Clinical trial NCT03565991
Conditions: Locally Advanced or Metastatic Solid Tumors Genes, BRCA 1
Keywords: BRCA, ATM
Sponsor: Pfizer
Start date: 2018-06-18; Completion date: 2023-02-03
Enrollment: 202 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Avelumab in combination with talazoparib will be investigated in patients with locally advanced or metastatic solid tumors with a BRCA or ATM defect.

Detailed description:
Avelumab is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) directed against programmed death ligand 1 (PD-L1). Avelumab selectively binds to PD-L1 and competitively blocks its interaction with programmed death receptor 1 (PD-1), thereby interfering with this key immune checkpoint inhibition pathway. Avelumab is currently being investigated as single agent and in combination with other anti cancer therapies in patients with locally advanced or metastatic solid tumors and various hematological malignancies.

Talazoparib is a potent, orally bioavailable poly (adenosine diphosphate \[ADP\] ribose) polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines harboring gene mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as synthetic lethality, and by trapping PARP protein on DNA thereby preventing DNA repair, replication, and transcription.

Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors with a BReast CAncer susceptibility gene (BRCA)1, or BRCA2, or ataxia telangiectasia mutated (ATM) gene defect.

Arms: arm 1: Single arm open label
Interventions: intervention 1: Avelumab intervention 2: Talazoparib
Intervention descriptions: intervention 1: IV treatment intervention 2: Oral treatment

Protocol documents:
Prot_000.pdf: 
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A PHASE 2 STUDY TO EVALUATE SAFETY AND ANTI-TUMOR ACTIVITY OF 
AVELUMAB IN COMBINATION WITH TALAZOPARIB IN PATIENTS WITH 
BRCA OR ATM MUTANT TUMORS
JAVELIN BRCA/ATM
Investigational Product Number:
MSB0010718C
MDV3800, BMN 673
Investigational Product Name:
Avelumab (MSB0010718C) 
Talazoparib (MDV3800, BMN 673)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2018-000345-39
ClinicalTrials.gov Registry Number:
NCT03565991
Protocol Number:
B9991032
Phase:
2b
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Original Protocol
15 March 2018
Not applicable (N/A)
Protocol 
Amendment 1
15 November 2018
 
 
 
 
 
 
2. To help facilitate study conduct, the 
Schedule of Activities has been 
modified with a -1 day window for the 
baseline physical examination and a 
+/-3 day window (formerly +/- 2 day) 
for treatment visits.
3. To help facilitate study conduct, the 
Schedule of Activities and Section 7.8 
has been modified to clarify that Patient 
Reported Outcome assessments are not 
required when not available in a 
language understood by the patient, and 
to provide a window for shipment of 
pre-treatment tumor tissue.
4. The background section has been 
updated with health authority approvals 
for Avelumab (Section 1.1.1) and 
Talazoparib (Section 1.1.2).
5. Consistent with the updated Avelumab 
Investigator’s Brochure (version 8, 
16 May 2018), the protocol was revised 
to update background information and 
recommendation for management of 
Grade 1 to 2 immune-related rash was 
updated (Section 5.4.6.5).
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6. Consistent with the updated Talazoparib 
Investigator’s Brochure (dated August 
2018), the protocol was revised to 
provide updated background 
information on clinical experience 
(Section 1.2.2.1) and pharmacokinetic 
information (Section 1.2.2.3), to 
increase the duration of contraception 
use (Exclusion criterion #24, 
Section 4.1; Section 4.3), and to 
simplify language regarding prohibited 
medication P-gp inhibitors (Exclusion 
criterion #19 and Section 5.7.10). 
7. Preliminary safety information and the 
recommended phase 2 dose from the 
B9991025 study has been added to the 
Background (Sections 1.2.5.2 and 
1.2.6), Allocation to Treatment 
(Section 5.1) and Talazoparib 
administration sections (Section 5.4.2 
and 5.4.6.2). 
8. Use of a Patient Enrollment Verification 
Form has been added to Section 4.0.
9. To facilitate participation by sites, 
requirements for specific laboratories 
for local germline testing has been 
simplified to be less restrictive: The 
presence of gene defects must have been 
determined by local assessment and 
classification using a test of either 
germline or tumor DNA, which was 
performed in a CAP/CLIA certified (or 
comparable local or regional 
certification) laboratory (Section 4.1). 
10. For increased consistency across tumor 
types, Inclusion criteria details for 
platinum sensitivity in breast cancer 
(Criterion #2.b) ‘any other advanced 
solid tumor’ (Criterion #2.e) have been 
modified to ‘patients must not have had 


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disease progression within 6 months of 
initiation of a platinum-containing 
regimen in Section 4.1.
11. Talazoparib starting dose for patients 
with renal impairment has been clarified 
in 5.4.2 and for consistency with other 
studies, dose modifications due to renal 
impairment during the study based on 
creatinine clearance have been removed 
from Sections 5.4.2, 5.4.6.2 and from 
Table 5.  
12. Permissible highly effective methods of 
contraception were updated as per 
current protocol standard, including the 
addition of sexual abstinence (Exclusion 
criterion #24; Section 4.3).
13. Definition of menopausal state has been 
revised as per current standard 
(Inclusion criterion #11; Section 4.3).
14. Compliance definitions have been added 
for avelumab (Section 5.2.1) and
Talazoparib (Section 5.2.2) and 
instructions on missed Talazoparib 
dosing have been added to 
Section 5.4.2. 
15. As separate withdrawal of consent form 
is not applicable to this study, reference 
to this was removed from Section 6.3.1. 
16. Pregnancy testing language has been 
simplified and aligned with current 
standards in Section 7.1.1.
17. Required safety laboratory tests 
(Table 8, Section 7.1.4) were updated as 
follows:

As many centers perform an 
activated partial thromboplastin time 
assessment (aPTT) rather than PTT, 
aPTT was added as an alternate 
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
Given potential variation in 
reporting of PT results across study 
centers, PT has been removed as a 
reportable test result in favor of 
collecting the INR result alone 
(Table 8, Section 7.1.4).
18. More detailed language regarding the 
informed consent process, from the new 
protocol template has been incorporated 
into Section 12.3.
Related editorial updates have been made 
for consistency and readability.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).  


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................12
LIST OF FIGURES .................................................................................................................12
APPENDICES .........................................................................................................................12
PROTOCOL SUMMARY.......................................................................................................14
SCHEDULE OF ACTIVITIES................................................................................................21
1. INTRODUCTION ...............................................................................................................28
1.1. Mechanism of Action/Indication.............................................................................28
1.1.1. Avelumab....................................................................................................28
1.1.2. Talazoparib .................................................................................................29
1.2. Background and Rationale ......................................................................................29
1.2.1. Avelumab Clinical Experience...................................................................29
1.2.1.1. Clinical Experience in Patients with Solid Tumors ..................32
1.2.1.2. Pharmacokinetics of Avelumab in Humans..............................34
1.2.2. Talazoparib .................................................................................................34
1.2.2.1. Talazoparib Clinical Experience ...............................................34
1.2.2.2. Clinical Efficacy in Patients with Advanced Solid Tumors......36
1.2.2.3. Pharmacokinetics of Talazoparib in Humans............................36
1.2.3. Clinical Experience in Patients Treated with Other PARP Inhibitors 
as a Single Agent or in Combination with Immunotherapy ............................37
1.2.3.1. PARP Inhibitor Experience in Ovarian Cancer (OC) ...............38
1.2.3.2. PARP Inhibitor Experience in Advanced Breast Cancer..........38
1.2.3.3. PARP Inhibitor Experience in Metastatic Castration 
Resistant Prostate Cancer (mCRPC) .................................................39
1.2.3.4. PARP Inhibitor Experience in Pancreatic Cancer.....................39
1.2.4. Study Rationale...........................................................................................40
1.2.5. Rationale for the Investigational Product Doses ........................................43
1.2.5.1. Avelumab ..................................................................................43
1.2.5.2. Talazoparib................................................................................43
1.2.6. Summary of Benefit/Risk Assessment .......................................................44
1.2.7. Rationale for Biomarker Assessments and Prospective Patient
Selection...........................................................................................................46
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2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................47
3. STUDY DESIGN.................................................................................................................49
3.1. Study Overview.......................................................................................................49
4. PATIENT ELIGIBILITY CRITERIA.................................................................................49
4.1. Inclusion Criteria.....................................................................................................49
4.2. Exclusion Criteria....................................................................................................54
4.3. Lifestyle Requirements ...........................................................................................57
4.4. Sponsor’s Qualified Medical Personnel..................................................................58
5. STUDY TREATMENTS.....................................................................................................59
5.1. Allocation to Treatment ..........................................................................................59
5.2. Patient Compliance .................................................................................................59
5.2.1. Avelumab Patient Compliance ...................................................................60
5.2.2. Talazoparib Patient Compliance.................................................................60
5.3. Investigational Product Supplies.............................................................................61
5.3.1. Dosage Forms and Packaging.....................................................................61
5.3.1.1. Avelumab ..................................................................................61
5.3.1.2. Talazoparib................................................................................61
5.3.2. Preparation and Dispensing........................................................................61
5.3.2.1. Avelumab ..................................................................................62
5.3.2.2. Talazoparib................................................................................62
5.4. Administration.........................................................................................................62
5.4.1. Combination Therapy Administration........................................................62
5.4.2. Talazoparib Administration........................................................................63
5.4.3. Avelumab Premedication............................................................................64
5.4.4. Avelumab Administration ..........................................................................64
5.4.4.1. Special Precautions for Avelumab Administration...................64
5.4.5. Food Requirements.....................................................................................64
5.4.6. Recommended Dose Modifications............................................................64
5.4.6.1. Dosing Interruptions..................................................................65
5.4.6.2. Dose Reductions of Talazoparib ...............................................65
5.4.6.3. Study Treatment Modifications for Avelumab and 
Talazoparib Drug-Related Toxicity (excluding infusion-related 
reactions and immune-related adverse events)..................................66


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5.4.6.4. Treatment Modifications for Infusion-Related Reactions 
Associated with Avelumab................................................................70
5.4.6.5. Immune-Related Adverse Events Toxicity Management .........71
5.4.7. Treatment After Initial Evidence of Radiological Disease 
Progression.......................................................................................................77
5.5. Investigational Product Storage ..............................................................................78
5.5.1. Avelumab Storage ......................................................................................79
5.5.2. Talazoparib Storage....................................................................................79
5.6. Investigational Product Accountability...................................................................79
5.6.1. Destruction of Investigational Product Supplies ........................................79
5.7. Concomitant Treatment...........................................................................................80
5.7.1. Supportive Care ..........................................................................................80
5.7.2. Hematopoietic Growth Factors...................................................................80
5.7.3. Anti-Diarrheal, Anti-Emetic Therapy.........................................................80
5.7.4. Anti-Inflammatory Therapy........................................................................81
5.7.5. Corticosteroids............................................................................................81
5.7.6. Bisphosphonates or Denosumab.................................................................81
5.7.7. Androgen Deprivation Therapy for Patients with CRPC ...........................81
5.7.8. Concomitant Surgery..................................................................................82
5.7.9. Concomitant Radiotherapy.........................................................................82
5.7.10. Prohibited Concomitant Medications and Therapies................................82
6. STUDY PROCEDURES .....................................................................................................83
6.1. Screening.................................................................................................................83
6.2. Treatment Period.....................................................................................................83
6.3. Patient Withdrawal/End of Treatment.....................................................................84
6.3.1. Withdrawal of Consent...............................................................................85
6.3.2. Lost to Follow-up .......................................................................................85
6.4. Short-Term Follow-up Visits ..................................................................................85
6.5. Long-Term Follow-up Visits ..................................................................................86
7. ASSESSMENTS..................................................................................................................86
7.1. Safety Assessments .................................................................................................86
7.1.1. Pregnancy Testing ......................................................................................87
7.1.2. Contraception Check ..................................................................................87


