targeting accuracy for those 
tumors that may be subject to respiratory motion.

Phase II – Apalutamide
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The treating radiation oncologist will identify the location of the tumor. Gross tumor volume 
(GTV) delineation will be performed on sequential axial computed tomography images. An 
SBRT treatment plan will be developed based on tumor geometry and location. The clinical 
tumor volume (CTV) will typically equal the GTV or ITV (internal target volume). The dose 
will be prescribed to the minimal isodose line that completely covers the planning target 
volume (PTV) PTV (=CTV plus a 5 mm margin), except in cases where dose constraints to 
neighboring organs necessitates under dosage of the PTV. Adjacent normal structures 
including but not limited to the heart, esophagus, aorta, spinal cord, kidneys, rectum, bowel, 
liver, and stomach within 5 cm of the CTV will be identified for the purpose of limiting 
incidental radiation to these structures. 
SBRT will be delivered in 1 to 5 fractions, and the dose and fractionation schedule will 
depend on the size and location of the lesion(s)/radiation field and the surrounding normal 
tissue constraints in accordance with AAPM Task Group 101 recommendations. Typical 
doses include 16 – 24 Gy in 1 fraction, 30 – 60 Gy in 3 fractions, and 30 – 60 Gy in 5 
fractions. For example, while isolated osseous lesions may be treated in a single fraction 
(depending on location), lesions in the lung and liver will be treated in 3 to 5 fractions 
depending on their size (5 fractions for ≥ 3 cm) or location (central tumors in close proximity 
to the mediastinum). 
Within three weeks of the initial treatment planning imaging study, SBRT will be 
administered using image-guidance. A vacuum lock bag (or equivalent immobilization 
approach) will be used to minimize movement of the chest, spine, and abdomen during 
treatment. During treatment, real time cone beam CT images of the patient’s body site of 
interest will be obtained. Cone beam CT scan will be obtained immediately prior to 
treatment and will be repeated until the treatment shift, required to align the CT planning 
scan and the cone beam CT scan performed on the day of treatment cone beam CT, is 
within tolerance for the body site.
Equivocal lesions/radiation fields on PSMA PET scan that are not definitive for metastasis 
will not count towards the limit of 5 radiation fields and will not undergo SBRT. Patients will 
be evaluated for adverse events/toxicities during their treatment.
6
CONCURRENT MEDICATIONS
All patients should be maintained on the same medications throughout the entire study 
period, as medically feasible, with minimum introduction of new chronic therapies. Every 
medication or treatment taken by the patient during the trial and the reason for its 
administration must be recorded on the CRF. Standard medical treatment as applicable is 
allowed except for treatments noted in the eligibility criteria and/or listed in the prohibited 
medications section below.
Continuous treatment with a LHRH analogue or surgical castration is mandatory for all 
patients in order to maintain castrate concentrations of testosterone (<50 ng/dL). The choice 
of LHRH analogue is at the discretion of the investigator. Dose and dose schedule (without 
interruption) will be consistent with the prescribing information and should only be adjusted 
if clinically indicated to maintain castrate concentrations of testosterone. Maintenance of 
castrate level of testosterone is mandatory during both the On-Treatment and Post-
Treatment periods of the study. 
All patients should receive oral calcium and vitamin D supplementation while receiving 
apalutamide. For patients at high estimated fracture risk based on baseline DXA bone 
density scan (> 3% estimated 10 year risk of hip fracture or > 20% major osteoporotic 
fracture per FRAX calculator (https://www.sheffield.ac.uk/FRAX/), treatment with a bone-
modifying agent (e.g. alendronate) should be administered as per institutional guidelines. 

Phase II – Apalutamide
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6.1PROHIBITED MEDICATIONS AND TREATMENTS
As a class effect, androgen receptor antagonists have been associated with seizures due to 
an off-target mechanism of action (GABAA inhibition). Patients will be closely monitored for 
seizures, but as a precautionary measure, drugs known to decrease the seizure threshold 
and/or cause seizure will be prohibited while on study. A list of these medications can be 
found in Appendix 5.
6.2RESTRICTED THERAPIES
Investigators should refer to the apalutamide Investigator’s Brochure (Sections 4.3.3.3 and 
5.10) and associated addenda for complete details on the drug interaction potential of 
apalutamide. Highlights of drug interaction are summarized below.

Strong CYP3A4 inducers: the potential for drug-drug interactions with apalutamide 
has not been tested clinically. Strong inducers of CYP3A4 (eg, phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, efavirenz, tipranavir, 
St. John's wort) should be avoided as much as possible. Additional information is 
provided in Appendix  5.

Apalutamide may also induce CYP3A4; therefore, caution should be taken when 
administered in conjunction with CYP3A4 substrates that have a narrow therapeutic 
index.

Strong CYP2C8 inhibitors (eg, gemfibrozil) should be used with caution with 
apalutamide.

The potential for drug-drug interaction between apalutamide and warfarin (e.g., 
Coumadin) is unknown at present. If a patient is taking warfarin, re-assess 
(prothrombin) PT/(international normalized ratio) INR as clinically indicated and 
adjust the dose of warfarin accordingly.

Corticosteroids (Oral, IV, or IM): due to possible resistance mechanisms, which may 
be contributed by glucocorticoid receptor signaling, concurrent use of corticosteroids 
during the study should be avoided whenever possible. Short term use of steroids (≤ 
4 weeks) will be allowed if clinically indicated, however, its use must be tapered off 
as soon as possible.
6.3LIFESTYLE GUIDELINES
To avoid risk of drug exposure through the ejaculate (even men with vasectomies), patients 
must use a condom during sexual activity while on study drug and for 3 months following 
the last dose of study drug. Donation of sperm is not allowed during the study and for 3 
months following the last dose of study drug.
There are no data on the use of apalutamide in pregnancy. Maternal use of an anti-
androgen is expected to produce changes in hormone levels that may affect fetal 
development. It is not known if apalutamide or its metabolites are present in semen.
If the patient is engaged in sexual activity with a woman of childbearing potential, a condom 
is required along with another effective contraceptive method consistent with local 
regulations regarding the use of birth control methods for patients participating in clinical 
studies and their partners. Highly effective forms of contraception include:

established use of oral, injected or implanted hormonal methods of contraception; 
placement of an intrauterine device (IUD) or intrauterine (IUS) system;

Phase II – Apalutamide
Page 31 of 65

barrier methods: condom with spermicidal foam/gel/film/cream/suppository or 
occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository;

vasectomy;

true abstinence (an option when this is in line with the preferred and usual lifestyle of 
the patient).
Two highly effective forms of contraception are required during the study and for 3 months 
after the last dose of study drug.
7
STUDY PROCEDURES AND GUIDELINES
A Schedule of Activities representing the required testing procedures to be performed 
during the study is diagrammed in Appendix 1.
Prior to conducting any study-related activities, written informed consent and any other 
authorizations must be signed and dated by the patient or patient’s legal representative.
7.1CLINICAL ASSESSMENTS
7.1.1
Demographics
Demographic information (e.g., date of birth, race) will be recorded at Screening.
7.1.2
Medical History
Relevant medical history, including history of current disease, other pertinent clinical 
conditions, and information regarding underlying diseases will be recorded at Screening.
7.1.3
Physical Examination
A complete physical examination will be performed by either the Investigator or a sub-
Investigator at Screening. Qualified staff (e.g., nurse practitioner or physician assistant) may 
complete either a full or abbreviated physical exam at all other visits. New abnormal 
physical exam findings must be documented and followed by a physician or other qualified 
staff at the next scheduled visit. All physical exams may be performed over a telemedicine 
visit.
7.1.4
Vital Signs
Heart rate and blood pressure will be recorded after resting for 5 minutes at Screening and 
every scheduled visit during treatment and at the end of treatment. If the physical exam is a 
telemedicine visit, BP and heart rate will be self-reported by the patient.
7.1.5
Performance Status
The Eastern Cooperative Oncology Group (ECOG) performance status scale will be used 
(Appendix 3) and will be assessed at Screening and every subsequent clinic visit.
7.1.6
Adverse Events
Assessment of adverse events will include type, incidence, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 
4.03), timing, seriousness, and relatedness (Appendix 4). Adverse events will be assessed 
at every clinic visit.

