Clinical trial NCT03016312
Conditions: Prostatic Neoplasms, Castration-Resistant
Sponsor: Hoffmann-La Roche
Start date: 2017-01-10; Completion date: 2022-12-20
Enrollment: 759 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase III, multicenter, randomized, open-label study will evaluate the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 \[anti-PD-L1\] antibody) in combination with enzalutamide compared with enzalutamide alone in participants with mCRPC after failure of an androgen synthesis inhibitor (e.g., abiraterone) and failure of, ineligibility for, or refusal of a taxane regimen. Participants will be randomized to one of the two treatment arms (atezolizumab in combination with enzalutamide, and enzalutamide alone) in a 1:1 ratio (experimental to control arm) in global randomized phase. Participants will receive treatment until investigator-assessed confirmed radiographic disease progression per Prostate Cancer Working Group 3 (PCWG3) criteria or unacceptable toxicity.

Detailed description:

Arms: arm 1: Participants will receive atezolizumab along with enzalutamide until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity (up to approximately 42 months). arm 2: Participants will receive enzalutamide alone until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity (up to approximately 42 months).
Interventions: intervention 1: Atezolizumab intervention 2: Enzalutamide
Intervention descriptions: intervention 1: Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg), intravenous (IV) infusion on Day 1 of each 21-day cycle. intervention 2: Enzalutamide capsules will be administered orally at a dose of 160 mg daily.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase III, Multicenter, Randomized Study of Atezolizumab (Anti-PD-
L1 Antibody) in Combination With Enzalutamide Versus Enzalutamide 
Alone in Patients With Metastatic Castration-Resistant Prostate 
Cancer After Failure of an Androgen Synthesis Inhibitor and Failure of, 
Ineligibility for, or Refusal of a Taxane Regimen 
NCT Number: NCT03016312 
Document Date: Protocol Version 8: 14 February 2020 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
Protocol CO39385, Version 8
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED 
STUDY OF ATEZOLIZUMAB (ANTIPD-L1 
ANTIBODY) IN COMBINATION WITH 
ENZALUTAMIDE VERSUS ENZALUTAMIDE 
ALONE IN PATIENTS WITH METASTATIC 
CASTRATION-RESISTANT PROSTATE CANCER 
AFTER FAILURE OF AN ANDROGEN SYNTHESIS 
INHIBITOR AND FAILURE OF, INELIGIBILITY FOR, 
OR REFUSAL OF A TAXANE REGIMEN
PROTOCOL NUMBER:
CO39385
VERSION NUMBER:
8
EUDRACT NUMBER:
2016-003092-22
IND NUMBER:
131196
TEST PRODUCTS:
Atezolizumab (RO5541267) and enzalutamide
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  29 September 2016
DATES AMENDED:
Version 2:  7 March 2017
Version 3:  4 April 2017
Version 4:  29 June 2017
Version 5: 2 March 2018
Version 6:  23 August 2018
Version 7:  5 August 2019
Version 8:  See electronic date stamp below.
 
14-Feb-2020 17:27:37
Title
Approver's Name
Company Signatory
Date and Time (UTC)




Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
3/Protocol CO39385, Version 8
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 27
1.1
Background on Prostate Cancer............................................ 27
1.1.1
Current Therapies for Metastatic Prostate Cancer ................ 27
1.1.2
Treatment Patterns for Metastatic Prostate 
Cancer................................................................................... 30
1.2
Background on Atezolizumab................................................ 31
1.3
Study Rationale and Benefit-Risk Assessment...................... 32
1.3.1
Rationale for Treatment with Atezolizumab ........................... 32
1.3.2
Rationale for Combination Treatment with 
Atezolizumab and Enzalutamide ........................................... 33
1.3.2.1
Androgen Deprivation Therapy.............................................. 33
1.3.2.2
Enzalutamide......................................................................... 33
1.3.2.3
Atezolizumab Tolerability Profile during 
Combination Treatment ......................................................... 34
1.3.3
Benefit-Risk Assessment....................................................... 34
2.
OBJECTIVES AND ENDPOINTS ............................................................... 34
3.
STUDY DESIGN......................................................................................... 38
3.1
Description of the Study......................................................... 38
3.2
Independent Data Monitoring Committee .............................. 42
3.3
End of Study and Length of Study......................................... 44
3.4
Rationale for Study Design.................................................... 44
3.4.1
Rationale for Atezolizumab Dose and Schedule.................... 44
3.4.2
Rationale for Patient Population ............................................ 45
3.4.3
Rationale for Choice of Enzalutamide ................................... 46
3.4.4
Rationale for Open-Label Design .......................................... 47
3.4.5
Rationale for Stratification Factors......................................... 47
3.4.6
Rationale for Safety Run-In ................................................... 48
3.4.7
Rationale for the Use of Response Criteria ........................... 49
3.4.7.1
PCWG3 Criteria..................................................................... 49


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3.4.8
Rationale for Treatment Beyond Radiographic 
Progression ........................................................................... 49
3.4.9
Rationale for Biomarker Assessments................................... 49
3.4.9.1
Rationale for Collection of Tumor Specimens 
(Fresh and/or Archival) .......................................................... 49
3.4.9.2
Rationale for Collection of Tumor Specimens at 
Progression ........................................................................... 50
3.4.9.3
Rationale for Blood and Urine Sampling for 
Biomarkers ............................................................................ 50
3.4.9.4
Rationale for Sampling for Genomics Analysis...................... 50
3.4.10
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 51
4.
MATERIALS AND METHODS .................................................................... 51
4.1
Patients.................................................................................. 51
4.1.1
Inclusion Criteria.................................................................... 52
4.1.2
Exclusion Criteria................................................................... 54
4.2
Method of Treatment Assignment and Blinding..................... 58
4.3
Study Treatment.................................................................... 59
4.3.1
Formulation, Packaging, and Handling.................................. 59
4.3.1.1
Atezolizumab......................................................................... 59
4.3.1.2
Enzalutamide......................................................................... 59
4.3.2
Dosage, Administration, and Compliance.............................. 59
4.3.2.1
Atezolizumab......................................................................... 59
4.3.2.2
Enzalutamide......................................................................... 60
4.3.3
Investigational Medicinal Product Accountability ................... 61
4.3.4
Post-Study Access to Atezolizumab ...................................... 61
4.4
Concomitant Therapy ............................................................ 62
4.4.1
Permitted Therapy................................................................. 62
4.4.2
Cautionary Therapy for Atezolizumab ................................... 63
4.4.3
Cautionary Therapy for Enzalutamide ................................... 64
4.4.4
Prohibited Therapy ................................................................ 64
4.5
Study Assessments ............................................................... 65
4.5.1
Informed Consent Forms and Screening Log........................ 65


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4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 65
4.5.3
Physical Examinations........................................................... 66
4.5.4
Vital Signs.............................................................................. 66
4.5.5
Tumor and Response Evaluations......................................... 66
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 67
4.5.7
Electrocardiograms................................................................ 71
4.5.8
Patient-Reported Outcomes .................................................. 72
4.5.8.1
EORTC QLQ-C30.................................................................. 73
4.5.8.2
EORTC Quality-of-Life:  Urinary Scale 
(QLQ-PR25) .......................................................................... 73
4.5.8.3
Pain Assessments:  Selected Questions from BPI 
and BPI-SF............................................................................ 73
4.5.8.4
Analgesic Log........................................................................ 74
4.5.8.5
PRO-CTCAE ......................................................................... 74
4.5.8.6
EQ-5D-5L .............................................................................. 74
4.5.9
Optional Samples for Research Biosample 
Repository ............................................................................. 75
4.5.9.1
Overview of the Research Biosample Repository.................. 75
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 75
4.5.9.3
Sample Collection.................................................................. 75
4.5.9.4
Confidentiality........................................................................ 76
4.5.9.5
Consent to Participate in the Research 
Biosample Repository............................................................ 76
4.5.9.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 77
4.5.9.7
Monitoring and Oversight....................................................... 77
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 77
4.6.1
Study Treatment Discontinuation........................................... 77
4.6.2
Patient Discontinuation from Study........................................ 79
4.6.3
Study Discontinuation............................................................ 79
4.6.4
Site Discontinuation............................................................... 79


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5.
ASSESSMENT OF SAFETY....................................................................... 80
5.1
Safety Plan ............................................................................ 80
5.1.1
Risks Associated with Atezolizumab ..................................... 80
5.1.2
Risks Associated with Enzalutamide ..................................... 80
5.1.3
Risks Associated with Combination Use of 
Atezolizumab and Enzalutamide ........................................... 80
5.1.4
Management of Patients Who Experience 
Specific Adverse Events........................................................ 81
5.1.4.1
Dose Modifications ................................................................ 81
5.1.4.2
Treatment Interruption ........................................................... 81
5.1.4.3
Management Guidelines........................................................ 81
5.2
Safety Parameters and Definitions ...................................... 109
5.2.1
Adverse Events ................................................................... 109
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 109
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 110
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 111
5.3.1
Adverse Event Reporting Period ......................................... 111
5.3.2
Eliciting Adverse Event Information..................................... 112
5.3.3
Assessment of Severity of Adverse Events ......................... 112
5.3.4
Assessment of Causality of Adverse Events ....................... 112
5.3.5
Procedures for Recording Adverse Events.......................... 113
5.3.5.1
Infusion-Related Reactions.................................................. 113
5.3.5.2
Diagnosis Versus Signs and Symptoms.............................. 114
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 114
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 114
5.3.5.5
Abnormal Laboratory Values ............................................... 115
5.3.5.6
Abnormal Vital Sign Values ................................................. 116
5.3.5.7
Abnormal Liver Function Tests............................................ 116
5.3.5.8
Deaths ................................................................................. 116
5.3.5.9
Preexisting Medical Conditions............................................ 117
5.3.5.10
Lack of Efficacy or Worsening of Prostate Cancer .............. 117


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5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 117
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 118
5.3.5.13
Patient-Reported Outcome Data ......................................... 119
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 119
5.4.1
Emergency Medical Contacts.............................................. 120
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 120
5.4.2.1
Events That Occur Prior to Study Treatment 
Initiation ............................................................................... 120
5.4.2.2
Events That Occur After Study Treatment 
Initiation ............................................................................... 120
5.4.3
Reporting Requirements for Pregnancies............................ 121
5.4.3.1
Pregnancies in Female Partners of Male Patients............... 121
5.5
Follow-Up of Patients After Adverse Events........................ 121
5.5.1
Investigator Follow-Up......................................................... 121
5.5.2
Sponsor Follow-Up .............................................................. 121
5.6
Adverse Events That Occur After the Adverse 
Event Reporting Period........................................................ 122
5.7
Expedited Reporting to Health Authorities,
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 122
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 123
6.1
Determination of Sample Size ............................................. 123
6.2
Summaries of Conduct of Study.......................................... 124
6.3
Summaries of Demographic and 
Baseline Characteristics ...................................................... 124
6.4
Efficacy Analyses ................................................................ 124
6.4.1
Primary Efficacy Endpoint.................................................... 124
6.4.2
Secondary Efficacy Endpoints............................................. 125
6.4.2.1
Radiographic PFS and Other Time-to-Event 
Endpoints............................................................................. 125
6.4.2.2
PSA Response Rates.......................................................... 126
6.4.2.3
Objective Response Rate in Soft Tissue Lesions................ 126
6.4.3
Exploratory Efficacy Endpoints............................................ 126


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6.4.4
Subgroup Analyses ............................................................. 127
6.5
Safety Analyses................................................................... 127
6.6
Pharmacokinetic Analyses................................................... 128
6.7
Immunogenicity Analyses.................................................... 128
6.8
Interim Analyses .................................................................. 129
6.8.1
Planned Interim Analyses.................................................... 129
6.8.2
Optional Interim Analysis..................................................... 130
7.
DATA COLLECTION AND MANAGEMENT ............................................. 130
7.1
Data Quality Assurance....................................................... 130
7.2
Electronic Case Report Forms............................................. 131
7.3
Electronic Patient-Reported Outcome Data......................... 131
7.4
Source Data Documentation................................................ 131
7.5
Use of Computerized Systems ............................................ 132
7.6
Retention of Records........................................................... 132
8.
ETHICAL CONSIDERATIONS.................................................................. 132
8.1
Compliance with Laws and Regulations .............................. 132
8.2
Informed Consent................................................................ 133
8.3
Institutional Review Board or Ethics Committee.................. 134
8.4
Confidentiality...................................................................... 134
8.5
Financial Disclosure ............................................................ 135
9.
STUDY DOCUMENTATION, MONITORING,
AND ADMINISTRATION........................................................................... 135
9.1
Study Documentation .......................................................... 135
9.2
Protocol Deviations.............................................................. 135
9.3
Site Inspections ................................................................... 136
9.4
Administrative Structure....................................................... 136
9.5
Dissemination of Data and Protection of 
Trade Secrets...................................................................... 136
9.6
Protocol Amendments ......................................................... 137
10. REFERENCES ......................................................................................... 138


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
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LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 35
Table 2
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 60
Table 3
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 84
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 112
Table 5
Causal Attribution Guidance ..................................................... 113
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 39
LIST OF APPENDICES
Appendix 1     Schedule of Activities................................................................. 147
Appendix 2     Criteria for Radiographic Progression Per Prostate Cancer 
Working Group 3....................................................................... 153
Appendix 3      Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 154
Appendix 4
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire:  EORTC QLQ-C30 ........ 164
Appendix 5
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire:  Urinary Scale from 
EORTC QLQ-PR25................................................................... 166
Appendix 6
EuroQol 5-Dimension Questionnaire:  EQ-5D-5L ..................... 167
Appendix 7
Pain Severity Assessments....................................................... 170
Appendix 8
Analgesic Quantification Algorithm Score Categories and 
Equianalgesic Potency Conversions......................................... 172
Appendix 9
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events .................................. 174
Appendix 10
Preexisting Autoimmune Diseases ........................................... 175
Appendix 11
Anaphylaxis Precautions........................................................... 176
Appendix 12
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 177
Appendix 13
Guidance on Reducing the Risks of Pharmacokinetic 
DrugDrug Interactions with Enzalutamide............................... 178


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
10/Protocol CO39385, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED 
STUDY OF ATEZOLIZUMAB (ANTIPD-L1 
ANTIBODY) IN COMBINATION WITH 
ENZALUTAMIDE VERSUS ENZALUTAMIDE ALONE 
IN PATIENTS WITH METASTATIC CASTRATION-
RESISTANT PROSTATE CANCER AFTER FAILURE 
OF AN ANDROGEN SYNTHESIS INHIBITOR AND 
FAILURE OF, INELIGIBILITY FOR, OR REFUSAL 
OF A TAXANE REGIMEN
PROTOCOL NUMBER:
CO39385
VERSION NUMBER:
8
EUDRACT NUMBER:
2016-003092-22
IND NUMBER:
131196
TEST PRODUCTS:
Atezolizumab (RO5541267) and enzalutamide
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form as instructed by your local study monitor.  
Please retain a signed copy for your study files.  


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
11/Protocol CO39385, Version 8
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED STUDY OF 
ATEZOLIZUMAB (ANTIPD-L1 ANTIBODY) IN COMBINATION 
WITH ENZALUTAMIDE VERSUS ENZALUTAMIDE ALONE IN 
PATIENTS WITH METASTATIC CASTRATION-RESISTANT 
PROSTATE CANCER AFTER FAILURE OF AN ANDROGEN 
SYNTHESIS INHIBITOR AND FAILURE OF, INELIGIBILITY FOR, 
OR REFUSAL OF A TAXANE REGIMEN
PROTOCOL NUMBER:
CO39385
VERSION NUMBER:
8
EUDRACT NUMBER:
2016-003092-22
IND NUMBER:
131196
TEST PRODUCTS:
Atezolizumab (RO5541267) and enzalutamide
PHASE:
III
INDICATION:
Metastatic castration-resistant prostate cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This is a Phase III, multicenter, randomized open-label study designed to evaluate the efficacy 
and safety of atezolizumab in combination with enzalutamide compared with enzalutamide 
alone in patients with metastatic castration-resistant prostate cancer (mCRPC) after failure of an 
androgen synthesis inhibitor and failure of, ineligibility for, or refusal of a taxane regimen.  
Specific objectives and corresponding endpoints for the study are outlined below.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
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Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab/enzalutamide
compared with enzalutamide alone
OS, defined as the time from randomization to death from 
any cause
Country-Specific Objective 
for China
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab/enzalutamide 
compared with enzalutamide alone 
in patients who are residents of 
China 
Same as the primary objective
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab/enzalutamide
compared with enzalutamide 
alone
OS probability at 12 and 24 months
Time to first SSE
An SSE is defined as external beam radiation therapy 
to relieve skeletal symptoms (including initiation of 
radium-223 dichloride or other types of radionuclide 
therapy to treat symptoms of bone metastases), new 
symptomatic pathologic bone fracture, clinically 
apparent occurrence of spinal cord compression, or 
tumor related orthopedic surgical intervention.
rPFS, as assessed by the investigator, and adapted 
from the PCWG3 criteria.  rPFS is defined as the time 
from randomization to the earliest occurrence of one of 
the following:
A patient is considered to have progressed by bone 
scan if:
The first bone scan with 2 new lesions 
compared to baseline is observed 12 weeks 
from randomization and is confirmed by a second 
bone scan taken 6 weeks later showing 
2 additional new lesions (a total of 4 new 
lesions compared to baseline); the date of 
progression is the date of the first post-treatment 
scan, OR
After the first post-treatment scan, 2 new lesions 
are observed relative to the first post-treatment 
scan, which is confirmed on a subsequent scan 
6 weeks later; the date of progression is the 
date of the post-treatment scan when 2 new 
lesions were first documented.
Progression of soft tissue lesions, as defined per 
PCWG3 modified RECIST v1.1 
Death from any cause
rPFS probability at 6 and 12 months


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Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objective 
(cont.)
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab/enzalutamide
compared with enzalutamide alone 
(cont.)
PSA response rate, defined as a 50% decrease in PSA 
from baseline that is confirmed after 3 weeks by a 
consecutive confirmatory PSA measurement
Time to PSA progression, defined as the time from 
randomization to the time of PSA progression, as 
defined per the PCWG3 criteria:
In patients with no PSA decline from baseline, PSA 
progression is defined as a 25% increase and an 
absolute increase of 2 ng/mL above the baseline 
value, 12 weeks after baseline.
In patients with an initial PSA decline from baseline, 
PSA progression is defined as a 25% increase and 
an absolute increase of 2 ng/mL above the nadir 
value, which is confirmed by a consecutive second 
value obtained 3 weeks later.

Objective response rate in soft tissue lesions, defined 
as the proportion of patients with either a CR or PR on 
two consecutive occasions 6 weeks apart, as 
determined by the investigator through use of PCWG3 
criteria
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab/enzalutamide
compared with enzalutamide alone
DOR in soft tissue lesions, defined for patients who had 
an objective response in soft tissue as the time from the 
first documented objective response in soft tissue to 
radiographic disease progression, as determined by the 
investigator through use of PCWG3 criteria
DCR, defined as the proportion of patients with a best 
response of confirmed CR or PR or stable disease in soft 
tissue lesions per PCWG3-modified RECIST v1.1 and/or 
no confirmed radiographic disease progression on bone 
scan per PCWG3 criteria
Modified progression free survival based on radiographic 
disease progression and unequivocal clinical progression, 
defined as the time from randomization to the earliest 
occurrence of one of the following:
Radiographic disease progression per PCWG3 criteria 
(as defined above)
Unequivocal clinical progression characterized as at 
least one of the following:
Symptomatic skeletal-related event (as defined 
above)
Deterioration in ECOG performance status by at 
least two points that is attributed to disease 
progression
Initiation of next systemic anti-cancer therapy 


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Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety and 
tolerability of atezolizumab and 
enzalutamide compared with 
enzalutamide alone
Incidence, nature, frequency, and severity of adverse 
events, with severity determined through use of the 
National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE v4.0)
Clinically significant changes in vital signs, and clinical 
laboratory results during and following study treatment 
administration
Pharmacokinetic Objectives
Corresponding Endpoints
To characterize the 
pharmacokinetics of atezolizumab 
when given in combination with 
enzalutamide
To characterize the 
pharmacokinetics of enzalutamide
and its active metabolite 
N-desmethyl enzalutamide when 
enzalutamide is administered 
alone or in combination with 
atezolizumab
Serum concentration of atezolizumab at specified 
timepoints
Plasma concentration of enzalutamide and N-desmethyl 
enzalutamide at specified timepoints in the safety run-in 
phase and in a PK cohort in the randomized phase 
(approximately 30 patients per treatment arm)
Exploratory Biomarker Objective
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to 
atezolizumab and/or 
enzalutamide (i.e., predictive 
biomarkers), are associated with 
progression to a more severe 
disease state (i.e., prognostic 
biomarkers), are associated with 
acquired resistance to 
atezolizumab and/or 
enzalutamide, are associated with 
susceptibility to developing 
adverse events, can provide 
evidence of atezolizumab and/or 
enzalutamide activity, or can 
increase the knowledge and 
understanding of disease biology 
on the basis of the following 
endpoint:
Relationship between biomarkers in blood, urine, and 
tumor tissue and efficacy, safety, PK, immunogenicity, or 
other biomarker endpoints


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Objectives and Corresponding Endpoints (cont.)
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response 
to atezolizumab
Incidence of anti-therapeutic antibodies (ATAs) against 
atezolizumab
Exploratory Immunogenicity 
Objective
Corresponding Endpoint
To evaluate potential effects of 
ATAs
Relationship between ATA status and efficacy, safety, or 
PK endpoints
AQAanalgesic quantification algorithm; ATAanti-therapeutic antibody; CRcomplete 
response; CRPCcastration-resistant prostate cancer; DCRdisease control rate; 
DORduration of response; ECOG Eastern Cooperative Oncology Group; NCI
CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
OSoverall survival; PCWG3Prostate Cancer Working Group 3; PFphysical function; 
PFSprogression-free survival; PKpharmacokinetic; PRpartial response; 
PSAprostate-specific antigen; rPFSradiographic progression-free survival; 
RECIST Response Evaluation Criteria in Solid Tumors; SSEsymptomatic skeletal event.
Study Design
Description of Study
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the safety 
and efficacy of atezolizumab in combination with enzalutamide compared with enzalutamide 
alone in patients with mCRPC after failure of an androgen synthesis inhibitor (e.g., abiraterone) 
and failure of, ineligibility for, or refusal of a taxane regimen. 
The study will include the following patients:

Patients who have progressed during treatment with an androgen synthesis inhibitor 
(e.g., abiraterone) for prostate cancer and have received a prior taxane regimen for 
metastatic hormone-sensitive and/or metastatic castration-resistant prostate cancer 

Patients who have progressed during treatment with an androgen synthesis inhibitor 
(e.g., abiraterone) for prostate cancer and who are not fit enough to receive a taxane
regimen for mCRPC

Patients who have progressed during treatment with an androgen synthesis inhibitor 
(e.g., abiraterone) for prostate cancer and who decline a taxane regimen for mCRPC after 
an informed discussion
Approximately 180 sites globally will participate in the study and approximately 730 patients will 
be enrolled (first 10 patients in the safety run-in cohort followed by 720 patients in the global 
randomized phase).
The Sponsor recommends that investigators use their clinical judgment to determine if the 
patients who remain on the study appear to be benefitting from their therapy, and discuss the 
benefits and risks with patients of remaining on their current treatment.  Patients who remain on 
treatment until the closure of the study will be able to continue to receive treatment as part of a 
post-trial access program.  Patients may start transferring to the program after the required 
approvals are available (as applicable).
Safety Run-In Phase
In the safety run-in phase of the study, 10 patients will be enrolled and will receive atezolizumab 
in combination with enzalutamide.  After 10 patients have been enrolled, enrollment will be 
stopped temporarily and all patients will be monitored closely for adverse events until the last 
patient has completed the first cycle (21 days).  Patients will continue to receive study treatment 
and be followed for safety and efficacy per the schedule of activities.


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After 10 patients have received study treatment and completed at least one cycle of study 
treatment (21 days), an independent Data Monitoring Committee (iDMC) will review available 
data and make a recommendation regarding initiation of the randomized phase of the study. 
Randomized Phase
Enrollment in the randomized phase of the study will be initiated after review of the safety run-in 
data by the iDMC and the Sponsor.  Approximately 720 patients will be enrolled in the 
randomized phase of the study.  Patients will be randomized to one of the following treatment 
arms in a 1:1 ratio (experimental to control arm): 

Arm A (experimental arm):  atezolizumab in combination with enzalutamide

Arm B (control arm):  enzalutamide alone
Randomization will be conducted with the aid of an interactive voice/Web response system 
(IxRS).
The randomization will be stratified by the following stratification factors:

Prior taxane-containing regimen for mCRPC, defined as at least 2 cycles of a 
taxanes-containing regimen (yes vs. no)

Presence of liver metastasis (yes vs. no)

LDH upper limit of normal (ULN) vs. ULN

Pain severity (Brief Pain Inventory Short Form [BPI-SF]) Question 3 assessing pain at its 
worst over the past 24 hours [score 4 vs. 4])
A stratified permuted-block randomization will be implemented to balance treatment assignment 
within stratum levels.
Patient recruitment will be capped with respect to two of the stratification factors:  the proportion 
of patients who have not received a prior taxane-containing regimen for mCRPC will be 
approximately 50% or less, and the proportion of patients with liver metastases at baseline will 
be approximately 10% or less.  Presence of liver metastases will be determined based on 
computed tomography (CT) or magnetic resonance imaging (MRI) scan.  The purpose of the 
cap is to ensure the prevalence of these two prognostic factors in the study population will be 
similar to that reported in the targeted population.
Atezolizumab will be administered at a fixed dose of 1200 mg by intravenous (IV) infusion on 
Day 1 of each 21-day cycle until investigator-assessed confirmed radiographic disease 
progression per Prostate Cancer Working Group 3 (PCWG3) or unacceptable toxicity.
Enzalutamide will be administered orally at a dose of 160 mg (four 40-mg capsules) daily until 
investigator-assessed confirmed radiographic disease progression per PCWG3 or unacceptable 
toxicity.
Patients will be permitted to continue study treatment after PCWG3 criteria are met for 
confirmed radiographic disease progression if they meet all of the following criteria (treatment 
until they are no longer clinically benefiting per PCWG3 recommendation).