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7.1.3. Adverse Events...........................................................................................87
7.1.4. Laboratory Safety Assessments..................................................................87
7.1.5. Physical Examinations and Vital Signs......................................................88
7.1.6. (12-Lead) Electrocardiograms....................................................................89
7.2. Pharmacokinetics Assessments...............................................................................89
7.2.1. Blood for PK Analysis of Avelumab..........................................................90
7.2.2. Blood for PK Analysis of Talazoparib .......................................................90
7.3. Immunogenicity Assessments.................................................................................90
7.4. Biomarker and Pharmacodynamic Assessments.....................................................91
7.4.1. Tumor Tissue Samples ...............................................................................91
7.4.1.1. Pretreatment Tumor Tissue Samples.........................................91
7.4.1.2. On Treatment and End of Treatment Tissue Samples...............93
7.4.2. Peripheral Blood Samples...........................................................................94
7.6. Tumor Response Assessment..................................................................................96
7.6.1. mCRPC Tumor Response Assessments .....................................................97
7.7. Blood Tests for Tumor Markers and Circulating Tumor Cells...............................98
7.7.1. CA-125 for Patients with Ovarian Cancer..................................................98
7.7.2. Prostate-Specific Antigen for Patients with mCRPC .................................98
7.7.3. Circulating Tumor Cells (CTCs) for Patients with mCRPC ......................98
8. ADVERSE EVENT REPORTING....................................................................................102
8.1. Requirements.........................................................................................................102
8.1.1. Additional Details on Recording Adverse Events on the CRF.................103
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8.1.2. Eliciting Adverse Event Information........................................................103
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Patient Withdrawal/End of Treatment section)..............................................103
8.1.4. Time Period for Collecting AE/SAE Information....................................104
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................104
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............104
8.1.5. Causality Assessment ...............................................................................104
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................105
8.2. Definitions.............................................................................................................105
8.2.1. Adverse Events.........................................................................................105
8.2.2. Abnormal Test Findings ...........................................................................106
8.2.3. Serious Adverse Events ............................................................................106
8.2.4. Hospitalization..........................................................................................107
8.3. Severity Assessment..............................................................................................108
8.4. Special Situations ..................................................................................................108
8.4.1. Protocol-Specified Serious Adverse Events.............................................108
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................109
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................110
8.4.4. Exposure During Pregnancy.....................................................................110
8.4.4.1. Exposure During Breastfeeding ..............................................112
8.4.4.2. Occupational Exposure ...........................................................112
8.4.5. Medication Errors .....................................................................................112
8.4.5.1. Medication Errors....................................................................112
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................113
9.1. Analysis Sets .........................................................................................................113
9.1.1. Full Analysis Set.......................................................................................113
9.1.2. Safety Analysis Set...................................................................................113
9.1.3. Pharmacokinetics Analysis Sets ...............................................................113
9.1.4. Immunogenicity Analysis Set...................................................................113
9.1.5. Biomarker Analysis Sets...........................................................................114
9.2. Sample Size Determination...................................................................................114
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9.3. Efficacy Analysis ..................................................................................................115
9.3.1. Analysis of the Primary Endpoint.............................................................115
9.3.2. Analysis of the Secondary Endpoints.......................................................116
9.4. Analysis of Pharmacokinetics and Pharmacodynamics ........................................118
9.4.1. Analysis of Pharmacokinetics of Investigational Products ......................118
9.4.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/Pharmacodynamic) Modeling......118
9.4.3. Analysis of Biomarker Secondary 
 Endpoints................118
9.4.4. Analysis of Immunogenicity Data of Avelumab......................................119
9.5. Safety Analysis......................................................................................................119
9.5.1. Adverse Events.........................................................................................119
9.5.2. Laboratory Test Abnormalities.................................................................119
9.5.3. Electrocardiogram.....................................................................................120
9.6. Analysis of Other Endpoints .................................................................................120
9.8. Interim Analysis ....................................................................................................121
9.9. Data Monitoring Committee .................................................................................121
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................121
11. DATA HANDLING AND RECORD KEEPING ...........................................................122
11.1. Case Report Forms/Electronic Data Record .......................................................122
11.2. Record Retention.................................................................................................122
12. ETHICS............................................................................................................................123
12.1. Institutional Review Board/Ethics Committee....................................................123
12.2. Ethical Conduct of the Study ..............................................................................123
12.3. Patient Information and Consent.........................................................................123
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................125
13. DEFINITION OF END OF TRIAL.................................................................................125
13.1. End of Trial in a Member State...........................................................................125
13.2. End of Trial in All Other Participating Countries...............................................125
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................125
15. PUBLICATION OF STUDY RESULTS........................................................................125
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15.1. Communication of Results by Pfizer ..................................................................125
15.2. Publications by Investigators ..............................................................................126
16. REFERENCES ................................................................................................................128
LIST OF TABLES
Table 1.
Schedule of Activities: Safety and Efficacy Assessments....................................22
Table 2.
Schedule of Activities: Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Assessments...........................................................................26
Table 3.
Avelumab: Efficacy Results .................................................................................33
Table 4.
Dose Levels for Dose Reductions of Talazoparib ................................................66
Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related AEs) .....67
Table 6.
Treatment Modification for Symptoms of Infusion-related Reactions 
Associated with Avelumab...................................................................................70
Table 7.
Management of Immune-Related Adverse Events...............................................71
Table 8.
Required Safety Laboratory Tests ........................................................................88
Table 9.
Sample Size and Exact 95% Confidence Intervals for ORR..............................115
LIST OF FIGURES
Figure 2.
Combination of Talazoparib (BMN 673) and Anti-mouse PD-L1 Treatment 
Significantly Prolongs Survival in an Ovarian Cancer Model .............................42
APPENDICES
Appendix 1. Abbreviations and Definitions of Terms...........................................................135
Appendix 2. ECOG Performance Status................................................................................141
Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines .......................................................................................142
Appendix 4. Assessment of Radiographic Response and Progression in Patients with
Metastatic CRPC ................................................................................................147
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PROTOCOL SUMMARY
Mechanism of Action/Indication
Avelumab is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) directed against 
programmed death-ligand 1 (PD-L1).  Avelumab selectively binds to PD-L1 and 
competitively blocks its interaction with programmed death receptor 1 (PD-1), thereby 
interfering with this key immune checkpoint pathway.  
In March 2017, avelumab received accelerated approval by the United States (US) Food and 
Drug Administration (FDA) as the first treatment for metastatic Merkel cell carcinoma 
(mMCC), with subsequent approvals in the European Union (EU), Switzerland, Japan, 
Australia, Israel and Canada. In May 2017, avelumab received accelerated approval by the 
US FDA for the treatment of patients with locally advanced or metastatic urothelial cancer 
(UC) with disease progression during or following platinum-containing chemotherapy, or 
within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.5  
 
 
Talazoparib is a potent, orally bioavailable poly (adenosine diphosphate [ADP]-ribose) 
polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines harboring gene 
mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as 
synthetic lethality, and by trapping PARP protein on DNA, thereby preventing DNA repair, 
replication, and transcription. 
The combination of avelumab and talazoparib is expected to produce additive or synergistic 
anti-tumor activity relative to each drug used as a single agent.  Avelumab in combination 
with talazoparib will be investigated in patients with locally advanced (primary or recurrent) 
or metastatic solid tumors with a pathogenic or likely pathogenic germline or loss-of-function 
somatic BReast CAncer susceptibility gene (BRCA)1, or BRCA2, or ataxia telangiectasia 
mutated (ATM) gene defect, as determined by local assessment and classification, who have 
received at least 1 line of standard of care (SOC) treatment for locally advanced or metastatic 
disease unless prior treatment requirements are otherwise specified.
Background
Avelumab, as a single agent, has demonstrated efficacy in patients across different tumor 
types, including previously untreated and treated non-small cell lung cancer (NSCLC), 
urothelial cancer, ovarian cancer, breast cancer, mMCC, gastric/gastroesophageal junction 
cancer (GC/GEJ) and castration-resistant prostate cancer (mCRPC).  The efficacy findings 
for avelumab are summarized in the table below.
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Avelumab: Efficacy Results 
Study 
Tumor Type (n)
Efficacy Results
EMR100070-003
(JAVELIN Merkel 
200)
mMCC5
2L, pretreated, metastatic (88)
ORR:a 33.0% (n=29, 95% CI: 23.3, 43.8)
DOR range, mo: 2.8, 23.3+
EMR100070-001
Urothelial Carcinoma5
Pretreated, advanced or metastatic 
(161, with 6 mo follow-up )
ORR:a 16.1% (n=26, 95% CI: 10.8, 22.8)
Median DOR, mo: NE (range: 1.4+, 17.4+)
Breast Cancer21
Pretreated, advanced or metastatic (168)
ORR:a 3% (n=5, 95% CI: 1.0, 6.8)
Median DOR, wk: NE (95% CI: 28.7, NE)
Median PFS, wk: 5.9 (95% CI: 5.9, 6.0)
PFS rate at 24 wk: 10.1% (95% CI: 5.9, 15.5)
Median OS, mo: 8.1 (95% CI: 6.4, NE)
mCRPC22
Progressed on previous treatment (18)
ORR: 0/18 patients 
(7 of 18 patients had stable disease >24 weeks 
post treatment)
NSCLC4
2L metastatic (184)
ORR:a 12% (n=22, 95% CI: 7.6, 17.5)
Median DOR, wk: NR (0.1, ongoing at 54.1)
Median PFS, wk: 11.6 (95% CI: 8.4, 13.7) 
PFS rate at 48 wk: 18% (95% CI: 12, 26)
Median OS, mo: 8.4 (95% CI: 7.3, 10.6)
OS rate at 12 mo: 36% (95% CI: 26, 46)
1L metastatic/recurrent (156)
ORR:b 22.4% (n=35, 95% CI: 16.2, 29.8) 
68.6% ongoing, median treatment duration 
20 weeks
Median PFS, wk: 17.6 (95% CI: 11.6, 23.6) 
PFS rate at 24 wk: 37.2% (95% CI: 28.6, 45.7)
Ovarian Cancer4
Pretreated, advanced or metastatic (124)
ORR:b 9.7% (n=12, 95% CI: 5.1, 16.3) 
50.0% ongoing, median follow-up 12.4 months
Median PFS, wk: 11.3 (95% CI: 6.1, 12.0) 
PFS rate at 48 wk: 5.5% (95% CI: 1.3, 14.2)
GC/GEJ Cancer4
Pretreated, advanced or metastatic
1L maintenance (89)
ORR:b 9% (n=8, 95% CI: 4.0, 16.9)
Median DOR, wk: 48.3 (95% CI: 3.0, NE)
2L therapy (62)
ORR:b 9.7% (n=6, 95% CI: 3.6, 19.9) 
Median DOR, wk: 12.3 (95% CI: 5.4, NE)
EMR100070-002
(Japan)
Gastric4
Pretreated, metastatic (20)
ORR:b 15.0% (n=3, 95% CI: 3.2, 37.9) 
Median PFS, wk: 11.9 (95% CI: 6.0, 12.3)
+ denotes a censored value
Abbreviations: 1L=first line, 2L=second line, CI: confidence interval, DOR=Duration of response, GC=gastric cancer, 
GEJ=gastroesophageal junction, mCRPC=metastatic castration resistant prostate cancer, mMCC=metastatic Merkel cell 
cancer, mo=months, NE=not estimable, NR=not reached, NSCLC=nonsmall cell lung cancer, ORR=objective response 
rate, PFS=progression free survival, OS=overall survival, SD=stable disease, wk=weeks
a.
Considering only confirmed responses.
b.
Considering both confirmed and unconfirmed responses.
These studies have also shown an acceptable safety profile for avelumab single agent 
treatment; most frequently observed treatment-related adverse events from pooled data have 
been fatigue (17.7%), infusion related reaction (17.0%), nausea (8.6%), diarrhea (7.1%), 
chills (6.7%), pyrexia (6.1%), decreased appetite (5.2%), and hypothyroidism (5.0%).