Phase II – Apalutamide
Page 32 of 65
7.1.7
Concomitant Medications/Therapies
All concomitant medication and concurrent therapies will be documented from screening 
until 30 days after the last dose of study drug. Name, indication for administration, and 
dates of medication or therapy will be captured.
7.1.8
Tumor Assessments
Whole body PSMA-PET imaging will be performed within 42 days of randomization during 
the Screening period. PSMA PET imaging may use Ga-PSMA-11 or other PSMA PET 
tracer. Either PSMA PET/MR or PET/CT is allowed. A certified trained nuclear medicine 
physician will evaluate the baseline PSMA-PET scan for purposes of eligibility determination 
to verify whether there are ≥ 1 but ≤ 5 discrete radiation fields. A treating radiation 
oncologist will review baseline scans to determine whether the lesion(s) identified on 
baseline PSMA PET scan are amenable to SBRT. 
If more than 5 radiation fields are identified on baseline PSMA PET scan the patient will be 
deemed Screen Failure and will be treated per investigator discretion. 
Patients will undergo optional follow up PSMA PET scan at the time of PSA progression by 
PCWG criteria. PSA progression will be defined as an increase of at least 2 ng/mL and 25% 
above the nadir or baseline on study, whichever is lower, confirmed by repeat PSA 
measurement at least 2 weeks later.  
7.1.9
Tumor Biopsy (DISCONTINUED)
An optional biopsy and biomarker blood collection was to be conducted under the 
PROMOTE study (CC155518, IRB# 15-18365), as an optional enrollment option. The 
PROMOTE study has closed to accrual and will no longer be able to financially support the 
biopsy, biomarker collection, and downstream correlatives. Therefore, we are discontinuing 
the biopsy and biomarker blood collection moving forward described in the italicized 
paragraph below (as of Amendment 8.0). Any specimens collected under prior protocol 
versions (i.e., prior to implementation of Amendment 8.0) may continue to be stored and/or 
used as permitted according to the PROMOTE study protocol and ICF.
Patients will undergo optional baseline image-guided core needle tumor biopsy of PSMA-
avid metastatic lesion if lesion is safely accessible. Lesions will be chosen based upon the 
strength of the evidence suggesting the presence of metastasis and with the goal of 
minimizing patient risk. Soft tissue lesions should be prioritized for biopsy. If the Radiologist 
in charge of the procedure cannot identify a lesion amenable for biopsy, the patient will still 
be treated on study.
Patients undergoing biopsy must have a PT or INR and a PTT < 1.5 times the institutional 
ULN within 14 days prior to biopsy. Patients on warfarin, aspirin, or other anti-coagulants 
may undergo biopsy, provided they are deemed able to tolerate discontinuation of anti-
coagulation for one week prior to the baseline biopsy. Conversion to low molecular weight 
heparin prior to biopsy is permitted per local standard operating procedures, provided there 
is agreement regarding the procedure between the treating physician, the interventional 
radiologist and the PI.
The biopsies will be performed in an interventional radiology suite with radiological guidance 
(typically CT or MRI) in accordance with the standard operating procedure according to 
institutional standards. Once the target lesion(s) identified, up to six (6) biopsies will be 
performed. Preferably, a 16 gauge BonoptyTM needle or biopsy needle with an equivalent 
16g bore will be used to biopsy the metastatic lesion. If the lesion is a bone metastasis, the 
Bonopty needle will be passed through the cortical bone and into the target lesion. Optimal 
results are obtained when the biopsies are performed on medullary bone directly adjacent 
to blastic lesion. Soft tissue biopsies should be taken so that a core of approximately 10 to 

Phase II – Apalutamide
Page 33 of 65
20 mm in length is obtained. Core biopsies will be extracted: up to 3 will be placed in 
neutral-buffered formalin and up to 3 will be immediately frozen on a pre-frozen bed of OCT 
(Optimal Cutting Temperature compound used for frozen sections), covered with additional 
OCT, and kept on dry ice or at -80° C.  
7.2CLINICAL LABORATORY MEASUREMENTS
Blood will be obtained at the time points described in the Schedule of Activities. Appendix 2 
lists all of the specific tests that will be performed.  
Investigators may have additional blood tests performed for the purpose of planning 
treatment administration, dose modification, or following adverse events.
7.2.1
PSA
Serum PSA will be measured using local laboratory during Screening, on C1D1, on D1 of 
every cycle thereafter during the 12 month treatment period, and every 28 days during 
follow up until the date of confirmed PSA progression by PCWG3 criteria. 
7.3EXPLORATORY BIOMARKERS (DISCONTINUED)
An optional biopsy and biomarker blood collection was to be conducted under the 
PROMOTE study (CC155518, IRB# 15-18365), as an optional enrollment option. The 
PROMOTE study has closed to accrual and will no longer be able to financially support the 
biopsy, biomarker collection, and downstream correlatives. Therefore, we are discontinuing 
the biopsy and biomarker blood collection moving forward described in the italicized 
paragraph below (as of Amendment 8.0). Any specimens collected under prior protocol 
versions (i.e., prior to implementation of Amendment 8.0) may continue to be stored and/or 
used as permitted according to the PROMOTE study protocol and ICF.
Metastatic tumor biopsy tissue acquired at UCSF will undergo genomic characterization as 
described in UCSF protocol CC# 155518. In brief, freshly frozen tissue will undergo laser 
capture microdissection and exome/transcriptome sequencing. Formalin-fixed paraffin 
embedded tissue will undergo pathologic evaluation and targeting next-generation 
sequencing using CLIA-certified laboratory. Whole blood for exploratory analysis of 
circulating nucleic acids including analysis of circulating tumor DNA and long noncoding 
RNA (lncRNA) will be collected on C1D1, every 3 cycles during protocol treatment, at the 
end of study treatment, and at the time of PSA progression. Germline mutation testing to 
evaluate for alterations in BRCA2 and other DNA repair pathway genes will be performed at 
baseline if patients give optional consent for testing. Germline mutation testing is not 
performed in a CLIA environment and, therefore, will not be reported back to patients.  
PSMA imaging characteristics including the number, distribution and avidity of metastatic 
lesions will be characterized by trained nuclear medicine physician. 
8
STUDY ASSESSMENTS BY VISIT (APPENDIX 1)
8.1SCREENING (WITHIN 42 DAYS OF RANDOMIZATION, UNLESS 
OTHERWISE SPECIFIED)

Review the study with the patient (patient’s legal representative) and obtain written 
informed consent

Collect archival primary prostate cancer tissue (optional)

Phase II – Apalutamide
Page 34 of 65

PSMA (prostate specific membrane antigen) PET scan. Imaging may use Ga-
PSMA-11 or other PSMA PET tracer. Either PET/MR or PET/CT is allowed (within 
12 weeks of randomization). 

Record demographics data

Record medical history, including history of prostate cancer, diagnosis date, and 
prior treatments

Record concomitant medications

Perform a physical examination 

Perform and record vital signs and ECOG performance status grade

Collect blood for clinical laboratory assessments including hematology tests, total 
bilirubin (and direct bilirubin if total bilirubin > 1.5 ULN), ALT, AST, alkaline 
phosphatase, BUN or creatinine, albumin, and LDH.

Collect blood for PSA

Collect blood for testosterone

Collect blood for Thyroid Stimulating Hormone (TSH)

Obtain DXA bone density scan (femoral neck and lumbar spine)

If patient is confirmed eligible by the medical monitor, randomize patient and 
proceed to Cycle 1 Day 1 visit (randomization can occur on C1D1 or within 7 days 
prior to C1D1)
8.2CYCLE 1 DAY 1

Record changes to concomitant medications

Record any adverse events

Perform abbreviated physical examination

Perform and record vital signs and ECOG performance status

Collect blood for clinical laboratory assessments including hematology tests, total 
bilirubin (and direct bilirubin if total bilirubin > 1.5 ULN), ALT, AST, alkaline 
phosphatase, BUN or creatinine, and LDH. Screening evaluations can be used if 
done within 4 days of Cycle 1 Day 1.