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs indicating unequivocal progression of disease

No decline in Eastern Cooperative Oncology Group (ECOG) Performance Status that can 
be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed and stabilized by protocol-allowed medical interventions

Written consent to acknowledge deferring other treatment options in favor of continuing 
study treatment at the time of initial disease progression
No crossover will be allowed from the control arm to the experimental arm.
Patients with rising prostate-specific antigen (PSA) levels only (i.e., in the absence of confirmed 
radiographic or clinical progression) should remain on study treatment per PCWG3 criteria and 
recommendations.  PSA rise without evidence of confirmed radiographic progression or a 
symptomatic skeletal-related event is strongly discouraged as a criterion to start a new systemic 


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anti-neoplastic therapy during the first 12 weeks of therapy and is discouraged as a criterion to 
start a new systemic anti-neoplastic therapy throughout the study.
Focal palliative radiography (e.g., external-beam radiotherapy to address single sites of 
disease), initiation of bisphosphonates or denosumab, standard-of-care corticosteroid use of no 
greater than the equivalent of 10 mg of prednisone or prednisolone per day and pain 
management are allowed and should not result in discontinuation of study treatment.  However, 
patients should be evaluated for clinically apparent symptomatic skeletal events (SSEs).
Initiation of radium-223 dichloride to manage symptomatic bone lesions is not permitted during 
study treatment.
Patients will undergo scheduled tumor assessments at baseline and every 9 weeks (3 days) 
for the first 27 weeks and every 12 weeks (6 days) thereafter until confirmed radiographic 
disease progression per PCWG3.  In the absence of confirmed radiographic progression, tumor 
assessments should continue, regardless of whether patients start new anti-cancer therapy, 
until death, loss of follow-up, withdrawal of consent, or study termination by the Sponsor, 
whichever occurs first.  For patients who continue to receive study treatment following 
confirmed disease progression, assessments will continue until loss of clinical benefit.
All primary imaging data used for tumor assessments may be collected by the Sponsor to 
enable the possibility of a centralized, independent review of response endpoints by an 
Independent Review Facility (IRF).
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0.  Laboratory safety assessments will include the regular 
monitoring of hematology and blood chemistry.
Serum samples will be collected in patients in Arm A (atezolizumab and enzalutamide) to 
monitor atezolizumab pharmacokinetics and to detect the presence of antibodies to 
atezolizumab.  Plasma samples to monitor enzalutamide and N-desmethyl enzalutamide 
pharmacokinetics will also be collected in the safety run-in phase and in a pharmacokinetic (PK) 
cohort in the randomized phase (approximately 30 patients per treatment arm).  Patient 
samples, including archival tumor tissues, as well as urine, serum, plasma and whole blood, will 
be collected for future exploratory biomarker assessments for all patients in the randomized 
phase.
It is recommended that patients undergo tumor biopsy sample collection, if deemed clinically 
feasible by the investigator, at the time of first evidence of confirmed radiographic disease 
progression according to PCWG3 criteria (within 40 days after confirmed radiographic 
progression or prior to the start of new anti-cancer treatment, whichever is sooner). 
These samples will be analyzed to evaluate the utility of the biopsy in distinguishing 
pseudoprogression (caused by tumor-infiltrating immune cells [ICs]) from true progression.  In 
addition, tumor tissue biomarkers related to resistance, disease progression, and clinical benefit 
of atezolizumab may be analyzed.
Patients who are withdrawn from study treatment will be evaluated within 30 days and 
approximately 120 days after last study treatment for a treatment discontinuation visit and safety 
visit, respectively. Thereafter, patients will enter a post-trial access program (as applicable).
Number of Patients
Approximately 180 sites globally will participate in the study and approximately 730 patients will 
be enrolled.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Ability to comply with the study protocol, in the investigator’s judgment

ECOG performance status of 0 or 1

Life expectancy 3 months


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
Histologically confirmed adenocarcinoma of the prostate
Disease must be either metastatic or locally confined inoperable disease that cannot be 
treated with definitive intent (no chance for a curative intervention)
Patients presenting with treatment emergent neuroendocrine differentiation, but not 
primary small cell features, are eligible

Known castrate-resistant disease, defined as meeting all of the following criteria:
Castrate serum testosterone level 50 ng/dL (1.7 nmol/L) at the screening visit
Bilateral orchiectomy or maintenance on androgen ablation therapy with luteinizing 
hormone-releasing hormone agonist or antagonist or polyestradiol phosphate for the 
duration of the study (including the follow-up period)

Progressive disease prior to screening by PSA or imaging per PCWG3 criteria during or 
following the direct prior line of therapy in the setting of medical or surgical castration.  
Disease progression for study entry is defined as one or more of the following three criteria:
PSA progression defined as two increases in PSA over a previous reference value of 
1 ng/mL (g/L) as the minimum starting value (i.e, a minimum of 3 PSA values total), 
with each progression measurement at least 1 week apart 
Soft tissue disease progression defined by RECIST v1.1 
Previously normal (1.0 cm) lymph nodes must have grown by 5 mm in the short 
axis to be considered to have progressed
Bone disease progression defined by two or more new lesions on bone scan

One prior regimen/line of a taxane-containing regimen for mCRPC or refusal or ineligibility
of a taxane-containing regimen
Patients who have received a taxane-containing regimen for metastatic HSPC are 
eligible.  
Patients who refuse or are ineligible for a taxane-containing regimen are eligible for 
enrollment if they have no intention to use cytotoxic chemotherapy within the next 
6 months after an informed discussion. 
A taxane-containing treatment should be considered in patients with symptomatic and 
extensive visceral disease who have not previously received and are good candidates 
for a taxane-containing regimen.

Progression on a prior regimen/line of an androgen synthesis inhibitor for prostate cancer 
(e.g., abiraterone, orteronel or galeterone)
Patients must have received at least 28 days of an androgen synthesis inhibitor. 
Prior treatment with first generation antiandrogens (e.g., nilutamide, bicalutamide), oral 
ketoconazole, vaccines (e.g., sipuleucel-T, prostvac VF), and radium-223 dichloride is 
also allowed in addition to one prior regimen or line of an androgen synthesis inhibitor 
for prostate cancer.

Patients receiving bisphosphonate or denosumab therapy must have been on a stable dose 
for at least 4 weeks.

Availability of a representative tumor specimen from a site not previously irradiated that is 
suitable for determination of PD-L1 status via central testing
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 15 slides containing unstained, freshly cut, serial sections must be 
submitted along with an associated pathology report prior to study enrollment.  If only 
1014 slides are available, the patient may still be eligible for the study, after discussion 
with and approval by the Medical Monitor.  If archival tumor tissue is unavailable or is 
determined to be unsuitable for required testing, tumor tissue must be obtained from a 
biopsy performed at screening.  No tissue will be collected for patients enrolled in the 
safety run-in phase.  Tissue from bone metastases might be acceptable after 
consultation with the Medical Monitor.


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
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment:
ANC 1.5 109/L (without granulocyte colony-stimulating factor support within 2 weeks 
prior to Cycle 1, Day 1)
Lymphocyte count 0.5 109/L
Platelet count 100 109/L without transfusion
Hemoglobin 9 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this criterion.
AST and ALT 2.5 ULN, with the following exception:
Patients with documented liver metastases:  AST and ALT 5 ULN
Serum bilirubin 1.5 ULN with the following exception:
Patients with known Gilbert disease:  serum bilirubin level 3 ULN
Creatinine clearance 30 mL/min (calculated using the Cockcroft-Gault formula)
Serum albumin 2.5 g/dL
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5 ULN within 
14 days prior to initiation of study treatment

For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen

For men who are not surgically sterile:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for at least 3 months after the last dose of 
enzalutamide.  Men must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for 3 months after the last dose of enzalutamide to avoid exposing 
the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-specific exclusions

Prior treatment with enzalutamide or any other newers hormonal androgen receptor 
inhibitor (e.g., apalutamide, ODM-201)

Treatment with any approved anti-cancer therapy, including chemotherapy, immunotherapy, 
radiopharmaceutical or hormonal therapy (with the exception of abiraterone), within 
4 weeks prior to initiation of study treatment
Palliative radiotherapy for bone metastases or soft tissue lesions should be completed 
7 days prior to baseline imaging.
Androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) 
analog (GnRH agonist or GnRH antagonist) is allowed.

Treatment with abiraterone within 2 weeks prior to study treatment

Use of herbal products that may have hormonal anti-prostate cancer activity and/or are 
known to decrease PSA levels (e.g., saw palmetto) within 4 weeks of enrollment

Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent within 4 weeks prior to initiation of study treatment


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
Planned palliative procedures for alleviation of bone pain such as radiation therapy (unless 
completed 7 days prior to baseline imaging) and surgery.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to initiation of study 
treatment.

Structurally unstable bone lesions suggesting impending fracture

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled hypercalcemia defined as one or more of the following criteria:
Ionized calcium 1.5 mmol/L
Serum calcium 12 mg/dL
Corrected serum calcium greater than ULN (if serum albumin 4.0 g/dL)

Known or suspected brain metastasis or active leptomeningeal disease

Patients with treated epidural lesions and no other epidural progression are allowed.
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated 
with spinal cord compression) should be considered for loco-regional therapy if 
appropriate prior to initiation of study treatment.
General medical exclusions

Malignancies other than mCRPC within 5 years prior to initiation of study treatment
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death 5% at 5 years) are eligible provided they meet all of the following 
criteria:
Malignancy treated with expected curative intent (e.g., adequately treated basal or 
squamous cell skin cancer)
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months 
prior to enrollment, unstable arrhythmia, or unstable angina
Patients with a known left ventricular ejection fraction (LVEF) 40% will be excluded.
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF 40%50% must be on a stable medical regimen that is 
optimized in the opinion of the treating physician, in consultation with a cardiologist if 
appropriate.  Patients with a history of clinically significant cardiac disease (including 
anatomic abnormality, coronary artery disease, congestive heart failure, abnormal 
LVEF, arrhythmia, or abnormal ECG) will be required to undergo a screening 
echocardiogram.
History of clinically significant ventricular dysrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, torsades de pointes)
History of a Mobitz II second degree or third degree heart block without permanent 
pacemaker in place
Hypotension (systolic blood pressure 86 mmHg) or bradycardia with a heart rate 
50 beats per minute at the screening visit
Uncontrolled hypertension as indicated by a resting systolic blood pressure 
170 mmHg or diastolic blood pressure 105 mmHg at the screening visit

Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study 
treatment or anticipation of need for a major surgical procedure during the course of the 
study


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
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications
Exclusion criteria related to atezolizumab 

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation

Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met:
Rash must cover 10% of body surface area
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months

Prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive HIV test at screening

Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative HBsAg 
test and a positive total hepatitis B core antibody (HBcAb) test at screening, are 
eligible for the study.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test 
followed by a positive HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive HCV 
antibody test.

Active tuberculosis

Severe infection within 4 weeks prior to initiation of study treatment including, but not limited 
to, hospitalization for complications of infection, bacteremia, or severe pneumonia

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study. 


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
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment 
or anticipation of need for such a vaccine during the course of the study

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiCTLA-4, antiprogrammed death-1 (PD-1), and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to 
initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor [TNF]-agents) within 2 weeks prior to initiation of study treatment or 
anticipation of need for systemic immunosuppressive medication during the course of the 
study, with the following exceptions:
Patients who received acute, low-dose, systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for in the study.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study.
The use of systemic corticosteroids of no greater than the equivalent of 10 mg of 
prednisone or prednisolone per day for symptomatic treatment of prostate cancer is 
allowed if the patient has been on a stable dose within 2 weeks prior to initiation of 
study treatment.  There should be no plans to taper the patient off treatment or 
increase the dose during the study.
Patients who are tapered off systemic corticosteroids as part of a prior anti-cancer 
regimen must have received the last dose 7 days prior to initiation of study treatment.
Exclusion criteria related to enzalutamide

Known allergy or hypersensitivity to components of the enzalutamide formulation

Unable to swallow the study treatment 

Gastrointestinal disorder affecting absorption of study treatment (e.g., gastrectomy or active 
peptic ulcer disease within last 3 months)

History of seizure or any condition that may predispose to seizure within 12 months prior to 
study treatment, including unexplained loss of consciousness or transient ischemic attack 
Exclusion criteria unique to patients enrolled in the enzalutamide PK cohort

Have used or plan to use the following substances within 30 days or 5 half-lives, whichever 
is longer, prior to initiation of study treatment through collection of the last enzalutamide PK 
sample:
Potent CYP2C8 and CYP3A4 inhibitors including, but not limited to, the following:  
boceprevir, clarithromycin, conivaptan, gemfibrozil, grapefruit juice, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, voriconazole
Potent or moderate CYP3A4 and CYP2C8 inducers including, but not limited to, the 
following:  anticonvulsants (carbamazepine, phenobarbital, phenytoin), 
antimycobacterials (rifabutin, rifampin, rifapentine), avasimibe, bosentan, efavirenz, 
etavirine, modafinil, nafcillin, St John's wort (hypericum perforatum)
End of Study
The end of the main global study phase is defined as the earliest date of the following:

Receipt of last data point from the last patient 

Sponsor decision to end the study


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Length of Study
The Sponsor has decided to close Study CO39385 (IMbassador250) following the 
recommendation of the iDMC to terminate the trial due to futility.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are atezolizumab and enzalutamide.  
The dose level of atezolizumab proposed to be tested in this study is 1200 mg (equivalent to an 
average body weight-based dose of 15 mg/kg) administered by IV infusion every 3 weeks 
(21 [±3] days).  The dose of enzalutamide is 160 mg (four 40-mg capsules) administered orally 
once daily.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is overall survival (OS), defined as the time from randomization to 
death from any cause.  Data for patients who are not reported as having died at of the date of 
analysis will be censored at the last date known to be alive.  Data for patients who do not have 
post-baseline information will be censored at the date of randomization plus 1 day.
The intent-to-treat (ITT) population is defined as all randomized patients regardless of whether 
the assigned study treatment was received.  For efficacy analyses, patients will be analyzed 
according to their randomized treatment assignment. 
The primary comparison of OS between treatment arms will be based on a stratified log-rank 
test.  The HR for death in the experimental arm compared with the control arm will be estimated 
using a stratified Cox regression model, and the 95% CI will be provided.  The stratification 
factors will be the same as the randomization stratification factors; however, stratification factors 
may be combined for analysis purposes if necessary to minimize small stratum cell sizes.  
Combination of stratification factors, if any, would be specified in the Statistical Analysis Plan 
(SAP) prior to analysis.  Values for the stratification factors will be as recorded in the IxRS at the 
time of randomization.  Results from an unstratified analysis will also be presented.
Kaplan-Meier plots will be constructed to provide a visual description of the difference between 
the treatment and control arms.  Kaplan-Meier methodology will also be used to estimate 
median OS for each treatment arm.  Brookmeyer-Crowley methodology will be used to 
construct the 95% CI for the median OS for each treatment arm.
The OS rate at key timepoints (12 months, 24 months) will be estimated using Kaplan-Meier 
methodology, along with 95% CIs calculated using the standard error derived from 
Greenwood’s formula.  The 95% CI for the difference in OS rates between the two treatment 
arms will be estimated by use of the normal approximation method.
Determination of Sample Size
A total of approximately 730 patients are planned to be enrolled in the global phase of this study:  
10 patients during the non-randomized safety run-in phase, and approximately 720 during the 
randomized phase of the study. 
The sample size of 10 patients for the safety run-in is based on clinical considerations.  No 
statistical hypothesis tests will be performed on data from the safety run-in phase.
The final analysis of the primary endpoint of OS will be performed when approximately 
540 deaths have occurred in the ITT population (75% of 720 patients). 
The calculations are based on the following assumptions:

Log-rank test

1:1 randomization

Two-sided alpha of 0.05

Median OS for the control (enzalutamide alone) arm of 12 months and estimated median 
OS in the experimental arm of 16.7 months, corresponding to a HR of 0.72

A drop-out rate of approximately 5% per 2-year period

One interim OS analysis
It is projected that an observed HR of 0.84 will result in a statistically significant difference 
between treatment arms (i.e., the HR of 0.84 will be the minimally detectable difference at the 


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final analysis).  This corresponds to an improvement of median OS from 12 months to 
14.3 months.
In case of proportional hazards, 540 events would provide 97% power to detect a difference in 
the duration of OS given the above assumptions. However, computer simulations show that the 
actual power of the log-rank test is likely lower in case of control patients switching to 
subsequent lines of immunotherapy following progression.  For example, if 15% of control 
patients receive subsequent treatment providing similar OS benefit as atezolizumab, the 
reduction in power is projected to be approximately 6%. 
Recruitment of the planned 720 patients is projected to be completed within 13 months.  On the 
basis of the above assumptions, the required number of OS events for the final analysis is 
projected to occur at approximately Month 38 after randomizing the first patient.  
Interim Analyses
A total of two analyses of OS will be performed:  one interim analysis and the final analysis.
The interim analysis of the primary endpoint of OS will be performed when approximately 
432 deaths have occurred (60% of 720 patients), corresponding to approximately 80% of the 
540 deaths required for the final analysis of OS.  The required number of deaths for the interim 
analysis is projected to occur at approximately Month 27 after randomizing the first patient.
The Lan-DeMets alpha-spending function approach will be used to determine the boundary 
values for statistical significance at the interim and final analysis.
For the primary endpoint of OS, the stopping boundaries will be based on the O’Brien-Fleming 
alpha-spending function.  At both the interim and final OS analysis, key secondary endpoints 
listed in Section 6.4.2 will be evaluated for statistical significance only if the difference in 
duration of OS is statistically significant at the appropriate boundary level.  For these secondary 
endpoints, the boundaries for statistical significance will be based on a Pocock alpha-spending 
function.  Key secondary endpoints will be tested at the appropriate significance level in the 
order specified in Section 6.4.2.  If for one endpoint in this list the null hypothesis cannot be 
rejected, then the results for this and all following endpoints are not statistically significant.
The hierarchical testing procedure with the boundaries determined as described above ensures 
that the overall type I error for the primary and key secondary endpoints will be controlled at 
0.05.
The interim OS analysis will be performed by the iDCC and reviewed by the iDMC.  The 
Sponsor will remain blinded to the results.  On the basis of its review of the data, the iDMC will 
provide a recommendation as to whether to release the study results early because of 
substantial evidence of efficacy.
Optional Interim Analyses
To adapt to information that may emerge during the course of this study, the Sponsor may 
choose to conduct one interim efficacy analysis for the primary endpoint of OS beyond what is 
specified in Section 6.8.1.  The decision to conduct the optional interim analysis, along with the 
rationale, timing, and statistical details for the analysis, will be documented in the SAP, and the 
SAP will be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis will be 
conducted by the iDCC and reviewed by the iDMC.  Interactions between the iDMC and 
Sponsor will be carried out as specified in the iDMC Charter. 
If there is a potential for the study to be stopped for positive efficacy as a result of the interim
analysis, the type I error rate will be controlled using the same Lan-DeMets approach as for the 
planned interim analysis described above.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADT
androgen deprivation therapy
AQA
analgesic quantification algorithm
ATA
anti-therapeutic antibody
BPI, BPI-SF
Brief Pain Inventory, Brief Pain Inventory-Short Form
CI
confidence interval
COPD
chronic obstructive pulmonary disorder
CR
complete response
CRPC
castration-resistant prostate cancer
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC QLQ-C30
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire Core Module 
30 items
ePRO
electronic patient-reported outcome
EQ-5D-5L
European Quality-of-Life 5-Dimension Questionnaire
FDA
(U.S.) Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
GHS
GnRH
global health status
gonadotropin-releasing hormone
HRQoL
health-related quality-of-life
HR
hazard ratio
HSPC
hormone-sensitive prostate cancer
IC
(tumor-infiltrating) immune cell
ICH
International Conference for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IRF
Independent Review Facility
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice/Web Response System
mCRPC
metastatic castration-resistant prostate cancer
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute


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Abbreviation
Definition
NGS
next-generation sequencing
NRS
numerical rating scale
ORR
objective response rate
OS
overall survival
PCWG3
Prostate Cancer Working Group 3
PD-1
programmed death1
PD-L1
programmed deathligand 1
PF
physical function
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
PRO-CTCAE
Patient-Reported Outcome version of the Common 
Terminology Criteria for Adverse Events
PSA
prostate-specific antigen
Q3W
every 3 weeks
QLQ-PR25
EORTC Quality-of-Life Questionnaire Prostate Module 
25 items:  Urinary Scale
QoL
quality of life
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
rPFS
radiographic progression-free survival
SAP
Statistical Analysis Plan
SSE
symptomatic skeletal event
TC
tumor cell
TNF(-)
tumor necrosis factor()
ULN
upper limit of normal
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON PROSTATE CANCER
With approximately 1.1 million newly diagnosed cases and more than 300,000 deaths 
each year worldwide, prostate cancer is the most commonly diagnosed cancer in men 
and the second leading cause of death in men in the Western world (Ferlay et al. 2013).  
The incidence rates are highest in developed regions, including North America 
(approximately 180,000 new cases and 26,000 deaths in the United States in 2016), 
Europe (approximately 70,000 deaths in 2013), and Australia/New Zealand 
(Malvezzi et al. 2013; Ferlay et al. 2013; Siegel et al. 2016).  Whereas most men with 
localized disease are cured with treatment, men with recurrent or newly diagnosed 
metastatic disease suffer significant morbidity and mortality (Kirby et al. 2011). 
For patients who have recurrence following localized treatment and for those patients 
identified with de novo metastatic disease, the goal of treatment is to extend survival 
while maintaining health-related quality of life (HRQoL).  Primary treatment is androgen 
deprivation therapy (ADT); however, up to one-third of patients will progress despite 
reduction in testosterone levels to castrate levels (50 ng/dL) either through surgical or 
medical castration (Kirby et al. 2011).  Castration-resistant prostate cancer (CRPC) is 
defined by disease progression, as measured by prostate-specific antigen (PSA) or 
radiographic measures despite adequate suppression of testosterone levels (Prostate 
Cancer Working Group 3 [PCWG3]; Scher et al. 2016).  Despite the current availability 
of life-extending therapies for metastatic CRPC (mCRPC), the majority of men will 
experience deterioration in HRQoL, disability and ultimately die of their disease (Kirby et 
al. 2011; Logothetis et al. 2012; Basch et al. 2014; Fizazi et al. 2014).  Up to 90% of 
patients with mCRPC develop bone metastasis, complications for which include severe 
pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression, and 
other nerve-compression syndromes (Roodman et al. 2004; Pezaro et al. 2013). The 
median life expectancy in patients diagnosed with mCRPC is less than three years and 
less than one year in patients who have failed two prior lines of therapy 
(Ryan et al. 2013; Beer et al. 2014; Roviello et al. 2015).  Overall, there is still a 
significant unmet medical need in this patient population.
1.1.1
Current Therapies for Metastatic Prostate Cancer
The number of treatment options for patients with metastatic prostate cancer have 
increased in the last decade, and paradigms have shifted to the earlier use of active 
agents (Parker et al. 2015; Mohler et al. 2016).  Docetaxel, a cytotoxic chemotherapy 
and microtubule inhibitor, was initially evaluated in combination with estramustine or 
prednisone in the castration-resistant setting and showed an improvement in median 
overall survival (OS) of approximately 2 months compared with mitoxantrone and 
prednisone (HR0.80; 95% confidence interval [CI]: 0.67, 0.97; p0.02, 
Petrylak et al. 2004; HR0.76; 95% CI: 0.620.94; p0.009, Tannock et al. 2004).  
Grade 3 and 4 neutropenic fevers, nausea and vomiting, cardiovascular events, 
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common in the groups that received docetaxel.  More recently, docetaxel was evaluated 
in the hormone-sensitive prostate cancer (HSPC) setting (also referred to as 
castration-naive setting), with two studies demonstrating statistically significant and 
clinically meaningful improvements in OS when combined with initiation of ADT for newly 
diagnosed metastatic disease (Sweeney et al. 2015; James et al. 2016).  Docetaxel plus 
ADT is now accepted as a standard-of-care treatment option for patients with HSPC with 
clinically measureable disease in appropriately selected patients (Parker et al. 2015; 
Mohler et al. 2016).
Subsequent to the approval of docetaxel in mCRPC, five drugs were approved for the 
treatment of mCRPC, including sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, 
and radium-223 dichloride.
Sipuleucel-T, an autologous active cellular immunotherapy, demonstrated a 4.1-month 
improvement in median survival (HR0.78; 95% CI: 0.61, 0.98; p0.03).  The time to 
radiographic and clinical disease progression was similar in the two study groups; one 
patient in the sipuleucel-T group had a partial response (PR) and PSA responses were 
low in both study groups.  Adverse events that were more frequently reported in the 
sipuleucel-T group than in the placebo group included chills, fever, and headache, with 
Grade 3 and 4 events reported in 6.8% versus 1.8% of patients in the sipuleucel-T and 
placebo group, respectively.  Sipuleucel-T is the only immunotherapy currently approved 
for prostate cancer (limited to the United States) for use in patients with minimal or no 
symptoms (Kantoff et al. 2010). 
Cabazitaxel is a novel microtubule inhibitor and, in combination with prednisone, was 
compared to mitoxantrone in combination with prednisone in patients in the 
post-docetaxel setting (de Bono et al. 2010).  A statistically significant improvement in 
the primary endpoint of OS was demonstrated (median OS:  15.1 vs. 12.7 months; 
HR0.70; 95% CI: 0.590.83; p0.0001).  Key secondary endpoints were similarly 
improved, including radiographic progression-free survival (rPFS) and time to PSA 
progression; there was no significant difference between the treatment groups in time to 
pain progression.  The most common clinically significant Grade 3 and 4 adverse events 
in the cabazitaxel group were neutropenia (including febrile neutropenia) and diarrhea.
Abiraterone is an inhibitor of the enzyme cytochrome P450 17A1 (CYP17:  
17-hydroxylase/C17, 20-lyase).  Abiraterone acts as an androgen synthesis inhibitor by 
blocking two enzymatic activities in the synthesis of testosterone in the testes, adrenals, 
and within the prostate tumor (Li et al. 2015).  Abiraterone in combination with 
prednisone was initially compared to prednisone alone in the post-docetaxel setting, and 
statistically significant improvement was demonstrated with the primary endpoint of OS 
when assessed at interim analysis (median OS: 14.8 vs. 10.9 months; HR0.646; 
95% CI: 0.543, 0.768; p0.0001; de Bono et al. 2011).  Supportive secondary endpoints
included rPFS and time to PSA progression, as well as, pain-related endpoints, including 
time to pain severity and time to pain interference progression, pain severity palliation, 