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While subsets of patients in a growing number of tumor types respond to treatment with a 
single agent PD-1 or PD-L1 inhibitor, most patients with advanced disease either do not 
respond to single-agent therapy or experience only a partial response.  Further, the majority 
of those patients who do respond will ultimately progress.  These findings of somewhat 
limited responses are observed regardless of either the PD-1 or PD-L1 inhibitor that is being 
tested or the tumor type in which the immune checkpoint inhibitor is being evaluated. 
Talazoparib, as a single agent, has demonstrated efficacy as well as an acceptable toxicity 
profile in patients with multiple types of solid tumors with DNA repair pathway 
abnormalities, particularly those associated with BRCA and phosphatase and tensin homolog 
gene (PTEN) dysfunction.  In the Phase 1 Study PRP-001, in patients treated with talazoparib 
1.0 mg/day with advanced breast cancer, ovarian/peritoneal cancer, and pancreatic cancer, an 
objective response rate (ORR) of 50.0% (7 of 14; 95% confidence interval [CI]: 23.0, 77.0), 
41.7% (5 of 12; 95% CI: 15.2, 72.3), and 20% (2 of 10) was observed, respectively.33  In the 
ongoing Phase 2 study in patients with locally advanced or metastatic breast cancer harboring 
BRCA mutations (Study 673-201), independently assessed OR has been observed in 
20.8% of 48 patients with disease progression after prior response to platinum-containing 
regimens and in 37.1% of 35 patients with disease progression after 3 or more non-platinum 
cytotoxic regimens. 
Data from the ongoing EMBRACA study presented in December 2017 (287 patients in 
talazoparib arm, 144 patients in physician’s choice therapy [PCT] arm) showed that median 
PFS was 8.6 months (95% CI: 7.2, 9.3) for patients treated with talazoparib and 5.6 months 
(95% CI: 4.2, 6.7) for those treated with chemotherapy (hazard ratio [HR]=0.54; 95% 
CI: 0.41, 0.71; p<0.0001).  Also, ORR was 62.6% for talazoparib vs 27.2% for chemotherapy 
(odds ratio for OR=4.99; 95% CI: 2.9, 8.8; p<0.0001; per Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST v 1.1), confirmation of CR/PR was not required) and 
median duration of response (DOR) was 5.4 months (interquartile range [IQR]: 2.8-11.2) for 
talazoparib and 3.1 months (IQR: 2.4-6.7) for PCT.  The overall survival (OS) data are still 
immature (38% deaths in each arm) and OS time was not statistically different between arms.  
The most common adverse events (AEs) observed with talazoparib (>20%, all grade) were 
anemia (52.8%), fatigue (50.3%), nausea (48.6%), neutropenia (34.6%), headache (32.5%), 
thrombocytopenia (26.9%), alopecia (25.2%), vomiting (24.8%), diarrhea (22%), 
constipation (22%), decreased appetite (21.3%), and back pain (21%).  The incidence of 
serious AEs was 31.8% in the talazoparib arm and 29.4% in the chemotherapy arm.  
Discontinuations due to AEs occurred in 7.7% of patients in the talazoparib arm and 9.5% of 
patients in the chemotherapy arm.24
Talazoparib is proposed for evaluation in combination with avelumab in patients with locally 
advanced (primary or recurrent) or metastatic solid tumors with a pathogenic or likely 
pathogenic germline or loss-of-function somatic BRCA1, or BRCA2, or ATM gene defect 
who have received at least 1 line of standard of care (SOC) treatment for locally advanced or 
metastatic disease unless prior treatment requirements are otherwise specified.  This is based 
on the acceptable safety and pharmacokinetic (PK) profiles observed for each of the 
investigational products when administered as single agents, on the clinical activity that has 
been observed for these investigational products, or an agent of the same class, and on 
proposed complementary mechanisms of action, detailed below. 


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The activity of avelumab depends on generation of a productive immune response.  DNA 
damage via talazoparib is expected to promote inflammation and prime an immune response 
by enhancing effective recognition and infiltration of tumors by immune cells.  Additionally, 
talazoparib treatment has been shown to lead to two to three fold increased expression of 
PD-L1 by tumor cells, suggesting that this may represent a means by which tumors function 
to inhibit talazoparib-mediated anti-tumor immunity.  Based on these interactions between 
DNA damage, PD-L1 expression and the immune response, the combination of talazoparib 
and avelumab is expected to lead to additive or synergistic anti-tumor activity. 
Preliminary data from other PARP and PD-L1 inhibitor combination studies for treatment of 
advanced tumors currently tested in clinical trials have shown promising activity and suggest 
that the combination has an acceptable safety profile.25,26,45
This expectation is supported by preclinical studies in syngeneic mouse models of ovarian 
and colorectal cancers, which demonstrated a significant improvement in overall survival 
(OS) in mice treated with the combination of talazoparib and an anti-mouse PD-L1, but not 
in mice treated with either talazoparib or anti-mouse PD-L1 alone.40
Clinical studies have indicated that the greatest sensitivity to PARP inhibitors, such as 
talazoparib, is observed in tumors with defective repair of DNA double strand breaks 
(DSBs); such breaks accumulate following PARP inhibition and in the absence of effective 
repair lead to cell death.41  One underlying reason for defective DSB repair is the presence of 
mutations in key genes, either at the germline or somatic level.  The BRCA1, BRCA2 and 
ATM genes are three of the best evidenced examples of such genes.  Mutations in either the 
BRCA1 or BRCA2 gene have been associated with increased response, or improved 
outcome, following treatment with a number of PARP inhibitors including olaparib, 
rucaparib, and niraparib while mutations in ATM have been associated with increased 
response to olaparib.42,43,44,54  Clinical development of most PARP inhibitors has been 
focused up to now in tumor types with a relatively high prevalence of BRCA1/2 defects, such 
as ovarian, breast, prostate and pancreatic cancers.  However, analysis of publicly available 
data within The Cancer Genome Atlas (TCGA56), indicates that mutations in BRCA 1/2 and 
ATM occur with variable frequency in many other tumor types, with an average prevalence 
across solid tumors of 7.7%.  It is expected that all tumors with such defects will present with 
increased sensitivity to talazoparib mediated DNA damage, and therefore have the potential 
to benefit from the combination of talazoparib and avelumab.
The primary purpose of this study is to assess the efficacy and safety of the avelumab plus 
talazoparib combination in approximately 200 patients with locally advanced (primary or 
recurrent) or metastatic solid tumors with a pathogenic or likely pathogenic germline or 
somatic BRCA1, or BRCA2, or ATM gene defect who have received at least 1 line of 
standard of care (SOC) treatment for locally advanced or metastatic disease unless prior 
treatment requirements are otherwise specified.  It is anticipated that these patients, who have 
limited therapeutic options after progression on chemotherapy, and whose tumors harbor 
sensitizing defects in BRCA 1/2, or ATM, will be most likely to benefit from the 
combination treatment, independent of their tumor type.  There remains a high unmet need in 
the management of these patients. 


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Study Objectives and Endpoints
Primary Objective:
Primary Endpoint:

To evaluate ORR of avelumab in combination with 
talazoparib, in patients with locally advanced or 
metastatic solid tumors harboring BRCA1, BRCA2 or 
ATM defect.

Confirmed OR in patients with locally advanced or 
metastatic solid tumors with BRCA 1/2 or ATM 
defect, as assessed by Blinded Independent Central 
Review (BICR), using RECIST v1.1 (Appendix 3) 
and, in patients with mCRPC, RECIST v1.1  and 
PCWG3 (bone) (Appendix 4).
Secondary Objectives:
Secondary Endpoints:

To assess the overall safety and tolerability of 
avelumab in combination with talazoparib.

To characterize the PK of avelumab and talazoparib 
when given in combination.

To evaluate the immunogenicity of avelumab when 
given in combination with talazoparib.

To assess other measures of the anti-tumor activity of 
avelumab in combination with talazoparib.

To assess the correlation of anti-tumor activity of 
avelumab in combination with talazoparib with PD-L1 
expression in baseline tumor tissue.

To assess the correlation of anti-tumor activity and 
emergence of resistance with defects in a panel of key 
oncogenes, including BRCA 1/2 and ATM, and TMB 
in circulating tumor DNA (ctDNA) and tumor tissue 
at baseline, during treatment and at the end of 
treatment.

Adverse Events as characterized by type, severity (as 
graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events 
[NCI CTCAE] v.4.03), timing, seriousness, and 
relationship to study therapy.

Laboratory abnormalities as characterized by type, 
severity (as graded by NCI CTCAE v.4.03) and 
timing.

PK parameters including: pre-dose/trough 
concentrations (Ctrough) for avelumab and talazoparib 
and post-dose concentrations (for talazoparib) and 
maximum concentrations (Cmax) for avelumab.

Avelumab Anti-drug antibody (ADA) levels and 
neutralizing antibodies (Nab) against avelumab.

Confirmed OR as assessed by the investigator, using 
RECIST v1.1 (Appendix 3) and, in patients with 
mCRPC, RECIST v1.1 and PCWG3 (Appendix 4).

Time to event endpoints: Endpoints as assessed by 
BICR and as assessed by the investigator, using 
RECIST v1.1 (Appendix 3) and in patients with 
mCRPC, RECIST v1.1 and PCWG3 (Appendix 4), 
including time to tumor response (TTR), duration of 
response (DR), and progression free survival (PFS).  
Additional time-to-event endpoints include overall 
survival (OS) for all patients and time to 
prostate-specific antigen (PSA) progression 
(25% increase) for mCRPC patients. 

PSA response 50% decrease and CTC count 
conversion for patients with mCRPC.

Cancer antigen (CA)-125 response 50% decrease 
for patients with ovarian cancer.

PD-L1 expression level in baseline tumor tissue.

Presence of defects in a panel of key oncogenes, 
including BRCA1/2 and ATM, and TMB in ctDNA 
and tumor tissue at baseline, during treatment, and at 
the end of treatment.


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Study Design
This is a Phase 2b, open-label, multi-center, non-randomized study of avelumab in 
combination with talazoparib in adult patients with locally advanced (primary or recurrent) or 
metastatic solid tumors with pathogenic or likely pathogenic germline or loss-of-function 
somatic BRCA1 or BRCA2, or ATM gene defect who have received at least 1 line of SOC 
treatment for locally advanced or metastatic disease unless prior treatment requirements are 
otherwise specified.  Two cohorts will be enrolled in parallel:
•
Cohort 1 will enroll up to approximately 150 patients with locally advanced or 
metastatic solid tumors with one or more defects in the BRCA1 or BRCA2 genes.
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
Cohort 2 will enroll up to approximately 50 patients with locally advanced or 
metastatic solid tumors with one or more defects in the ATM gene.
Note: in the event that a patient has concomitant defects in more than 1 of the three genes 
(BRCA1 or BRCA2 or ATM), they will be enrolled in Cohort 1. 
Study Treatments
All patients enrolled will receive avelumab and talazoparib. 
Avelumab will be administered as a 1-hour IV infusion every 2 weeks (Q2W) on Days 1 and 
15 of each 28-day cycle at a dose of 800 mg. 
Talazoparib will be self-administered orally once daily (QD) at a dose of 1 mg QD. Patients 
with moderate renal impairment will receive 0.75 mg QD.
Avelumab will be administered at the investigator site on an outpatient basis.  On days when 
both drugs are administered, talazoparib will be administered first, followed by initiation of 
the avelumab infusion within 30-60 minutes. See Section 5.4 for premedication and 
administration details.
Statistical Methods
The primary endpoint is confirmed OR in patients with locally advanced or metastatic solid 
tumors with BRCA 1/2 or ATM defect, as assessed by BICR using RECIST v1.1 and, in 
patients with mCRPC, RECIST v1.1 and PCWG3.
Up to approximately 150 patients will be enrolled in Cohort 1 and 50 patients in Cohort 2.  
Thus, a total of up to approximately 200 patients will be enrolled. 
With 150 and 50 treated patients in Cohort 1 and Cohort 2, respectively, ORR can be 
estimated with a maximum standard error of 0.041 and 0.071, respectively.  Further, 
assuming a beta (0.5, 0.5) prior,

Cohort 1: if 66 responders (out of 150 patients, ORR of 43%) are observed, the 
posterior probability of a true ORR 40% (considered a clinically relevant effect) will 
be 0.80 (0.841).

Cohort 2: if 23 responders (out of 50 patients, ORR of 46%) are observed, the 
posterior probability of a true ORR 40% (considered a clinically relevant effect) will 
be 0.80 (0.807).
Within each cohort, ORR will be estimated and the 2-sided exact 95% confidence intervals 
(CIs) will be calculated.