Collect blood for PSA

Collect blood for TSH

Dispense study drug
8.3DAY 1 OF CYCLES 2-4, THEN DAY 1 OF EVERY 2 CYCLES STARTING 
FROM CYCLE 5 THROUGH C13 (C5, C7, C9, C11, C13) (+/- 7 days) UNLESS 
OTHERWISE SPECIFIED

Record any adverse events

Record changes to concomitant medications

Phase II – Apalutamide
Page 35 of 65

Dispense study drug

Assess study drug compliance

Perform abbreviated physical examination

Perform and record vital signs and ECOG performance status

Collect blood for clinical laboratory assessments (including hematology tests, total 
bilirubin (and direct bilirubin if total bilirubin > 1.5 ULN), ALT, AST, alkaline 
phosphatase, BUN or creatinine, and LDH.

Collect blood for PSA measurement (Day 1 of every treatment cycle)

Stereotactic body radiation therapy administered 60 days following initiation of 
apalutamide therapy

Collect blood for thyroid stimulating hormone test every 4 cycles starting Cycle 5 
Day 1 (C5D1, C9D1, C13D1). 
8.4END OF TREATMENT VISIT 

Record any adverse events

Record changes to concomitant medications

Assess study drug compliance

Perform abbreviated physical examination

Perform and record vital signs and ECOG performance status

Collect blood for clinical laboratory assessments (including hematology tests, total 
bilirubin (and direct bilirubin if total bilirubin > 1.5 ULN), ALT, AST, alkaline 
phosphatase, BUN or creatinine, and LDH.

Collect blood for PSA measurement

Collect blood for TSH
8.5SAFETY FOLLOW-UP (30 DAYS FOLLOWING THE LAST DOSE OF STUDY 
DRUG)

Record any adverse events

Record changes to concomitant medications
8.6POST-TREATMENT PERIOD UNTIL CONFIRMED PSA PROGRESSION BY 
PCWG CRITERIA

Collect blood for PSA measurement every 28 days (+/- 7 days) until confirmed PSA 
progression by PCWG3 criteria. In the event of disease progression per PCWG3 or 
initiation of a new non-protocol therapy, patients will be discontinued from the study, 
and further PSA tracking will no longer be required
8.7AT CONFIRMED PSA PROGRESSION (+ 28 day window)

PSMA PET scan (optional)

Phase II – Apalutamide
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
All patients can be treated at their physician’s discretion as standard of care, after 
coming off study treatment.  

Perform and record ECOG performance status
9
ADVERSE EVENT REPORTING REQUIREMENTS
9.1DEFINITIONS
9.1.1
Adverse Events (AE)
An AE is any untoward medical occurrence in a clinical study patient administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have 
a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational or non-investigational) product, 
whether or not related to that medicinal (investigational or non-investigational) product. 
(Definition per International Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities.
Examples of AEs include but are not limited to:

Clinically significant abnormal laboratory findings (see below)

Clinically significant signs and symptoms

Changes in physical examination findings

Worsening of signs and symptoms of the malignancy under study. Disease 
progression assessed by measurement of malignant lesions on radiographs or other 
methods should not be reported as an adverse event, unless the outcome is fatal 
during the study or within the safety reporting period – see definition of serious 
adverse event below.

Signs or symptoms resulting from dose overdose, dependency, withdrawal, abuse, 
and/or misuse

Drug interactions

Exposure in utero (pregnancy)
For laboratory abnormalities, the criteria for determining whether an abnormal test finding 
should be reported as an adverse event are as follows:

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy, and/or Test result is considered to be an adverse 
event by the Investigator

Phase II – Apalutamide
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9.1.2
Adverse Events of Special Interest
Adverse events of special interest are events that Janssen Scientific Affairs is actively 
monitoring as a result of a previously identified signal (even if non-serious). 
There are no adverse events of special interest identified for apalutamide. 
9.1.3
Serious Adverse Events (SAE)
A serious adverse event (SAE) based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:

Results in death. 

Is life-threatening (i.e., immediate risk of death from the reaction as it occurred). 

Requires or prolongs inpatient hospitalization (i.e., the event required at least a

24-hour hospitalization or prolonged a hospitalization beyond the expected length of 
stay). Hospitalization admissions and/or surgical operations scheduled to occur 
during the study period, but planned prior to study entry are not considered SAEs if 
the illness or disease existed before the person was enrolled in the trial, provided 
that it did not deteriorate in an unexpected manner during the trial (e.g., surgery 
performed earlier than planned)

Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions

Results in a congenital anomaly or birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is an important medical event when, based upon appropriate medical judgment, it 
may jeopardize the participant and require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home; blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse
Events not considered to be SAEs are hospitalizations for:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that did not worsen

Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission

Respite care or social admissions
9.1.4
Expectedness
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed 
in the Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed.
Unexpected, as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the Investigator’s Brochure as occurring with a class of 

Phase II – Apalutamide
Page 38 of 65
drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation. Such events 
would be considered unexpected until they have been observed with the drug under 
investigation.
9.1.5
Attribution
A suspected adverse reaction means any adverse event for which there is reasonable 
possibility that the study drug caused the adverse event. For the purposes of IND safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.
The Investigator will assign attribution of the possible association of the event with the study 
drug using the following definitions:

Unrelated to study drug: The adverse event is clearly not related or is doubtfully 
related to the study drug

Related to study drug: The adverse event may be related, is likely related, or is 
clearly related to the study drug
9.1.6
Severity
Signs or symptoms should be graded and recorded by the Investigator according to the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03 (Appendix 4). When specific adverse events are not listed in the CTCAE, they 
are to be graded as mild, moderate, severe, or life-threatening according to the following 
grades and definitions:
Table 2
AE Severity Grading
Severity 
(Toxicity 
Grade)
Description
Grade 
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 
2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age- appropriate instrumental activities of daily living (ADL)
Grade 
3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL
Grade 
4
Life-threatening consequences; urgent intervention indicated
Grade 
5
Death related to AE

Phase II – Apalutamide
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9.1.7
Individual Case Safety Report (ICSR)
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements.
1.
an identifiable subject (but not disclosing personal information such as the subject’s 
name, initials or address)
2.
an identifiable reporter (investigational site)
3.
a Janssen medicinal product
4.
an adverse event, outcome, or certain special situations
The minimum information required is:
1.
suspected Janssen medicinal product (doses, indication)
2.
date of therapy (start and end date, if available)
3.
batch or lot number, if available
4.
subject details (subject ID and country)
5.
gender
6.
age at AE onset
7.
reporter ID
8.
adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available)
9.
protocol ID
9.1.8
Special Reporting Situations
Safety events of interest for a Janssen medicinal product that require expediting reporting 
and/or safety evaluation include, but are not limited to:

Drug exposure during pregnancy (maternal and paternal)

Overdose of a Janssen medicinal product 

Exposure to a Janssen medicinal product from breastfeeding 

Suspected abuse/misuse of a Janssen medicinal product

Inadvertent or accidental exposure to a Janssen medicinal product 

Medication error involving a Janssen medicinal product (with or without patient 
exposure to the Janssen medicinal product, e.g., name confusion)

Suspected transmission of any infectious agent via administration of a medicinal 
product
These safety events may not meet the definition of an adverse event; however, from 
Janssen Scientific Affairs perspective, they are treated in the same manner as adverse 
events. Special situations should be recorded on the Adverse Event page of the CRF.