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skeletal-related events, as well as improvement in prostate-related symptoms including 
fatigue and HRQoL (de Bono et al. 2011; Logothetis et al. 2012; Harland et al. 2013; 
Sternberg et al. 2013).  In the pre-docetaxel setting in asymptomatic and mildly 
symptomatic patients, abiraterone and prednisone was again compared with prednisone 
alone; rPFS and OS were assessed as co-primary endpoints.  At interim analysis, the 
study demonstrated statistically significant improvement in rPFS as assessed by 
independent radiographic review (Ryan et al. 2013) with a trend in OS (third interim 
analysis; median; 35.3 vs. 30.1 months; HR0.792; p0.0151 [did not cross statistical 
boundaries for early stopping]).  As with the post-docetaxel study, supportive secondary 
endpoints included delay in opiate use for prostate cancer pain, initiation of cytotoxic 
chemotherapy, deterioration in Eastern Cooperative Oncology Group (ECOG)
performance status, and PSA progression (Basch et al. 2013).  Grade 3 or
4 mineralocorticoid-related adverse events, including fluid retention, hypertension and 
hypokalemia, and abnormalities in liver function were more common with the abiraterone 
and prednisone combination in both studies.
More recently, abiraterone and prednisone/prednisolone were evaluated in the HSPC 
setting, with two studies demonstrating statistically significant and clinically meaningful 
improvements in OS when combined with ADT (Fizazi et al. 2017; James et al. 2017).  
The LATITUDE study compared ADT plus abiraterone and prednisone with ADT plus 
placebo in patients with metastatic HSPC, and a statistically significant improvement 
was demonstrated with the primary endpoints of OS (HR0.62; p0.001) and 
progression-free survival (PFS) (median: 33.0 months vs. 14.8 months; HR0.47; 
p0.001 [Fizazi et al. 2017]).  The STAMPEDE study compared ADT plus abiraterone 
and prednisolone with ADT alone in patients with HSPC, and statistically significant 
improvement was demonstrated for the primary outcome of OS (HR0.63; p0.001) 
and the intermediate primary outcome of failure-free survival (HR0.29; p0.001) 
(James et al. 2017).
Enzalutamide is an oral androgen receptor blocker that impacts receptor signaling at 
multiple steps, including competitive binding to the androgen receptor, inhibition of 
nuclear translocation, and consequently prevention of binding of the androgen receptor 
to relevant activation sequences in the nucleus.  Enzalutamide demonstrated statistically 
significant improvement over placebo in the primary endpoint of OS in the 
post-docetaxel setting in mCRPC patients (18.4 vs. 13.6 months; HR0.631, p0.0001).  
Additionally, key secondary endpoints demonstrated statistically significant differences 
including rPFS, time to first skeletal-related event, and time to PSA progression 
(Scher et al. 2012).  In a second pivotal study in the pre-docetaxel setting in 
asymptomatic and mildly symptomatic patients, enzalutamide demonstrated statistically 
significant improvement over placebo in the co-primary endpoints of rPFS (not yet 
reached vs. 3.9 months; HR0.186; p0.0001) and OS (32.4 vs. 30.2 months; 
HR0.706; p0.0001 [Beer et al. 2014]).  Other key secondary endpoints, which 
supported the rPFS and OS data, included time to first skeletal-related event, time to 


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initiation of cytotoxic chemotherapy, and time to PSA progression.  Rates of fatigue and 
hypertension were higher in the enzalutamide groups in both studies.  Seizures were 
reported in less than 1% of patients receiving enzalutamide.
Radium-223 dichloride is an alpha-emitting calcium mimetic radioisotope, which 
localizes to bone forming regions of cancer metastases (Parker et al. 2013).  It is an 
applicable treatment for symptomatic patients without visceral disease.  Radium-223 
was compared to placebo in patients with symptomatic mCRPC with bone-only disease 
and demonstrated significant improvement in the primary endpoint of OS (14.9 vs.
11.3 months; HR0.70; p0.001); additionally, the key secondary endpoint of time to 
first symptomatic skeletal-related event was similarly improved (15.6 vs. 9.8 months; 
HR0.66; p0.001).  Radium-223 dichloride was associated with low myelosuppression 
rates and fewer adverse events than the placebo group.
Despite recent advances in the treatment of prostate cancer described above, patients 
with mCRPC experience significant morbidity and mortality related to their disease and 
the median life expectancy from time of first metastatic diagnosis remains less than 
3 years. 
1.1.2
Treatment Patterns for Metastatic Prostate Cancer
With the approval of the aforementioned agents for metastatic prostate cancer, 
physicians now have several treatment options available.  In the context of incurable 
metastatic disease, practice guidelines in the United States and European Union agree 
that the goal of treatment is to provide the best possible quality of life for as long as 
possible (Basch et al. 2014; Heidenreich et al. 2014; Parker et al. 2015; Mohler et al. 
2016).  Consequently, they generally consider hormonal-based therapies as appropriate 
first-line treatment for patients with asymptomatic or mildly (or “minimally”) symptomatic 
disease, whereas patients with symptomatic disease or disease refractory to hormonal 
agents should be treated with cytotoxic chemotherapy.  However, there is limited data to 
define the appropriate sequence to optimize outcomes for patients and no expert 
consensus exists for the best sequencing of agents. In the absence of data informing 
the best treatment sequence in prostate cancer, the choice between hormonal treatment 
and taxane-based chemotherapy after prior treatment failure remains unclear.  Clinical 
practice guidelines in the United States and European Union generally do not 
recommend a preferred next treatment option, and enzalutamide and abiraterone can be 
given to patients not previously treated with the other drug (Basch et al. 2014; 
Heidenreich et al. 2014; Parker et al. 2015; Mohler et al. 2016).
Although options exist for mCRPC, the magnitude of benefit in patients treated with a 
hormonally-based therapy may be attenuated after a taxane-containing therapy and vice 
versa (de Bono et al. 2011; Scher et al. 2012; Ryan et al. 2013; Beer et al. 2014), 
possibly partly due to a cross-resistance mechanism in which microtubule inhibition may 
alter translocation of the androgen receptor (van Soest et al. 2013).


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Furthermore, gene aberrations in the androgen receptor and the presence of androgen 
receptor splice variants may also contribute to impaired clinical efficacy when 
abiraterone and enzalutamide are used sequentially (Antonarakis et al. 2014; Azad et al. 
2015; Romanel et al. 2015). Consequently, outcomes in patients who have failed two 
prior lines of therapy remain poor with response rates of approximately 10%15%, PFS 
of approximately 3 months, and an OS of less than one year (Caffo et al. 2015; Roviello 
et al. 2015). 
However, enzalutamide has demonstrated anti-tumor activity in mCRPC patients 
previously treated with abiraterone. A recent prospective Phase IV, open-label study 
evaluated the efficacy and safety of enzalutamide in patients with mCRPC who had 
progressed after at least 24 weeks of abiraterone and prednisone treatment.  In this 
study, enzalutamide demonstrated anti-tumor activity with an rPFS of 8.1 months, a PSA 
response rate of 26.5%, and a median time to PSA progression of 5.7 months (de Bono 
et al. 2017).  
Despite a proven survival benefit, the overall use of docetaxel-based chemotherapy in
patients with mCRPC remains low due to concerns about tolerability and patient 
preference not to receive chemotherapy.  Population-based studies from Sweden and 
the United Kingdom suggest that only approximately 20% of patients who die from 
prostate cancer had received docetaxel, with significantly higher treatment rates among 
younger patients and patients with fewer comorbidities (Harris et al. 2011; 
Lissbrant et al. 2013).  Additional studies of treatment patterns conducted in the 
United States describe docetaxel treatment rates of approximately 40%, and 16% in the 
elderly (Onukwugha et al. 2011; Lafeuille et al. 2013).
Given the above limitations of current treatments available for patients, improved and 
tolerable treatment options following initial treatment with a newer hormonal agent are 
needed.
1.2
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab (TECENTRIQ®), formerly known as MPDL3280A, is a humanized IgG1 
MAb consisting of two heavy chains (448 amino acids) and two light chains (214 amino 
acids) and is produced in Chinese hamster ovary cells.  It targets programmed death 
ligand-1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, 
programmed death-1 (PD-1) and B7-1 (also known as CD80), both of which function as 
inhibitory receptors expressed on T cells.  Therapeutic blockade of PD-L1 binding by 
atezolizumab has been shown to enhance the magnitude and quality of tumor-specific 
T-cell responses, resulting in improved anti-tumor activity (Fehrenbacher et al. 2016; 
Rosenberg et al. 2016).  Atezolizumab has minimal binding to Fc・receptors, thus 
eliminating detectable Fc-effector function and associated antibody-mediated clearance 
of activated effector T cells.


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Atezolizumab shows anti-tumor activity in both nonclinical models and patients with 
cancer and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic urothelial carcinoma.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.3.1
Rationale for Treatment with Atezolizumab
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant clinical benefit to patients across a broad array of advanced 
malignancies (Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012).
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity.
In prostate cancer, a study evaluating PD-L1 expression in primary tissue at the time of 
radical prostatectomy demonstrated moderate to high PD-L1 expression in 61.7% of 
resection specimens; PD-L1 expression was prognostic for biochemical recurrence 
(Gevensleben et al. 2016).  Similarly, PD-L1 expression was detected in in 50% of 
prostate adenocarcinomas in a different data set, with 19% of cases showing high 
positivity (2score; Massari et al. 2016).  A study evaluating PD-L1 expression on 
immune cells (ICs) in the tumor area using the Ventana/Roche antiPD-L1 (SP142) 
assay on prostate cancer tissue from 92 patients detected PD-L1 expression on 
tumor-infiltrating ICs in 39% of the samples (defined as 1% PD-L1 expression on 
tumor- infiltrating ICs).  PD-L1 expression on tumor cells was limited to 2% of the 
samples (defined as 1%PD-L1 expression on tumor cells; unpublished data).


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Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 
nonsmall cell lung cancer (NSCLC), urothelial carcinoma, renal cell carcinoma (RCC), 
melanoma, colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and 
sarcoma (see Atezolizumab Investigator's Brochure for detailed efficacy results).
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza-like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see Atezolizumab Investigator's Brochure 
for detailed safety results).  To date, these events have been manageable with treatment.
1.3.2
Rationale for Combination Treatment with Atezolizumab and 
Enzalutamide
Hormonal therapies have been shown to have several immune modulatory effects, 
including the promotion of thymopoiesis, an increase in prostate immune infiltrate, and 
inhibition of tolerance to prostatic antigens (Schweizer et al. 2014).
1.3.2.1
Androgen Deprivation Therapy
Nonclinical data describing restoration of thymic architecture, normalization of thymocyte 
differentiation, proliferation and increase in peripheral naive T cells in surgically 
castrated mice have recently been corroborated by similar findings in humans 
(Sutherland et al. 2005).  In addition, androgen ablation therapy induced T-cell infiltration 
of prostate cancer tissue, induced prostate-specific humoral immune responses and 
increased T-cell proliferative responsiveness in patients (Mercader et al. 2001; 
Roden et al. 2004; Nesslinger et al. 2007; Gannon et al. 2009; Morse et al. 2010).  
In mouse models, the presence of invasive prostate cancer leads to prostate antigen 
recognition by T cells and subsequent development of immune tolerance.  Androgen 
ablation therapy administered in the presence of prostate cancer reversed this acquired 
immune tolerance (Drake et al. 2005; Arredouani et al. 2010).  Similarly, 
castration-enhanced antigen specific IFN-production after vaccination and castrated 
mice had elevated IL-2 and IFN-production capacity compared to sham-castrated mice 
(Viselli et al. 1995; Koh et al. 2009).
1.3.2.2
Enzalutamide
Enzalutamide is a modern anti-androgen therapy and has only recently been studied 
with regard to its immune modulatory properties.  Similar to ADT, murine and human 
data demonstrated that enzalutamide enhances thymic production of naive T cells 
(Ardiani et al. 2013; Donahue et al. 2016).  Other immune activating properties 
described in humans include, but are not limited to, an increase in natural killer cells, a 
decrease in myeloid derived suppressor cells, and an increased activation of IFN-
signaling in peripheral blood mononuclear cells (Donahue et al. 2016).  Preliminary 


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clinical data of enzalutamide in combination with a PD-1-inhibitor, pembrolizumab, 
showed almost complete PSA responses in three out of ten patients who had previously 
failed enzalutamide or abiraterone and enzalutamide (Graff et al. 2016).  Two of these 
3 patients had measurable disease at study entry; both achieved a PR. 
Murine studies further suggest that enzalutamide sensitizes tumor cells to cytotoxic 
T- cell mediated lysis and promotes tumor apoptosis, which may lead to an increase in 
tumor-associated antigens and antigen presentation (Guerrero et al. 2013; 
Ardiani et al. 2013).  Moreover, a combination of enzalutamide with a vaccine improved 
survival in mice compared to no treatment, vaccine alone, and enzalutamide alone 
(Ardiani et al. 2013; Kwilas et al. 2015).
In summary, these clinical and nonclinical data support combining enzalutamide and 
immunotherapy, with enzalutamide hypothesized to serve as an immune adjuvant.
1.3.2.3
Atezolizumab Tolerability Profile during 
Combination Treatment
In studies investigating the combination of atezolizumab with other anti-cancer agents, 
the incidence of adverse events in the treatment arms with combined use was consistent 
with the known safety profiles of the individual study drugs.  Fatigue, decreased appetite, 
nausea and cough were adverse events reported in more than 10% of patients treated 
with atezolizumab monotherapy and in combination therapy.  Through appropriate 
routine evaluations, investigational workup, and early mitigations such as management 
guidelines, the majority of patients were able to continue atezolizumab therapy (see 
Atezolizumab Investigator's Brochure for detailed safety results).
In summary, the immune modulatory properties of hormonal therapy and especially 
enzalutamide, the tolerability of atezolizumab when given in combination therapy and the 
unmet need in the proposed patient population, provide a rationale for the proposed 
study.  This treatment strategy could provide a meaningful clinical benefit to patients with 
mCRPC with a manageable tolerability profile. 
1.3.3
Benefit-Risk Assessment
This study will enroll patients with mCRPC after failure of an androgen synthesis 
inhibitor (e.g., abiraterone) and failure of, ineligibility for, or refusal of a taxane regimen.  
Given the relatively poor prognosis and limited treatment options for these patients, 
this population is considered appropriate for studies of novel therapeutic candidates.  
Patients in both treatment arms will receive a standard-of-care treatment, 
(i.e., enzalutamide).  The benefit-risk ratio for atezolizumab in combination with 
enzalutamide versus enzalutamide alone is expected to be acceptable in this setting.
2.
OBJECTIVES AND ENDPOINTS
This is a Phase III, multicenter, randomized open-label study designed to evaluate the 
efficacy and safety of atezolizumab in combination with enzalutamide compared with 


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enzalutamide alone in patients with mCRPC after failure of an androgen synthesis 
inhibitor and failure of, ineligibility for, or refusal of a taxane regimen.  Specific objectives 
and corresponding endpoints for the study are outlined in Table 1.
Table 1
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab/enzalutamide
compared with enzalutamide alone
OS, defined as the time from randomization to death from 
any cause
Country-Specific Objective 
for China
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab/enzalutamide 
compared with enzalutamide alone 
in patients who are residents of 
China
Same as the primary objective
Secondary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab/enzalutamide
compared with enzalutamide alone
OS probability at 12 and 24 months
Time to first SSE
An SSE is defined as external beam radiation therapy to 
relieve skeletal symptoms (including initiation of 
radium-223 dichloride or other types of radionuclide 
therapy to treat symptoms of bone metastases), new 
symptomatic pathologic bone fracture, clinically 
apparent occurrence of spinal cord compression, or 
tumor related orthopedic surgical intervention.
rPFS, as assessed by the investigator, and adapted from 
the PCWG3 criteria (Scher et al. 2016; see Appendix 2).  
rPFS is defined as the time from randomization to the 
earliest occurrence of one of the following:
A patient is considered to have progressed by bone scan 
if:
The first bone scan with 2 new lesions compared to 
baseline is observed 12 weeks from randomization 
and is confirmed by a second bone scan taken 
6 weeks later showing 2 additional new lesions (a 
total of 4 new lesions compared to baseline); the 
date of progression is the date of the first 
post-treatment scan, OR
After the first post-treatment scan, 2 new lesions are 
observed relative to the first post-treatment scan, 
which is confirmed on a subsequent scan 6 weeks 
later; the date of progression is the date of the 
post-treatment scan when 2 new lesions were first 
documented.
Progression of soft tissue lesions, as defined per 
PCWG3 modified RECIST v1.1 
Death from any cause


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Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Efficacy Objective 
(cont.)
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab/enzalutamide
compared with enzalutamide alone
(cont.)
rPFS probability at 6 and 12 months
PSA response rate, defined as a 50% decrease in PSA 
from baseline that is confirmed after 3 weeks by a 
consecutive confirmatory PSA measurement
Time to PSA progression, defined as the time from 
randomization to the time of PSA progression, as defined 
per the PCWG3 criteria (Scher et al. 2016):
In patients with no PSA decline from baseline, PSA 
progression is defined as a 25% increase and an 
absolute increase of 2 ng/mL above the baseline 
value, 12 weeks after baseline.
In patients with an initial PSA decline from baseline, 
PSA progression is defined as a 25% increase and an 
absolute increase of 2 ng/mL above the nadir value, 
which is confirmed by a consecutive second value 
obtained 3 weeks later.
Objective response rate in soft tissue lesions, defined as 
the proportion of patients with either a CR or PR on two 
consecutive occasions 6 weeks apart, as determined 
by the investigator through use of PCWG3 criteria 
(see Appendix 2)
Exploratory Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
atezolizumab/enzalutamide
compared with enzalutamide alone
DOR in soft tissue lesions, defined for patients who had an 
objective response in soft tissue as the time from the first 
documented objective response in soft tissue to 
radiographic disease progression, as determined by the 
investigator through use of PCWG3 criteria
DCR, defined as the proportion of patients with a best 
response of confirmed CR or PR or stable disease in soft 
tissue lesions per PCWG3-modified RECIST v1.1 and/or 
no confirmed radiographic disease progression on bone 
scan per PCWG3 criteria (see Appendix 2)
Modified progression free survival based on radiographic 
disease progression and unequivocal clinical progression, 
defined as the time from randomization to the earliest 
occurrence of one of the following:
Radiographic disease progression per PCWG3 criteria 
(as defined above)
Unequivocal clinical progression characterized as at least 
one of the following:
Symptomatic skeletal-related event (as defined above)
Deterioration in ECOG performance status by at least 
two points that is attributed to disease progression
Initiation of next systemic anti-cancer therapy 


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Table 1
Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety and 
tolerability of atezolizumab and 
enzalutamide compared with 
enzalutamide alone
Incidence, nature, frequency, and severity of adverse 
events, with severity determined through use of the 
National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE v4.0)
Clinically significant changes in vital signs, and clinical 
laboratory results during and following study treatment 
administration
Pharmacokinetic Objectives
Corresponding Endpoints
To characterize the 
pharmacokinetics of atezolizumab 
when given in combination with 
enzalutamide
To characterize the 
pharmacokinetics of enzalutamide
and its active metabolite 
N-desmethyl enzalutamide when 
enzalutamide is administered 
alone or in combination with 
atezolizumab
Serum concentration of atezolizumab at specified 
timepoints
Plasma concentration of enzalutamide and N-desmethyl 
enzalutamide at specified timepoints in the safety run-in 
phase and in a PK cohort in the randomized phase 
(approximately 30 patients per treatment arm)
Exploratory Biomarker Objective
Corresponding Endpoints
To identify biomarkers that are 
predictive of response to 
atezolizumab and/or enzalutamide 
(i.e., predictive biomarkers), are 
associated with progression to a 
more severe disease state (i.e., 
prognostic biomarkers), are 
associated with acquired 
resistance to atezolizumab and/or 
enzalutamide, are associated with 
susceptibility to developing 
adverse events, can provide 
evidence of atezolizumab and/or 
enzalutamide activity, or can 
increase the knowledge and 
understanding of disease biology 
on the basis of the following 
endpoint:
Relationship between biomarkers in blood, urine, and 
tumor tissue (listed in Section 4.5.6) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints


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Table 1
Objectives and Corresponding Endpoints (cont.)
Immunogenicity Objective
Corresponding Endpoint
To evaluate the immune response 
to atezolizumab
Incidence of anti-therapeutic antibodies (ATAs) against 
atezolizumab
Exploratory Immunogenicity 
Objective
Corresponding Endpoint
To evaluate potential effects of 
ATAs
Relationship between ATA status and efficacy, safety, or 
PK endpoints
AQAanalgesic quantification algorithm; ATAanti-therapeutic antibody; CRcomplete 
response; CRPCcastration-resistant prostate cancer; DCRdisease control rate; 
DORduration of response; ECOG Eastern Cooperative Oncology Group; NCI
CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events; 
OSoverall survival; PCWG3Prostate Cancer Working Group 3; PFphysical function; 
PFSprogression-free survival; PKpharmacokinetic; PRpartial response; 
PSAprostate-specific antigen; rPFSradiographic progression-free survival; 
RECIST Response Evaluation Criteria in Solid Tumors; SSEsymptomatic skeletal event.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, multicenter, randomized, open-label study designed to evaluate the 
safety and efficacy of atezolizumab in combination with enzalutamide compared with 
enzalutamide alone in patients with mCRPC after failure of an androgen synthesis 
inhibitor (e.g., abiraterone) and failure of, ineligibility for, or refusal of a taxane regimen. 
Specifically, the study will include the following patients:

Patients who have progressed during treatment with an androgen synthesis inhibitor 
(e.g., abiraterone) for prostate cancer and have received a prior taxane regimen for 
metastatic hormone-sensitive and/or metastatic castration-resistant prostate cancer 

Patients who have progressed during treatment with an androgen synthesis inhibitor 
(e.g., abiraterone) for prostate cancer and who are not fit enough to receive a 
taxane regimen for mCRPC

Patients who have progressed during treatment with an androgen synthesis inhibitor 
(e.g., abiraterone) for prostate cancer and who decline a taxane regimen for 
mCRPC after an informed discussion


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Figure 1
Study Schema
CRPCcastration-resistant prostate cancer; iDMCindependent Data Monitoring Committee.
Notes:  Enzalutamide:  160 mg orally per day.  Atezolizumab:  1200 mg by IV infusion on Day 1 
of each 21-day cycle.  Treatment will continue until lack of clinical benefit, worsening of 
symptoms, decline in performance status, or tumor progression at a critical site that cannot be 
managed with protocol-accepted therapy.  No crossover will be allowed from the control arm to 
the experimental arm.
Safety run-in phase:  Ten patients will be followed for at least 1 cycle (21 days) after which the 
iDMC will make a recommendation regarding initiating enrollment in the randomized phase of the 
study.  Patients in the safety run-in phase will continue to receive study treatment and be 
followed for safety and efficacy.
Approximately 180 sites globally will participate in the study and approximately 
730 patients will be enrolled (first 10 patients in the safety run-in cohort followed by 
720 patients in the global randomized phase).
The Sponsor recommends that investigators use their clinical judgment to determine if 
the patients who remain on the study appear to be benefitting from their therapy, and 
discuss the benefits and risks with patients of remaining on their current treatment.  
Patients who remain on treatment until the closure of the study will be able to continue to 
receive treatment as part of a post-trial access program.  Patients may start transferring 
to the program after the required approvals are available (as applicable).
Safety Run-In Phase
In the safety run-in phase of the study, 10 patients will be enrolled and will receive 
atezolizumab in combination with enzalutamide.  After 10 patients have been enrolled, 
enrollment will be stopped temporarily and all patients will be monitored closely for 
adverse events until the last patient has completed the first cycle (21 days).  Patients will 
continue to receive study treatment and be followed for safety and efficacy per the 
schedule of activities in Appendix 1.
After 10 patients have received study treatment and completed at least one cycle of 
study treatment (21 days), an independent Data Monitoring Committee (iDMC) will 
review available data and make a recommendation regarding initiation of the 
randomized phase of the study.  For further information on the iDMC, see Section 3.2. 


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Randomized Phase
Enrollment in the randomized phase of the study will be initiated after review of the 
safety run-in data by the iDMC and the Sponsor.  Approximately 720 patients will be
enrolled in the randomized phase of the study.  Patients will be randomized to one of the 
following treatment arms in a 1:1 ratio (experimental to control arm): 

Arm A (experimental arm):  atezolizumab in combination with enzalutamide

Arm B (control arm):  enzalutamide alone
Randomization will be conducted with the aid of an interactive voice/Web response 
system (IxRS).
The randomization will be stratified by the following stratification factors:

Prior taxane-containing regimen for mCRPC, defined as at least two cycles of a 
taxane-containing regimen (yes vs. no)

Presence of liver metastasis (yes vs. no)

LDH upper limit of normal (ULN) vs. ULN

Pain severity (BPI-Short Form [SF] Question 3 assessing pain at its worst over the 
past 24 hours [score 4 vs. 4]) (Appendix 7)
A stratified permuted-block randomization will be implemented to balance treatment 
assignment within stratum levels.
Patient recruitment will be capped with respect to two of the stratification factors:  the 
proportion of patients who have not received a prior taxane-containing regimen for 
mCRPC will be approximately 50% or less, and the proportion of patients with liver 
metastases at baseline will be approximately 10% or less.  Presence of liver metastases 
will be determined based on CT or MRI scan.  The purpose of the cap is to ensure the 
prevalence of these two prognostic factors in the study population will be similar to that 
reported in the targeted population.
Atezolizumab will be administered at a fixed dose of 1200 mg by IV infusion on Day 1 of 
each 21-day cycle until investigator-assessed confirmed radiographic disease 
progression per PCWG3 or unacceptable toxicity.
Enzalutamide will be administered orally at a dose of 160 mg (four 40-mg capsules) daily 
until investigator-assessed confirmed radiographic disease progression per PCWG3 or 
unacceptable toxicity.