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An interim analysis will be performed to allow early termination of the cohorts for futility.  
Within each cohort, ORR based on confirmed partial or complete responses by BICR 
assessment will be estimated after at least 20 patients are treated and followed for 24 weeks, 
without holding patient enrollment in either cohort.  If based on the observed ORR, the 
probability of a true ORR 40% is 0.05 then the cohort will be stopped for futility.  For 
example if 4 or less responders are observed out of 20 patients treated in a cohort (ORR 
20%) after the minimum follow-up specified above, then the cohort will be stopped for 
futility.
SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
Refer to the STUDY PROCEDURES and ASSESSMENTS sections of the protocol for 
detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the 
Schedule of Activities table, in order to conduct evaluations or assessments required to 
protect the well-being of the patient. 


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Table 1.
Schedule of Activities: Safety and Efficacy Assessments
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
28 Days 
Prior to 
Enrollment
Cycle 1
Cycle 2
Cycles 3
End of Treatment21 Short-Term Follow-Up 
(Day 30, Day 60 and 
Day 90 after last dose)22
Long-Term 
Follow-Up 
(Every 12 weeks)23
Day 
1
Day 
15
Day 
1 
Day 
15
Day 
1 
Day 
15
Visit Window (Days)
3
3
3
3
3
+7
±7
±14
Informed Consent1
X
Demography
X
Tumor History2
X
Medical History3
X
Height
X
Contraception Check4
X
X
X
X
X
X
X
Laboratory and Safety Assessments – Must be performed pre-dose during the Treatment Period
Physical Examination, weight5
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Hematology6
X
X
X
X
X
X
X
X
X
Blood Chemistry6
X
X
X
X
X
X
X
X
X
Coagulation6
X
As clinically indicated
Urinalysis7
X
As clinically indicated 
Serum/Urine Pregnancy Test (for 
women of childbearing potential 
only)8
X
X
X 
X
X
Hepatitis B and Hepatitis C Virus 
tests
X
ACTH and Thyroid Function 
Tests
X
Every 2 
cycles 
(Cycles 3, 
5, 7, etc) 
X
X
Testosterone (for CRPC patients 
only)
X
12-Lead ECG9
X
As clinically indicated 
Enrollment and Treatment
Enrollment10
X
Talazoparib Administration11
Daily 


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Table 1.
Schedule of Activities: Safety and Efficacy Assessments
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
≤28 Days 
Prior to 
Enrollment
Cycle 1
Cycle 2
Cycles ≥3
End of Treatment21 Short-Term Follow-Up 
(Day 30, Day 60 and 
Day 90 after last dose)22
Long-Term 
Follow-Up 
(Every 12 weeks)23
Day 
1
Day 
15
Day 
1 
Day 
15
Day 
1 
Day 
15
Visit Window (Days)
±3
±3
±3
±3
±3
+7
±7
±14
Premedication for Avelumab12
X
X
X 
X
Optional 
Administration, at PI 
discretion, based on 
presence/severity of 
prior infusion reactions
Avelumab Administration13
X
X
X
X
X
X
Tumor Assessments by RECIST 
(for all tumor types except
CRPC)14
X
Every 8 weeks (±7 days) for 52 weeks from C1D1, then every 16 weeks (±7 days) thereafter until progressive disease as assessed 
by BICR, regardless of initiation of subsequent anti-cancer therapy
Tumor Assessments by RECIST 
for mCRPC patients ONLY14
X
Every 8 weeks (±7 days) for 24 weeks from C1D1, then every 12 weeks (±7 days) until progressive disease as assessed by BICR, 
regardless of initiation of subsequent anti-cancer therapy. 
Bone scans, for mCRPC patients 
only
X
Every 8 weeks (±7 days) for 24 weeks from C1D1, then every 12 weeks (±7 days) until progressive disease as assessed by BICR, 
regardless of initiation of subsequent anti-cancer therapy. 
PSA Tumor Marker Blood Test, 
for mCRPC patients ONLY; 
pre-dose
X
X
X
X
Blood Test for circulating tumor 
cells (CTC) (for mCRPC patients 
ONLY)
X
X
X15
CA-125 Tumor Marker Blood 
Test (for ovarian cancer patients 
ONLY)
X
X
X
X
Other Clinical Assessments
Serious and Non-Serious Adverse 
Event Monitoring16
X
Monitored and recorded continually
X
X
Concomitant Treatments17
X
Monitored and recorded continually
X
X
Subsequent Anti-Cancer 
Treatment 
X
X
Survival
X20
Patient-Reported Outcomes
 
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Table 1.
Schedule of Activities: Safety and Efficacy Assessments
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
≤28 Days 
Prior to 
Enrollment
Cycle 1
Cycle 2
Cycles ≥3
End of Treatment21 Short-Term Follow-Up 
(Day 30, Day 60 and 
Day 90 after last dose)22
Long-Term 
Follow-Up 
(Every 12 weeks)23
Day 
1
Day 
15
Day 
1 
Day 
15
Day 
1 
Day 
15
Visit Window (Days)
±3
±3
±3
±3
±3
+7
±7
±14
ACTH=adrenocorticotropic hormone, C=Cycle; C1D1=Cycle 1 Day 1; CA-125=Cancer antigen 125; CRPC=castration-resistant prostate cancer; CTC: circulating tumor cells; 
 ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group performance status; 
 PI=principal investigator; 
.
Footnotes for Safety and Efficacy Assessments Schedule of Activities:
1.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure and may be obtained >28 days prior to enrollment.
2.
Tumor History: Tumor history includes oncology history such as information on tumor diagnosis, including existing PD-L1, BRCA1, BRCA2 and ATM testing results, prior 
regimens (duration of administration, best overall response [BOR] observed, and recurrence date), surgery, and radiation therapy. Gleason score (from initial diagnosis) is 
collected for  mCRPC.
3.
Medical History: Medical history includes history of diseases or injuries (active or resolved) and concomitant illnesses that are not considered to be the disease under study. 
4.
Contraception Check: Investigator to confirm the patient has been instructed in correct use of highly effective contraception, as applicable and for the duration as detailed in 
Sections 4.3. See also Section 7.1.2. 
5.
Physical Examination: Full physical examination at screening.  Subsequent visits to include major body systems (focused and/or as clinically indicated); baseline physical 
exam may be performed with 1 day window before treatment. See Section 7.1.5.
6.
Hematology, Coagulation, Blood Chemistry, ACTH and Thyroid Function Tests: Required safety laboratory tests including at a minimum: hematology (hemoglobin, 
platelets, and white blood cells), and chemistry (ALT, AST, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, sodium, potassium, and glucose) must be 
reviewed prior to study drug administration on Days 1 and 15 of each treatment cycle.  See Section 7.1.4 for the list of required Laboratory Tests and Section 5.4.6 for 
requirements to perform additional laboratory tests to monitor toxicity related to either investigational product.  It is not necessary to repeat on Cycle 1 Day 1 (C1D1) if 
performed within 7 days prior to C1D1 as part of Screening.
7.
Urinalysis: See Section 7.1.4.
8.
Serum/Urine Pregnancy Test (for women of childbearing potential only): Pregnancy test results must be reviewed prior to study drug administration on Days 1 of each 
treatment cycle.  See Section 4.1 for criteria defining women of childbearing potential.  See Section 7.1.1 for additional pregnancy testing details.
9.
12-Lead ECG: See Section 7.1.6 for details regarding ECGs and the procedure to follow if mean QTc is prolonged (>500 msec). 
10. Enrollment: Patients meeting all entry criteria will be enrolled using the Interactive Response Technology (IRT) system and will initiate investigational product 
administration preferably on the same day as enrollment (investigational product administration must begin within 3 days after enrollment).  See Section 5.1.
11. Talazoparib Administration: See Section 5.4.2 for details.  On Day 1 and Day 15 of each cycle, the daily dose of talazoparib should not be taken prior to the study visit and 
will be taken at the clinic after all procedures/assessments have been completed and before the avelumab infusion.  Drug supply must be taken into account when scheduling 
visits, taking the visit windows into consideration.
12. Premedication for Avelumab: See Section 5.4.3 for details on the premedication and Section 5.4.1 on the administration of the study combination treatment. 
C
C
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13. Avelumab Administration: After the patient has taken talazoparib and the premedication was administered, avelumab 800 mg IV as a 1-hour infusion must start 
30-60 minutes after the premedication.  See Section 5.4.4.1 for special precautions for avelumab administration. 
14. Tumor Assessments: See Section 7.6 for details on tumor assessments using RECIST version 1.1 (See Appendix 3) and, for mCRPC patients, PCWG3 (See Appendix 4).  
Brain and bone imaging are mandatory at baseline.  Baseline scans are to be performed within 28 days prior to the first dose of study treatment.  Imaging should be performed 
with contrast agents unless contraindicated for medical reasons.  Timing of disease assessment should follow calendar days and should not be adjusted for delays in cycle 
starts.  Tumor assessments should also be performed whenever disease progression is suspected.  For tumor types other than mCRPC, if bone metastases are present at 
baseline (screening), then repeat bone imaging is required every 16 weeks during the first 52 weeks  of study treatment and every 24 weeks thereafter.
15. CTC Blood Test: Blood sample for CTCs will be collected on Day 1 of Cycles 3 and 4 (in addition to Day 1 of Cycles 1 and 2).  See Section 7.7.3 for additional details. 
16. Serious and Non-Serious Adverse Event Monitoring: See Section 8 for guidance on the time period for collecting and reporting AE and SAEs. 
17. Concomitant Treatments: See Section 5.7 for additional details on concomitant treatments; see Section 5.7.10 for prohibited medications.
 
 
 
 
 
 
20. Survival: See Section 6.5 for Long-Term Follow-up.
21. End of Treatment: Perform tests/procedures if not completed during the previous 7 days.
22. Short-term Follow-up Serious and Non-Serious Adverse Event Monitoring: See Section 6.4.
23. Long-Term Follow-up: See Section 6.5.
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Table 2.
Schedule of Activities: Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Assessments
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
≤28 Days 
Prior to
Enrollment
Cycle 1
Cycle 2
Cycles ≥3
End of 
Treatment
Short-Term Follow-Up   
(Day 30, Day 60 and 
Day 90 after last dose)
Long-Term 
Follow-Up 
(Every 3 months)
Day 
1
Day 
15
Day 
1 
Day 15
Day 
1 
Day 
15
Visit Window (Days)
±3
±3
±3
±3
±3
+7
±7
±14
Pre-treatment tumor tissue1
X
Blood Draw for DNA Analysis2
X
Blood Draw for Talazoparib PK3
X
X
Cycle 3 only 
Blood Draw for Avelumab PK4
X
X
Cycles 3, 6, 12, 
18, and 24 only 
Blood Draw for Immunogenicity (ADA) 
Testing5
X
X
Cycles 3, 6, 12, 
18, and 24 only 
X
 
 
Blood draw to generate plasma for 
circulating tumor (ct)DNA analysis7
X
X
Cycle 3 only
X
 
 
 
 
X
Tumor Biopsy11
Optional
X12
ADA=anti-drug antibodies; BRCA=BReast CAncer susceptibility gene; ATM=ataxia telangiectasia mutated; C=Cycle; C1D1=Cycle 1 Day 1; 
DNA=deoxyribonucleic acid; PI=principal investigator; PK=pharmacokinetics; 
Footnotes for Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Assessments Schedule of Activities:
Please refer to Laboratory Manual for instructions on sample collection, processing and shipment for all Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic tests listed in
Table 2.
1.
Pre-treatment Tumor Tissue: All patients must submit fresh or recent formalin-fixed paraffin-embedded (FFPE) tumor tissue sample as described in Section 7.4.1.1. 
Availability of tumor tissue sample must be confirmed during screening prior to enrollment, and sample must be sent within 28 days after enrollment.  
2.
Blood Draw for DNA Analysis: A 4-mL whole blood biospecimen will be collected prior to dosing on Day 1 of Cycle 1.  See Section 7.4.2.
3.
Blood Draw for Talazoparib PK: Blood samples (3-mL whole blood) will be collected at pre-dose (within 1 hour prior to taking talazoparib dose); and at the end of the 
avelumab infusion (within 10 minutes after the avelumab infusion ends) on Day 1 and Day 15 of Cycle 1, and then on Day 1 of Cycle 3.  See Section 7.2.2.
4.
Blood Draw for Avelumab PK: Blood samples (3.5-mL whole blood) will be collected at pre-dose (within 1 hour prior to taking talazoparib dose) and at the end of infusion 
(within 10 minutes after the avelumab infusion ends) on Day 1 and Day 15 of Cycle 1, on Day 1 of Cycles 3, 6, 12, 18, and 24.  See Section 7.2.1.
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5.
Blood Draw for Avelumab Immunogenicity (ADA) Testing: Blood samples (3.5-mL whole blood) for avelumab immunogenicity testing will be collected pre-dose on 
Day 1 and Day 15 of Cycles 1, on Day 1 of Cycle 3 and then on Day 1 of Cycles 6, 12, 18, 24, and at the EOT.  See Section 7.3.
 