Phase II – Apalutamide
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Any special situation that meets the criteria of a serious adverse event should be recorded 
on a Serious Adverse Event Report Form and be reported to the Sponsor-Investigator, who 
will then report the event to Janssen Scientific Affairs within 24 hours of becoming aware 
of the event.
9.1.9
Pregnancy
Because the Janssen medicinal product may have an effect on sperm, pregnancies in 
partners of male subjects exposed to a Janssen medicinal product will be reported by the 
Principal Investigator within 24 hours of their knowledge of the event using the Serious 
Adverse Event Form.”
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required.
9.2ADVERSE EVENTS MONITORING
All adverse events, whether or not unexpected, and whether or not considered to be 
associated with the use of the study drug, will be entered into OnCore®, as noted above.
The Investigator will assess all adverse events and determine reportability requirements to 
the UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review 
Board (IRB); and, when the study is conducted under an Investigational New Drug 
Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA reporting 
criteria.
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s).
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings. The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s).
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will 
be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing 
basis and discussed at DSMC meetings, which take place every six weeks.
For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2 
or 3 Institutional Study at the Helen Diller Comprehensive Cancer Center please refer to 
Appendix 6 Multicenter Institutional Studies.
9.3REPORTING REQUIREMENTS
All AEs and SAEs whether reported by the patient, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be 
recorded in the patient’s medical record and on the appropriate study-specific CRFs.
Analyses will be performed for all patients having received at least one dose of study drug.  
The study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and 
modified criteria for hematologic adverse events, see Appendix 4.
The Sponsor-Investigator at the UCSF Coordinating Center will hold the role of Study Chair 
(Dr. Rahul Aggarwal).  The Study Chair is responsible for the overall conduct of the study 
and for monitoring its safety and progress at all participating sites.
Anticipated events will be recorded and reported as described in Section 9.3.3.

Phase II – Apalutamide
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9.3.1
SAE Reporting to the Sponsor-Investigator and Janssen
All participating sites will report SAEs to the Sponsor-Investigator within 24 hours of 
knowledge of the event. The Sponsor-Investigator will report to Janssen within 24 
hours of being notified of the event, using MedWatch forms, as outlined below:
Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Janssen Medicinal Products to Janssen
All adverse events and special situations, whether serious or non-serious, related or not 
related, following exposure to a Janssen medicinal product are to be documented by the 
investigator and recorded in the CRF and in the subject’s source records. Investigators 
must record in the CRF their opinion concerning the relationship of the adverse event to a 
Janssen medicinal product. 
All (serious and non-serious) adverse events reported for a Janssen medicinal product 
should be followed-up in accordance with clinical practice.
SAEs and Special Reporting Situations
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed 
until any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct

It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts)
All participating sites will report all SAEs and special situations following exposure to a 
Janssen product under study to the Sponsor-Investigator within 24 hours of knowledge of 
the event, using MedWatch forms. UCSF and the Sponsor-Investigator will transmit all 
SAEs and special situations following exposure to a Janssen product under study using 
MedWatch form within 24-hours of becoming aware of the event(s).
All follow-up information for serious adverse events that are not resolved at the end of the 
study or by the time of patient withdrawal must be reported by participating sites to the 
Sponsor-Investigator within 24 hours of knowledge of the event. SAE follow-up 
information will be reported directly to Janssen by the Sponsor-Investigator, within 24 
hours becoming aware, using the MedWatch form. The Sponsor-Investigator will also 
notify the UCSF DSMC of any SAEs.
Reporting Deaths: Regardless of relationship to study drug, all deaths on study should be 
reported to Janssen through and including 30 days after the last dose of study. Deaths 
occurring after the safety follow-up period do not have to be reported as SAEs unless 
considered related to study drug. All study drug related deaths should be reported to the 
UCSF DSMC within 1 business day of becoming aware. All deaths will be reviewed by the 
UCSF DSMC.
All available clinical information relevant to the evaluation of a related SAE or special 
situation is required.

Phase II – Apalutamide
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
For all SAEs, the Investigator is obligated to pursue and provide information to the 
Sponsor-Investigator and Janssen in accordance with the timeframes for reporting 
specified above. In addition, an Investigator may be requested to obtain specific 
additional follow-up information in an expedited fashion. This information may be 
more detailed than that captured on the AE CRF. In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.

Information on other possible causes of the event, such as concomitant medications 
and illnesses must be provided. In the case of a patient death, a summary of 
available autopsy findings must be submitted as soon as possible to the Sponsor-
Investigator or designated representative and Janssen.

UCSF and the Sponsor-Investigator is responsible for ensuring that these cases are 
complete and if not are promptly followed-up. A safety report is not considered 
complete until all clinical details needed to interpret the case are received. Reporting 
of follow-up information should follow the same timeline as initial reports.
All events should be followed to their resolution, until the Investigator assesses them as 
stable, irreversible, or until the patient is lost to follow-up, whichever comes first. Any SAEs 
occurring any time after the reporting period must be promptly reported if a causal 
relationship to apalutamide is suspected.
Copies of SAE Reporting to Regulatory Authorities to Janssen within 24 hours: 
Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association with 
the Janssen Product under study, are to be provided to Janssen within 24 hours of 
such report or correspondence being sent to applicable regulatory authorities.
Product Quality Complaint (PQC) Handling:
A product quality compliant is defined as any suspicion of a product defect related to a 
potential quality issue during manufacturing, packaging, release testing, stability monitoring, 
dose preparation, storage or distribution of the product, or delivery system.  Not all PQCs 
involve a subject.  Lot and batch numbers are of high significance and need to be collected 
whenever available.
Examples of PQC include but not limited to:

Functional Problem: e.g., altered delivery rate in a controlled release product

Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules

Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe

Suspected Contamination

Suspected Counterfeit
PQC Reporting:
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and Janssen, and are mandated by regulatory agencies 
worldwide. Janssen has established procedures in conformity with regulatory requirements 
worldwide to ensure appropriate reporting of PQC information. Lot and/or Batch #s shall be 

Phase II – Apalutamide
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collected or any reports failure of expected pharmacological action (i.e., lack of effect). The 
product should be quarantined immediately and if possible, take a picture.
All initial PQCs involving a Janssen medicinal product under study must be reported by 
participating sites to the Sponsor-Investigator within 24 hours of knowledge of the event. 
The Sponsor-Investigator will report all initial PQCs to  Janssen within 24 hours after 
being made aware of the event. The Janssen contact will provide additional 
information/form to be completed.
If the defect for a Janssen medicinal product under study is combined with either a serious 
adverse event or non-serious adverse event, the Sponsor-Investigator must report the PQC 
to Janssen and the UCSF coordinating center according to the serious adverse event 
reporting timelines.  A sample of the suspected product should be maintained for further 
investigation if requested by Janssen. 
Transmission Methods:
The following methods are acceptable for transmission of safety information to Janssen:

Electronically via Janssen SECURE Email service (preferred)

For business continuity purposes, if SECURE Email is non-functional:
o
Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report

Telephone (if fax is non-functional).
Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-Janssen Medicinal Products 
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the site should notify the UCSF coordinating center, and the 
UCSF Sponsor-Investigator should notify the appropriate regulatory/competent authority or 
the manufacturer of that medicinal product (in the absence of appropriate local legislation) 
as soon as possible.
9.3.2
Non-Serious AE Reporting
Adverse events should be recorded on the AE CRF from the time the patient has signed the 
informed consent at screening (see Section 8.2) until 30 days after the last dose of study 
drug. All events should be followed to their resolution, until the Investigator assesses them 
as stable, irreversible, or until the patient is lost to follow-up, whichever comes first. If a 
patient begins a new systemic anti-cancer therapy, the AE reporting period for non-SAEs 
ends at the time the new treatment is started.
All non-serious adverse events should be reported to the Sponsor-Investigator and UCSF, 
who will report this to Janssen.
9.3.3
UCSF Sponsor-Investigator Reporting Requirements to 
Regulatory Authorities
Adverse events reporting, including suspected serious unexpected adverse reactions, will 
be carried out in accordance with applicable local regulations. The Sponsor-Investigator or 
its designee will be responsible for determining whether or not the suspected adverse 
reaction meets the criteria for expedited reporting.