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Patients will be permitted to continue study treatment after PCWG3 criteria are met for 
confirmed radiographic disease progression if they meet all of the following criteria 
(treatment until they are no longer clinically benefiting per PCWG3 recommendation 
[Scher et al. 2016]).

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs indicating unequivocal progression of disease

No decline in ECOG performance status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed and stabilized by protocol-allowed medical 
interventions

Written consent to acknowledge deferring other treatment options in favor of 
continuing study treatment at the time of initial disease progression
No crossover will be allowed from the control arm to the experimental arm.
Patients with rising PSA levels only (i.e., in the absence of confirmed radiographic or 
clinical progression) should continue to receive study treatment per PCWG3 criteria and 
recommendations (Scher et al. 2016).  PSA rise without evidence of confirmed 
radiographic progression or a symptomatic skeletal-related event is strongly discouraged 
as a criterion to start a new systemic anti-neoplastic therapy during the first 12 weeks of
therapy and is discouraged as a criterion to start a new systemic anti-neoplastic therapy 
throughout the study.
Focal palliative radiography (e.g., external-beam radiotherapy to address single sites of 
disease), initiation of bisphosphonates or denosumab, standard-of-care corticosteroid 
use of no greater than the equivalent of 10 mg of prednisone or prednisolone per day 
and pain management are allowed and should not result in discontinuation of study 
treatment.  However, patients should be evaluated for clinically apparent SSE.
Initiation of radium-223 dichloride to manage symptomatic bone lesions is not permitted 
during study treatment.
Patients will undergo scheduled tumor assessments at baseline and every 9 weeks 
(3 days) for the first 27 weeks and every 12 weeks (6 days) thereafter until confirmed 
radiographic disease progression per PCWG3.  In the absence of confirmed 
radiographic progression, tumor assessments should continue, regardless of whether 
patients start new anti-cancer therapy, until death, loss of follow-up, withdrawal of 
consent, or study termination by the Sponsor, whichever occurs first.  For patients who 
continue to receive study treatment following confirmed disease progression, 
assessments will continue until loss of clinical benefit.


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All primary imaging data used for tumor assessments may be collected by the Sponsor 
to enable the possibility of a centralized, independent review of response endpoints by 
an Independent Review Facility (IRF).
Safety assessments will include the incidence, nature, and severity of adverse events 
and laboratory abnormalities graded per the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory 
safety assessments will include the regular monitoring of hematology and blood 
chemistry.
Serum samples will be collected in patients in Arm A (atezolizumab and enzalutamide) 
to monitor atezolizumab pharmacokinetics and to detect the presence of antibodies to 
atezolizumab.  Plasma samples to monitor enzalutamide and N-desmethyl enzalutamide 
pharmacokinetics will also be collected in the safety run-in phase and in a PK cohort in 
the randomized phase (approximately 30 patients per treatment arm).  Patient samples, 
including archival tumor tissues, as well as urine, serum, plasma and whole blood, will 
be collected for future exploratory biomarker assessments for all patients in the 
randomized phase.
It is recommended that patients undergo tumor biopsy sample collection, if deemed 
clinically feasible by the investigator, at the time of first evidence of confirmed 
radiographic disease progression according to PCWG3 criteria (within 40 days after 
confirmed radiographic progression or prior to the start of new anti-cancer treatment, 
whichever is sooner). These samples will be analyzed to evaluate the utility of the 
biopsy in distinguishing pseudoprogression (caused by tumor-infiltrating ICs) from true 
progression.  In addition, tumor tissue biomarkers related to resistance, disease 
progression, and clinical benefit of atezolizumab may be analyzed.
Patients who are withdrawn from study treatment will be evaluated within 30 days and 
approximately 120 days after last study treatment for a treatment discontinuation visit 
and safety visit, respectively.  Thereafter, patients will enter a post-trial access program
(as applicable).
An external iDMC will evaluate safety and efficacy data according to policies and 
procedures detailed in an iDMC Charter (see Section 3.2).
A schedule of activities is provided in Appendix 1.
3.2
INDEPENDENT DATA MONITORING COMMITTEE
An iDMC will be convened to evaluate efficacy and safety data during the study.  
Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  The iDMC will conduct its first review of safety 
data when 10 patients in the safety run-in have completed at least 1 cycle of study 
treatment.


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On the basis of the different mechanisms of action for each product, the overlapping 
toxicities of enzalutamide and atezolizumab are thought to not significantly increase the 
incidence and type of adverse events seen in respective monotherapy studies.  In a 
study investigating enzalutamide in combination with an antiPD-1 antibody, immune 
mediated toxicities observed were consistent with other studies investigating the 
anti-PD-1 antibody alone in solid tumors (Graff et al 2016).
The iDMC will specifically evaluate clinically relevant toxicities that are known to be 
associated with atezolizumab and/or enzalutamide.  Refer to Table 3 of the protocol and 
Section 6 of the Atezolizumab Investigator’s Brochure, and enzalutamide local 
prescribing information.  These adverse events include, but are not limited to, the 
following:

Gastrointestinal toxicities including diarrhea and immune-mediated colitis

Immune-mediated hepatitis

Immune-mediated pancreatitis 

Immune-mediated pneumonitis 

Immune-mediated endocrinopathies (i.e., diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, and hypophysitis) 

Immune-mediated myocarditis 

Neurologic disorders including immune-mediated meningoencephalitis, 
immune-mediated neuropathies (i.e., myasthenic syndrome and/or myasthenia 
gravis, Guillain-Barré syndrome), vertigo and/or dizziness, falls, seizures and 
posterior reversible encephalopathy syndrome (PRES)
The iDMC will evaluate safety data and compare the type and frequency of events 
observed to the type and frequency of events described in the Atezolizumab 
Investigator’s Brochure and enzalutamide local prescribing information.  On the basis of
this evaluation, the iDMC may recommend that an additional 10 patients be enrolled into 
the safety run-in portion of the study. Furthermore, the iDMC may request an extension 
of the observation period until the last patient has completed two cycles (42 days) or an 
increase in the periodic safety monitoring frequency during the randomized phase of the 
study.
After the safety run-in is completed, the iDMC will make a recommendation regarding 
initiating enrollment in the randomized phase of the study.
During the randomized phase of the study, the iDMC will continue to evaluate safety 
data on a periodic basis, approximately every 3 months for the first year and 
approximately every 6 months thereafter, until the time of the analysis of the primary 
efficacy endpoint.  The safety data will include demographics and baseline 
characteristics, study drug exposure, deaths, adverse events, serious adverse events, 
and relevant laboratory data.  Following their data review, the iDMC will provide a 


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recommendation as to whether the study may continue, modifications to the protocol 
should be implemented, or the study should be stopped. 
For management of patients who experience specific adverse events during the safety 
run-in and randomized phase of the study, see Section 5.1.4.
One OS interim efficacy analysis will be conducted according to the methods described 
in Section 6.8.1.  The iDMC will review results of the interim efficacy analysis and, on the 
basis of the predefined stopping criteria specified in the iDMC Charter, the iDMC will 
provide its recommendation whether to release the study results early because of 
substantial evidence of efficacy.
The Sponsor will remain blinded to the study results until the time of the primary analysis 
of the primary endpoint (or the time of the OS interim analysis if the interim results are 
released).  All summaries and analyses by treatment arm for the iDMC review will be 
prepared by an external independent Data Coordinating Center (iDCC). 
The final decision on whether to follow the iDMC’s recommendations will rest with 
the Sponsor.
Any outcomes of these efficacy and safety reviews that affect study conduct will be 
communicated by the Sponsor in a timely manner to Health Authorities and to 
investigators for notification to their Institutional Review Boards/Ethics Committees
(IRB/EC).
3.3
END OF STUDY AND LENGTH OF STUDY
The Sponsor has decided to close Study CO39385 (IMbassador250) following the 
recommendation of the iDMC to terminate the trial due to futility.
3.4
RATIONALE FOR STUDY DESIGN
3.4.1
Rationale for Atezolizumab Dose and Schedule
The fixed dose of 1200 mg (equivalent to an average body weightbased dose of 
15 mg/kg) every three weeks (Q3W) was selected on the basis of both nonclinical 
studies and available clinical data from a Phase I study, PCD4989g, as described below.
The target exposure for atezolizumab was projected on the basis of clinical and 
nonclinical parameters, including nonclinical tissue distribution data in tumor-bearing 
mice, target-receptor occupancy in the tumor, and observed atezolizumab interim 
pharmacokinetics in humans.  The target trough concentration (Ctrough) was projected 
to be 6 g/mL on the basis of several assumptions, including the following:  
1) 95% tumor-receptor saturation is needed for efficacy and 2) the tumor interstitial 
concentrationto-plasma ratio is 0.30 on the basis of tissue distribution data in 
tumor-bearing mice.


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The atezolizumab dose is also informed by available clinical activity, safety, PK, and 
immunogenicity data.  Anti-tumor activity has been observed in doses ranging from 1 to 
20 mg/kg.  The maximum tolerated dose of atezolizumab was not reached, and no 
dose-limiting toxicities have been observed at any dose in Study PCD4989g.  Available 
preliminary PK data (0.0320 mg/kg) from Study PCD4989g suggest that for doses 
1 mg/kg, overall, atezolizumab exhibits pharmacokinetics that are both linear and 
consistent with typical IgG1 antibodies.
ATAs to atezolizumab were associated with changes in pharmacokinetics for some 
patients in the lower dose cohorts (0.3, 1, and 3 mg/kg), but patients treated at 10, 15, 
and 20 mg/kg maintained the expected target trough levels of drug despite the detection 
of ATAs.  To date, no relationship has been observed between the development of 
measurable ATAs and safety or efficacy.  After review of available PK and ATA data for 
a range of doses, 15 mg/kg Q3W was identified as the lowest atezolizumab dosing 
regimen that would maintain Ctrough at 6 g/mL while further safeguarding against 
interpatient variability and the potential for ATAs to lead to subtherapeutic levels of 
atezolizumab.
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose compared with a body weightadjusted dose.  Therefore, 
patients in this study will be treated Q3W at a fixed dose of 1200 mg (equivalent to an 
average body weightbased dose of 15 mg/kg).
3.4.2
Rationale for Patient Population
Despite multiple approvals in prostate cancer in the last 5 years, a strong unmet need 
exists for agents with durable disease control in patients who have failed an androgen 
synthesis inhibitor and have failed, are ineligible for, or refused a taxane regimen.  
Generally, outcomes in patients who have failed two prior lines of therapy remain poor 
with response rates of approximately 10%15%, PFS of approximately 3 months and an 
OS of less than one year (Caffo et al. 2015; Roviello et al. 2015).
Docetaxel, with or without prednisone, is considered standard of care for patients with 
symptomatic metastatic disease (Petrylak et al. 2004; Tannock et al. 2004); however, it 
is poorly tolerated in the elderly.  Indeed, population-based studies from Sweden and the 
United Kingdom suggest that only approximately 20% of patients who die from prostate 
cancer had received docetaxel, with significantly higher treatment rates among younger 
patients and patients with little comorbidities (Harris et al. 2011; Lissbrant et al. 2013).  
U.S. studies describe docetaxel treatment rates of approximately 40%, and 16% in the 
elderly (Onukwugha et al. 2011; Lafeuille et al. 2013).  Low treatment rates with a taxane 
regimen could be attributed to different reasons such as the associated toxicity profile or
unwillingness of patients to receive chemotherapy.
Recently, trials have evaluated the addition of therapies earlier in the clinical course of 
prostate cancer. The addition of docetaxel to ADT in patients with newly diagnosed, 


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metastatic HSPC was evaluated in two studies, both of which demonstrated statistically 
significant improvements in OS (Sweeney et al. 2015; James et al. 2016), rendering 
docetaxel plus ADT as a standard-of-care treatment for patients with metastatic HSPC 
(Parker et al. 2015; Mohler et al. 2016).
Similarly, the addition of abiraterone and prednisone/prednisolone to ADT in patients 
with HSPC recently demonstrated a significantly improved OS and rPFS in these 
patients compared to ADT alone (Fizazi et al. 2017; James et al. 2017). The LATITUDE 
study, which enrolled patients with HSPC, demonstrated that the concomitant 
administration of abiraterone with ADT would have a similar improvement in progression 
free survival (33 months) as sequential administration of ADT for HSPC (14.8 months) 
followed by abiraterone on progression to mCRPC (16.5 months) (Ryan et al. 2013; 
Fizazi et al. 2017), suggesting that the patients progressing after these therapies may be 
biologically similar.
Despite the introduction of these life-prolonging therapies for HSPC, patients who 
progress to develop mCRPC continue to have only limited treatment options that 
improve their overall outcome.
In summary, based on the poor survival prognosis despite treatment, low rates of taxane 
use in clinical practice and potential cross-resistance between hormonal treatments, 
patients who progress on an androgen synthesis inhibitor and have failed, are not fit, or 
unwilling, to receive subsequent taxane therapy represent a patient population in clinical 
practice with an unmet need.  With a relatively poor survival prognosis of approximately 
one year, this population is considered appropriate for this Phase III study.
3.4.3
Rationale for Choice of Enzalutamide
Enzalutamide is an oral androgen receptor blocker that impacts receptor signaling at 
multiple steps, including competitive binding to the androgen receptor, inhibition of 
nuclear translocation, and consequently prevention of binding of the androgen receptor 
to relevant activation sequences in the nucleus.  Enzalutamide demonstrated statistically 
significant improvement over placebo in the primary endpoint of OS in the 
post-docetaxel setting in mCRPC patients (18.4 vs. 13.6 months; HR0.631, p0.0001).  
Additionally, key secondary endpoints demonstrated statistically significant differences 
including rPFS, time to first skeletal-related event, and time to PSA progression 
(Scher et al. 2012).  In a second pivotal study in the pre-docetaxel setting in 
asymptomatic and mildly symptomatic patients, enzalutamide demonstrated statistically 
significant improvement over placebo in the co-primary endpoints of rPFS (not yet 
reached vs. 3.9 months; HR0.186, p0.0001) and OS (32.4 vs. 30.2 months; 
HR0.706, p0.0001 [Beer et al. 2014]).  Other key secondary endpoints that 
supported the rPFS and OS data included time to first skeletal-related event, time to 
initiation of cytotoxic chemotherapy, and time to PSA progression.


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On the basis of the results of these studies, enzalutamide has been approved for 
treatment of mCRPC by the U.S. Food and Drug Administration (FDA) and for treatment 
of adult men with mCRPC whose disease has progressed on or after docetaxel and 
treatment of adult men with mCRPC who are asymptomatic or mildly symptomatic after 
failure of ADT in whom chemotherapy is not yet clinically indicated by the European 
Medicines Agency (Xtandi® U.S. Prescribing Information and Summary of Product 
Characteristics).  According to a recent study analyzing the treatment evolution for 
mCRPC in the United States, 75% of patients received newer hormonal treatment in 
first-line.  Hormonal treatment remained the therapy of choice in second-line with 
approximately 60% of patients receiving abiraterone or enzalutamide (Flaig et al. 2015).
This study enrolls patients with mCRPC after failure of an androgen synthesis inhibitor 
and failure of, ineligibility for, or refusal of a taxane regimen.  Enzalutamide is indicated 
for and is commonly used as a treatment for mCRPC and can thus be considered a 
reasonable standard of care and relevant control.
3.4.4
Rationale for Open-Label Design
This is an open-label study.  The use of a placebo control was not considered 
appropriate in this elderly study population due to the patient burden associated with 
repeated placebo intravenous infusions and the associated risk for infusion-related
complications.
3.4.5
Rationale for Stratification Factors
The randomization will be stratified on the basis of prior taxane-containing regimen for 
mCRPC (yes vs. no), pain severity (BPI-SF Question 3 Score 4 vs. 4), presence of 
liver metastasis (yes vs. no), and serum LDH (ULN vs ULN).
These stratification factors have been identified as critical prognostic factors for patients 
with mCRPC.  The magnitude of benefit in patients treated with a hormonally-based 
therapy may be attenuated after a taxane-containing therapy (de Bono et al. 2011; 
Scher et al. 2012; Ryan et al. 2013; Beer et al. 2014), possibly partly due to a 
cross-resistance mechanism in which microtubule inhibition may alter translocation of 
the androgen receptor (van Soest et al. 2013).  Prior taxane treatment for mCRPC is 
defined as administration of at least 2 cycles of a taxane-containing regimen.
Presence of pain, visceral disease, especially liver metastases, and elevation of LDH 
have been consistently and independently associated with worse prognosis in 
multivariate analysis and disease nomograms (Armstrong et al. 2010; Halabi et al. 2014;  
Chi et al. 2016).  Patients with a BPI-SF score on Question 3 of 4, presence of lung 
and/or liver metastasis, and LDH elevation at baseline had inferior median OS compared 
to patients with respective good prognostic characteristics in the pivotal Phase III study 
investigating enzalutamide versus placebo post-docetaxel (Scher et al. 2012).


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3.4.6
Rationale for Safety Run-In
Currently, no safety data is available with the combination of atezolizumab and 
enzalutamide.  Based on the different mechanism of action for each product, the 
overlapping risks of enzalutamide and atezolizumab are thought to be minimal and are 
not expected to significantly increase the incidence of adverse events seen in 
monotherapy studies.  Nonetheless, potential overlapping toxicities between 
enzalutamide and atezolizumab might include common adverse reactions of 
asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, 
peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, 
hypertension, and liver function abnormalities.  Signs and symptoms suggestive of 
posterior reversible encephalopathy syndrome for enzalutamide or meningitis 
encephalitis for atezolizumab have been reported. 
In studies investigating the combination of atezolizumab with other anti-cancer agents, 
the incidence of adverse events in the treatment arms with combined use was consistent 
with the known safety profiles of the individual study drugs.  Fatigue, decreased appetite, 
nausea and cough were adverse events reported in more than 10% of patients treated 
with atezolizumab monotherapy and in combination therapy.  Through appropriate 
routine evaluations, investigational work-up, and early mitigations such as
implementation of management guidelines, the majority of patients were able to continue 
atezolizumab therapy (see Atezolizumab Investigator's Brochure for detailed safety 
results). 
In a study investigating enzalutamide in combination with an antiPD-1 antibody in 
10 patients with mCRPC, immune toxicities observed were consistent with other studies 
investigating the antiPD-1 antibody alone in solid tumors (Graff et al. 2016).
Appropriate measures will be taken to ensure the safety of patients participating in this 
study (see Section 5.1).  A safety run-in phase is incorporated into the study design, 
which will allow evaluation of the preliminary safety profile of atezolizumab in 
combination with enzalutamide prior to initiating the randomized phase of the study.
Ten patients will be enrolled and will receive atezolizumab in combination with 
enzalutamide.  After 10 patients have received study treatment and completed at least 
one cycle of study treatment (21 days), an iDMC will review available data and make a 
recommendation regarding initiation of the randomized phase of the study.
In the randomized phase of the study, the iDMC will be convened to evaluate safety data 
approximately every 3 months for the first year and approximately every 6 months 
thereafter, until the time of the analysis of the primary efficacy endpoint. For further 
details regarding the iDMC see Section 3.2.


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3.4.7
Rationale for the Use of Response Criteria
3.4.7.1
PCWG3 Criteria 
Measurable disease occurs infrequently in prostate cancer, whereas bone metastases 
develop in upwards to 90% of patients (Pezaro et al. 2013).  An international expert 
committee of prostate cancer investigators, the PCWG3, met between 2012 and 2015 to 
formulate criteria to define meaningful clinical endpoints in mCRPC (Scher et al. 2016).  
This study will follow the expert recommendations to assess radiographic disease 
progression (see Appendix 2).
3.4.8
Rationale for Treatment beyond Radiographic Progression
In studies of immunotherapeutic agents, complete response (CR), PR, and stable 
disease have each been shown to occur after radiographic evidence of an apparent 
increase in tumor burden.  This initial increase in tumor burden caused by immune cell 
infiltration in the setting of a T-cell response has been termed pseudoprogression 
(Hales et al. 2010).  In Study PCD4989g, evidence of tumor growth followed by a 
response was observed in several tumor types.  In some responding patients with 
radiographic evidence of ICs there are no viable cancer cells.
In addition, it is likely that a patient with mCRPC has heterogeneous disease with 
multiple clones and foci of malignancy (clinical and/or subclinical).  A patient with 
confirmed disease progression at one or more lesions may have other clones and foci of 
disease that may be benefiting from continued treatment with study medication.  As a 
consequence, Phase III studies in mCRPC, including a study investigating enzalutamide 
versus placebo in the post-docetaxel setting, allowed patients to continue to receive
study treatment in the absence of unequivocal clinical progression (De Bono et al. 2011; 
Scher et al. 2012; Ryan et al. 2013). 
In this study, selected patients may be considered for treatment after PCWG3 criteria for 
confirmed radiographic disease progression are met, provided the benefit-risk ratio is 
judged to be favorable (see criteria in Section 3.1) and the patient provides written 
consent to continue treatment.  Patients should be discontinued for unacceptable toxicity 
or symptomatic deterioration attributed to disease progression as determined by the 
investigator after an integrated assessment of radiographic and biochemical data, biopsy 
results (if available), and clinical status.
3.4.9
Rationale for Biomarker Assessments
3.4.9.1
Rationale for Collection of Tumor Specimens 
(Fresh and/or Archival)
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPD-1 and antiPD-L1 therapy (Topalian et al. 2012; Herbst et al. 2014; 
Borghaei et al. 2015; Fehrenbacher et al. 2016; Herbst et al. 2016; 
Rosenberg et al. 2016).  In the current study, archival or baseline tumor specimens will 
be collected from patients and tested for PD-L1 expression by a central laboratory.  In 
addition to the assessment of PD-L1 status, other exploratory biomarkers, such as 


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potential predictive and prognostic biomarkers related to the clinical benefit and safety of 
atezolizumab, tumor immunobiology, mechanisms of resistance, or tumor type will be 
analyzed.  An archival specimen, if available, should also be submitted in patients who 
choose to undergo a fresh biopsy.
Patients who have additional pre-study tumor tissue samples (i.e., beyond those 
required to meet eligibility requirements) from procedures performed at different times 
during the course of their prostate cancer may consent (but are not required) to also 
submit these samples for central testing.  Tissue samples that are obtained at multiple 
times from individual patients may contribute to an improved understanding of the 
dynamics of immunobiology and relationship with intervening anti-cancer therapy.  
Discussion of optional samples collected from consenting patients for exploratory 
biomarker analyses may be found in Section 4.5.9, Optional Samples for the Research 
Biosample Repository (RBR).
3.4.9.2
Rationale for Collection of Tumor Specimens at Progression
It is recommended that patients undergo tumor biopsy sample collection, if deemed 
clinically feasible by the investigator, at the time of first evidence of confirmed 
radiographic disease progression according to PCWG3 criteria.  These samples will be 
analyzed to evaluate the utility of the biopsy in distinguishing pseudoprogression 
(caused by immune cell infiltration) from true progression.  In addition, tumor tissue 
biomarkers related to resistance, disease progression, and clinical benefit of 
atezolizumab may be analyzed.
3.4.9.3
Rationale for Blood and Urine Sampling for Biomarkers
Blood and urine samples will be collected at baseline and during the study to evaluate 
changes in surrogate biomarkers.  Changes in biomarkers such as cytokines associated 
with T-cell activation, circulating tumor DNA (ctDNA) concentration, and lymphocyte 
subpopulations may provide evidence of biologic activity of atezolizumab in humans.  
Correlations between these biomarkers and safety and efficacy endpoints will be 
explored to identify blood and urine-based biomarkers that might predict which patients 
are more likely to benefit from atezolizumab.
3.4.9.4
Rationale for Sampling for Genomics Analysis
Tumor tissue and blood samples collected at baseline and, if deemed clinically feasible 
by the investigator, tumor tissue collected at the time of disease progression will enable 
whole exome sequencing (WES) and/or next-generation sequencing (NGS) to identify 
somatic mutations that are predictive of response to study treatment, are associated with 
progression to a more severe disease state, are associated with acquired resistance to 
study treatment, are associated with susceptibility to developing adverse events, or can 
increase the knowledge and understanding of disease biology.
Genomics is increasingly informing researcher understanding of disease pathobiology.  
WES provides a comprehensive characterization of the exome and, along with clinical 


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data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
3.4.10
Rationale for Patient-Reported Outcome Assessments
Note:  Patientreported outcome (PRO) assessments are no longer required.
Symptomatic bone metastases are associated with high pain severity, which interferes 
with patients’ ability to function.  These two concepts cannot be observed and therefore 
are best documented through standardized PROs.
In this study, PROs will provide relevant information regarding the treatment effect on 
prostate cancer-related symptoms and their impact on patients’ daily lives.  In addition, 
PROs will also document whether treatment efficacy comes at the expense of patients’ 
quality of life due to deleterious treatment-related symptoms.
Patients will be reporting on very specific symptoms (e.g., pain, fatigue) and their 
functional impact, which are concepts proximal to patients’ experience with the disease 
and treatment.  Although an assessor bias cannot be disregarded in an open-label
setting, it is unlikely that this bias would be of such magnitude as to invalidate the data 
collected through PROs.
Instruments implemented in the studynamely the European Organisation for Research 
and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30), 10-point 
pain severity (measured at its worst) numerical rating scale (NRS) selected items from 
the BPI, the BPI-SF, and the Urinary Scale of the European Organisation for Research 
and Treatment of Cancer Quality-of-Life Questionnaire Prostate Module (EORTC 
QLQ-PR-25)have been selected on the basis of their content validity and performance 
and to minimize patients’ completion burden.  These instruments have been previously 
used in clinical studies in patients with prostate cancer (Logothetis et al. 2012; 
Fizazi et al. 2014) and have been recommended by PCWG3 (Scher et al. 2016).
The NCI-developed PRO-CTCAE will be used to document the patients’ perspective 
regarding commonly experienced treatment-related symptoms.
In addition, the EQ-5D-5L will be completed to inform pharmacoeconomic models. 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 730 patients with mCRPC who have failed an androgen synthesis 
inhibitor (e.g., abiraterone) and have failed, are ineligible for, or refused a taxane 
regimen will be enrolled in this study.