7.
Blood draw to generate plasma for ctDNA: A 20 mL whole blood specimen for processing to plasma will be collected on Day 1 of Cycle 1, 2 and 3 and at EOT.  See 
Section 7.4.2.
 
 
 
11. Tumor Biopsy during Treatment Period (Optional): Tumor tissue is requested for study purposes for patients who undergo tumor biopsy or resection as part of routine 
clinical care at any time during the treatment period.  See Section 7.4.1.2.
12. Tumor Biopsy at End of Treatment: Every effort should be made to obtain EOT (±14 days) biopsies in cases of RECIST v1.1 or PCWG3 confirmed disease progression if 
a patient discontinues study treatment due to disease progression, except in instances where the procedure, as performed in the clinical research setting, poses an unacceptable 
risk to the patient.  See Section 7.4.1.2. 
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1. INTRODUCTION
This is a Phase 2 study to assess the safety and efficacy of the avelumab plus talazoparib 
combination in up to approximately 200 patients with locally advanced (primary or recurrent) 
or metastatic solid tumors with a pathogenic or likely pathogenic germline or somatic 
BRCA1, BRCA2, or ATM gene defect, as determined by local assessment and classification.  
Patients with these gene defects have limited therapeutic options after their disease has 
progressed on standard of care (SOC) chemotherapy.  It is anticipated that patients with 
tumors harboring defects in the BRCA1, BRCA2, or ATM gene will likely benefit from 
treatment with the combination of avelumab plus talazoparib, independent of their tumor 
type, and that the combination may produce additive or synergistic anti-tumor activity
relative to each drug used as a single agent. 
1.1. Mechanism of Action/Indication
1.1.1. Avelumab
Avelumab is a human immunoglobulin (Ig)G1 mAb directed against PD-L1.  Avelumab 
selectively binds to PD-L1 and competitively blocks its interaction with programmed death 
receptor 1 (PD-1), thereby interfering with this key immune checkpoint pathway.  Compared 
with anti-PD-1 antibodies that target T cells, avelumab targets tumor cells, and therefore is 
expected to have fewer side effects, including a lower risk of autoimmune-related safety 
issues, as blockade of PD-L1 leaves the programmed death ligand 2 (PD-L2)/PD-1 pathway 
intact to promote peripheral self-tolerance.1,2  For complete details of the in vitro and 
nonclinical studies, refer to the avelumab Investigator’s Brochure (IB).4  In March 2017, 
avelumab received accelerated approval by the United States (US) Food and Drug 
Administration (FDA) as the first treatment for metastatic Merkel cell carcinoma (mMCC);5
this was followed by approvals in the European Union (EU), Switzerland, Japan, Australia, 
Israel and Canada.6,7,8 In May 2017, avelumab received accelerated approval by the US FDA 
for the treatment of patients with locally advanced or metastatic UC with disease progression 
during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant 
or adjuvant platinum-containing chemotherapy.5 
 
While subsets of patients in a growing number of tumor types respond to treatment with a 
single agent PD-1 or PD-L1 inhibitor, most patients with advanced disease either do not 
respond to single agent therapy or experience only a partial response.  Further, the majority 
of those patients who do respond will ultimately progress.  These findings of somewhat 
limited responses are observed regardless of either the PD-1 or PD-L1 inhibitor that is being 
tested or the tumor type in which the immune checkpoint inhibitor is being evaluated.
Additional information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab IB.4
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1.1.2. Talazoparib
Talazoparib is a potent, orally bioavailable PARP inhibitor, which is cytotoxic to human 
cancer cell lines harboring gene mutations that compromise DNA repair, an effect referred to 
as synthetic lethality, by inhibiting PARP catalytic activity and trapping PARP protein on 
DNA, thereby preventing DNA repair, replication, and transcription.9,10,11  Although other 
PARP inhibitors also possess both activities, in vitro studies demonstrated that talazoparib 
has more potent PARP trapping activity than other PARP inhibitors in clinical 
development.10,12  
DNA damage promotes inflammation via the NF-κB pathway13 and the stimulation of 
interferon genes (STING) pathway,14,15 and has been shown to increase the intrinsic 
immunogenicity of tumor cells via up-regulation of major histocompatibility complex 
(MHC), natural killer group 2 member D Ligand (NKG2DL), and inducible costimulator 
ligand (ICOSL).16,17  As such, increased DNA damage via PARP inhibition is expected to 
enhance effective recognition and infiltration of tumors by immune cells.  In keeping with 
this expectation, talazoparib has been shown to promote T cell and natural killer (NK) cell 
infiltration and activation in a mouse model of ovarian cancer.18  Additionally, talazoparib 
treatment has been shown to lead to increased expression of PD-L1 by tumor cells,20
suggesting that this may represent a means by which tumors function to inhibit 
talazoparib-mediated anti-tumor immunity. 
 
Talazoparib was approved by the FDA on 16 October 2018 for the treatment of adult patients 
with deleterious or suspected germline BRCA-mutated HER2-negative locally advanced or 
metastatic breast cancer. 
Additional information for talazoparib may be found in the SRSD, which for this study is the 
talazoparib IB.23
1.2. Background and Rationale
1.2.1. Avelumab Clinical Experience
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono and is 
indicated for the treatment of adults and pediatric patients 12 years and older with mMCC 
and in adult patients having UC with disease progression during or following 
platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant 
platinum-containing chemotherapy.  
 
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The safety profile of avelumab administered intravenously (IV) as single agent at a dose of 
10 mg/kg every 2 weeks (Q2W) has been characterized primarily in 1738 adult patients from 
studies EMR100070-001 in various solid tumors (N=1650) and EMR100070-003 Part A in 
mMCC (N=88).  Study EMR100070-001 consists of 2 parts, a dose escalation phase and a 
dose expansion phase, which is performed in selected tumor types. 
As of 09 June 2016, 53 patients, in total, were treated in the dose escalation phase of the 
EMR100070-001 study, with 4, 13, 15, and 21 patients treated with avelumab doses of 1, 3, 
10, and 20 mg/kg Q2W, respectively.  None of the patients treated with doses up to 10 mg/kg 
experienced a dose-limiting toxicity (DLT), and the 10 mg/kg dose of avelumab was thus 
considered a safe and well tolerated dose for further investigation in the dose expansion 
cohorts.  One DLT (a Grade 3 immune-related adverse event characterized by increased 
creatine kinase, myositis, and myocarditis) was observed in 1 patient at the dose of 20 mg/kg.
The dose expansion phase of study EMR100070-001 included patients with NSCLC, gastric 
cancer, breast cancer, colorectal cancer, CRPC, adrenocortical carcinoma, melanoma, 
mesothelioma, UC, ovarian cancer, RCC, and squamous cell cancer of the head and neck.  
Study EMR100070-003 Part A was conducted in patients with mMCC. 
A summary of pooled safety data from patients treated at 10 mg/kg Q2W in studies 
EMR100070-001 and EMR100070-003 (N=1738) is provided here. 
Treatment-emergent adverse events (TEAEs) were observed in 1697 (97.6%) patients, with 
the most frequent (10%) being fatigue (32.4%), nausea (25.1%), diarrhea (18.9%), 
constipation (18.4%), decreased appetite (18.4%), infusion-related reaction (17.1%), weight 
decreased (16.6%), vomiting (16.2%), anemia (14.9%), abdominal pain (14.4%), 
cough (13.8%), pyrexia (13.6%), dyspnea (13.2%), edema peripheral (11.9%), 
back pain (11.8%), and arthralgia (10.4%). 
Treatment-related TEAEs were observed in 1164 (67.0%) patients, and the most frequent 
(5%) were fatigue (17.7%), infusion-related reaction (17.0%), nausea (8.6%), 
diarrhea (7.1%), chills (6.7%), pyrexia (6.1%), decreased appetite (5.2%), and 
hypothyroidism (5.0%). 
A total of 177 patients (10.2%) experienced Grade 3 treatment-related TEAEs, and the most 
frequent (0.5%) were fatigue (1.0%), lipase increased (1.0%), gamma-glutamyl transferase 
(GGT) increased (0.6%), infusion-related reaction (0.6%), and aspartate aminotransferase 
(AST) increased (0.5%). 
A total of 777 (44.7%) patients had at least 1 serious TEAE.  Treatment-related serious 
TEAEs were reported in 108 (6.2%) patients, with the most frequent (0.2%) being 
infusion-related reaction (0.9%), pneumonitis (0.6%), pyrexia (0.3%), adrenal insufficiency 
(0.3%), and hypothyroidism, diarrhea, vomiting, autoimmune disorder, autoimmune 
hepatitis, transaminases increased, dyspnea, and colitis (0.2% each). 
There were 911 deaths (52.4%) in the pooled safety data set.  The majority of deaths were 
due to progressive disease (744, 42.8%).  There were 59 deaths (3.4%) attributed to TEAEs 
not related to trial treatment, and 4 deaths (0.2%) attributed to a treatment-related TEAE by 


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the investigator and which occurred up to 30 days after the last dose of avelumab: 
pneumonitis (1 case), acute liver failure (1 case), respiratory distress (in the context of sepsis) 
(1 case), and autoimmune hepatitis with hepatic failure (1 case).  In addition, 1 patient died 
with acute respiratory failure (in the context of lung cancer progression) considered related to 
avelumab by the investigator 37 days after the last dose of avelumab.  The cause of death was 
marked as “other” or “unknown” in 17 (1.0%) and 83 (4.8%) cases, respectively. 
A total of 244 patients (14.0%) permanently discontinued avelumab treatment due to TEAEs, 
including 107 patients (6.2%) discontinuing because of treatment-related TEAEs.  The most 
frequent treatment-related TEAEs leading to treatment discontinuation were infusion-related 
reaction (1.8%), GGT increased (0.4%), and diarrhea, fatigue, autoimmune disorder, alanine 
aminotransferase (ALT) increased, blood creatine phosphokinase (CPK) increased, lipase 
increased, arthralgia, and pneumonitis (0.2% each).
Immune-Related Adverse Events (irAEs): in the pooled safety data (N=1738), a total of 
247 patients (14.2%) experienced irAEs, defined as adverse events requiring use of 
corticosteroids (and/or hormonal therapy for endocrinopathies), and no clear alternate 
etiology.  The median time to first onset of an irAE was 11.7 weeks.  The most frequent 
irAEs were thyroid disorders including hypothyroidism (5.2%), hyperthyroidism (0.4%) and 
thyroiditis (0.2%), immune-related rash (5.2%), immune-related colitis (1.5%), 
immune-related pneumonitis (1.2%), immune-related hepatitis (0.9%), adrenal insufficiency 
(0.5%), and immune-related myositis (0.5%).  In addition, irAEs reported in 0.1% of patients 
in the pooled safety dataset included:  type 1 diabetes mellitus, immune-related 
nephritis/renal dysfunction, hypopituitarism, uveitis, and Guillain-Barre Syndrome.  The 
majority of irAEs were Grade 1 or Grade 2 in severity, with 39 (2.2%) being of 
Grade 3 severity.  Fatal outcome was reported in 1 patient (0.1%) with immune-related 
pneumonitis, and 2 patients (0.1%) with immune-related hepatitis.  Other relevant irAEs 
reported with avelumab outside the pooled safety dataset included 1 case of fatal 
immune-related myocarditis in Study B9991002 (avelumab in combination with axitinib for 
RCC), 1 case of non-fatal immune-related myocarditis in the 20 mg/kg cohort of the dose 
escalation phase of Study EMR100070-001, and 2 patients with non-fatal graft versus host 
disease (GVHD) in Study B9991007 (avelumab in patients with classical Hodgkin’s 
lymphoma).
Infusion-Related Reactions (IRRs): a total of 439 patients (25.3%) experienced at least 
1 IRR, defined as a TEAE coded under the preferred terms of infusion-related reaction, drug 
hypersensitivity, hypersensitivity, anaphylactic reaction, type I hypersensitivity, chills, 
pyrexia, back pain, dyspnea, hypotension, flushing, and abdominal pain according to a 
predefined case definition.  The most common preferred terms that met the definition for an 
IRR included: infusion-related reaction (17.0%), chills (5.4%), and pyrexia (3.6%).  Most of 
the events were of Grade 1 or Grade 2 severity.  Grade 3 IRRs occurred in 12 patients 
(0.7%) including 3 patients (0.2%) who experienced Grade 4 IRRs.  No Grade 5 IRRs were 
reported.  In most cases, the first occurrence of an IRR was related to the first infusion, with 
only 6 patients experiencing the first IRR at the fifth or later infusion.  All Grade 3 IRRs 
occurred with the first (7 patients) or second (5 patients) infusion.  Overall, 21.6% of patients 
had 1 IRR, 2.6% of patients had 2 IRRs, 14 patients (0.8%) had 3 IRRs, and 3 patients had 