Phase II – Apalutamide
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For anticipated events reported as individual serious adverse events Janssen will make a 
determination of relatedness in addition to and independent of the investigator’s 
assessment. Janssen will periodically evaluate the accumulating data and, when there is 
sufficient evidence and Janssen has determined there is a reasonable possibility that the 
drug caused a serious anticipated event, they will submit a safety report in narrative format 
to the investigators and the Study Chair.
Reporting to the UCSF Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study 
drug(s) or to a study procedure, the Investigator or his/her designee must notify the 
Sponsor-Investigator, who will then notify the DSMC Chair (or qualified alternate) within 1 
business day of knowledge of the event.  The contact may be by phone or e-mail.
Reporting to the UCSF Institutional Review Board
The Sponsor-Investigator must report events meeting the UCSF IRB definition of 
“Unanticipated Problem” (UP) within 5 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration
The Sponsor-Investigator or its designee will be responsible for reporting relevant SAEs to 
the FDA.  
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is 
both serious and unexpected.  The Sponsor-Investigator needs to ensure that the event 
meets all three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as 
an expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days 
after the Investigator determines that the suspected adverse reaction qualifies for reporting 
(21 CFR 312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA 
no later than 7 calendar days after the Investigator’s initial receipt of the information (21 
CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report 
will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
Provide Copies SAE Reporting to Regulatory Authorities to Janssen
Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association with 

Phase II – Apalutamide
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the Janssen Product under study, are to be provided to Janssen within 24 hours of such 
report or correspondence being sent to applicable regulatory authorities. 
10 END OF TREATMENT 
A patient may be discontinued from study treatment at any time if the patient or the 
Investigator feels that it is not in the patient’s best interest to continue on study. If a patient’s 
study treatment must be discontinued, this will not result in automatic withdrawal of the 
patient from the study.
Study treatment with apalutamide will be discontinued for the following reasons, whichever 
occurs first:

Disease progression by PCWG criteria. PSA progression is defined as increase of at 
least 2 ng/mL and 25% above the nadir or baseline on study, whichever is lower, 
confirmed on repeat measurement at least two weeks later. 

Completion of 13 cycles of study therapy (52 weeks)

Any episode of seizure

Any other adverse event that cannot be adequately managed with dose 
modifications, including dose interruption for treatment-related adverse events that 
do not improve to Grade 1 or baseline within 14 days, will require study drug 
discontinuation

Protocol violation requiring discontinuation of study treatment

Patient is not compliant with study procedures

Lost to follow-up

Patient withdrawal of consent

Janssen’s request for early termination of study
All patients discontinuing study treatment in the absence of disease progression will enter 
the Post-Treatment Period for PSA monitoring until the time of confirmed PSA progression. 
Follow up on study will continue at least the first occurrence of one of the following:

Disease progression by PCWG criteria. 

Protocol violation requiring discontinuation of study treatment

Patient is not compliant with study procedures

Lost to follow-up

Patient withdrawal of consent

Janssen’s request for early termination of study
If a patient is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the patient and determine the reason for discontinuation/withdrawal. 
The measures taken to follow up must be documented. When a subject withdraws before 
completing the study, the reason for withdrawal is to be documented in the CRF and in the 
source document. Study drug assigned to the withdrawn subject may not be assigned to 
another subject. Subjects who withdraw will not be replaced.

Phase II – Apalutamide
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11 PROTOCOL VIOLATIONS
A protocol violation occurs when the patient or Investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, patient safety and primary endpoint 
criteria.  Protocol violations for this study include, but are not limited to, the following:

Failure to meet inclusion/exclusion criteria [no waivers will be granted to meet the 
eligibility criteria]

Use of a prohibited concomitant medication

Dose modifications that are not within the protocol specifications

Any other deviation that presents significant risk or safety concerns to the patient
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The Sponsor-Investigator will determine if a protocol violation should result in 
withdrawal of a patient.
12 STATISTICAL METHODS AND CONSIDERATIONS
12.1 ANALYSIS POPULATIONS
Safety Analysis Population [SAFETY]: All patients who receive at least one dose of study 
drug, with treatment assignments designated according to actual study treatment received 
will be the primary population for evaluating safety and treatment compliance and 
administration.
12.2 ANALYTIC PLAN
12.2.1
Analysis of Primary Endpoint
The primary endpoint for the study is the proportion of patients with undetectable serum 
PSA (< 0.2 ng/mL) at 6 months following completion of apalutamide therapy (18 months 
from date of randomization). Fisher’s exact test will be used to compare the proportion in 
the two treatment arms.  Patients who discontinue apalutamide prior to completion of 12 
months of therapy for reasons other than disease progression by PCWG criteria, as well as 
patients who withdraw or are lost to follow up, will be considered inevaluable for this 
analysis. Patients who discontinue treatment for radiographic or clinical progression, even if 
occurring prior to receipt of SBRT in the experimental arm), would be evaluable for analysis 
of the primary endpoint. 
12.2.2
Analyses of Secondary Endpoints
Comparison of time to PSA progression will be performed using a two-sided log-rank test. 
Kaplan-Meier methods will be used to estimate medians for each treatment arm. Cox 
proportional-hazard models, including the same factors as above, will be used to estimate 
the hazard ratio and its 95% confidence interval (CI). 
Adverse events (AEs) will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. All AEs reported from the first dose of study drug 
until 30 days after the last dose of study drug will be considered as treatment-emergent AEs 
and will be summarized by treatment arm. For each treatment arm, adverse event incidence 
rates will be summarized with frequency and percentage, with all patients treated in that 
treatment arm as the denominator, unless otherwise specified.  In addition, AE incidence 
rates will also be summarized by severity and relationship to study drug. Treatment-related 
AEs are those judged by the Investigator to be at least possibly related to the study 
treatment. Adverse events with missing severity or relationship to study drug will be 
classified as severe and treatment-related, respectively. 

Phase II – Apalutamide
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12.2.3
Analysis of Exploratory Endpoints
The number and distribution of lesions detected on PSMA PET scan at baseline and at the 
time of PSA progression will be summarized using descriptive statistics for each treatment 
arm. 
To determine the genomic factors associated with the development of oligometastatic 
disease, patient tumor biopsies will be compared to independent datasets of RNA/DNA 
sequencing from tumors obtained from patients with localized prostate cancer as well as 
those with more widespread castration-resistant prostate cancer. These analyses will be 
largely descriptive in nature. 
Gene expression levels and genomic alterations (single nucleotide variants and/or copy 
number changes) in metastatic tumor biopsies and in germline DNA will be investigated for 
an association with efficacy outcomes using appropriate statistical methods (e.g. categorical 
or survival models), depending on the endpoints. Analyses may be performed within and 
between each treatment group. Other clinical covariates (such as baseline clinical disease 
characteristics and patient demographics) may also be included in the model. Association of 
biomarkers with clinical response or relevant time-to-event endpoints will also be explored 
in the overall population to identify “high-risk” biomarker profiles that are correlated with 
poor outcome.
Note: The italicized endpoints above were discontinued in Protocol v. 8.0. See 
Section 7.3 for additional information.
Whenever available, archival primary prostate cancer tissue for patients enrolled on the 
current study will be analyzed for gene expression patterns and compared to the patterns of 
gene expression observed in the baseline and progression tumor biopsies obtained at from 
an oligometastatic site of disease. 
The number and site of oligometastatic sites of disease on baseline PSMA PET scan, as 
well as the PSMA avidity (SUVmax) for each lesion will be descriptively reported. Intra- and 
inter-lesional heterogeneity of uptake will be characterized using descriptive statistics.  The 
association between patterns of uptake on baseline PSMA PET with outcomes on study will 
be investigated using appropriate statistical methods (e.g. categorical or survival models) as 
appropriate, within and across treatment groups. 
12.2.4
Interim Analysis
No interim analysis will be performed, as the primary endpoint (PSA undetectable rate 6 
months following completion of protocol treatment) will not be evaluable until after all 
patients have been accrued on study. 
12.2.5
Determination of Sample Size
The sample size is based upon the primary endpoint of the study, the proportion of patients 
with an undetectable serum PSA (< 0.2 ng/mL) 6 months following completion of protocol 
therapy with apalutamide. Assuming a 10% inevaluable/drop-out rate per treatment arm, a 
sample size of 60 patients (30 patients/arm) provides 84% power to detect a difference in 
proportion of patients with undetectable PSA of 25% in the apalutamide + SBRT arm vs. 2.5 
% in the apalutamide without SBRT treatment arm, with a unidirectional level of significance 
of 0.10 using Fisher’s exact test.