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4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Ability to comply with the study protocol, in the investigator’s judgment

ECOG performance status of 0 or 1

Life expectancy 3 months

Histologically confirmed adenocarcinoma of the prostate
Disease must be either metastatic or locally confined inoperable disease that 
cannot be treated with definitive intent (no chance for a curative intervention)
Patients presenting with treatment emergent neuroendocrine differentiation, but 
not primary small cell features, are eligible

Known castrate-resistant disease, defined as meeting all of the following criteria:
Castrate serum testosterone level 50 ng/dL (1.7 nmol/L) at the screening visit
Bilateral orchiectomy or maintenance on androgen ablation therapy with 
luteinizing hormone-releasing hormone agonist or antagonist or polyestradiol 
phosphate for the duration of the study (including the follow-up period)

Progressive disease prior to screening by PSA or imaging per PCWG3 criteria 
during or following the direct prior line of therapy in the setting of medical or surgical 
castration.  Disease progression for study entry is defined as one or more of the 
following three criteria:
PSA progression defined as two increases in PSA over a previous reference 
value of 1 ng/mL (g/L) as the minimum starting value (i.e., a minimum of 
3 PSA values total), with each progression measurement at least 1 week apart
Soft tissue disease progression defined by RECIST v1.1 
Previously normal (1.0 cm) lymph nodes must have grown by 5 mm in 
the short axis to be considered to have progressed
Bone disease progression defined by two or more new lesions on bone scan

One prior regimen/line of a taxane-containing regimen for mCRPC or refusal or 
ineligibility of a taxane-containing regimen
Patients who have received a taxane-containing regimen for metastatic HSPC
are eligible.
Patients who refuse or are ineligible for a taxane-containing regimen are eligible 
for enrollment if they have no intention to use cytotoxic chemotherapy within the 
next 6 months after an informed discussion. 
A taxane-containing treatment should be considered in patients with 
symptomatic and extensive visceral disease who have not previously received 
and are good candidates for a taxane-containing regimen.


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
Progression on a prior regimen/line of an androgen synthesis inhibitor for prostate 
cancer (e.g., abiraterone, orteronel or galeterone)
Patients must have received at least 28 days of an androgen synthesis inhibitor. 
Prior treatment with first generation antiandrogens (e.g., nilutamide, 
bicalutamide), oral ketoconazole, vaccines (e.g., sipuleucel-T, prostvac VF), 
and radium-223 dichloride is also allowed in addition to one prior regimen or 
line of an androgen synthesis inhibitor for prostate cancer.

Patients receiving bisphosphonate or denosumab therapy must have been on a 
stable dose for at least 4 weeks.

Availability of a representative tumor specimen from a site not previously irradiated 
that is suitable for determination of PD-L1 status via central testing
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 15 slides containing unstained, freshly cut, serial sections 
must be submitted along with an associated pathology report prior to study 
enrollment.  If only 1014 slides are available, the patient may still be eligible 
for the study, after discussion with and approval by the Medical Monitor.  If 
archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, tumor tissue must be obtained from a biopsy performed at 
screening.  No tissue will be collected for patients enrolled in the safety run-in 
phase.  Refer to Section 4.5.6 for additional information on tumor specimens 
collected at screening. Tissue from bone metastases might be acceptable after 
consultation with the Medical Monitor.

Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment:
ANC 1.5109/L (without granulocyte colony-stimulating factor support within 
2 weeks prior to Cycle 1, Day 1)
Lymphocyte count 0.5109/L
Platelet count 100109/L without transfusion
Hemoglobin 9 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this criterion
AST and ALT 2.5ULN, with the following exception:
Patients with documented liver metastases:  AST and ALT 5ULN
Serum bilirubin 1.5ULN with the following exception:
Patients with known Gilbert disease:  serum bilirubin level 3ULN
Creatinine clearance 30 mL/min (calculated using the Cockcroft-Gault formula)
Serum albumin 2.5 g/dL
For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5ULN 
within 14 days prior to initiation of study treatment

For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen


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
For men who are not surgically sterile:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year during the treatment period and for at least 
3 months after the last dose of enzalutamide.  Men must refrain from donating 
sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for 3 months after the last dose of 
enzalutamide to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-specific exclusions

Prior treatment with enzalutamide or any other newer hormonal androgen receptor 
inhibitor (e.g., apalutamide, ODM-201)

Treatment with any approved anti-cancer therapy, including chemotherapy, 
immunotherapy, radiopharmaceutical or hormonal therapy (with the exception of 
abiraterone), within 4 weeks prior to initiation of study treatment
Palliative radiotherapy for bone metastases or soft tissue lesions should be 
completed 7 days prior to baseline imaging.
ADT with a gonadotropin-releasing hormone (GnRH) analog (GnRH agonist or 
GnRH antagonist) is allowed.

Treatment with abiraterone within 2 weeks prior to study treatment

Use of herbal products that may have hormonal anti-prostate cancer activity and/or 
are known to decrease PSA levels (e.g., saw palmetto) within 4 weeks of enrollment

Treatment with any other investigational agent or participation in another clinical 
study with therapeutic intent within 4 weeks prior to initiation of study treatment

Planned palliative procedures for alleviation of bone pain such as radiation therapy 
(unless completed 7 days prior to baseline imaging) and surgery.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated prior 
to initiation of study treatment.

Structurally unstable bone lesions suggesting impending fracture


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
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX®) are allowed.

Uncontrolled hypercalcemia defined as one or more of the following criteria:
Ionized calcium 1.5 mmol/L
Serum calcium 12 mg/dL
Corrected serum calcium greater than ULN (if serum albumin 4.0 g/dL)

Known or suspected brain metastasis or active leptomeningeal disease

Patients with treated epidural lesions and no other epidural progression are allowed.
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to initiation of study treatment.
General medical exclusions

Malignancies other than mCRPC within 5 years prior to initiation of study treatment
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk 
of metastasis or death 5% at 5 years) are eligible provided they meet all of the 
following criteria:
Malignancy treated with expected curative intent (e.g., adequately 
treated basal or squamous cell skin cancer)
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers

Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction or cerebrovascular accident 
within 3 months prior to enrollment, unstable arrhythmia, or unstable angina
Patients with a known left ventricular ejection fraction (LVEF) 40% will be 
excluded.
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or LVEF 40%50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation 
with a cardiologist if appropriate.  Patients with a history of clinically significant 
cardiac disease (including anatomic abnormality, coronary artery disease, 
congestive heart failure, abnormal LVEF, arrhythmia, or abnormal ECG) will be 
required to undergo a screening echocardiogram.
History of clinically significant ventricular dysrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, torsades de pointes)
History of a Mobitz II second degree or third degree heart block without 
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Hypotension (systolic blood pressure 86 mmHg) or bradycardia with a heart 
rate 50 beats per minute at the screening visit
Uncontrolled hypertension as indicated by a resting systolic blood pressure 
170 mm Hg or diastolic blood pressure 105 mm Hg at the screening visit

Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of 
study treatment or anticipation of need for a major surgical procedure during the 
course of the study

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications
Exclusion criteria related to atezolizumab 

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary
cells or any component of the atezolizumab formulation

Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 10 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met:
Rash must cover 10% of body surface area
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months

Prior allogeneic stem cell or solid organ transplantation


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
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive HIV test at screening

Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a 
positive hepatitis B surface antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative 
HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at 
screening, are eligible for the study.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test followed by a positive HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive HCV 
antibody test.

Active tuberculosis

Severe infection within 4 weeks prior to initiation of study treatment including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study. 

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation of need for such a vaccine during the course of the study

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2) within 4 weeks or five half-lives of the drug, whichever is 
shorter, prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [TNF]-agents) within 2 weeks prior to initiation of study 
treatment or anticipation of need for systemic immunosuppressive medication during 
the course of the study, with the following exceptions:
Patients who received acute, low-dose, systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study.


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Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study.
The use of systemic corticosteroids of no greater than the equivalent of 10 mg 
of prednisone or prednisolone per day for symptomatic treatment of prostate 
cancer is allowed if the patient has been on a stable dose within 2 weeks prior 
to initiation of study treatment.  There should be no plans to taper the patient off 
treatment or increase the dose during the study.
Patients who are tapered off systemic corticosteroids as part of a prior 
anti-cancer regimen must have received the last dose 7 days prior to initiation 
of study treatment.
Exclusion criteria related to enzalutamide

Known allergy or hypersensitivity to components of the enzalutamide formulation

Unable to swallow the study treatment 

Gastrointestinal disorder affecting absorption of study treatment (e.g., gastrectomy 
or active peptic ulcer disease within last 3 months)

History of seizure or any condition that may predispose to seizure within 12 months 
prior to study treatment, including unexplained loss of consciousness or transient 
ischemic attack 
Exclusion criteria unique to patients enrolled in the enzalutamide PK cohort

Have used or plan to use the following substances within 30 days or 5 half-lives, 
whichever is longer, prior to initiation of study treatment through collection of the last 
enzalutamide PK sample:
Potent CYP2C8 and CYP3A4 inhibitors including, but not limited to, the 
following:  boceprevir, clarithromycin, conivaptan, gemfibrozil, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, voriconazole
Potent or moderate CYP3A4 and CYP2C8 inducers including, but not limited to, 
the following:  anticonvulsants (carbamazepine, phenobarbital, phenytoin), 
antimycobacterials (rifabutin, rifampin, rifapentine), avasimibe, bosentan, 
efavirenz, etavirine, modafinil, nafcillin, St John's wort (hypericum perforatum)
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.
A stratified permuted-block randomization will be implemented to balance treatment 
assignment across levels of stratification factors.


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After written informed consent has been obtained and eligibility has been established, 
the study site will enter demographic and baseline characteristics in the IxRS.  For those 
patients who are eligible for enrollment, the study site will obtain the patient’s 
identification number and treatment assignment from the IxRS.
Patients will be randomized to one of the following treatment arms in a 1:1 ratio 
(experimental to control arm): 

Arm A (experimental arm):  atezolizumab in combination with enzalutamide

Arm B (control arm):  enzalutamide alone
The randomization will be stratified by the following stratification factors:

Prior taxane-containing regimen for mCRPC, defined as at least 2 cycles of a 
taxane-containing regimen (yes vs. no) 

Presence of liver metastasis (yes vs. no)

Lactate dehydrogenase (LDH, ULN vs ULN)

Pain severity (BPI-SF Question 3 score 4 vs. 4)
Patient recruitment will be capped with respect to two of the stratification factors:  the 
proportion of patients who have not received a prior taxane-containing regimen for 
mCRPC, and the proportion of patients with liver metastases at baseline (see 
Section 3.1).
4.3
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are atezolizumab and 
enzalutamide.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab 
Atezolizumab will be supplied by the Sponsor as a sterile liquid in 20-mL glass vials.  
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution, but may 
contain more than the stated volume to enable delivery of the entire 20-mL volume. For 
information on the formulation and handling of atezolizumab, refer to the Investigator’s 
Brochure and Pharmacy Manual.
4.3.1.2
Enzalutamide
For information on the formulation, packaging, and handling of enzalutamide see the 
local prescribing information for enzalutamide.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Atezolizumab 
The dose level of atezolizumab proposed to be tested in this study is 1200 mg 
(equivalent to an average body weight-based dose of 15 mg/kg) administered by IV 
infusion Q3W (21 [± 3] days).


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Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.  
For anaphylaxis precautions, see Appendix 11.  Atezolizumab infusions will be 
administered per the instructions outlined in Table 2.
Table 2
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions
No premedication is permitted.
Vital signs (heart rate, respiratory rate, blood 
pressure, and temperature) should be 
recorded within 60 minutes prior to the 
infusion.
Atezolizumab should be infused over 60 (15) 
minutes.
If clinically indicated, vital signs should be 
recorded during the infusion at 15, 30, 45, and 
60 minutes (5 minutes for all timepoints) 
during the infusion and at 30 (10) minutes 
after the infusion.
Patients should be informed about the 
possibility of delayed post-infusion symptoms 
and instructed to contact their study physician 
if they develop such symptoms.
If the patient experienced an infusion-related 
reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator.
Vital signs should be recorded within 
60 minutes prior to the infusion.
Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction
with the previous infusion.
If the patient experienced an infusion-related 
reaction with the previous infusion or if 
clinically indicated, vital signs should be 
recorded during the infusion and at 
30 (5) minutes after the infusion.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Table 3.
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation are provided in Section 5.1.4.
Any overdose or incorrect administration of study treatment should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of atezolizumab should be 
recorded on the Adverse Event eCRF.
4.3.2.2
Enzalutamide
Enzalutamide will be administered according to the local prescribing information.  The 
dose of enzalutamide is 160 mg (four 40-mg capsules) administered orally once daily.


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Enzalutamide doses should be taken as close to the same time each day as possible.  If 
dosing is missed on one day for any reason, double-dosing should not occur the 
following day.  Patients should hold their dose of enzalutamide on clinic visit days; they 
will be instructed when to take their study drug.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4.
Any overdose or incorrect administration of enzalutamide should be noted on the 
Study Drug Administration eCRF. Adverse events associated with an overdose or 
incorrect administration of enzalutamide should be recorded on the Adverse Event eCRF.  
Section 5.3.5.12 summarizes available safety data related to overdosing of enzalutamide. 
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab and enzalutamide) will be 
provided by the Sponsor.  The study site will acknowledge receipt of IMPs, using the 
IxRS to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Study Access to Atezolizumab
The Sponsor will offer post-study access to Sponsor study drug (atezolizumab) free of 
charge to eligible patients in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Sponsor study drug after completing the study if all of 
the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them


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A patient will not be eligible to receive Sponsor study drug after completing the study if 
any of the following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for metastatic castration-resistant prostate cancer

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for metastatic castration-resistant prostate cancer

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated study treatment from 7 days prior to initiation of 
study treatment to the treatment discontinuation visit.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients who have not undergone bilateral orchiectomy must be maintained on a GnRH 
analog or GnRH antagonist throughout the study (i.e., both treatment phase and 
follow-up). 
Patients are permitted to use the following therapies during the study:

Prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin; for potential drug-drug interaction of enzalutamide and warfarin see 
Appendix 13)

Inactivated influenza vaccinations

Mineralocorticoids (e.g., fludrocortisone)

Corticosteroids administered for COPD or asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Standard-of-care corticosteroid use of no greater than the equivalent of 10 mg of 
prednisone or prednisolone per day

Palliative surgical procedures to treat skeletal related events


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
Focal palliative radiotherapy (e.g., external-beam radiotherapy to address single 
sites of disease).  Treatment with atezolizumab and enzalutamide may be continued 
during palliative radiotherapy.
Patients receiving bisphosphonates or denosumab prior to enrollment should be 
maintained on bisphosphonate or denosumab therapy during screening and while 
actively treated with study drug.  Initiation of bisphosphonates or denosumab is 
discouraged during the treatment phase of the study due to potential immunomodulatory 
properties.  However, initiation of such treatment should not result in discontinuation of 
study treatment.
An analgesic log will be completed between clinic visits to document opiate analgesic 
use for cancer-related pain until the end of treatment visit.
Blood transfusions are allowed throughout the study.
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator.
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 11).
4.4.2
Cautionary Therapy for Atezolizumab
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations in which 
systemic corticosteroids or TNF-inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered.  If the alternatives are not feasible, 
systemic corticosteroids and TNF-inhibitors may be administered at the discretion of 
the investigator.
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with atezolizumab therapy (refer 
to Table 3 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for 
details).
Concomitant use of herbal therapies is not recommended because their 
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unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section 4.4.4) may be used during the study at the discretion of the investigator.
4.4.3
Cautionary Therapy for Enzalutamide
In vitro data suggest that enzalutamide is metabolized by and/or induces CYP2C8, 
CYP2C9, CYP2C19, CYP3A4, uridine 5’-diphospho-glucuronosyltransferase (UGT), and 
the efflux transporter P-glycoprotein (P-gp) via activation of the nuclear pregnane 
X receptor (PXR), and there is a moderate to high potential for drug-drug interaction with 
any medication that is metabolized by or strongly inhibits or induces these enzymes or 
transporter.  Co-administration of enzalutamide with substrates of these enzymes or 
transporter may reduce the oral bioavailability and/or increase the clearance of the 
substrate, resulting in decreased exposures.  In consideration of the half-life of 
enzalutamide (approximately 1 week), effects on enzymes and transporters may persist 
for one month or longer after stopping enzalutamide.
Appendix 13 provides a list of medicinal products that have a potential for drug-drug 
interactions with enzalutamide.  Medications listed in Appendix 13 should be avoided.  
When the use of one of these medications is necessary, a discussion with the Medical 
Monitor is encouraged. If the patient has been enrolled in the enzalutamide PK cohort, 
notify the Medical Monitor immediately.
If concomitant use of strong CYP2C8 inhibitors cannot be avoided, then the dose of 
study drug should be reduced to 80 mg/day (2 capsules).
For further information on drug-drug interactions with enzalutamide, consult the local 
prescribing information.
4.4.4
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Concomitant therapy intended for the treatment of cancer whether health 
authorityapproved or experimental, is prohibited for various time periods prior to 
starting study treatment, depending on the agent (see Section 4.1.2), and during 
study treatment until disease progression is documented and the patient has 
discontinued study treatment, except as outlined in Section 4.4.1.
Therapy intended for the treatment of cancer may include, but is not limited to, 
chemotherapy, hormonal therapy (other than protocol required treatment with 
GnRH analog or GnRH antagonist), immunotherapy, radiotherapy including 
radium-223 dichloride, and herbal therapy

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 4 weeks prior to initiation of study treatment and during study treatment.

Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 months 
after the last dose of atezolizumab.


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
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or five half-lives of the drug, whichever is longer, 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab.

Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  Patients will be 
closely monitored for safety and tolerability throughout the study.  Patients should be 
assessed for toxicity prior to each dose; dosing will occur only if the clinical assessment 
and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Patients who show apparent radiographic progression at a tumor response evaluation 
must sign a consent form at that time to acknowledge deferring other treatment options 
in favor of continuing study treatment.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including stage, date of diagnosis, and prior cancer therapies and procedures), and 
smoking history, will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to initiation of 
study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
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4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.
Vital signs should be measured at every cycle for all patients. Vital signs should be
measured within 60 minutes prior to each atezolizumab infusion and, if clinically 
indicated, during or after the infusion.  In addition, vital signs should be measured at 
other specified timepoints as outlined in the schedule of activities (see Appendix 1).
4.5.5
Tumor and Response Evaluations
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days prior to initiation of study treatment may be used rather than 
repeating tests.
Tumor assessments will be performed at baseline, every 9 weeks (approximately every 
three cycles) following randomization for 27 weeks, and every 12 weeks thereafter 
regardless of dose delays, with additional scans as clinically indicated.  Assessments will 
continue until confirmed radiographic disease progression per PCWG3 criteria (see 
Appendix 2).  
Tumor assessments should continue regardless of whether patients start new 
anti-cancer therapy in the absence of confirmed radiographic disease progression 
unless they withdraw consent.  Patients who discontinue study treatment for reasons 
other than confirmed radiographic disease progression (e.g., toxicity) should continue to 
undergo scheduled tumor assessments as if they were on the protocol schedule until the 
patient dies, experiences confirmed radiographic disease progression per PCWG3 
criteria, withdraws consent, or until the study closes, whichever occurs first.  For patients 
who continue to receive study treatment following confirmed radiographic disease 
progression, assessments will continue until loss of clinical benefit.  If an optional biopsy 
is to be performed at approximately the same timepoint of a tumor assessment or as a 
result of the radiographic determination (e.g., response or progression), samples should 
be acquired after all imaging scans have been performed, if at all possible.


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Screening assessments must include CT scans (with oral or IV contrast) or MRI scans of 
the chest, abdomen, and pelvis.  A spiral CT scan of the chest may be obtained but is 
not a requirement.  If a CT scan with contrast is contraindicated (i.e., in patients with 
contrast allergy or impaired renal clearance), a non-contrast CT scan of the chest may 
be performed and MRI scans of the abdomen and pelvis should be performed.  A CT or 
MRI scan of the head should be performed as clinically indicated to confirm or refute the 
diagnosis of CNS metastases at baseline.  CT scans of the neck or extremities should 
also be performed if clinically indicated and repeated throughout the study if there is 
evidence of disease at screening. At the investigator’s discretion, other methods 
of assessment of measurable disease as per RECIST v1.1 may be used.
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan.
A technetium-99m bone scan will be performed at screening and at each tumor 
assessment during the study to evaluate bone metastasis.  For adequate assessment of 
bone lesions, it is expected that the radiologist will adjust window leveling accordingly.
Measurable and non-measurable disease should be documented at screening and re-
assessed at each subsequent tumor evaluation.  The same radiographic procedures 
used to assess disease sites at screening should be used for subsequent tumor 
assessments (e.g., the same contrast protocol for CT scans).
Response and/or progression will be assessed by the investigator using PCWG3 criteria 
(see Appendix 2).  Assessments should be performed by the same evaluator, if possible, 
to ensure internal consistency across visits.  Results must be reviewed by the 
investigator before dosing at the next cycle.
All primary imaging data used for tumor assessments may be collected by the Sponsor 
to enable the possibility of a centralized, independent review of response endpoints by 
an IRF.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Note:  Local laboratory assessments should continue to be conducted to enable ongoing 
patient care, and central laboratory assessments are no longer required (as per 
Appendix 1).
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)


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
Chemistry panel (serum):  sodium, potassium, magnesium, chloride, bicarbonate, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total 
bilirubin, alkaline phosphatase, ALT, AST, LDH (In countries where serum 
bicarbonate is not considered a standard chemistry measurement [e.g., Japan], 
serum bicarbonate is not required as a laboratory study in the screening or on-study 
serum measurements.)

Coagulation:  INR and aPTT or PTT

Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3, or 
total T3 for sites where free T3 is not performed), free thyroxine (also known as T4), 

HIV serology

HBV serology:  HBsAg, hepatitis B surface antibody, total HBcAb
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test should be performed at screening. 

HCV serology:  if HCV antibody test is positive, HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has active HCV infection.

Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); 
dipstick permitted 

Testosterone

PSA
The following samples will be sent to one or several central laboratories or to the 
Sponsor for analysis:

Serum samples for analysis of autoantibodies:  anti-nuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody

Serum samples for assay of atezolizumab concentrations through use of a validated 
immunoassay

Plasma samples for assay of enzalutamide and N-desmethyl enzalutamide 
concentrations through use of a validated methods

Serum samples for assessment of ATAs to atezolizumab through use of validated 
immunoassays

Blood, plasma, serum, and urine samples for exploratory research on biomarkers


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
Archival tumor tissue sample collected at baseline for determination of tumor PD-L1 
status and for exploratory research on biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
15 slides containing unstained, freshly cut, serial sections must be submitted 
along with an associated pathology report prior to study enrollment.  If only 
1014 slides are available, the patient may still be eligible for the study, after 
discussion with and approval by the Medical Monitor.  No tissue will be 
collected for patients enrolled in the safety run-in phase.  After signing of the 
Informed Consent Form, retrieval and submission of an archival tumor sample 
can occur more than 28 days prior to start of study treatment but must be 
submitted prior to enrollment.
If archival tissue is unavailable or is determined to be unsuitable for required 
testing, a pretreatment tumor biopsy is required.  A pretreatment tumor biopsy 
may also be performed if a patient's archival tissue test results do not meet 
eligibility criteria.
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples should contain a minimum of 50 viable tumor cells that preserve 
cellular context and tissue architecture regardless of needle gauge or retrieval 
method.  Acceptable samples include those from resections, core-needle 
biopsies (at least three cores, embedded in a single paraffin block), or 
excisional, incisional, punch, or forceps biopsies.  Fine-needle aspiration 
(defined as samples that do not preserve tissue architecture and yield cell 
suspension and/or smears), brushing, cell pellets from pleural effusion, and 
lavage samples are not acceptable. 
Tissue from soft tissue metastases or the primary tumor is preferred, with a 
preference for the most recent tumor tissue obtained prior to screening.  
Tissue from bone metastases might be acceptable after consultation with the 
Medical Monitor. 
Patients having additional tissue samples from procedures performed at 
different times (e.g., earlier metastatic biopsy, prostatectomy specimen, 
transrectal biopsy, etc.) during the course of their prostate cancer will be 
requested (but not required) to also submit these samples for central testing.  
Tissue samples obtained at multiple times for individual patients will greatly 
contribute to an improved understanding of the dynamics of PD-L1 expression 
and relationship with intervening anti-cancer therapy.
For enrolled patients, remaining archival tumor tissue blocks will be returned to 
the site upon request or 18 months after final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival 
tumor tissue blocks will be returned to the site no later than 6 weeks after 
eligibility determination.


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
Tumor tissue sample collected at the time of progression, if deemed clinically 
feasible by the investigator, for exploratory research on biomarkers
Biopsies should be performed within 40 days after progression or prior to the 
next anti-cancer therapy, whichever is sooner.  Preferably, growing lesions 
should be selected. Preferred samples include those from resections,
core-needle biopsies (at least three cores preferred), or excisional or punch 
biopsies.
Tissue from soft tissue metastases or the primary tumor is preferred.  Tissue 
from bone metastases might be acceptable after consultation with the Medical 
Monitor. 
Exploratory biomarker research may include, but will not be limited to, analysis of PD-L1 
and CD8 expression on tumor tissues, expression of T-effector-associated genes 
(e.g., CD8A, perforin, granzyme A, granzyme B, interferon-gamma, CXCL9, CXCL10), 
activated stroma-associated genes (e.g., TGF beta, fibroblast-activated protein, 
podoplanin, collagens, biglycan, etc.), myeloid-derived suppressor cell-associated genes 
(e.g., CD68, CD163, FoxP3, androgen-regulated gene 1, etc.), androgen-receptor (AR) 
genes, germline and somatic mutations from tumor tissue and/or from circulating tumor 
DNA in blood (including, but not limited to, mutation load, MSI, and MMR defects), 
identified through whole genome sequencing (WGS) and/or next-generation sequencing 
(NGS), and plasma-derived cytokines and tumor antigens.  
NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator can obtain results from these analyses performed on the tissue sample 
collected at progression in the form of an NGS report, which is available upon request 
directly from Foundation Medicine, given that enough tumor tissue is provided for 
analysis.  If allowed by local laws, the investigator may share and discuss the results 
with the patient, unless the patient chooses otherwise.  The Foundation Medicine NGS 
assay has not been cleared or approved by health authorities.  The NGS report is 
generated for research purposes and is not provided for the purpose of guiding future 
treatment decisions. Results may not be available if the tissue does not meet testing 
criteria. Results will not be made available for screening tissue. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.9.1), biological samples will be destroyed 
when the final Clinical Study Report (CSR) has been completed, with the following 
exceptions:

Residual PK and ATA samples may be needed for additional immunogenicity 
characterization and PK and immunogenicity assay development and validation; 
therefore, these samples will be destroyed no later than 5 years after the final CSR 
has been completed.