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>3 IRRs.  IRR recurrence after the fourth infusion was rare (15 patients) and all recurrent 
IRRs were of Grade 1 or 2 severity.  In 35 patients (2.0%), treatment was permanently 
discontinued because of an IRR.
Immunogenicity of Avelumab in Humans: immunogenicity assessment included all patients 
from Studies EMR100070-001 and EMR100070-003 treated with 10 mg/kg of avelumab 
Q2W and who had at least one valid anti-drug antibody (ADA) result as of the data cut-off 
date of 09 June 2016.  Of the 1738 patients treated with avelumab, 1558 were evaluable for 
treatment-emergent ADAs and 64 (4.1%) tested positive.  Titers were generally low across 
ADA ever-positive patients, with no clear relationship between the duration of 
immunogenicity response and the maximum observed titer.  Current data suggest there is no 
clinically meaningful impact of ADA positivity on the pharmacokinetics (PK), efficacy, or 
safety of avelumab.
1.2.1.1. Clinical Experience in Patients with Solid Tumors
In Study EMR100070-001, avelumab as a single agent has been evaluated for efficacy in 
patients with multiple types of solid tumors (see Table 1).  The study includes efficacy data 
from a cohort of 156 patients with advanced NSCLC who had not been previously treated 
systemically for metastatic or recurrent disease and were without an activating epidermal 
growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) 
rearrangement; a separate cohort enrolled 184 patients with advanced NSCLC who had 
progressed after at least 1 line of platinum-containing doublet chemotherapy for metastatic or 
locally advanced disease.  A cohort of 161 patients with locally advanced or metastatic UC 
were either cisplatin ineligible or had progressive disease (PD) after at least 1 line of 
platinum-based therapy in 2 different cohorts.  A cohort of 124 patients with recurrent or 
refractory ovarian cancer were enrolled who had progression within 6 months of 
platinum-based therapy or progression after subsequent therapy in previous relapse.  A 
cohort included 168 patients were enrolled with metastatic breast cancer refractory to or 
progressing after standard-of-care therapy; 72 patients (42.9%) were human epidermal 
growth factor receptor 2 (HER2)-negative and estrogen receptor (ER)-positive or 
progesterone receptor-positive, 58 patients (34.5%) were triple-negative breast cancer 
(TNBC), 26 patients (15.5%) were HER2-positive, and 12 patients (7.1%) had unknown 
biomarker status.  Other cohorts included 151 patients with advanced GC/GEJ who were 
treated with avelumab, either as first-line maintenance (89 patients) or second-line therapy 
(62 patients), and 18 patients with mCRPC.22  
Study EMR 100070-001 also provides preliminary avelumab efficacy data from 53 patients 
with advanced mesothelioma (ORR 9.4%; 95% CI: 3.1, 20.7) and 37 patients with 
adrenocortical carcinoma (ORR 10.5%; 05% CI: 1.3, 33.1%).  Further details are available in 
the IB. 
Preliminary efficacy data for the ongoing Phase 1 Trial EMR100070-002 are available from 
a data cutoff of 11 March 2015 for 20 patients being treated with 10 mg/kg of avelumab once 
every 2 weeks in the gastric cancer expansion cohort.  All 20 patients are Japanese patients.  
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Trial EMR100070-003 enrolled 88 patients with mMCC whose disease had progressed after 
at least one prior line of chemotherapy in the metastatic setting.  The median follow-up was 
10.4 months (range of 6.0 to 19.3).  The confirmed ORR was 31.8% (95% CI: 21.9, 43.1), 
consisting of 8 complete responses (CRs) and 20 partial responses (PRs).  Responses to 
avelumab were durable, with median duration of response not yet reached 
(95% CI: 8.3 months – not estimable). 
Table 3.
Avelumab: Efficacy Results
Study 
Tumor Type (n)
Efficacy Results
EMR100070-003
(JAVELIN 
Merkel 200)
mMCC5
2L, pretreated, metastatic (88)
ORR:a 33.0% (n=29, 95% CI: 23.3, 43.8)
DOR range, mo: 2.8, 23.3+
EMR100070-001
Urothelial Carcinoma5
Pretreated, advanced or metastatic 
(161, with 6 mo follow-up )
ORR:a 16.1% (n=26, 95% CI: 10.8, 22.8)
Median DOR, mo: ongoing (95% CI: 1.4+, 17.4+)
Breast Cancer21
Pretreated, advanced or metastatic (168)
ORR:a 3% (n=5, 95% CI: 1.0, 6.8)
Median DOR, wk: NE (95% CI: 28.7, NE)
Median PFS, wk: 5.9 (95% CI: 5.9, 6.0)
PFS rate at 24 wk: 10.1% (95% CI: 5.9, 15.5)
Median OS, mo: 8.1 (95% CI: 6.4, NE)
mCRPC22
Progressed on previous treatment (18)
ORR: 0/18 patients 
(7 of 18 patients had stable disease >24 weeks post 
treatment)
NSCLC4
2L metastatic (184)
ORR:a 12% (n=22, 95% CI: 7.6, 17.5)
Median DOR, wk: NR (0.1, ongoing at 54.1)
Median PFS, wk: 11.6 (95% CI: 8.4, 13.7) 
PFS rate at 48 wk: 18% (95% CI: 12, 26)
Median OS, mo: 8.4 (95% CI: 7.3, 10.6)
OS rate at 12 mo: 36% (95% CI: 26, 46)
1L metastatic/ recurrent (156)
ORR:b 22.4% (n=35, 95% CI: 16.2, 29.8) 
68.6% ongoing, median treatment duration 20 weeks
Median PFS, wk: 17.6 (95% CI: 11.6, 23.6) 
PFS rate at 24 wk: 37.2% (95% CI: 28.6, 45.7)
Ovarian Cancer4
Pretreated, advanced or metastatic (124)
ORR:b 9.7% (n=12, 95% CI: 5.1, 16.3) 
50.0% ongoing, median follow-up 12.4 months
Median PFS, wk: 11.3 (95% CI: 6.1, 12.0) 
PFS rate at 48 wk: 5.5% (95% CI: 1.3, 14.2)
GC/GEJ Cancer4
Pretreated, advanced or metastatic
1L maintenance (89)
ORR:b 9% (n=8, 95% CI: 4.0, 16.9)
Median DOR, wk: 48.3 (95% CI: 3.0, NE)
2L therapy (62)
ORR:b 9.7% (n=6, 95% CI: 3.6, 19.9) 
Median DOR, wk: 12.3 (95% CI: 5.4, NE)
EMR100070-002
(Japan)
Gastric4
Pretreated, metastatic (20)
ORR:b 15.0% (n=3, 95% CI: 3.2, 37.9) 
Median PFS, wk: 11.9 (95% CI: 6.0, 12.3)
+ denotes a censored value
Abbreviations: 1L=first line, 2L=second line, CI: confidence interval, DOR=Duration of response, GC=gastric cancer, 
GEJ=gastroesophageal junction, mCPRC=metastatic castration resistant prostate cancer, mMCC=metastatic Merkel cell 
cancer, mo=months, NE=not estimable, NR=not reached, NSCLC=nonsmall cell lung cancer, ORR=objective response 
rate, PFS=progression free survival, OS=overall survival, SD=stable disease, wk=weeks
a.
Considering only confirmed responses.
b.
Considering both confirmed and unconfirmed responses.


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1.2.1.2. Pharmacokinetics of Avelumab in Humans
Available pharmacokinetic (PK) data from Study EMR100070-001 show that the 
concentration at the end of the dosing interval (Ctrough) increased more than proportionally to 
dose between 1 to 10 mg/kg, and proportionally to dose for doses above 10 mg/kg.  The 
terminal half-life (t1/2) also increased with dose; however, the geometric mean values for 
t1/2 were similar for the 10 mg/kg and 20 mg/kg dose levels, at 94.6 hours (3.96 days) and 
99.1 hours (4.1 days), respectively.  This PK characteristic suggests that target-mediated drug 
disposition is involved in the clearance of avelumab, and that high PD-L1 target receptor 
occupancy (TO) is likely achieved throughout the dosing interval at doses of 10 mg/kg and 
20 mg/kg given Q2W.
The 10 mg/kg dose Q2W achieved high TO (mean TO >90%) of PD-L1 in peripheral blood 
mononuclear cells (PBMC) during the entire dosing interval, as determined from ex vivo 
studies.  Based on the in vitro TO data and the observed trough serum avelumab levels in the 
dose escalation cohorts of Study EMR100070-001, TO was predicted to reach or exceed
95% throughout the entire dosing interval in more patients in the 10 mg/kg dose group than 
in the 3 mg/kg dose group.  For the purposes of the current study, a fixed dosing strategy will 
be used for avelumab as described below in Section 1.2.5.1.
Avelumab is eliminated by intracellular lysosomal proteolytic degradation throughout the 
entire body and therefore is not expected to be affected by small molecule drugs that are 
cytochrome P450 (CYP450) enzyme modulators or by transporter modulators.  Furthermore, 
avelumab itself is not expected to interfere with either absorption or elimination of small 
molecule drugs that are substrates of transporters, are metabolized via CYP450, hydrolysis or 
conjugation, and/or are renally excreted.  Therefore, on this study there is very low potential 
for a drug-drug interaction (DDI) between avelumab and talazoparib, which is a small 
molecule cleared primarily via excretion of unchanged parent drug and metabolized to a 
minor extent via oxidation and dehydrogenation.
Population PK analysis did not show any meaningful effects on clearance of avelumab from 
premedication with acetaminophen (paracetamol) or diphenhydramine, nor from concomitant 
medication with ibuprofen, acetylsalicylic acid, opioids, corticosteroids, and biological 
therapies evaluated to date.
1.2.2. Talazoparib
1.2.2.1. Talazoparib Clinical Experience
Talazoparib is a potent, orally bioavailable, small molecule PARP inhibitor in development 
for the treatment of a variety of human cancers.
As of 31 Janurary 2018, approximately 659 patients have received talazoparib in 
company-sponsored studies in hematologic malignancies and solid tumors.  Studies in solid 
tumors include a Phase 1 study (PRP-001) in advanced or recurrent solid tumors, a Phase 1 
study in advanced malignancies (PRP-002), a Phase 2 study (673-201) in locally advanced 
and/or metastatic breast cancer patients with a germline BReast CAncer (BRCA) 1 or 
BRCA 2 defect, a Phase 3 study (673-301) in locally advanced or metastatic breast cancer 