Phase II – Apalutamide
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13 STUDY MANAGEMENT
13.1 INVESTIGATOR RESPONSIBILITIES
The investigator is responsible for ensuring that the study is performed in accordance with 
current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good clinical practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety, 
and well-being of the study subjects are protected, consistent with the principles that 
originated in the Declaration of Helsinki, and that the study data are credible.
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number. All study records will be kept in a locked file 
cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet. Clinical information will not be released 
without written permission of the patient, except as necessary for monitoring by the FDA. 
The Investigator must also comply with all applicable privacy regulations (e.g., Health 
Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC).
13.2 PRE-STUDY DOCUMENTATION
This study will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and 
all applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject 
recruitment materials, and any other written information to be provided to subjects before 
any protocol related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under 
the Investigational Drug Application (IND) is allowed to proceed or the Investigator has 
received a letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of 
Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable 
regulatory requirements.  The IRB must comply with the regulations in 21 CFR §56 and 
applicable regulatory requirements.
13.3 INSTITUTIONAL REVIEW BOARD APPROVAL
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) will be reviewed and 
approved by the UCSF Institutional Review Board or the IRB of the participating site.  For 
UCSF, prior to obtaining IRB approval, the protocol must be approved by the Helen Diller 
Family Comprehensive Cancer Center Site Committee and by the Protocol Review 
Committee (PRC).  The initial protocol and all protocol amendments must be approved by 
each respective IRB prior to implementation.  
13.4 INFORMED CONSENT
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their participation.  
Participants must sign the IRB-approved informed consent form prior to participation in any 

Phase II – Apalutamide
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study specific procedure.  The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained in 
the medical record or research file.
13.5 CHANGES IN THE PROTOCOL
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must 
be documented in the form of an amendment.  The amendment must be signed by the 
Investigator and approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, 
an amendment may be implemented prior to IRB approval.  In this circumstance, however, 
the Investigator must then notify the IRB in writing within five (5) working days after 
implementation.  
The Study Chair and the UCSF study team will be responsible for updating any participating 
sites.
13.6 HANDLING AND DOCUMENTATION OF CLINICAL SUPPLIES
The UCSF Principal Investigator (Sponsor-Investigator) and each participating site will 
maintain complete records showing the receipt, dispensation, return, or other disposition of 
all investigational drugs.  The date, quantity and batch or code number of the drug, and the 
identification of patients to whom study drug has been dispensed by patient number and 
initials will be included.  The sponsor-investigator will maintain written records of any 
disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any 
individuals other than to qualified study patients.  Furthermore, the Principal Investigator will 
not allow the investigational drug to be used in any manner other than that specified in this 
protocol.
13.7
CASE REPORT FORMS (CRFs)
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon 
as possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the 
UCSF DSMC and regulatory agencies.
The Principal Investigator will be responsible for ensuring the accurate capture of study 
data.  At study completion, when the CRFs have been declared to be complete and 
accurate, the database will be locked.  Any changes to the data entered into the CRFs after 

Phase II – Apalutamide
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that time can only be made by joint written agreement among the Study Chair, the Trial 
Statistician, and the Protocol Project Manager.
Each participating site will complete study specific CRFs for safety monitoring and data 
analysis.  Each site will enter the study data into OnCore® via standardized CRFs in 
accordance with the CTMS study calendar, using single data entry with a secure access 
account. The participating site’s Clinical Research Coordinator (CRC) will complete the 
CRFs; the Investigator will review and approve the completed CRFs – this process must be 
completed within 3 business days of the visit. Study data from the participating site will be 
reported and reviewed in aggregate with data from patients enrolled at the coordinating 
center, UCSF.  All source documentation and CTMS data will be available for 
review/monitoring as needed.
13.8
OVERSIGHT AND MONITORING PLAN
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all 
adverse events and suspected adverse reactions considered “serious”.  The DSMC will 
audit study-related activities to ensure that the study is conducted in accordance with the 
protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice 
(GCP).  Significant results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as applicable.  See Appendix 6 Data and Safety Monitoring Plan for a Phase 2 or 3 
Multicenter Institutional Study, for additional information.
13.9
MULTICENTER COMMUNICATION
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical trial.  
The UCSF Coordinating Center will also coordinate, at minimum, quarterly conference calls 
with the participating sites or more frequently as needed to discuss risk assessment.  The 
following issues will be discussed as appropriate:

Enrollment information 

Adverse events (i.e., new adverse events and updates on unresolved adverse 
events and new safety information)

Protocol violations

Other issues affecting the conduct of the study
13.10 RECORD KEEPING AND RECORD RETENTION
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the 
disposition of the drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the 
investigation. Case histories include the case report forms and supporting data (e.g., signed 
and dated consent forms and medical records, such as progress notes of the physician, the 
individual's hospital chart(s), and the nurses' notes. The case history for each individual 
shall document that informed consent was obtained prior to participation in the study.

Phase II – Apalutamide
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Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
patient consent forms).
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 
years following the date a marketing application is approved for the drug for the indication 
for which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and FDA is 
notified.
13.11 REGULATORY DOCUMENTATION
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved 
by the UCSF IRB. Prior to implementing this protocol at the participating sites, approval for 
the UCSF IRB approved protocol must be obtained from the participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating site 
can be initiated and begin enrolling participants: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form, and HIPAA authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 

Curriculum vitae and medical license for each investigator and consenting 
professional 

Documentation of Human Subject Research Certification training for investigators 
and key staff members at the Participating Site 

Participating site laboratory certifications and normals. 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the 
site and grant permission to proceed with enrollment.
14 PROTECTION OF HUMAN SUBJECTS
14.1 PROTECTION FROM UNNECESSARY HARM
Each clinical site is responsible for protecting all subjects involved in human 
experimentation. This is accomplished through the IRB mechanism and the process of 
informed consent. The IRB reviews all proposed studies involving human experimentation 
and ensures that the subject’s rights and welfare are protected and that the potential 
benefits and/or the importance of the knowledge to be gained outweigh the risks to the 
individual. The IRB also reviews the informed consent document associated with each study 
in order to ensure that the consent document accurately and clearly communicates the 
nature of the research to be done and its associated risks and benefits.

Phase II – Apalutamide
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14.2 PROTECTION OF PRIVACY
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, 
they will be asked to sign the HIPAA form and informed consent documents. The original 
signed document will become part of the patient’s medical records, and each patient will 
receive a copy of the signed document. The use and disclosure of protected health 
information will be limited to the individuals described in the informed consent document.
In order to maintain patient confidentiality, only a site number and patient number will 
identify all study patients on blood samples and tumor specimens.  
Long-term Storage of Samples for Future Research
Samples collected for biomarker assessments are planned to be stored until testing and for 
up to 5 years after the end of the study at the Feng laboratory at UCSF. All samples will be 
labeled with unique study ID number, and no personal identifying information will be 
attached to the sample. 