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
Blood samples collected for WGS will be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).

Blood, plasma, serum, urine, and tumor tissue samples collected for exploratory 
research on biomarkers will be destroyed no later than 5 years after the final CSR 
has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.7
Electrocardiograms
An ECG is required at screening, at Day 1 of Cycle 4 and every 4 cycles thereafter 
during treatment, at the end of treatment visit, and when clinically indicated.  ECGs for 
each patient should be obtained from the same machine wherever possible.  Lead 
placement should be as consistent as possible.  ECG recordings must be performed 
after the patient has been resting in a supine position for at least 10 minutes.
ECGs will be reviewed by the investigator to determine patient eligibility at screening.  
Baseline evaluation of left ventricular ejection fraction should be considered for all 
patients, especially in those with cardiac risk factors and/or history of coronary artery 
disease.  Patients with a history of clinically significant cardiac disease (including 
anatomic abnormality, coronary disease, congestive heart failure, abnormal LVEF, 
arrhythmia, or abnormal ECG) will be required to undergo a screening echocardiogram.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.


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4.5.8
Patient-Reported Outcomes
Note:  PRO assessments are no longer required.
To more fully characterize the clinical profile of atezolizumab, PRO data will be 
obtained through use of the following instruments:  the EORTC QLQ-C30and selected 
items from the QLQ-PR25, the BPI, the BPI-SF, the PRO-CTCAE, and EQ-5D-5L.  To 
reduce completion burden, only relevant items and scales were selected for completion.

Question 3 from the BPI-SF (pain severity over the past 24 hours) will be completed 
at screening to be used for stratification. 

An analgesic log that captures the use of opioids for cancer pain only will be 
completed at home starting at Day 1 of Cycle 1 until the end of treatment visit 
(included).

Questions 12 and 23 from the BPI (pain severity and pain interference over the past 
7 days), the EORTC QLQ-C30, the 8-item Urinary Symptoms Scale (URI) from the 
QLQ-PR25, the EQ-5D-5L and selected items from the PRO-CTCAE will be 
completed at the clinical site on Day 1 of Cycle 1 and every cycle thereafter until the 
end of treatment visit (included) and at unscheduled visits.

Selected scales from the EORTC QLQ-C30 (physical functioning [PF], role 
functioning [RF], global health status [GHS]), Question 12 from the BPI (pain 
severity over the past 7 days), and the complete EQ-5D-5L will also be completed 
by patients after end of treatment as part of the safety visit and long-term follow-up. 
It is imperative that each questionnaire aforementioned be completed on Day 1 of 
Cycle 1.  All PRO questionnaires that are completed at the clinic are required to be 
completed prior to the administration of study treatment and/or prior to any other study 
assessment(s) that could bias patient’s responses.
The questionnaires will be translated in the country language(s) and as feasible in the 
local language.  
Question 3 from the BPI-SF at screening will be administered on paper and documented 
on the appropriate eCRF.  Patients will use an electronic device to capture all other PRO 
data. For situations that preclude the use of the electronic device, a backup paper 
option may be utilized. Instructions to use the e-device and to complete the PRO 
questionnaires will be provided by site staff once the patient is randomized and before 
initiation of study treatment.  The data will be transmitted to a centralized database 
maintained by the vendor and will be available for access by appropriate study 
personnel at the site.
PRO data will not be collected for patients enrolled in the safety run-in phase of the 
study.


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4.5.8.1
EORTC QLQ-C30
The EORTC QLQ-C30 is a validated, reliable self-reported measure 
(Aaronson et al. 1993; see Appendix 4).  It consists of 30 questions that assess five 
aspects of patient functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, pain), global health/QoL, and six
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties) with a recall period of the previous week.  Items besides items forming the 
GHS scale are rated on a 4-point categorical scale.  A high score (4) for a functional 
scale represents a high or healthy level of functioning, a high score (7) for the GHS/QoL 
represents a high QoL, but a high score for a symptom scale or item represents a high 
level of symptomatology or problems.
The EORTC QLQ-C30 will be completed in its entirety.  It takes approximately 
10 minutes to complete.  To understand patients’ symptom experience post treatment 
and the course of their HRQoL, the PF, RF, and GHS scales will be completed as part of 
the follow-up visits.  These scales were selected for their content validity in documenting 
patients’ functioning in daily activities and QoL.
4.5.8.2
EORTC Quality-of-Life:  Urinary Scale (QLQ-PR25)
The 8-item urinary symptoms scale of the QLQ-PR25 form the URI scale to capture 
commonly reported urinary symptoms associated with prostate cancer.  The items use 
the same rating scale as the EORTC QLQ-C30.  The scale has demonstrated good 
psychometric performance (van Andel et al. 2008) (see Appendix 5).
The other scales from the QLQ-PR25, namely, use of incontinence aid, bowel symptoms, 
hormonal treatment-related symptoms, sexual activity, and sexual functioning were 
disregarded on the basis of their lack of content validity in patients with CRPC in second 
and third line of therapy.  
4.5.8.3
Pain Assessments:  Selected Questions from BPI and BPI-SF
The BPI and its shorter version, the BPI-SF, have become the most widely used 
measurement tools for assessing clinical cancer pain.  The instruments allow patients to 
rate the severity of their pain and the degree to which their pain interferes with common 
dimensions of feeling and function.  Both instruments include additional questions 
regarding analgesic use or location of pain that are not considered in the scoring 
algorithm for pain severity or pain interference and therefore do not contribute to the 
scores validity (Cleeland et al. 2009).  The two instruments differ in their recall periods; 
the BPI uses a 7-day recall whereas the BPI-SF uses a 24-hour recall.  Each item uses 
a 0 to 10-point NRS, with 10 indicating a high symptom severity or a high impact on 
functioning.
The measure of pain intensity that is most commonly used in clinical studies is a single 
item that asks patients to self-report their worst pain (Cleeland et al. 2013; 
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respectively, were selected as they both assess patients’ pain at its worst using a 
10-point NRS.  Question 3 from the BPI-SF will be completed at screening for the 
purpose of stratifying patients on the basis of their pain severity.  Question 12 and 
Question 23 from the BPI will allow capture of patients’ symptomatic experience on a
longer time window (7 days) (see Appendix 7).
4.5.8.4
Analgesic Log 
A country-specific analgesic log will be used to document opiate analgesic use for 
cancer-related pain (e.g., name of molecule, form, dose per day).
The opiate medications prescribed for cancer-related pain will be entered into the 
analgesic log, and patients or caregivers will document actual opioid intake on the 
analgesic log. Actual intake will be transcribed into the eCRF. Oral morphine 
equivalents (OME) per molecule will be derived and interpreted using the Analgesic 
Quantification Algorithm (AQA) by the Sponsor.  AQA scores range from 0 to 7, in which 
0 is no analgesic use and 7 is strong opioid use (Chung et al. 2014).  Equianalgesic 
potency conversions and AQA are displayed in Appendix 8.
4.5.8.5
PRO-CTCAE
The PRO-CTCAE is an instrument developed by the National Cancer Institute in 
recognition that clinician reporting of symptomatic adverse events lacks reliability; 
clinicians under-report the incidence and severity of symptoms compared to patients’ 
direct reports, and patient reports better reflect underlying health status than clinician 
reports (Basch et al. 2014).  Items from the PRO-CTCAE item bank were selected on 
the basis of the understanding of the symptoms most commonly reported in patients who
received atezolizumab in completed and ongoing clinical studies and enzalutamide as 
described in its local prescription information.  The Sponsor therefore intends to 
document fatigue (2 items), GI symptoms including constipation (1 item), diarrhea 
(1 item), lack of appetite (2 items), and rash (1 item).  In addition, a global item asking 
whether patients were disturbed by their side effects will be added (see Appendix 9).
4.5.8.6
EQ-5D-5L
The EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L), is a validated 
self-report health status questionnaire that is used to calculate a health status utility 
score for use in health economic analyses (EuroQoL Group, 1990; Brooks et al. 1996; 
Herdman et al. 2011; Janssen et al. 2013) (see Appendix 6).  There are two components 
to the EQ-5D-5L:  a five-item health state profile that assesses mobility, self-care, usual
activities, pain/discomfort, and anxiety/depression, as well as a visual analogue scale 
(VAS) that measures health state.  Published weighting systems allow for creation of a 
single composite score of the patient’s health status.  The EQ-5D-5L takes 
approximately 3 minutes to complete.  It will be utilized in this study for informing 
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4.5.9
Optional Samples for Research Biosample Repository
4.5.9.1
Overview of the Research Biosample Repository
Note:  The collection of specimens for the RBR is no longer required.
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB or EC and, if applicable, an appropriate regulatory 
body.  If a site has not been granted approval for RBR sampling, this section of the 
protocol (Section 4.5.9.2) will not be applicable at that site.
4.5.9.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including but not limited to research on biomarkers related to atezolizumab, 
enzalutamide and disease biology:

An optional blood sample collected at any time during the study

Tumor tissue samples from biopsies performed at the investigator's discretion 
during the study

Leftover blood, plasma, serum, urine and tumor tissue samples (with the exception 
of leftover tissue from archival FFPE blocks, which will be returned to sites) and 
any derivatives thereof (e.g., DNA, RNA, proteins, peptides), including leftover 
tissue samples from additional tumor biopsies or medically indicated procedures 
(e.g., bronchoscopy, esophagogastroduodenoscopy, colonoscopy) performed at the 
investigator's discretion during the course of the study 


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The above samples may be sent to one or more laboratories for analysis of germline 
mutations or somatic mutations via WGS, NGS, or other genomic analysis methods.
Genomics is increasingly informing researcher understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are used 
up.  However, the RBR storage period will be in accordance with the IRB/EC-approved 
Informed Consent Form and applicable laws (e.g., health authority requirements).
4.5.9.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.9.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 


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time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether the patient has given consent to participate 
and (if applicable) the date(s) of consent, by completing the RBR Research Sample 
Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.9.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the study is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  The patient will be 
provided with instructions on how to withdraw consent after the study is closed.  A 
patient's withdrawal from Study CO39385 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study CO39385.
4.5.9.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment (atezolizumab and/or 
enzalutamide) if they experience any of the following:

Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment


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
Use of another nonprotocol-specified anti-cancer therapy

Symptomatic deterioration attributed to disease progression

Radiographic disease progression per PCWG3 criteria, with the following exception:
Patients will be permitted to continue study treatment after experiencing 
confirmed radiographic disease progression per PCWG3 criteria if they meet all 
of the following criteria:
Evidence of clinical benefit, as determined by the investigator after an 
integrated assessment of radiographic data, biopsy results (if available), 
and clinical status
Absence of symptoms and signs (including laboratory values, such as new 
or worsening hypercalcemia) indicating unequivocal progression of 
disease
Absence of decline in ECOG performance status that can be attributed to 
disease progression
Absence of tumor progression at critical anatomical sites (e.g., 
leptomeningeal disease) that cannot be managed by protocol-allowed 
medical interventions

Investigator or Sponsor determines it is in the best interest of the patient
Patients with rising PSA levels only (i.e., in the absence of confirmed radiographic or 
clinical progression) should continue to receive study treatment per PCWG3 criteria and 
recommendations (Scher et al. 2016).  PSA rise without evidence of confirmed 
radiographic progression or a symptomatic skeletal-related event is strongly discouraged 
as a criterion to start a new systemic anti-neoplastic therapy during the first 12 weeks of 
therapy and is discouraged as a criterion to start a new systemic anti-neoplastic therapy 
throughout the study.
Focal palliative radiography (e.g., external-beam radiotherapy to address single sites of 
disease), initiation of bisphosphonates or denosumab, standard-of-care corticosteroid 
use of no greater than the equivalent of 10 mg of prednisone or prednisolone per day, 
and pain management are allowed and should not result in discontinuation of study 
treatment.  However, patients should be evaluated for clinically apparent SSE.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patient withdrawal of consent may be a reason for discontinuation of 
study treatment. Patients enrolled in the safety run-in period who discontinue study 
treatment without completing the first 21-day treatment cycle may be replaced.  All other
patients who discontinue study treatment prematurely will not be replaced.
Patients will return to the clinic for a treatment discontinuation visit 30 days after the 
last dose of study treatment.  The visit at which the tumor assessment shows confirmed 
progressive disease may be used as the treatment discontinuation visit. 


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After treatment discontinuation, patients will be asked to return to the clinic 120 days 
30 days after the last study treatment for a safety visit.  Thereafter, patients will enter a 
post-trial access program.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Withdrawal of consent

Study termination or site closure

Patients who are, in the opinion of the Investigator or Medical Monitor, grossly 
non-compliant with the protocol’s requirements
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients enrolled in the safety run-in phase who withdraw from the 
study without completing the first 21-day assessment window may be replaced.  All other 
patients who withdraw from the study prematurely will not be replaced.  
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference for Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and enzalutamide in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Sections 5.1.1 and 5.1.2).  Guidelines for 
management of patients who experience specific adverse events are provided in Table 3
(see Section 5.1.4). 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of atezolizumab will be performed in a 
monitored setting in which there is immediate access to trained personnel, and adequate 
equipment and medicine to manage potentially serious reactions.  Adverse events will 
be reported as described in Section 5.3.5.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, myocarditis, pancreatitis, diabetes 
mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis, nephritis, and immune-mediated myositis.  Immune-mediated 
reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis and macrophage activation syndrome (considered to be potential 
risks for atezolizumab).  Refer to Table 3 of the protocol and Section 6 of the 
Atezolizumab Investigator's Brochure for a detailed description of anticipated safety risks 
for atezolizumab.
5.1.2
Risks Associated with Enzalutamide
Enzalutamide has been associated with risks such as the following:  seizures, falls, 
non-pathologic fractures, cognitive disorder, PRES, neutropenia and hypertension.  For 
further adverse reactions, warnings, and precautions for enzalutamide, see local 
prescribing information.
5.1.3
Risks Associated with Combination Use of Atezolizumab 
and Enzalutamide
On the basis of the different mechanism of action for each product, the overlapping risks 
of enzalutamide and atezolizumab are thought to be minimal and are not expected to 
significantly increase the incidence of adverse events seen in monotherapy studies.  
Nonetheless, potential overlapping toxicities between enzalutamide and atezolizumab 
might include common adverse reactions of asthenia/fatigue, back pain, decreased 
appetite, constipation, arthralgia, diarrhea, peripheral edema, dyspnea, musculoskeletal 
pain, weight decreased, headache, hypertension, and liver function abnormalities.  Signs 
and symptoms suggestive of posterior reversible encephalopathy syndrome for 


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enzalutamide or meningitis encephalitis for atezolizumab have been reported.  Many 
signs and symptoms are commonly seen in prostate cancer patients.
5.1.4
Management of Patients Who Experience Specific 
Adverse Events
5.1.4.1
Dose Modifications
There will be no dose modifications for atezolizumab in this study.
Study treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to enzalutamide.  Re-starting enzalutamide at a reduced dose 
may be acceptable and requires written approval of the Medical Monitor (or designee). 
5.1.4.2
Treatment Interruption
Atezolizumab and/or enzalutamide may be managed independently according to their 
respective risk profile.  They may be temporarily suspended in patients experiencing 
toxicity considered to be related to the respective study drug.  Risks associated with 
atezolizumab and enzalutamide are described in Section 5.1.1 and Section 5.1.2, 
respectively.
If corticosteroids are initiated for treatment of the toxicity, they must be tapered over 
1 month to 10 mg/day oral prednisone or equivalent before atezolizumab can be 
resumed.
Atezolizumab and/or enzalutamide treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.  If corticosteroids are 
initiated for treatment of an immune-mediated toxicity, they must be tapered over 
1 month to 10 mg/day oral prednisone or equivalent before atezolizumab can be 
resumed.  If atezolizumab and/or enzalutamide are withheld for 12 weeks, the patient 
will be discontinued from atezolizumab and/or enzalutamide.  However, atezolizumab 
may be withheld for 12 weeks to allow for patients to taper off corticosteroids prior to 
resuming treatment.  Atezolizumab can be resumed after being withheld for 12 weeks if 
the Medical Monitor agrees that the patient is likely to derive clinical benefit.  
Atezolizumab and/or enzalutamide treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor approval.  The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption.
5.1.4.3
Management Guidelines
Atezolizumab and/or enzalutamide may be managed independently according to their 
respective risk profile and be temporarily suspended in patients experiencing toxicity 
considered to be related to the respective study drug.  Risks associated with 
atezolizumab and enzalutamide are described in Section 5.1.1 and Section 5.1.2, 
respectively.


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Guidelines for management of patients who experience specific adverse events are 
provided in Table 3.  For adverse events associated with enzalutamide that are not listed 
in Table 3, refer to the local prescribing information.
Infusion-Related Reactions and Cytokine-Release Syndrome
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-
release syndrome (CRS) with atezolizumab may receive premedication with 
antihistamines, anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated 
IRRs because of its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells 
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 3.
Hemophagocytic Lymphohistiocytosis And Macrophage Activation 
Syndrome
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS), which are considered to be potential risks for atezolizumab.  For management 
guidelines see Table 3.  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of 
the following eight criteria are met:

Fever 38.5°C

Splenomegaly


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
Peripheral blood cytopenia consisting of at least two of the following:
– Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
– Platelet count 100 109/L (100,000/L)
– ANC 1.0 109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should 
be classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
– Platelet count 181 109/L (181,000/L)
– AST 48 U/L
– Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
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Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events
Event
Action to Be Taken
Anaphylaxis 
For anaphylaxis precautions, see Appendix 11.
Continue enzalutamide after symptoms have resolved to 
baseline.
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome
Grade 1 a
Fever b with or without 
constitutional symptoms

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then 
restart infusion at half the rate being given at the time of 
event onset.

If the infusion is tolerated at the reduced rate for 30 
minutes, the infusion rate may be increased to the original 
rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance 
of IV fluids for hydration.

In case of rapid decline or prolonged CRS (2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS.