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with a germline BRCA 1/2 defect, a Phase 1 hepatic impairment study (MDV3800-02), a 
Phase 1 absorption, distribution, metabolism and excretion (ADME) study (MDV3800-03) 
and a Phase 1 study on cardiac repolarization (MDV3800-14).23
As of 31 January 2018, aggregate safety data from 5 company-sponsored clinical studies 
evaluating talazoparib monotherapy at the proposed dose of 1 mg QD in patients with 
advanced malignancies ((PRP-001, 673-201, 673-301, MDV3800-13, and 
MDV3800-14; 502 patients total) provide the basis for the most common TEAEs.  The most 
common study drug-related TEAEs associated with talazoparib (>20%) occurring in patients 
who received 1 mg QD talazoparib were anemia (45.8%), fatigue (36.1%), nausea (32.5%),
neutropenia (21.9%), and alopecia (20.1%).  The most common Grade 3 or higher 
drug-related TEAEs occurring in 5% of patients were anemia (34.1%), neutropenia 
(12.2%). thrombocytopenia (10.6%), and platelet count decreased (5.4%). 
Serious adverse events (SAEs) occurred in 164 of 502 patients (32.7%) who received 
talazoparib 1 mg QD. SAEs occurring in ≥2% of patients were anemia (5.2%) and dyspnea 
and pleural effusion (2.2% each).  Forty-seven patients had SAEs considered related to 
talazoparib.  Study drug-related SAEs occurring in ≥1% of patients were anemia (4.6%); 
thrombocytopenia (1.2%); and platelet count decreased (1.2%). A total of 23 of 502 patients
who received 1 mg QD talazoparib had a TEAE that led to death (8 associated with the 
underlying malignancy including 1 also associated with pneumonia; 2 dyspnea; and 2 general 
physical health deterioration, 3 disease progression, and 1 each lung infection, cerebral 
hemorrhage, cerebrovascular accident, fatigue (after data cutoff date of 31 January 2018 the 
AE of Grade 5 fatigue was changed to Grade 5 failure to thrive), liver disorder, neurological 
symptom, respiratory failure, and veno-occlusive disease).  Of these events, only veno-
occlusive disease was assessed as related to talazoparib. A 34 year old female patient with 
advanced breast cancer metastatic to the axilla and bone developed asymptomatic 
Grade 3 liver test abnormalities (ALT and AST with normal bilirubin) while receiving 
talazoparib at 0.75 mg.  Ten days after talazoparib dosing was discontinued due to 
Grade 4 thrombocytopenia, the patient had acute hepatic failure attributed to veno-occlusive 
disease of the liver by the Investigator.  The sponsor considered veno occlusive disease of the 
liver an unlikely etiology, a consideration supported by 2 independent hepatologists who 
reviewed the case.  
Among the 502 patients who received 1 mg QD talazoparib, 63.9% had a TEAE that led to 
dose reduction and 61.2% had a TEAE that led to dose interruption.  The most common 
TEAEs that led to dose reduction or interruption were associated with myelosuppression.
Twenty of 502 patients (4.0%) treated with talazoparib at a dose of 1 mg QD permanently 
discontinued talazoparib due to a TEAE.  The TEAEs that led to study drug discontinuation 
were anemia (3 patients), increased ALT (2 patients), and accidental overdose, increased 
AST, metastatic breast cancer, cerebral hemorrhage, dyspnea, glioblastoma multiforme, 
headache, metastases to meninges, muscular weakness, neutropenia, obstructive airways 
disorder, thrombocytopenia, transient ischemic attack, and vomiting (1 patient each).23


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1.2.2.2. Clinical Efficacy in Patients with Advanced Solid Tumors
A total of 110 patients with advanced tumors with DNA repair pathway abnormalities, 
particularly those associated with BRCA 1/2 and phosphatase tensin homolog (PTEN) 
dysfunction, were enrolled in the Phase 1 study PRP-001, which was completed in March 
2015.  The maximum tolerated dose (MTD) of talazoparib was defined as 1 mg QD and it 
was used in the expansion phase of the study in patients with breast, ovarian/primary 
peritoneal, and pancreatic cancer with deleterious germline mutations; small cell lung cancer 
(SCLC); and Ewing sarcoma.  In the Phase 1 Study PRP-001, in patients treated with 
talazoparib 1.0 mg/day with advanced breast cancer, ovarian/peritoneal cancer, and 
pancreatic cancer, an ORR of 50.0% (7 of 14; 95% CI: 23.0, 77.0), 41.7% (5 of 12; 
95% CI: 15.2, 72.3 ), and 20% (2 of 10) was observed, respectively.23
1.2.2.2.1. Clinical Efficacy in Patients with Germline BRCA 1/2 Mutations and Locally 
Advanced and/or Metastatic Breast Cancer
The ongoing Phase 2, open-label, 2-stage, 2-cohort study, 673-201, is evaluating talazoparib 
in patients with locally advanced or metastatic breast cancer with deleterious germline 
BRCA 1/2 mutations.  Enrolled patients included those who were platinum-sensitive 
(Cohort 1) and patients who received at least 3 prior chemotherapy regimens and no prior 
platinum therapy (Cohort 2).  As of 01 September 2016, the data cut-off for the primary 
analysis, 83 patients with locally advanced or metastatic breast cancer with deleterious 
germline BRCA 1/2 mutations were tumor evaluable (48 patients in Cohort 1; 35 patients in 
Cohort 2), and 9 patients were continuing on treatment.  Efficacy analyses were conducted by 
independent central radiology assessment. The ORR was 20.8% (95% CI: 10.47, 34.99) in 
Cohort 1, 37.1% (95% CI: 21.47, 55.08) in Cohort 2 and 27.7% (95% CI: 18.45, 38.62) 
overall.  This response rate, which included 2 CRs and 8 PRs in Cohort 1 and 13 PRs in 
Cohort 2, is considered clinically meaningful as these populations have a poor
prognosis.23
Data from the ongoing EMBRACA study presented in December 2017 (287 patients in 
talazoparib arm, 144 patients in PCT arm) showed that median PFS was 8.6 months 
(95% CI: 7.2, 9.3) for patients treated with talazoparib and 5.6 months (95% CI: 4.2, 6.7) for 
those treated with chemotherapy (HR=0.54; 95% CI: 0.41, 0.71; p<0.0001).  Also, ORR was 
62.6% for talazoparib vs 27.2% for chemotherapy (odds ratio for OR=4.99; 95% CI: 2.9, 8.8; 
p<0.0001; per RECIST 1.1, confirmation of CR/PR was not required) and median duration of 
response (DOR) was 5.4 months (IQR: 2.8-11.2) for talazoparib and 3.1 months (IQR: 
2.4-6.7) for PCT.  The OS data are still immature (38% deaths in each arm) and OS time was 
not statistically different between arms.24
1.2.2.3. Pharmacokinetics of Talazoparib in Humans
Talazoparib plasma exposure was dose proportional in the dose range of 0.025 mg to 2 mg 
QD suggesting linear PK. Talazoparib absolute bioavailability is at least 54.6%. After 
administration of a single 1 mg dose of talazoparib to cancer patients, the median Time to 
Maximum Plasma Concentration (Tmax) ranged from 0.5 to 2.0 hours across studies. 
Administration of talazoparib with food (a high-fat, high-calorie meal) had no impact on the 
Area Under the Curve (AUC) while food reduced the Maximum Plasma Concentration


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(Cmax) by 46%. The reduction in the rate of absorption with food is not expected to be 
clinically relevant as efficacy is driven by total exposure. Therefore, talazoparib can be taken 
without regard of food.
Mean talazoparib binding to human plasma proteins is 74%. Population PK analysis showed 
that talazoparib apparent steady-state volume of distribution (Vss/F) was 420 L, which is 
greater than total body water (42 L), indicating that talazoparib extensively distributes to 
peripheral tissues.
Talazoparib undergoes minimal hepatic metabolism. Based on population PK analysis, there 
was no effect of mild hepatic impairment (total bilirubin ≤upper limit of normal [ULN] and 
aspartate aminotransferanse [AST] >ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) 
on talazoparib exposure. No dose adjustment is necessary for patients with mild hepatic 
impairment. The effect of hepatic impairment on talazoparib PK is being investigated in the 
ongoing study MDV3800-02.
Talazoparib was eliminated slowly with a mean terminal plasma half-life (t½) of 89.8 hours. 
Talazoparib accumulated after 1 mg QD dosing with a median accumulation ratio, based on 
AUC ranging from 2.33 to 5.15, consistent with its t½. Population PK analysis showed that 
talazoparib apparent oral clearance (CL/F) was 6.45 L/hr. Excretion of unchanged 
talazoparib in urine was the major route of elimination accounting for 54.6% of the 
administered dose. Population PK analysis showed that talazoparib CL/F was reduced by 
14.4% and 37.1% in patients with mild renal impairment (creatinine clearance [CrCl], 60-89 
mL/min) and moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), respectively, 
compared to that of patients with normal renal function (CrCl >90 mL/min). No dose 
adjustment is recommended for patients with mild renal impairment. The starting dose of 
talazoparib for patients with moderate renal impairment is discussed in Section 1.2.5.2. The 
effect of renal impairment on talazoparib PK is being investigated in the ongoing study 
MDV3800-01.
In vitro studies showed that talazoparib is a substrate for the efflux transporters 
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Population PK analysis 
indicated that concomitant administration of strong P-gp inhibitors with talazoparib increased 
talazoparib exposure by 44.7% relative to talazoparib administered alone. Guidelines for 
concomitant use of talazoparib with P-gp inhibitors or inducers and BCRP inhibitors are 
provided in Section 5.7.10. 
1.2.3. Clinical Experience in Patients Treated with Other PARP Inhibitors as a Single 
Agent or in Combination with Immunotherapy 
Reports of clinical activity from other agents of the same class as talazoparib, alone and in 
combination with other immunotherapies, support the investigation of talazoparib with 
avelumab for the treatment of tumors with high prevalence of BRCA 1/2 or ATM in similar 
therapeutic setting.  Clinical data is summarized below by tumor type. 


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1.2.3.1. PARP Inhibitor Experience in Ovarian Cancer (OC)
OC is most frequently diagnosed at an advanced stage, and despite high response rates to 
initial taxane-platinum-based chemotherapy, the majority of patients will develop persistent 
or recurrent disease.  There remains a particularly urgent unmet need for well-tolerated 
treatments which will improve outcomes for patients who have received multiple lines of 
chemotherapy. 
Olaparib has been approved as monotherapy in patients with deleterious or suspected 
deleterious germline BRCA 1/2-mutated advanced OC who have been treated with three or 
more prior lines of chemotherapy.  From a Phase 2 single-arm study in which 137 patients 
with BRCA 1/2- mutated OC who had received 3 prior lines of chemotherapy were 
administered olaparib monotherapy until disease progression or intolerable toxicity, the ORR 
was 34% (46 of 137 patients; 95% CI: 26%-42%), and the median duration of response was 
7.9 months (95% CI: 5.6-9.6).  ORR in platinum-resistant tumors was 30%.  Median DoR for 
platinum-sensitive and platinum-resistant disease was similar: 8.2 months (95% CI: 5.6-13.5) 
compared with 8.0 months (95% CI: 4.8–14.8), respectively.27  Olaparib is being further 
evaluated in combination with the PD-L1 inhibitor durvalumab in a Phase 1 dose-escalation 
study in women’s cancers and found to provide durable anti-cancer activity in heavily 
pretreated patients; three of four women with BRCA wild-type platinum-resistant ovarian 
carcinoma had durable responses of 9 months.  No dose-limiting toxicities were observed.25  
Rucaparib has been approved for the treatment of patients with deleterious BRCA 1/2 
mutation (germline and/or somatic) associated advanced OC who have been treated with two 
or more chemotherapies.  Approval was based on data from two multicenter, single-arm, 
open label clinical trials that evaluated the efficacy of rucaparib in 106 patients with 
advanced ovarian cancer who had progressed after treatment with two or more prior 
chemotherapies.  Investigator-assessed ORR was 54% (57/106; 95% CI: 44-64%).  Median 
DoR for the 57 responders (investigator-assessed) was 9.2 months (95% CI: 6.6, 11.6).  ORR 
(investigator-assessed) was 66% (52/79; 95% CI: 54-76%) in platinum-sensitive patients, 
25% (5/20; 95% CI: 9-49%) in platinum-resistant patients and 0% (0/7; 95% CI: 0-41%) in 
platinum-refractory patients.  ORR was similar for patients with a BRCA1 gene mutation or 
BRCA2 gene mutation.28
Preliminary phase 1 data from the combination of niraparib with PD-1 inhibitor 
pembrolizumab (TOPACIO) in patients with platinum resistant OC has shown preliminary 
efficacy (response in 5 of 9 patients) with no significant overlapping toxicity.29  As of August 
2017, in the ongoing Phase 2 study, 5 of 27 TNBC patients and 6 of 29 OC patients had a 
≥30% decrease in tumor lesion size; no new safety signals were identified.30
1.2.3.2. PARP Inhibitor Experience in Advanced Breast Cancer 
Several Phase 1 and 2 studies have shown that PARP inhibitors have single-agent activity in 
patients with metastatic breast cancer and a germline BRCA 1/2 mutation.31,32,33