Phase II – Apalutamide
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15 REFERENCES
1.
Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for 
prostate cancer treatment. Cancer Res 2012; 72(6):1494-503. 
2.
Antonarakis ES, Ryan CJ, et al. Phase 2 study of the safety and antitumor activity of 
apalutamide (ARN-509), a potent androgen receptor antagonist, in the high-risk 
nonmetastatic castration-resistant prostate cancer cohort. Eur Urol 2016; 70(6):963-
70. 
3.
Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free 
survival in prostate cancer. New Engl J Med 2018; 378:1408-1418. 
4.
Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective comparison of 18F-
fluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who 
have rising PSA after curative treatment and are being considered for targeted 
therapy. J Nucl Med 2015; 56(8):1185-90. 
5.
Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of hybrid 68Ga-PSMA ligand 
PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J 
Nucl Med 2015; 56(5):668-74. 
6.
Afshar-Oromieh A, Avtzi E, Giesel FL, et al. The diagnostic value of PET/CT imaging 
with the 68Ga-labeled PSMA ligand HBED-CC in the diagnosis of recurrent prostate 
cancer. Eur J Nucl Med Mol Imaging 2015; 42(2):197-209. 
7.
Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE. A 
phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J 
Radiat Oncol Biol Phys.  2005 Aug 1; 62(5): 1371-1378.
8.
Okunieff P, Petersen AL, Philip A, Milano MT, Katz AW, Boros L, Schell MC. 
Stereotactic body radiation therapy (SBRT) for lung metastases. Acta Oncol.  2006; 
45(7): 808-817
9.
Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995 Jan; 13(1): 8-
10.
10. Bacci G, Rocca M, Salone M, Balladelli A, Ferrari S, Palmerini E, Forni C, Briccoli A. 
High grade osteosarcoma of the extremities with lung metastases at presentation: 
Treatment with neoadjuvant chemotherapy and simultaneous resection of primary 
and metastatic lesions. J Surg Oncol.  2008 Nov1; 98(6): 415-420.
11. Fong Y, Cohen AM, Fortner JG, Enker WE, Turnbull AD, Coit DG, Marrero AM, 
Prasad M, Blumgart LH, Brennan MF. Liver resection for colorectal metastases. J 
Clin Oncol.  1997 Mar; 15(3): 938-946.
12. Steele G,Jr, Bleday R, Mayer RJ, Lindblad A, Petrelli N, Weaver D. A prospective 
evaluation of hepatic resection for colorectal carcinoma metastases to the liver: 
Gastrointestinal tumor study group protocol 6584. J Clin Oncol.  1991 Jul; 9(7): 
1105-1112.
13. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical 
resection of hepatic metastases from colorectal cancer: A systematic review of 
published studies. Br J Cancer.  2006 Apr10; 94(7): 982-999. PMCID: PMC2361241.
14. Lo SS, Fakiris AJ, Teh BS, Cardenes HR, Henderson MA, Forquer JA, Papiez L, 
McGarry RC, Wang JZ, Li K, Mayr NA, Timmerman RD. Stereotactic body radiation 
therapy for oligometastases. Expert Rev Anticancer Ther.  2009 May; 9(5): 621-635.

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15. Milano MT, Katz AW, Muhs AG, Philip A, Buchholz DJ, Schell MC, Okunieff P. A 
prospective pilot studyof curative-intent stereotactic body radiation therapy in 
patients with 5 or fewer oligometastatic lesions. Cancer.  2008 Feb 1; 112(3): 650-
658.
16. Milano MT, Katz AW, Schell MC, Philip A, Okunieff P. Descriptive analysis of 
oligometastatic lesions treated with curative-intent stereotactic body radiotherapy. Int 
J Radiat Oncol Biol Phys.  2008 Dec 1; 72(5): 1516-1522.
17. Le QT, Loo BW, Ho A, Cotrutz C, Koong AC, Wakelee H, Kee ST, Constantinescu 
D, Whyte RI, Donington J. Results of a phase I dose-escalation study using single-
fraction stereotactic radiotherapy for lung tumors. J Thorac Oncol.  2006 Oct; 1(8): 
802-809.
18. Gibbs IC, KamnerdsupaI phon P, Ryu MR, Dodd R, Kiernan M, Chang SD, Adler 
JR,Jr. Image-guided robotic radiosurgery for spinal metastases. Radiother 
Oncol.  2007 Feb; 82(2): 185-190
19. Lo SS, Fakiris AJ, Abdulrahman R, Henderson MA, Chang EL, Suh JH, Timmerman 
RD. Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy in 
pediatric brain tumors. Expert Rev Neurother.  2008 Jan; 8(1): 121-132.
20. Ost P, Jereczek-Fossa BA, Van As N, et al. Progression-free survival following 
stereotactic body radiotherapy for oligometastatic prostate cancer treatment-naïve 
recurrence: a multi-institutional analysis. Eur Urol 2016; 69(1):9-12. 
21. Tosalan et al Nature Reviews 2017
22. Stevens DJ and Sooriakumaran P. Oligometastatic prostate cancer. Current 
Treatment Options in Oncology 2016; 17:62.

Phase II – Apalutamide
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APPENDIX 1:
SCHEDULE OF ACTIVITIES
Screening
Treatment Phase
Post treatment
Activities and Forms to be 
Completed
42
Days Prior to 
Randomization
Cycle 1
Day 1
D1 C2-C4, D1 
of
every 2 cycles 
starting at C5 to 
C13
(+/- 7 days)
Every 16 
weeks 
(Starting 
on C1D1)
End-of- 
Treatment
Safety 
Follow- 
up
At PSA 
PD by 
PCWG (+ 
28 days)
Screening
Informed Consent
X
Medical/Oncological History [3]
X
Inclusion/Exclusion Criteria
X
Randomization [4]
X
Study Treatment Administration
Apalutamide Administration [5]
240 mg per day taken orally 
SBRT [6]
X
Assess Study Drug 
Compliance
X
X
Laboratory Studies
Hematology [7]
X
X
X
X
Blood Chemistry [7]
X
X
X
X
Serum Albumin
X
PSA [8]
X
X
X
X
X
Testosterone 
X
Thyroid-Stimulating Hormone [9]
X
X
X
X
Efficacy
ECOG Performance Status
X
X
X
X
X
PSMA PET Scan [10]
X
X

Phase II – Apalutamide
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Screening
Treatment Phase
Posttreatment
Activities and Forms to be 
Completed
42
Days Prior to 
Randomization
Cycle 1
Day 1
D1 C2-C4, D1 of
every 2 cycles 
starting at C5 to 
C13,
(+/- 7 days)
Every 16 
weeks 
(Starting 
on C1D1)
End-of- 
Treatment 
[1]
Safety 
Follow- 
up [2]
At PSA 
PD by 
PCWG  (+ 
28 days)
Safety
Physical Examination [12]
X
X
X
X
Vital Signs (BP and heart 
rate)
X
X
X
X
DXA Bone density test 
(femoral neck and lumbar 
spine)
X
Adverse Events
Continuous until 30 days after the last dose of study drug
Concomitant Medications 
Continuous until 30 days after the last dose of study drugs
Exploratory Biomarkers
Archival FFPE blocks/slides [11]
X
C1D1=Cycle 1 Day 1; BICR=blinded independent central review; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EQ-5D=Euro QoL; FACT-P=functional assessment of cancer therapy-prostate; FFPE=formalin-fixed paraffin-
embedded; PSA=prostate specific antigen
Footnotes
1.
End-of-Treatment: These assessments do not need to be completed if they have been performed within 1 week of the last dose of study drug
2.
Safety Follow-Up: Patients should be evaluated for safety up to 30 days after the last dose of study drug. All AEs should be followed to their resolution, until the Investigator 
assesses them as stable, irreversible, or until the patient is lost to follow-up, whichever comes first. If a patient begins a new systemic anti-cancer therapy, the AE reporting 
period for non-SAEs ends at the time the new treatment is started.
3.
Medical/Oncological History: Includes oncologic history, demographics, history of other disease processes (active or resolved) and concomitant illnesses.
4.
Study Randomization: The Cycle 1 Day 1 visit can occur on the same day or within 7 days after randomization. 
5.
Apalutamide: Patients in both treatment arms will receive oral daily apalutamide continuously, starting on Cycle 1 Day 1. One cycle consists of 28 days.
6.
Stereotactic body radiation therapy (SBRT): Patients randomized to SBRT arm must begin treatment within 90 days following initiation of apalutamide therapy. 
7.
Samples for Hematology, Blood Chemistry: All laboratory assessments will be performed by local laboratory. On Cycle 1 Day 1 only, clinical laboratory tests do not need to be 
repeated if the Screening tests were done within 4 days of Cycle 1 Day 1. See Appendix 2 for complete list of hematology and blood chemistry tests.
8. Samples for PSA: PSA evaluations will be performed by local laboratories. On Cycle 1 Day 1 only, the PSA evaluation does not need to be repeated if the Screening tests were 
done within 4 days of Cycle 1 Day 1. During the treatment period, PSA will be measured on Day 1 of every cycle (+/- 7 days). During the post-treatment period PSA will be 
measured every 28 days (+/- 7 days). 
9. TSH: TSH will be completed during Screening and Day 1 of each cycle for the first four cycles, then every 4 cycles starting at Cycle 5
10. PSMA PET imaging:  Whole body (vertex to toes) PSMA PET imaging will be performed during Screening (within 12 weeks of randomization). At the time of PSA progression by 
PCWG criteria there is optional follow up PSMA PET scan. PSMA PET imaging may use Ga-PSMA-11 or other PSMA PET tracer. Either PET/MR or PET/CT may be 
performed. 
11. Collection of archival primary prostate cancer tissue (optional): Archival tumor specimens will be collected whenever available.