Continue enzalutamide after symptoms have resolved to 
baseline.
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level 
positive airway pressure; CAR chimeric antigen receptor; CPAP continuous positive 
airway pressure; CRS cytokine-release syndrome; CTCAE Common Terminology Criteria 
for Adverse Events; eCRF electronic Case Report Form; HLH hemophagocytic 
lymphohistiocytosis; ICU intensive care unit; IRR infusion-related reaction; 
MAS macrophage activation syndrome; NCCN National Cancer Comprehensive Network; 
NCI National Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellmediated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
85/Protocol CO39385, Version 8
Table 3: Guidelines for Management of Patients Who Experience Specific AEs (cont)
Event
Action to Be Taken
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome (cont.)
Grade 2 a
Fever b with hypotension not 
requiring vasopressors
and/or
Hypoxia requiring low-flow 
oxygen d by nasal cannula or 
blow-by
Immediately interrupt infusion.
Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.
If symptoms recur, discontinue infusion of this dose.
Administer symptomatic treatment. c
For hypotension, administer IV fluid bolus as needed.
Monitor cardiopulmonary and other organ function closely (in 
the ICU, if appropriate).  Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ 
toxicities as per institutional practice.
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS as 
described in Section 5.1.4.3 and this table.
Consider IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours).
Consider anti-cytokine therapy. e
Consider hospitalization until complete resolution of symptoms.  
If no improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical 
Monitor.
If symptoms resolve to Grade 1 or better for 3 consecutive days, 
the next dose of atezolizumab may be administered.  For 
subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS.
If symptoms do not resolve to Grade 1 or better for 
3 consecutive days, contact Medical Monitor.
Continue enzalutamide after symptoms have resolved to 
baseline.
ASTCT American Society for Transplantation and Cellular Therapy; CRS cytokine-release 
syndrome; CTCAE Common Terminology Criteria for Adverse Events; eCRF electronic 
Case Report Form; HLH hemophagocytic lymphohistiocytosis; ICU intensive care unit; 
IRR infusion-related reaction; MAS macrophage activation syndrome; NCCN National 
Cancer Comprehensive Network; NCI National Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of chimeric antigen receptor T-cellmediated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF. Organ toxicities associated with CRS 
should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade).  In this case, the grade 
is driven by the presence of hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e
There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not 
been established.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
86/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome (cont.)
Grade 3 a
Fever b with hypotension 
requiring a vasopressor (with or 
without vasopressin)
and/or
Hypoxia requiring high-flow 
oxygen d by nasal cannula, face 
mask, non-rebreather mask, or 
Venturi mask
Permanently discontinue atezolizumab and contact Medical 
Monitor. f
Administer symptomatic treatment. c
For hypotension, administer IV fluid bolus and vasopressor as 
needed.
Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids 
as clinically indicated, and manage constitutional symptoms 
and organ toxicities as per institutional practice.
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS as 
described in Section 5.1.4.3 and this table.
Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours).
Consider anti-cytokine therapy. e
Hospitalize patient until complete resolution of symptoms.  If 
no improvement within 24 hours, manage as per Grade 4, that 
is, admit patient to ICU and initiate hemodynamic 
monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed; for patients who are refractory to 
anti-cytokine therapy, experimental treatments may be 
considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Continue enzalutamide after symptoms have resolved 
to baseline.
ASTCT American Society for Transplantation and Cellular Therapy; CRS cytokine-release 
syndrome; CTCAE Common Terminology Criteria for Adverse Events; eCRF electronic 
Case Report Form; HLH hemophagocytic lymphohistiocytosis; ICU intensive care unit; 
IRR infusion-related reaction; MAS macrophage activation syndrome; NCCN National 
Cancer Comprehensive Network; NCI National Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of chimeric antigen receptor T-cellmediated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e
There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not 
been established.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
87/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome (cont.)
Grade 4 a
Fever b with hypotension 
requiring multiple vasopressors 
(excluding vasopressin)
and/or
Hypoxia requiring oxygen by 
positive pressure (e.g., CPAP, 
BiPAP, intubation and 
mechanical ventilation)
Permanently discontinue atezolizumab and contact Medical 
Monitor. f
Administer symptomatic treatment. c
Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed.  Monitor other organ function closely.  Manage 
constitutional symptoms and organ toxicities as per 
institutional practice.
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS as 
described in Section 5.1.4.3 and this table.
Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours).
Consider anti-cytokine therapy. e  For patients who are 
refractory to anti-cytokine therapy, experimental treatments g
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Hospitalize patient until complete resolution of symptoms.
Continue enzalutamide after symptoms have resolved to 
baseline.
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level positive 
airway pressure; CAR chimeric antigen receptor; CPAP continuous positive airway 
pressure; CRS cytokine-release syndrome; CTCAE Common Terminology Criteria for 
Adverse Events; eCRF electronic Case Report Form; HLH hemophagocytic 
lymphohistiocytosis; ICU intensive care unit; IRR infusion-related reaction; 
MAS macrophage activation syndrome; NCCN National Cancer Comprehensive Network; 
NCI National Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management of 
CAR T-cellmediated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade).  In this case, the grade 
is driven by the presence of hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
e
There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not been 
established.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be considered 
after consulting the Medical Monitor and considering the benefitrisk ratio.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
88/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity 
Diarrhea or colitis, Grade 1 
Continue atezolizumab.
Initiate symptomatic treatment.
Endoscopy is recommended if symptoms persist for 7 days.
Monitor closely.
Continue enzalutamide.
Diarrhea or colitis, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Initiate symptomatic treatment.
Patient referral to GI specialist is recommended.
For recurrent events or events that persist 5 days, initiate 
treatment with 12 mg/kg/day oral prednisone or equivalent.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Continue enzalutamide.
Diarrhea or colitis, Grade 3 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist for evaluation and confirmatory 
biopsy.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide. In case of 
uncertain relationship and/or recurrent Grade 3 or 4 diarrhea or 
colitis, rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
89/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Gastrointestinal toxicity (cont.)
Diarrhea or colitis, Grade 4
Permanently discontinue atezolizumab and contact 
Medical Monitor. c
Refer patient to gastrointestinal specialist for evaluation and 
confirmation biopsy.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide. In case of 
uncertain relationship and/or recurrent Grade 3 or 4 diarrhea or 
colitis, rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
Hepatotoxicity
Hepatic event, Grade 1 
Continue atezolizumab. 
Monitor LFTs until values resolve to within normal limits.
Continue enzalutamide.
LFTliver function test.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
90/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Hepatotoxicity (cont.)
Hepatic event, Grade 2
All events:
Monitor LFTs more frequently until return to baseline values.
Events of 5 days in duration:
Withhold atezolizumab for up to 12 weeks after event onset. a
Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.
If event resolves to Grade 1 or better resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Continue enzalutamide.
Hepatic event, Grade 3 or 4
Permanently discontinue atezolizumab and contact 
Medical Monitor. c
Consider patient referral GI specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury.
Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 or 4 hepatic 
injury, rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
Pulmonary events, including pneumonitis
Pulmonary event, Grade 1
Continue atezolizumab and monitor closely.
Re-evaluate on serial imaging.
Consider patient referral to pulmonary specialist.
Continue enzalutamide.
GIgastrointestinal; LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
91/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Pulmonary events, including pneumonitis (cont.)
Pulmonary event, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to pulmonary and infectious disease specialists 
and consider bronchoscopy or BAL.
Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
For recurrent events, treat as a Grade 3 or 4 event.
Continue enzalutamide.
Pulmonary event, Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Bronchoscopy or BAL is recommended.
Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 or 4 
pneumonitis, rechallenge with enzalutamide might be 
considered after consultation with the Medical Monitor. d
Cardiac events
Immune-mediated myocarditis, 
Grade 1 
Refer patient to cardiologist.
Initiate treatment as per institutional guidelines.
Continue enzalutamide.
BALbronchoalveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
92/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Cardiac events (cont.)
Immune-mediated
myocarditis, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset
and contact Medical Monitor. a
Refer patient to cardiologist.
Initiate treatment per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD as 
appropriate.
Consider treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Continue enzalutamide.
Immune-mediated myocarditis, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Refer patient to cardiologist.
Initiate treatment per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, and VAD
as appropriate.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 or 4 
myocarditis, rechallenge with enzalutamide might be 
considered after consultation with the Medical Monitor. d
ECMOextracorporeal membrane oxygenation; VADventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
93/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Endocrine events
Asymptomatic hypothyroidism
Continue atezolizumab.
Initiate treatment with thyroid replacement hormone.
Monitor TSH weekly.
Continue enzalutamide.
Symptomatic hypothyroidism
Withhold atezolizumab.
Initiate treatment with thyroid-replacement hormone.
Monitor TSH weekly.
Consider patient referral to endocrinologist.
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Consider withholding enzalutamide.
Resume enzalutamide when diagnosis of immune-mediated
hypothyroidism is confirmed and appropriate treatment is 
initiated or symptoms are controlled and thyroid function is 
improving.
Asymptomatic hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:
Continue atezolizumab.
Monitor TSH every 4 weeks.
Continue enzalutamide.
TSH 0.1 mU/L:
Follow guidelines for symptomatic hyperthyroidism.
Symptomatic hyperthyroidism
Withhold atezolizumab.
Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
Consider patient referral to endocrinologist. 
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism. c
Consider withholding enzalutamide.
Resume enzalutamide when symptoms are controlled and 
thyroid function is improving.
TSHthyroid-stimulating hormone.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
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Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Endocrine events (cont.)
Symptomatic adrenal 
insufficiency, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist.
Perform appropriate imaging.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b
If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Continue enzalutamide.
Symptomatic adrenal 
insufficiency, Grade 3 or 4
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist.
Perform appropriate imaging.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b
If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 or 4 
symptomatic adrenal insufficiency, rechallenge with 
enzalutamide might be considered after consultation with the 
Medical Monitor. d
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
95/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Endocrine events (cont.)
Hyperglycemia, Grade 1 or 2
Continue atezolizumab.
Initiate treatment with insulin if needed.
Monitor for glucose control.
Continue enzalutamide.
Hyperglycemia, Grade 3 or 4
Withhold atezolizumab.
Initiate treatment with insulin.
Monitor for glucose control.
Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
Consider withholding enzalutamide.
Resume enzalutamide when symptoms resolve and glucose 
levels are stable.
Hypophysitis 
(pan-hypopituitarism),
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist. 
Perform brain MRI (pituitary protocol).
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
Initiate hormone replacement as clinically needed.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
For recurrent hypophysitis, treat as a Grade 4 event.
Continue enzalutamide.
MRImagnetic resonance imaging.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
96/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Endocrine events (cont.)
Hypophysitis 
(pan-hypopituitarism), Grade 3
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to endocrinologist. 
Perform brain MRI (pituitary protocol).
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
Initiate hormone replacement as clinically needed.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and
contact Medical Monitor. c
For recurrent hypophysitis, treat as a Grade 4 event.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 hypophysitis, 
rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
MRImagnetic resonance imaging.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
97/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Endocrine events (cont.)
Hypophysitis 
(pan-hypopituitarism), Grade 4
Permanently discontinue atezolizumab and contact 
Medical Monitor. c
Refer patient to endocrinologist.
Perform brain MRI (pituitary protocol).
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
Initiate hormone replacement as clinically needed.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 4 hypophysitis, 
rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
MRImagnetic resonance imaging.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
98/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Dermatologic events
Dermatologic event, Grade 1 
Continue atezolizumab.
Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Continue enzalutamide.
Dermatologic event Grade 2
Continue atezolizumab.
Consider patient referral to dermatologist.
Initiate treatment with topical corticosteroids.
Consider treatment with higher-potency topical corticosteroids 
if event does not improve
Continue enzalutamide.
Dermatologic event, Grade 3 
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to dermatologist.
Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 dermatologic 
event, rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
99/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Dermatologic event, Grade 4
Permanently discontinue atezolizumab and contact 
Medical Monitor.c
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 4 dermatologic 
event, rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
Neurologic disorders
Immune-mediated neuropathy,
Grade 1 
Continue atezolizumab.
Investigate etiology.
Continue enzalutamide.
Immune-mediated neuropathy, 
Grade 2 
Withhold atezolizumab for up to 12 weeks after event onset. a
Investigate etiology.
Initiate treatment as per institutional guidelines.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Continue enzalutamide.
Immune-mediated neuropathy, 
Grade 3 or 4
Permanently discontinue atezolizumab and contact 
Medical Monitor.c
Initiate treatment as per institutional guidelines.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 or 4 
neuropathy, rechallenge with enzalutamide might be 
considered after consultation with the Medical Monitor. d
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
100/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Myasthenia gravis and 
Guillain-Barré syndrome (any 
grade)
Permanently discontinue atezolizumab and contact 
Medical Monitor. c
Refer patient to neurologist.
Initiate treatment as per institutional guidelines.
Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
Consider withholding enzalutamide.
Resumption of enzalutamide might be considered in patients 
who have fully recovered and/or if event is deemed unrelated to 
enzalutamide after consultation with the Medical Monitor.
Immune-mediated
meningoencephalitis, 
all grades or PRES
Permanently discontinue atezolizumab and contact 
Medical Monitor. c
Refer patient to neurologist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
Permanently discontinue enzalutamide.
Seizure, all grades
Withhold atezolizumab.
Refer patient to neurologist.
Initiate treatment as per institutional guidelines.
Resume atezolizumab in patients who have fully recovered 
and if event is deemed unrelated to atezolizumab.
Permanently discontinue enzalutamide.
PRESposterior reversible encephalopathy syndrome.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be rechallenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
101/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Pancreatic events, including pancreatitis
Amylase and/or lipase elevation, 
Grade 2
Continue atezolizumab.
Monitor amylase and lipase weekly.
For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Continue enzalutamide.
Amylase and/or lipase elevation, 
Grade 3 or 4
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist.
Monitor amylase and lipase every other day.
If no improvement, consider treatment with 12 mg/kg/day oral 
prednisone or equivalent.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor.c
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 or 4 amylase or 
lipase elevation, rechallenge with enzalutamide might be 
considered after consultation with the Medical Monitor. d
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
102/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Pancreatic events, including pancreatitis (cont.)
Immune-mediated pancreatitis, 
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Continue enzalutamide.
Immune-mediated pancreatitis, 
Grade 3
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to GI specialist.
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 pancreatitis, 
rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
103/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Pancreatic events, including pancreatitis (cont.)
Immune-mediated pancreatitis, 
Grade 4
Permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Refer patient to GI specialist. 
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month. 
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 4 pancreatitis, 
re-challenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
Ocular events
Ocular event, Grade 1
Continue atezolizumab.
Patient referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy.
If symptoms persist, treat as a Grade 2 event.
Continue enzalutamide.
GIgastrointestinal.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
104/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Ocular events
Ocular event, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Patient referral to ophthalmologist is strongly recommended.
Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Continue enzalutamide
Ocular event, Grade 3 or 4
Permanently discontinue atezolizumab and contact 
Medical Monitor. c
Refer patient to ophthalmologist.
Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 or 4 ocular 
event, rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
Renal events
Renal event, Grade 1
Continue atezolizumab.
Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values.
Continue enzalutamide.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d
Approval by the investigator and Medical Monitor must be documented.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
105/Protocol CO39385, Version 8
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Renal events (cont.)
Renal event, Grade 2
Withhold atezolizumab for up to 12 weeks after event onset. a
Refer patient to renal specialist.
Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Continue enzalutamide.
Renal event, Grade 3 or 4
Permanently discontinue atezolizumab and contact Medical 
Monitor. 
Refer patient to renal specialist and consider renal biopsy.
Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
Consider withholding enzalutamide.
Resume enzalutamide if event resolves to Grade 2 and/or if 
event is deemed unrelated to enzalutamide.  In case of 
uncertain relationship and/or recurrent Grade 3 or 4 event, 
rechallenge with enzalutamide might be considered after 
consultation with the Medical Monitor. d
Other Grade 3 or 4 treatment-
mediated toxicities (i.e., not 
described above)
Withhold atezolizumab and/or enzalutamide if event is 
considered to be related to the respective study drug.
Resume atezolizumab and/or enzalutamide if event resolves to 
Grade 2 or baseline. 
In case of uncertain relationship and/or recurrent Grade 3 or 
4 event, consult with the Medical Monitor.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
d Approval by the investigator and Medical Monitor must be documented.


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Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Immune-mediated myositis
Immune-mediated myositis,
Grade 1
Continue atezolizumab.
Refer patient to rheumatologist or neurologist.
Initiate treatment as per institutional guidelines.
Immune-mediated myositis,
Grade 2
Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor. 
Refer patient to rheumatologist or neurologist.
Initiate treatment as per institutional guidelines.
Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.
If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent.
If event resolves to Grade 1 or better, resume atezolizumab. b
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


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Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Immune-mediated myositis (cont.)
Immune-mediated myositis,
Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus 
if patient is severely compromised (e.g., cardiac or 
respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
For recurrent events, treat as a Grade 4 event.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


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Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Immune-mediated myositis (cont.)
Immune-mediated myositis,
Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus 
if patient is severely compromised (e.g., cardiac or 
respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
Suspected HLH or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care 
monitoring if indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
HLH hemophagocytic lymphohistiocytosis; IVintravenous; MAS macrophage activation 
syndrome.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
regardless of whether it is considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7) 

Suspected transmission of an infectious agent by the study treatment, as defined 
below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of study treatment is suspected.

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, or 
hyperthyroidism and hypophysitis


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
Hepatitis, or AST or ALT 10ULN

Systemic lupus erythematosus

Neurologic disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

Nephritis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, and systemic inflammatory response syndrome

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade2cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for serious adverse event criteria), 
severity (Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study treatment, all adverse events will be reported until 30 days 
after the last dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first, and serious adverse events and adverse events of 
special interest will continue to be reported until 90 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.


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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  On the basis of the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 


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accordingly.  The following guidance should be taken into consideration (see also 
Table 5):

Temporal relationship of event onset to the initiation of study treatment

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as 
applicable)

Known association of the event with study treatment or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 


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should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 


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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology studies, certain abnormal values may not qualify as 
adverse events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).


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5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with 
clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of prostate cancer should be recorded on the 
Death Attributed to Progressive Disease eCRF.  All other on-study deaths, regardless of 


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relationship to study treatment, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  An independent monitoring 
committee will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Prostate Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on PCWG3 criteria.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.


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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study treatment should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
No safety data related to overdosing of atezolizumab are available.
On the basis of the increased incidence of seizures that were observed at doses higher 
than 160 mg (3.5%; 3 of 85 patients), patients may be at increased risk of seizures 
following an overdose of enzalutamide.  One overdose was reported in the clinical study 
database for a patient enrolled in the early phase dose-escalation Study S-3100-1-01 
who was assigned a dose of 240 mg/day, but received 640 mg/day for 8 days. During 
this period, adverse events for Grade 2 fatigue and asthenia were reported and were 
self-limiting.  Enzalutamide was studied in Study S-3100-1-01 of castration-resistant 
prostate cancer patients in daily doses ranging from 30 mg to 600 mg.  Five dose-limiting 
toxicities were observed in four patients at doses exceeding 160 mg per day.  These 
included three seizures (1 each at 360-, 480-, and 600-mg doses [the 600-mg case 
included confusion]) and rash (1 at 600 mg).


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5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data and safety analyses will not be 
performed using PRO data.  No attempt will be made to reconcile the findings from 
reports of treatment-related symptoms by the clinicians (NCI CTCAE) and from the 
patients (NCI PRO-CTCAE) given the different ways in which these two data sources 
are collected.
Although sites are not expected to review the PRO data, it is possible that an 
investigator could become aware of PRO data that may be indicative of an adverse 
event.  Under these circumstances, the investigator will determine whether the criteria 
for an adverse event have been met and, if so, will report the event on the Adverse 
Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality on the basis of new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor:
, M.D., Ph.D.
Email:
Telephone No.:
Back-up Medical Monitor Contact Information 
Medical Monitor:
, M.D.
Email:
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment (or until 
initiation of new systemic anti-cancer therapy, whichever occurs first).  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 


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the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.
Instructions for reporting serious adverse events that occur 90 days after the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of enzalutamide.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study treatment.  When permitted,
the pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy. If the 
authorization has been signed, the investigator should submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  An investigator who is contacted by the male patient or his pregnant
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the investigator and/or 
obstetrician.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or study-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 


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hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 90 days after the last dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event or Adverse 
Event of Special Interest that are believed to be related to prior exposure to study 
treatment, the event should be reported through use of the Adverse Event eCRF.  
However, if the EDC system is not available, the investigator should report these events 
directly to the Sponsor or its designee, either by faxing or by scanning and emailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the fax 
number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Atezolizumab Investigator's Brochure

Local prescribing information for enzalutamide
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Analysis populations are defined as follows:

The intent-to-treat (ITT) population is defined as all randomized patients regardless 
of whether the assigned study treatment was received.  For efficacy analyses, 
patients will be analyzed according to their randomized treatment assignment. 

Objective response rate in soft tissue lesions will be analyzed in patients in the ITT 
population with measurable soft tissue lesions at baseline.

The duration of response (DOR)-evaluable population is defined as patients with an 
objective response in soft tissue lesions.

The safety population is defined as patients who received any amount of any 
component of the study treatments (atezolizumab, or enzalutamide).  Patients will 
be allocated to treatment arms according to the treatment they actually received (i.e., 
patients randomized to enzalutamide alone who received at least one full or partial 
dose of atezolizumab will be included in the atezolizumab arm for safety).
Safety run-in patients are not included in the populations defined above.  Safety and 
efficacy data from these patients will be presented separately.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of study treatment. 
6.1
DETERMINATION OF SAMPLE SIZE
A total of approximately 730 patients are planned to be enrolled in the global phase of
this study:  10 patients during the non-randomized safety run-in phase, and 
approximately 720 during the randomized phase of the study. 
The sample size of 10 patients for the safety run-in is based on clinical considerations.  
No statistical hypothesis tests will be performed on data from the safety run-in phase.
The final analysis of the primary endpoint of OS will be performed when approximately 
540 deaths have occurred in the ITT population (75% of 720 patients).
The calculations are based on the following assumptions:

Log-rank test

1:1 randomization

Two-sided alpha of 0.05

Median OS for the control (enzalutamide alone) arm of 12 months and estimated 
median OS in the experimental arm of 16.7 months, corresponding to a HR of 0.72

A drop-out rate of approximately 5% per 2-year period

One interim OS analysis


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It is projected that an observed HR of 0.84 will result in a statistically significant 
difference between treatment arms (i.e., the HR of 0.84 will be the minimally detectable 
difference at the final analysis). This corresponds to an improvement of median OS from 
12 months to 14.3 months.
In case of proportional hazards, 540 events would provide 97% power to detect a
difference in the duration of OS given the above assumptions. However, computer 
simulations show that the actual power of the log-rank test is likely lower in case of 
control patients switching to subsequent lines of immunotherapy following progression.
For example, if 15% of control patients receive subsequent treatment providing similar 
OS benefit as atezolizumab, the reduction in power is projected to be approximately 6%. 
Recruitment of the planned 720 patients is projected to be completed within 13 months.  
On the basis of the above assumptions, the required number of OS events for the final 
analysis is projected to occur at approximately Month 38 after randomizing the first 
patient.  
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment and reasons for discontinuation from the study will be summarized by 
treatment arm for the ITT population.  Major protocol deviations, including major 
deviations of inclusion and/or exclusion criteria, will be summarized by treatment arm for 
the ITT population.  Study treatment administration and reasons for discontinuation from 
study treatment will be summarized.
6.3
SUMMARIES OF DEMOGRAPHIC AND 
BASELINE CHARACTERISTICS
Demographic characteristics, such as age, sex, race/ethnicity, baseline disease 
characteristics, etc., will be summarized by treatment arm for the ITT population.  
Continuous variables will be summarized using means, standard deviations, medians, 
and ranges.  Categorical variables will be summarized by frequencies and percentages.
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is OS, defined as the time from randomization to death 
from any cause.  Data for patients who are not reported as having died at of the date of 
analysis will be censored at the last date known to be alive.  Data for patients who do not 
have post-baseline information will be censored at the date of randomization plus 1 day.
The primary comparison of OS between treatment arms will be based on a stratified 
log-rank test.  The HR for death in the experimental arm compared with the control arm 
will be estimated using a stratified Cox regression model, and the 95% CI will be 
provided.  The stratification factors will be the same as the randomization stratification 
factors; however, stratification factors may be combined for analysis purposes if 


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necessary to minimize small stratum cell sizes.  Combination of stratification factors, if 
any, would be specified in the SAP prior to analysis.  Values for the stratification factors 
will be as recorded in the IxRS at the time of randomization.  Results from an unstratified 
analysis will also be presented.
Kaplan-Meier plots will be constructed to provide a visual description of the difference 
between the treatment and control arms.  Kaplan-Meier methodology will also be used to 
estimate median OS for each treatment arm.  Brookmeyer-Crowley methodology will be 
used to construct the 95% CI for the median OS for each treatment arm.
The OS rate at key timepoints (12 months, 24 months) will be estimated using 
Kaplan-Meier methodology, along with 95% CIs calculated using the standard error 
derived from Greenwood’s formula.  The 95% CI for the difference in OS rates between 
the two treatment arms will be estimated by use of the normal approximation method.
6.4.2
Secondary Efficacy Endpoints
Analyses of the primary endpoint of OS and the key secondary efficacy endpoints listed 
below will be performed in a hierarchical fashion with type 1 error control (see 
Section 6.8.1).  The primary endpoint of OS will be analyzed first.  If the null hypothesis 
for the OS endpoint is rejected, then the key secondary endpoints will be in the order 
provided:
1. Time to cancer-related pain progression 
2. Time to first symptomatic skeletal event (SSE)
3. rPFS 
If for one endpoint in this list the null hypothesis cannot be rejected, then the results for 
this and all following endpoints are not considered to be statistically significant. Analyses 
of other secondary endpoints of this study will be considered as descriptive in nature, 
and no formal hypothesis testing will be conducted.
6.4.2.1
Radiographic PFS and Other Time-to-Event Endpoints
The following secondary time -to -event endpoints will be analyzed using similar 
methods as those described for OS above: 

Time to cancer-related pain progression

Time to first SSE

rPFS

Immune-modified rPFS

Time to initiation or increased opiate analgesic use for cancer pain

Time to PSA progression


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Data for patients who do not have post -baseline information will be censored at the date 
of randomization plus 1 day. Data for patients who have not experienced an event at the 
time of the analysis will be censored at the last available assessment.
Hazard ratios and 95% CI from a stratified Cox proportional hazards model will be 
provided.  Kaplan-Meier methodology will be used to estimate median time to event and 
the 95% CI will be provided.  Analyses of rPFS will also include the rPFS rate at 6 and 
12 months. 
6.4.2.2
PSA Response Rates
An estimate of the PSA response rate and its 95% CI will be calculated for each 
treatment arm using the Clopper Pearson method.  The difference of PSA response 
rates and 95% CI between the two treatment arms will be estimated by use of the 
normal approximation to the binomial distribution.
6.4.2.3
Objective Response Rate in Soft Tissue Lesions
The analysis population for objective response rate (ORR) will be all patients in the ITT 
population with measurable soft tissue lesions at baseline.
ORR is defined as the proportion of patients who had a confirmed response in soft tissue 
lesions.  An estimate of ORR will be calculated for each treatment arm, and its 95% CI 
will be calculated using the Clopper Pearson method.  The CI for the difference in ORRs 
between the two treatment arms will be determined using the normal approximation to 
the binomial distribution.
6.4.3
Exploratory Efficacy Endpoints
The methodologies outlined for the ORR in soft tissue lesions analysis will be used for 
the DCR analysis.
The following exploratory time-to-event endpoints will be analyzed using the same 
methods as outlined in the section on secondary time-to-event endpoints.

Modified PFS based on radiographic disease progression and unequivocal clinical 
progression

DOR in soft tissue lesions

Time to initiation of next systemic anti-cancer therapy

Time to unequivocal clinical progression
DOR will be assessed in patients who had an objective response in soft tissue lesions as 
determined by the investigator.
DOR is defined as the time from the first occurrence of a CR or PR (whichever status is 
recorded first) until the first date progressive disease or death is documented, whichever 
occurs first.  Patients who have not progressed and who have not died at the time of 


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analysis will be censored at the time of last tumor assessment date.  If no tumor 
assessments were performed after the date of the first occurrence of a CR or PR, DOR 
will be censored at the date of the first occurrence of a CR or PR plus 1 day.
The statistical methods applied to DOR will be the same as for rPFS described above.  
However, it should be noted that DOR is evaluated in a non-randomized subset of 
patients (those who achieved an objective response in soft tissue); therefore, results of 
this analysis will be provided for descriptive purposes only.
6.4.4
Subgroup Analyses
Subgroup analyses will be performed in an exploratory manner in order to investigate 
consistency of the treatment effect across different subgroups. Subgroup categories will 
include demographic characteristics (e.g., age, sex, and race/ethnicity), baseline disease 
characteristics (e.g., prior taxane-containing therapy, type of disease progression [PSA 
only vs. radiographic disease progression], sites of metastases), and stratification factors, 
and other subgroups as appropriate.
Subgroup analyses will use similar methods as those used for the study population as a 
whole. Results for efficacy parameters in subgroups will be presented in Forest plots
and descriptive summary tables. 
It is not planned to investigate the homogeneity of the treatment effect across individual 
centers because with approximately 180 recruiting centers the average number of 
patients per center would be too small to detect any meaningful differences between 
them.
Additional details will be provided in the Statistical Analysis Plan (SAP) prior to 
performing the analyses.
6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety-evaluable population, which is defined 
as all randomized patients from the global enrollment phase who receive any amount of
any component of study treatments.  Patients will be summarized according to the 
treatment actually received.  Specifically, for patients randomized to the enzalutamide 
alone arm, if atezolizumab was received by mistake, patients will be grouped under the 
atezolizumab arm in the safety analyses.
Exposure to study treatment will be summarized to include treatment duration, number 
of doses, and dose intensity.
Verbatim description of adverse events will be coded to MedDRA preferred terms and 
graded according to NCI CTCAE v4.0.  All adverse events occurring during or after the 
first study-drug dose will be summarized by treatment arm and NCI CTCAE grade.  In 
addition, serious adverse events, Grade3 adverse events, adverse events of special 


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interest (see Section 5.2.2), adverse events leading to treatment discontinuation, and/or 
modification will be summarized.
Laboratory abnormalities will be summarized by treatment arm and grade.
Changes in selected vital signs will be summarized by treatment arm.
Deaths and causes of death reported during the study treatment period and those 
reported during the follow-up period after treatment completion/discontinuation will be 
summarized by treatment arm.
In addition, safety data will be presented in summary tables split by subgroups defined 
by age, sex, and race/ethnicity, as well as other potential risk factors as appropriate.  
Additional details will be provided in the SAP prior to performing the analyses.
6.6
PHARMACOKINETIC ANALYSES
PK analyses will be performed on the PK-evaluable population, which is defined as 
patients who have received at least one dose of study drug and have at least one 
post-dose PK sample.  The PK population for each study drug and specific timepoint will 
vary, depending on the availability of results with adequately documented dose time and 
PK sampling time.
Atezolizumab serum concentration data (minimum [Cmin] and maximum [Cmax]) will be 
reported and summarized (e.g., mean, standard deviation, coefficient of variation [CV%], 
median, range, geometric mean, geometric mean coefficient of variation [CVb]) for each 
cycle where collected as appropriate.
Plasma concentrations of enzalutamide and N-desmethyl enzalutamide will be reported 
and summarized using descriptive statistics as described above for each cycle and 
treatment arm, as appropriate. Data may be excluded from PK analysis if a patient has 
taken concomitant medications that are known to affect enzalutamide PK (see 
Appendix 13).  For patients enrolled in China, plasma samples for enzalutamide and 
N-desmethyl enzalutamide will not be collected.
Additional PK and pharmacodynamic analyses will be conducted as appropriate on the 
basis of the available data.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analyses will include all patients enrolled, with patients grouped 
according to treatment received.
The numbers and proportions of ATA-positive patients and ATA-negative patients at 
baseline (baseline prevalence) and after baseline (post-baseline incidence) will be 
summarized by treatment group.  When determining post-baseline incidence, patients 


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are considered to be ATA positive if they are ATA negative or are missing data at 
baseline but develop an ATA response following study drug exposure 
(treatment-induced ATA response), or if they are ATA positive at baseline and the titer of 
one or more post-baseline samples is at least 0.60-titer units higher than the titer of the 
baseline sample (treatment-enhanced ATA response).  Patients are considered to be 
ATA negative if they are ATA negative or are missing data at baseline and all 
post-baseline samples are negative, or if they are ATA positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60-titer units higher than the 
titer of the baseline sample (treatment unaffected).
The relationship between ATA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics.
6.8
INTERIM ANALYSES
6.8.1
Planned Interim Analyses
A total of two analyses of OS will be performed:  one interim analysis and the final 
analysis.
The interim analysis of the primary endpoint of OS will be performed when 
approximately 432 deaths have occurred (60% of 720 patients), corresponding to 
approximately 80% of the 540 deaths required for the final analysis of OS.  The required 
number of deaths for the interim analysis is projected to occur at approximately 
Month 27 after randomizing the first patient.
The Lan-DeMets alpha-spending function approach will be used to determine the 
boundary values for statistical significance at the interim and final analysis (DeMets and 
Lan 1994).
For the primary endpoint of OS, the stopping boundaries will be based on the
O’Brien-Fleming alpha-spending function. At both the interim and final OS analysis, key 
secondary endpoints listed in Section 6.4.2 will be evaluated for statistical significance 
only if the difference in duration of OS is statistically significant at the appropriate 
boundary level. For these secondary endpoints, the boundaries for statistical 
significance will be based on a Pocock alpha-spending function. Key secondary 
endpoints will be tested at the appropriate significance level in the order specified in
Section 6.4.2. If for one endpoint in this list the null hypothesis cannot be rejected, then 
the results for this and all following endpoints are not statistically significant.
The hierarchical testing procedure with the boundaries determined as described above 
ensures that the overall type I error for the primary and key secondary endpoints will be
controlled at 0.05 (Hung et al. 2007; Glimm et al. 2010).
The interim OS analysis will be performed by the iDCC and reviewed by the iDMC (see 
Section 3.2).  The Sponsor will remain blinded to the results.  On the basis of its review 


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of the data, the iDMC will provide a recommendation as to whether to release the study 
results early because of substantial evidence of efficacy.
6.8.2
Optional Interim Analysis 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim efficacy analysis for the primary endpoint of OS 
beyond what is specified in Section 6.8.1.  The decision to conduct the optional interim 
analysis, along with the rationale, timing, and statistical details for the analysis, will be 
documented in the SAP, and the SAP will be submitted to relevant health authorities at 
least 2 months prior to the conduct of the interim analysis.
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis 
will be conducted by the iDCC and reviewed by the iDMC.  Interactions between the 
iDMC and Sponsor will be carried out as specified in the iDMC Charter. 
If there is a potential for the study to be stopped for positive efficacy as a result of the 
interim analysis, the type I error rate will be controlled using the same Lan-DeMets 
approach as for the planned interim analysis described above.  
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Data will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data, other than the data obtained from Question 3 of the BPI-SF at screening, will 
be collected through the use of an electronic device provided by a vendor.  For situations 
that preclude the use of the electronic device, a backup paper option may be utilized. 
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with FDA, regulations for electronic records (21 CFR Part 11).  
The electronic data are available for view access only via secure access to a vendor 
hosted, password protected web portal.  Only identified and trained users may view the 


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data, and their actions become part of the audit trail.  The Sponsor will have view access 
only.  System backups for data stored by the Sponsor and records retention for the study 
data will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
An electronic device will be used to capture PRO data at the site visit and at home 
between study visits. It is critical that patients are reminded to bring their provisioned 
electronic device at each visit. The data will be transmitted to a centralized database 
maintained by the electronic device vendor.  Once the study is complete, the data, audit 
trail, and study and system documentation will be archived.  The investigator will receive 
patient data for the site in both human and machine-readable formats on an 
archival-quality compact disc that must be kept with the study records as source data.  
Acknowledgement of receipt of the compact disc is required.  In addition, the Sponsor 
will receive all data in a machine-readable format.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 


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entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
study-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 


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Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.