Phase II – Apalutamide
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12. Physical exams may be performed via a telemedicine visit. Vital signs (BP and heart rate) will be self-reported by the patient if the physical exam visit is through telemedicine.

Phase II – Apalutamide
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APPENDIX 2:
REQUIRED LABORATORY TESTS
Hematology (See Appendix 1 
for timing)
Chemistry and PSA 
(See Appendix 1 for 
Other
Hemoglobin
Total bilirubin (Note: if
Platelet count
> 1.5 x ULN, include analysis of
Thyroid
stimulating
hormone
Red blood cell count
direct and indirect bilirubin)
(TSH); See Appendix 1
White blood cell count
Alanine transaminase (ALT)
White blood cell differential
Aspartate transaminase (AST)
Alkaline phosphatase
Blood urea nitrogen (BUN) or 
Creatinine
Prostate specific antigen (PSA)
Lactate dehydrogenase

Phase II – Apalutamide
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APPENDIX 3:
ECOG PERFORMANCE STATUS GRADES
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair
5
Dead

Phase II – Apalutamide
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APPENDIX 4:
NATIONAL CANCER INSTITUTE (NCI) COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE)
The NCI CTCAE (Version 4.03) may be reviewed on-line at the following NCI website: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm

Phase II – Apalutamide
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APPENDIX 5:
PROHIBITED OR RESTRICTED MEDICATIONS OR 
SUPPLEMENTS WHILE ON STUDY
Medications that are PROHIBITED while on study:

Aminophylline/theophylline

Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone)

Bupropion

Lithium

Meperidine and pethidine

Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine)

Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, 
imipramine, maprotiline, mirtazapine)
Supplements that are RESTRICTED while on study:

Pomegranate
Medications that are RESTRICTED while on study:
Investigators should refer to the apalutamide Investigator’s Brochure (Sections 4.3.3.3 and 5.10) 
and associated addenda for complete details on the drug interaction potential of apalutamide. 
Highlights of drug interaction are summarized below.

Strong CYP3A4 inducers: the potential for drug-drug interactions with apalutamide has 
not been tested clinically. Strong inducers of CYP3A4 (eg, phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital, efavirenz, tipranavir, St. John's wort) 
should be avoided as much as possible.

Apalutamide may also induce CYP3A4; therefore, caution should be taken when 
administered in conjunction with CYP3A4 substrates that have narrow therapeutic index

Strong CYP2C8 inhibitors (eg, gemfibrozil) should be used with caution with apalutamide

The potential for drug-drug interaction between apalutamide and warfarin (e.g., 
Coumadin) is unknown at present. If a patient is taking warfarin, re-assess (prothrombin) 
PT/(international normalized ratio) INR as clinically indicated and adjust the dose of 
warfarin accordingly.

Corticosteroids (Oral, IV, or IM): due to possible resistance mechanisms, which may be 
contributed by glucocorticoid receptor signaling, concurrent use of corticosteroids during 
the study should be avoided whenever possible; short term use (≤ 4 weeks) will be 
allowed if clinically indicated, however, its use must be tapered off as soon as possible.
Additional Information on CYP450 Drug Interactions 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractio 
nslabeling/ucm093664.htm

Phase II – Apalutamide
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APPENDIX 6: DATA AND SAFETY MONITORING PLAN
Data and Safety Monitoring Plan for a Multicenter Study Phase II or III Trial 
1. Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes:  

Semiannual auditing (depending on accrual). 

Review of serious adverse events. 

Minimum of a biennial regulatory auditing visit. 
2. Monitoring and Reporting Guidelines 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  The 
Study Chair is responsible for the overall conduct of the trial and for auditing its safety and 
progress at all participating sites.  The Study Chair will conduct continuous review of data 
and participant safety at monthly UCSF Site Committee meetings.  The discussions are 
documented in the UCSF Site Committee meeting minutes.   
All institutional Phase II or III therapeutic trials are designated with a moderate risk 
assessment. The data is audited by a DSMC Monitor/Auditor on a semiannual basis with a 
random selection of twenty percent of the participants (or at least three participants if the 
calculated value is less than three).   The DSMC Monitor/Auditor will audit a maximum of 5 cycles 
of treatment in the participants selected for review or until the selected participants discontinue 
study participation or the trial is closed with the IRB.  Additionally, the assigned DSMC 
Monitor/Auditor will review no more than 10 total participant charts during the course of auditing 
this trial.  DSMC Monitor/Auditors will send a follow-up report to the study team within 20 business 
days after the monitoring visit is complete for the PI and the study team to resolve all action items 
from this report within 20 business days.  An abbreviated regulatory review (i.e., reviewing 
protocol and consent versions, SAEs, PVs, DOA logs, 1572 forms, etc.) will occur at each 
participant monitoring review; however, a full regulatory review will occur on a biennially basis by 
the DSMC for regulatory compliance. 
The participating site’s source documents are audited remotely via either review of redacted 
source documents downloaded by the site into the CRA console of OnCore and/or via access to 
the site’s electronic medical records.  The DSMC Monitor/Auditor will audit no more than three 
participant charts at each participating site during the course of auditing this trial. 
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 

Phase II – Apalutamide
Page 63 of 65
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.   
Multicenter communication 
The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites.  The 
following issues will be discussed as appropriate: 

Enrollment information.  

Adverse events (i.e., new adverse events and updates on unresolved adverse events 
and  new safety information). 

Protocol Violations. 

Other issues affecting the conduct of the study. 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The data (i.e., copies of source documents) from the 
participating sites will be downloaded into the PC console of OnCore prior to 
the remote monitoring visits in order for the DSMC to monitor the participating site’s compliance 
with the protocol and applicable FDA regulations. 
3. Review and Oversight Requirements 
3.1 Adverse Event Monitoring  
All Grade 3-5 adverse events (AEs), regardless of being unexpected or considered to 
be  associated with the use of the study drug will be entered into OnCore®, UCSF’s Clinical  Trial 
Management System.   
Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse events are further given an assignment of attribution or 
relationship to the investigational agent(s) or study procedure.  Attribution categories  are: 

Definite – The adverse event is clearly related to the investigational agent(s) 
or study procedure. 

Probable – The adverse event is likely related to the investigational agent(s) 
or study procedure. 

Possible – The adverse event may be related to the investigational agent(s) 
or study procedure. 

Unrelated – the adverse event is clearly not related to the investigational 
agent(s) or study procedure. 

Phase II – Apalutamide
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All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings.  All adverse events entered into OnCore® will be reviewed on a 
monthly basis at the UCSF Coordinating Center Site Committee meetings.  All grade 3-5 adverse 
events must be reported to the UCSF Coordinating  Center by the participating sites within 10 
business days of becoming aware of the event or during the next scheduled monthly conference 
call, whichever is sooner.  The UCSF Site Committee will review and discuss the selected toxicity, 
the toxicity grade, and attribution assignment from the UCSF Coordinating Center and the 
participating sites.  
3.2 Serious Adverse Event Reporting  
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria: 

Death. 

Life-threatening (i.e., results in an immediate risk of death). 

Requires inpatient hospitalization or prolongation of existing hospitalization. 

Permanent or significant disability/incapacity. 

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience 
that  suggests a significant hazard, contraindication, side effect, or precaution that 
may  require medical or surgical intervention to prevent one of the outcomes listed  above. 

Event occurring in a gene therapy study. 

Event that changes the risk/benefit ratio of a study. 

Any other event the Principal Investigator judges to be serious or which would suggest a 
significant hazard, contraindication, side effect, or precaution. 
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med 
Watch form.   
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event 
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 
All Serious adverse events are entered into OnCore®, as well as submitted to the IRB (per IRB 
guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be reported to the UCSF 
Coordinating Center within one business days of becoming aware of the event.  The SAEs are 
reviewed and audited by the UCSF Data and Safety Monitoring Committee on an ongoing basis 
and discussed at DSMC meetings, which take place every six weeks.  The date the SAE was sent 
to all required reporting agencies will be documented in OnCore®.