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For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 


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be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted clinical study reports 
and other summary reports will be provided upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., receipt of the last 
data point required for the final analysis of the primary efficacy endpoint or sponsor 
decision to end the study, whichever occurs first).
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.


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9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 180 sites globally will participate in the study and approximately 
730 patients will be enrolled.
Enrollment in the safety run-in and randomized phases of the study will occur through an 
IxRS system.  In the randomized phase, randomization will be managed by IxRS.  
Central facilities will be used for study assessments throughout the study (e.g., specified 
laboratory tests, PK analyses, and medical imaging).
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An iDMC will be convened to evaluate safety data during the study according to policies 
and procedures detailed in an iDMC Charter.
9.5
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
European Medicines Agency, and in peer-reviewed journals. The Sponsor will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical study results within 6 months after the 
availability of the respective CSR.  In addition, for all clinical studies in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.


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The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
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Appendix 1
Schedule of Activities
Screening a
Treatment 
(Each cycle21 days)
Treatment 
Discontinuation
(30 Days) b
Safety Visit c
(120 Days 
30 Days)
Study 
Termination d
Days
–28 to –1
Day 1
(3 Days for Cycles 2)
Informed consent a
x
Medical, surgical, and cancer histories and baseline 
conditions, including demographic information e
x
Viral serology f
x
Concomitant medications g
x
x
x
Opiate analgesics use for cancer pain h
x
x
Tumor assessment i
x
Every 9 weeks (3 days) for the first 27 weeks and every 12 weeks 
(6 days) thereafter until confirmed radiographic disease progression,
death, or loss of follow-up
Complete physical examination j
x
x
Limited physical examination k
x l
x
ECOG performance status
x
x l
x
x
Vital signs m
x
x
Electrocardiogram n
x
x n
x
Echocardiogram n
x
Weight
x
x
x
Height
x
Hematology o
x
x l
x
x
Serum chemistry p
x
x l
x
x


Appendix 1
Schedule of Activities (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
148/Protocol CO39385, Version 8
Screening a
Treatment 
(Each Cycle 21 days)
Treatment 
Discontinuation
(30 Days) b
Safety Visit c
(120 Days 
30 Days)
Study 
Termination d
Days
–28 to –1
Day 1
(3 Days for Cycles 2)
Coagulation panel (INR, and aPTT or PTT) q
x
x
x
TSH, free T3, free T4 r
x
x l
x
x
Autoantibody testing
x
Testosterone
x
Historic values for PSA velocity s
x
PSA t
x
x
x
x t
x t
Archival and/or fresh FFPE tumor tissue specimen or 
15 unstained slides u
x
Tumor biopsy v
At the time of confirmed radiographic progression


Appendix 1
Schedule of Activities (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
149/Protocol CO39385, Version 8
Screening a
Treatment 
(Each Cycle 21 days)
Treatment 
Discontinuation
(30 Days) b
Safety Visit c
(120 Days 
30 Days)
Study 
Termination d
Days
–28 to –1
Day 1
(3 Days for Cycles 2)
Symptomatic skeletal events w
x
Atezolizumab infusion x
x
Enzalutamide treatment y
x
Adverse events z
x
x
Survival and anti-cancer therapy follow-up d
x
x
ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; FFPEformalin fixed paraffin embedded; HBcAbhepatitis B 
core antibody; HBsAbhepatitis B surface antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; 
IVintravenous; PCWG3Prostate Cancer Working Group 3; PD-L1programmed death-ligand 1; RECIST Response Evaluation Criteria in Solid 
Tumors; SSEsymptomatic skeletal event;T3triiodothyronine; T4thyroxine; TSHthyroid-stimulating hormone.
Notes:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted.
a Written informed consent is required for performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur outside 
the 28-day screening period.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days 
prior to study entry (except where otherwise specified) may be used for screening assessments rather than repeating such tests.  If re-screening is 
required, then HBV, HCV, HIV, and autoantibody testing from the initial screening may be acceptable for screening assessment if performed60 
days from Cycle 1 Day 1.  
b Patients will be asked to return to the clinic not more than 30 days after the last study treatment for a treatment discontinuation visit.
c Patients will be asked to return to the clinic 120 days 30 days after the last study treatment for a safety visit.  Only patients taking atezolizumab are 
required to return for the safety visit.
d All patients will be followed for survival until study termination unless the patient requests to be withdrawn from the study; this request must be 
documented in the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff may use a public 
information source (e.g., county records) to obtain information about survival status only. 
e Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes age, sex, and self-reported 
race/ethnicity.  Smoking history should also be captured.


Appendix 1
Schedule of Activities (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
150/Protocol CO39385, Version 8
f
At screening, patients will be tested for HIV, HBsAg, HBsAb, total HBcAb, and HCV antibody. If a patient has a negative HBsAg test and a 
positive total HBcAb test at screening, an HBV DNA test should be performed. If a patient has a positive HCV antibody test at screening, an 
HCV RNA test must also be performed to determine if the patient has an active HCV infection.
g Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to initiation of study treatment should be documented.  At subsequent visits, changes to current medications or 
medications used since the last documentation of medications will be recorded.
h At screening, any opiate analgesic medications a patient has used within the 7 days prior to initiation of study treatment should be documented.  
i
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1 may be used rather 
than repeating tests.  All measurable and evaluable lesions should be assessed and documented at the screening visit.  The same radiographic 
procedure must be used throughout the study for each patient.  Results must be reviewed by the investigator before dosing at the next cycle.  
Tumor assessments will be performed at baseline, every 9 weeks (approximately every three cycles) following randomization for 27 weeks, and 
every 12 weeks thereafter, with additional scans as clinically indicated.  Assessments will continue until confirmed radiographic disease 
progression per PCWG3 criteria.  For patients who continue to receive study treatment following confirmed disease progression, assessments 
will continue until loss of clinical benefit.  If an optional biopsy is to be performed at approximately the same time point of a tumor assessment or 
as a result of the radiographic determination (e.g., response or progression), samples should be acquired after all imaging scans have been 
performed, if at all possible. Once patients discontinue study treatment, tumor assessments should no longer be performed as per this study, 
and should be performed as per standard of care as determined by the investigator.
j
Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.
k Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
l
ECOG performance status, limited physical examination, and local laboratory assessments may be obtained 4 days before Day 1 of each cycle.
m Vital signs include heart rate, respiratory rate, blood pressures, and temperature.  Record abnormalities observed at baseline on the General 
Medical History and Baseline Conditions eCRF.  Vital signs should be measured at every cycle for all patients. Vital signs should be measured 
within 60 minutes prior to each atezolizumab infusion and, if clinically indicated, during or after the infusion. 
n ECG recordings will be obtained as part of the screening assessment, at Day 1 of Cycle 4 and every 4 cycles thereafter during treatment, at the 
end of treatment visit, and when clinically indicated.  ECGs will be reviewed by the investigator to determine patient eligibility at screening.  
Baseline evaluation of left ventricular ejection fraction should be considered for all patients, especially in those with cardiac risk factors and/or 
history of coronary artery disease.  For patients with a history of clinically significant cardiac disease (including anatomic abnormality, coronary 
disease, congestive heart failure, abnormal LVEF, arrhythmia, or abnormal ECG) will be required to undergo a screening echocardiogram.


Appendix 1
Schedule of Activities (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
151/Protocol CO39385, Version 8
o Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, 
eosinophils, monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated. Absolute 
neutrophil count, lymphocyte count, platelet count, and hemoglobin for study inclusion-related tests must be obtained 14 days prior to initiation of 
study treatment.
p Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, total protein, and albumin.  In countries where serum bicarbonate is not 
considered a standard chemistry measurement (e.g., Japan), serum bicarbonate is not required as a laboratory study in the screening or on-
study serum measurements. AST, ALT, bilirubin, creatinine, and albumin for study inclusion-related tests must be obtained 14 days prior to 
initiation of study treatment.
q Coagulation panel for study inclusion-related tests must be obtained 14 days prior to initiation of study treatment.
r
TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every fourth cycle 
thereafter.
s
At least two PSA samples (obtained at least 1 week apart) will be assessed locally at screening.  Samples analyzed prior to screening do not 
have to be repeated.  Historic values of PSA will be collected to calculate PSA velocity.
t
The PSA sample will be assessed locally. PSA should be performed as per standard of care once patient discontinues study treatment.
u After signing the Informed Consent Form, retrieval and submission of archival tumor sample can occur more than 28 days prior to start of study 
treatment but must be submitted prior to enrollment.  Tissue samples will not be collected for patients in the safety run-in phase. See 
Section 4.5.6 for tissue sample requirements.  
v Tumor specimens are recommended at the time of confirmed radiographic disease progression per PCWG3 criteria, unless the location of the 
tumor renders the biopsy medically unsafe or infeasible per investigator decision.  Biopsies should be performed within 40 days after progression 
or prior to the next anti-cancer therapy, whichever is sooner.  See Section 4.5.6 for tissue sample requirements.  Preferably, growing lesions 
should be selected. 
w An SSE is defined as external beam radiation therapy to relieve skeletal symptoms (including initiation of radium-223 dichloride or other types of 
radionuclide therapy to treat symptoms of bone metastases), new symptomatic pathologic bone fracture, clinically apparent occurrence of spinal 
cord compression, or tumor related orthopedic surgical intervention
x The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first infusion is tolerated without infusion-associated adverse 
events, the second infusion may be delivered over 30 (10) minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be 
delivered over 30 (10) minutes.
y Enzalutamide will be administered at a dose of 160 mg orally once daily.  Study drug doses should be taken as close as possible to the same 
time each day.  The study drug can be taken with or without food.


Appendix 1
Schedule of Activities (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
152/Protocol CO39385, Version 8
z After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study 
drug or initiation of another systemic anti-cancer therapy, whichever occurs first and serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug or initiation of another systemic anti-cancer therapy, whichever occurs first.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to 
prior study treatment.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is 
assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or study-related procedures until a final outcome can be reported.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
153/Protocol CO39385, Version 8
Appendix 2
Criteria for Radiographic Progression per Prostate Cancer 
Working Group 3
Date 
Progression 
Detected 
(Visit) a
Criteria for Progression
Criteria for Confirmation 
of Progression 
(requirement and timing)
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan
Week 9
Bone lesions: Two or 
more new lesions 
compared to baseline
bone scan by PCWG3
Timing: at least 6 weeks 
after progression 
identified or at Week 18 
visit. c
Two or more new bone 
lesions on bone scan 
(compared to Week 9 
scan).
Soft tissue lesions: 
Progressive disease on 
CT or MRI by modified 
RECIST v1.1 b
No confirmatory scan 
required for soft tissue 
disease progression.
NA
Week 18 or later Bone lesions: Two or 
more new lesions on 
bone scan compared to 
Week 9 bone scan
Timing: at least 6 weeks 
after progression 
identified. Required for 
bone lesions observed 
on bone scan c
Persistent d or increase in 
number of bone lesions 
on bone scan compared 
to prior scan.
Soft tissue lesions: 
Progressive disease on 
CT or MRI by modified 
RECIST v1.1 b
No confirmatory scan 
required for soft tissue 
disease progression.
NA
CTcomputed tomography; MRImagnetic resonance imaging; NAnot applicable; 
PCWG3Prostate Cancer Working Group 3, RECISTResponse Evaluation Criteria in Solid 
Tumors.
Note:  Adapted from Scher et al. 2016.
a Progression detected by bone scan at an unscheduled visit will require a confirmatory scan at 
least 6 weeks later and should follow confirmation criteria outlined in the table for the next 
scheduled scan. Progression detected by bone scan at an unscheduled visit prior to Week 12 
will require a confirmatory scan at least 6 weeks later showing two or more new bone lesions on 
bone scan.
b For RECIST v1.1 see Appendix 3. Up to five lesions per site of spread will be recorded as 
target lesions (lung, liver, adrenal, nodal).
c Confirmation must occur at the next available scan.
d For confirmation, at least two of the lesions first identified as new must be present at that next 
available scan.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
154/Protocol CO39385, Version 8
Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009), are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
                                           
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
155/Protocol CO39385, Version 8
DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
156/Protocol CO39385, Version 8
METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
157/Protocol CO39385, Version 8
forward.  Care must be taken in measurement of target lesions and interpretation of 
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions (a maximum of 
five lesions per organ) representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline.  Other lesions (albeit 
measurable) will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
158/Protocol CO39385, Version 8
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (eCRF) (e.g., "multiple enlarged pelvic lymph nodes" or
"multiple liver metastases").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
Measuring Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if CR criteria are met, since a normal lymph node is defined as having a short axis of 
10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the eCRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
159/Protocol CO39385, Version 8

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked).
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  Non-
target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the eCRF as part of the assessment of non-
target lesions.
RESPONSE CRITERIA
CRITERIA FOR TARGET LESIONS
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below:

CR:  Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

PR:  At least a 30% decrease in the sum of diameters of all target lesions, taking as 
reference the baseline sum of diameters, in the absence of CR


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
160/Protocol CO39385, Version 8

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters on study (including 
baseline) 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD
CRITERIA FOR NON-TARGET LESIONS
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  Whereas some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities.

CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.
Patients with Non-Measurable Disease Only
For patients with non-measurable disease only, the same general concepts apply as 
noted above.  However, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-measurable disease cannot be easily quantified (by definition, if all 
lesions are truly non-measurable), a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
161/Protocol CO39385, Version 8
burden based on the change in non-measurable disease is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from "trace" to "large" or an increase in lymphangitic 
disease from localized to widespread.  If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point.  Whereas it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial.
NEW LESIONS
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
"new" cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
162/Protocol CO39385, Version 8
Table 1
Criteria for Overall Response at a Single Timepoint:  
Patients with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
Table 2
Criteria for Overall Response at a Single Timepoint:  
Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
     Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a "Non-CR/non-PD" is preferred over "stable disease" for non-target disease 
since stable disease is increasingly used as an endpoint for assessment 
of efficacy in some trials; thus, assigning "stable disease" when no lesions 
can be measured is not advised.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesions would not change the assigned timepoint response.  This would be most likely to 
happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and during the study only two lesions were assessed, but those 


Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
163/Protocol CO39385, Version 8
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1 and Table 2. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.  


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
164/Protocol CO39385, Version 8
Appendix 4
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  EORTC QLQ-C30


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
165/Protocol CO39385, Version 8
Appendix 4
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  EORTC QLQ-C30 (cont.)


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
166/Protocol CO39385, Version 8
Appendix 5
European Organisation for Research and Treatment of Cancer
Quality-of-Life Questionnaire:  Urinary Scale from EORTC 
QLQ-PR25
Patients sometimes report that they have the following symptoms or problems.  Please indicate 
the extent to which you have experienced these symptomsor problems during the past week.  
Please answer by circuling the number that best applies to you.
Not at
A
Quite
Very
All
Little
a Bit
Much
31.
Have you had to urinate frequently during the day?
1
2
3
4
32.
Have you had to urinate frequently at night?
1
2
3
4
33.
When you felt the urge to pass urine, did you have to hurry
to get to the toilet?
1
2
3
4
34.
Was it difficult for you to get enough sleep because you needed
to get up frequently at night to urinate?
1
2
3
4 
35.
Have you had difficulties going out of the house because you
needed to be close to a toilet?
1
2
3
4
36.
Have you had any unintentional release (leakage) of urine?
1
2
3
4
37.
Did you have pain when you urinated?
1
2
3
4
39.
Have your daily activities been limited by your urinary problems? 
1
2
3
4


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
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Appendix 6
EuroQol 5-Dimension Questionnaire:  EQ-5D-5L
Health Questionnaire
English version for the USA
Under each heading, please check the ONE box that best describes your health 
TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family 
or leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN/DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort



Appendix 6
EuroQol 5-Dimension Questionnaire:  EQ-5D-5L (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
168/Protocol CO39385, Version 8
I have extreme pain or discomfort

ANXIETY/DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed



Appendix 6
EuroQol 5-Dimension Questionnaire:  EQ-5D-5L (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
169/Protocol CO39385, Version 8


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
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Appendix 7
Pain Severity Assessments
Pain Severity Assessment (Screening) from BPI-SF a
1. Please rate your pain by tapping the one number that best describes your pain at its worst in 
the last 24 hours.
0
1
2
3
4
5
6
7
8
9
10
No 
Pain
Pain as bad as 
you can imagine
Pain Severity Assessment (Day 1 of Cycle 1 and following Assessments) from BPI a
1. Please rate your pain by tapping the one number that best describes your pain at its worst in 
the last week.
0
1
2
3
4
5
6
7
8
9
10
No 
Pain
Pain as bad as 
you can imagine
2. Tap the one number that describes how, during the past week, pain has interfered with 
your:
A. General Activity
0
1
2
3
4
5
6
7
8
9
10
Does 
not 
interfere
Completely 
interferes
B. Mood
0
1
2
3
4
5
6
7
8
9
10
Does 
not 
interfere
Completely
interferes
C. Walking Ability
0
1
2
3
4
5
6
7
8
9
10
Does 
not 
interfere
Completely 
interferes
D. Normal Work (includes both work outside the home and housework)
0
1
2
3
4
5
6
7
8
9
10
Does 
not 
interfere
Completely 
interferes


Appendix 7
Pain Severity Assessments (cont.)
Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
171/Protocol CO39385, Version 8
E. Relations with other people
0
1
2
3
4
5
6
7
8
9
10
Does 
not 
interfere
Completely 
interferes
F. Sleep
0
1
2
3
4
5
6
7
8
9
10
Does 
not 
interfere
Completely 
interferes
G. Enjoyment of life
0
1
2
3
4
5
6
7
8
9
10
Does 
not 
interfere
Completely 
interferes
a Questions from Brief Pain Inventory and Brief Pain Inventory-Short Form per author 
permission.


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Appendix 8
Analgesic Quantification Algorithm Score Categories and 
Equianalgesic Potency Conversions
Analgesic Quantification Algorithm Score Categories
Score
Description
0
No analgesic
1
Non-opioid analgesics
2
Weak opioids (i.e., codeine and tramadol
when not used in combination with other 
opioids)
3
Strong opioids 75 mg OME/day
4
Strong opioids 75150 mg OME/day
5
Strong opioids 150300 mg OME/day
6
Strong opioids 300600 mg OME/day
7
Strong opioids 600 mg OME/day
OMEoral morphine equivalent.


Atezolizumab and Enzalutamide—F. Hoffmann-La Roche Ltd
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Appendix 8
Analgesic Quantification Algorithm Score Categories and 
Equianalgesic Potency Conversions (cont.)
Equianalgesic Potency Conversions
Name
Equianalgesic Dose (mg)
IV
SC
IM
TM
PO
OME
Morphine
10
10
10
—
30
30
Fentanyl
0.1
0.1
0.1
0.1
2.4
30
Hydromorphone
1
1
1
—
5
20
Methadone
10
10
10
—
20
30
Oxycodone
10*
—
—
—
20
30
Hydrocodone
—
—
—
—
40
40
Codeine
120
120
120
—
200
30
Tramadol
100
100
100
—
100
30
Meperidine †
75
75
75
—
300
30
Buprenorphine
0.3
0.3
0.3
0.3
0.2
30
Butorphanol
—
—
2
—
—
30
Nalbuphine
10
10
10
—
—
30
Pentazocine
60
60
60
—
60
20
IVintravenous; SCsubcutaneous; IMintramuscular; TMtransdermal; OMEoral morphine 
equivalent; PO oral.
* Based on 1:2 ratio for IV to PO conversion as described by manufacturer.
† Based on Demystifying opioid conversions calculations: A guide for effective dosing. 
McPherson ML, 2009.
REFERENCE
Adapted from Chung KC, PharmD MS, Barlev A, et al. Assessing analgesic use in 
patients with advanced cancer: Development of a new scalethe Analgesic 
Quantification Algorithm. Pain Med 2014;15:22532.


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Appendix 9
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events
How much bothered were you with the side effect of your treatment?
Not at all           A little bit                Somewhat             Quite a bit        Very much


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Appendix 10
Preexisting Autoimmune Diseases
Subjects should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Subjects with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be subjects with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty over autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated 
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody 
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory 
demyelinating 
polyneuropathy
Churg-Strauss syndrome
Crohn disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquisita
Gestational pemphigoid
Giant cell arteritis
Goodpasture syndrome
Graves disease
Guillain-Barré syndrome
Hashimoto disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease, chronic
Meniere syndrome
Mooren ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis


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Appendix 11
Anaphylaxis Precautions
EQUIPMENT NEEDED

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Apply a tourniquet proximal to the injection site to slow systemic absorption 
of study treatment.  Do not obstruct arterial flow in the limb.
3.
Maintain an adequate airway.
4.
Administer antihistamines, epinephrine, or other medications as required by 
patient status and directed by the physician in charge.
5.
Continue to observe the patient and document observations.


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Appendix 12
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance 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 housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead


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Appendix 13
Guidance on Reducing the Risks of Pharmacokinetic DrugDrug 
Interactions with Enzalutamide
For information on drug-drug interactions with enzalutamide, please see the local 
prescribing information.
There is a potential for other medicinal products to affect enzalutamide exposures and 
for enzalutamide to affect exposures to other medicinal products.  Examples of drugs 
with the potential for drug-drug interactions with enzalutamide are provided below.  For 
the most current list of drugs that may be subject to drug-drug interactions, consult the 
following sources:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf

http://medicine.iupui.edu/clinpharm/ddis/table.aspx
Potential for Other Medicinal Products to Affect Enzalutamide Exposures
CYP2C8 inhibitors and inducers
Clinical data indicate that CYP2C8 plays an important role in the metabolism of 
enzalutamide; therefore, strong inhibitors (e.g., gemfibrozil) or inducers (e.g., rifampicin) 
of CYP2C8 should be used with caution during enzalutamide treatment.  If concomitant 
use of strong CYP2C8 inhibitors cannot be avoided, then the dose of study drug should 
be reduced to 80 mg per day (2 capsules).
Potential for Enzalutamide to Affect Exposures to Other Medicinal Products
Enzyme induction
Clinical data indicate that enzalutamide is a strong inducer of CYP3A4 and a moderate 
inducer of CYP2C9 and CYP2C19.  UGT may be induced as well.  These results 
suggest that enzalutamide causes enzyme induction via activation of PXR.  Medicinal 
products with a narrow therapeutic range that are substrates of CYP3A4, CYP2C9, 
CYP2C19, or UGT should be used with caution when administered concomitantly with 
enzalutamide and may require dose adjustment to maintain therapeutic plasma 
concentrations.  Such substrates include, but are not limited to:

Macrolide antibiotics (e.g., clarithromycin, doxycycline)

Benzodiazepines (e.g., diazepam, midazolam, zolpidem)

Immune modulators (e.g., cyclosporine, tacrolimus)

HIV antivirals (e.g., indinavir, ritonavir)

Anti-epileptics (e.g., carbamazepine, clonazepam, phenytoin, primidone, 
valproic acid)

Coumarins (e.g., warfarin)
In consideration of the long half-life of enzalutamide (approximately 1 week), effects on 
enzymes may persist for 1 month or longer after stopping enzalutamide.


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Appendix 13
Guidance on Reducing the Risks of Pharmacokinetic DrugDrug 
Interactions with Enzalutamide (cont.)
P-gp substrates
In vitro data indicate that enzalutamide may be a P-gp inhibitor.  The effects of 
enzalutamide on P-gp substrates have not been evaluated in vivo; however, under 
conditions of clinical use, enzalutamide may be an inducer of P-gp via activation of PXR.  
Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g., 
colchicine, dabigatran etexilate, digoxin) should be used with caution when administered 
concomitantly with enzalutamide and may require dose adjustment to maintain optimal 
plasma concentrations.