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The randomized, Phase 3 OlympiAD trial showed that, among patients with HER2-negative 
metastatic breast cancer and a germline BRCA 1/2 mutation, progression-free survival (PFS) 
was significantly longer with single-agent PARP inhibitor olaparib than with standard 
chemotherapy (capecitabine, eribulin mesylate, or vinorelbine) (median PFS 7.0 months 
vs. 4.2 months; hazard ratio (HR) for PFS= 0.58; 95% CI: 0.43 - 0.80).  The response rate in 
the olaparib group was approximately double the rate in the standard-therapy group 
(59.9% vs. 28.8%).34
The MEDIOLA study with the combination of olaparib and PD-L1 inhibitor durvalumab 
demonstrated a disease control rate of 80% (90% CI 62-92%) and ORR of 52% (95% CI,
31%-72%) in 25 pretreated BRCA-mutant metastatic breast cancer patients; no enhanced 
toxicity was observed with olaparib and no change was seen from the expected toxicity of 
durvalumab.26
For efficacy evidence of talazoparib in advanced breast cancer with germline BRCA 1/2 
mutations please see Section 1.2.2.2.
1.2.3.3. PARP Inhibitor Experience in Metastatic Castration Resistant Prostate Cancer 
(mCRPC) 
Olaparib given as single agent was evaluated in a Phase 2 study in 50 patients with 
previously treated mCRPC.43  Of the 50 patients, all patients had received prior treatment 
with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had 
received cabazitaxel.  Of the 49 patients evaluable for response (defined either as an 
objective response according to RECIST v1.1, or as a reduction of at least 50% in the 
prostate-specific antigen (PSA) level or a confirmed reduction in the circulating tumor-cell 
count from 5 or more cells per 7.5 mL of blood to less than 5 cells per 7.5 mL), 16 patients 
achieved a response (33%; 95% CI: 20.0, 48.0), including patients previously treated with 
docetaxel.  Homozygous deletions, deleterious mutations, or both were identified in 
DNA-repair genes in 16 patients (33%) and 14 of these patients (88%) achieved a response.
The combination of olaparib with durvalumab is under evaluation in a Phase 1/2 study 
patients with mCRPC.  Overall, 5 out of 7 patients have had a reduction in PSA level 
50% from baseline.  Based on data thus far, the combination appears to have an acceptable 
safety profile.45
1.2.3.4. PARP Inhibitor Experience in Pancreatic Cancer
In a multicenter Phase 2 study evaluating responses to PARP inhibitor olaparib across 
different tumor types associated with germline BRCA 1/2 mutations and recurrent cancer, 
23 patients with advanced pancreatic cancer were enrolled.  17 (74%) had a BRCA2
mutation, and one had a mutation in both BRCA1 and BRCA2.  The mean number of prior 
therapies was two (standard deviation= 1.6; range: 1-8); all but one patient had received 
gemcitabine, and 65% had received prior platinum. 


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Median PFS was 4.6 months.  ORR was 22% (95% CI: 7.5, 43.7).  Stable disease that 
persisted 8 weeks was observed in 34.8% of patients (n= 8; 95% CI: 16.4, 57.3).  Median 
duration of response was 134 days.  There was no apparent difference in response rates in 
those with (20%; 95% CI: 4.3, 48.1) or without (25%; 95% CI: 3.2, 65.1) prior platinum for 
pancreatic cancer.  Median OS was 9.8 months.32
Rucaparib also showed promise in a Phase 2 study in previously treated patients with 
pancreatic cancer who have the mutation.27  Overall, a clinical benefit was observed in 
32% of patients (6 of 19) treated with rucaparib.  The ORR (including confirmed and 
unconfirmed responses) was 16% (3 of 19).  The duration of confirmed responses was 36 and 
49 weeks (both ongoing), the response in the third patient was not confirmed. 
Cancer patients harboring BRCA mutations who do not respond to platinum based 
chemotherapy display decreased sensitivity to PARP inhibitors.  For this reason, 
platinum-refractory patients are excluded from enrollment.  In particular, pancreatic cancer 
patients who have progressed within 6 months of starting previous platinum-based 
chemotherapy are not eligible.46
1.2.4. Study Rationale
Based on the mechanisms of action discussed in Sections 1.1.1 and 1.1.2, talazoparib and 
avelumab have the potential to produce additive or synergistic anti-tumor activity, with 
talazoparib functioning to promote immune priming and tumor immunogenicity and 
avelumab functioning to overcome PD-L1-mediated inhibition of any resulting anti-tumor 
immune response.
Specifically, the activity of avelumab depends on generation of a productive immune 
response, composed of effective antigen presentation, T-cell priming, infiltration of tumors, 
and recognition and killing of tumor cells.49  Talazoparib, via its ability to promote increased 
DNA damage, has the potential to promote several of these key stages of the immune 
response. Firstly, talazoparib-mediated cell death, via either PARP trapping or via increased 
DNA damage, has the potential to release antigens into the tumor microenvironment, 
promoting effective antigen presentation; this has been described for other therapies that lead 
to increased tumor cell death.50  Secondly, DNA damage promotes inflammation via two 
alternative pathways, the first being activation of the NF-κB pathway via 
ataxia-telangiectasia mutated (ATM)-mediated phosphorylation of the NF-κB essential 
modulator (NEMO),13 and the second being activation of the STING pathway via generation 
and detection of cytosolic DNA.14,15  Activation of these pathways leads to increased 
pro-inflammatory signaling that enhances effective recognition and infiltration of tumors by 
immune cells, and has recently been shown to be critical to the response to checkpoint 
inhibition in mice.51  Finally, DNA damage has been shown to lead to up-regulation of MHC, 
NKG2DL, and ICOSL,16,17 which would be expected to increase the intrinsic 
immunogenicity of tumor cells and enhance their recognition and killing by T cells and 
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In keeping with these critical links between DNA damage and immune priming, talazoparib 
has been shown to drive the activation of STING and downstream target genes in cultured 
cell lines 
 and to promote T cell and NK cell infiltration and activation in a mouse 
model of ovarian cancer.18
 
 
 
 
 
However, talazoparib treatment has also been shown to lead to 2-3 fold increased expression 
of PD-L1 by tumor cells,20 suggesting that this may represent a mechanism of resistance to 
possible talazoparib-mediated anti-tumor immunity, and suggesting that the combination of 
talazoparib and anti-PD-L1 may further enhance anti-tumor activity.  This hypothesis is 
supported by preclinical studies in syngeneic mouse models of ovarian (Figure 2) and 
colorectal cancer, which demonstrate a significant improvement in overall survival in mice 
treated with the combination of talazoparib and an anti-mouse PD-L1, but not in mice treated 
with either talazoparib or anti-mouse PD-L1 alone.
CCI
CCI
CCI
CCI


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Figure 2.
Combination of Talazoparib (BMN 673) and Anti-mouse PD-L1 Treatment 
Significantly Prolongs Survival in an Ovarian Cancer Model
1st
2nd
3rd
*
*
*
Survival curves from 3 independent experiments comparing the combination of BMN 673 (0.33 mg/kg daily by 
oral gavage) and anti-PD-L1 (200 g/mouse every 3 days) to talazoparib alone, anti-PD-L1 alone, or IgG 
control.  In the left and middle panels, mice were treated for 3 weeks and treatment was stopped to monitor 
survival of the mice.  In the right panel, mice were treated continuously until the mice met criteria for 
euthanasia and survival was monitored.  Statistical analysis was conducted by log rank test.  The combination 
treatment significantly improved mouse survival compared to IgG control in three experiments (p <0.01).40
Given the proposed mechanism of the avelumab and talazoparib combination, one subgroup 
of patients likely to benefit most from the combination will be those whose tumors are most 
sensitive to talazoparib mediated DNA damage.  Clinical and preclinical studies have 
indicated that such sensitivity is increased in tumors with defective repair of double strand 
DNA breaks (DSBs).41  One underlying reason for defective DSB repair is the presence of 
mutations in key genes, either at the germline or somatic level.  The BRCA1, BRCA2 and 
ATM genes are three of the best evidenced examples of such genes and have been associated 
with increased response, or improved outcome, following treatment with a number of PARP 
inhibitors including olaparib, rucaparib, and niraparib.42,43,44,54  Analysis of publicly available 
data within The Cancer Genome Atlas (TCGA),56 indicates presence of mutations in 
BRCA 1/2 and ATM occur with variable frequency across many tumor types, with an 
average prevalence across solid tumors of 7.7%.  It is expected that all tumors with such 
defects will present with increased sensitivity to talazoparib mediated DNA damage, and 
therefore have the potential to benefit from the combination of talazoparib and avelumab. 
It is important to note that, since avelumab is an immunoglobulin (Ig)G1 mAb eliminated by 
intracellular lysosomal proteolytic degradation throughout the entire body while talazoparib 
is a small molecule cleared primarily via excretion of unchanged parent drug and 
metabolized to a minor extent via oxidation and dehydrogenation, no PK DDI is anticipated 
between avelumab and talazoparib when given in combination.


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In conclusion, considering the above described mechanism of action and the preliminary 
clinical activity observed for the investigational products or one agent of the same class (see 
Section 1.2.1.1, Section 1.2.2.2, and Section 1.2.3), the avelumab and talazoparib 
combination is proposed for evaluation in patients with locally advanced (primary or 
recurrent) or metastatic solid tumors with a BRCA1, BRCA2, or ATM gene defect (based on 
local assessment of germline or tumor DNA) who have received at least 1 line of SOC 
treatment for locally advanced or metastatic disease unless prior treatment requirements are 
otherwise specified.
1.2.5. Rationale for the Investigational Product Doses
1.2.5.1. Avelumab
To date, avelumab has been administered at the clinically active, safe, and tolerable dose of 
10 mg/kg Q2W to more than 1700 patients across multiple indications.  Furthermore, this 
10 mg/kg Q2W avelumab dosing regimen has been approved by the FDA as the first 
treatment for mMCC.5  Avelumab was originally dosed on a mg/kg basis in order to reduce 
inter-patient variability in drug exposure.  However, emerging data for mAbs, including the 
marketed PD-1 and PD-L1 immune checkpoint inhibitors nivolumab, pembrolizumab and 
atezolizumab, reveal that body weight-based dosing regimens do not result in less variability 
in measures of exposure over fixed (ie, body-weight independent) dosing regimens.59,60,61  
Additionally, fixed dosing offers the advantages of less potential for dispensing errors, 
shorter dose preparation times in a clinical setting, and greater ease of administration.
Population PK analysis was conducted based on the acquired data across 3 single-agent 
avelumab studies in 1827 patients with 14 different types of cancer.  PK simulations suggest 
that exposures to avelumab across the available range of body weights are less variable with 
800 mg Q2W compared with 10 mg/kg Q2W; exposures were similar near the population 
median weight.  Low-weight patients tended towards marginally lower exposures relative to 
the rest of the population when weight-based dosing was used, and marginally higher 
exposures when flat dosing was applied.  However, the implications of these exposure 
differences are not expected to be clinically meaningful at any weight across the whole 
population.  Furthermore, the 800 mg Q2W dosing regimen is expected to result in Ctrough
>1 g/mL required to maintain avelumab serum concentrations at >95% TO throughout the 
entire Q2W dosing interval in all weight categories. Flat dosing for avelumab of 800 mg 
Q2W has recently been approved in the US for the Merkel Cell Carcinoma (MCC) and UC 
indications [avelumab United States Package Insert (USPI), October 19, 2018].   
Therefore, in this clinical trial, a fixed dosing regimen of 800 mg administered as a 1-hour IV 
infusion Q2W will be utilized for avelumab. 
1.2.5.2. Talazoparib
The dose levels of talazoparib to be evaluated in this study are supported by clinical studies 
in patients with advanced malignancies.  In the PRP-001 Phase 1 study in patients with 
advanced or recurrent solid tumors, talazoparib was escalated from 0.025 to 1.1 mg QD and 
the recommended dose for further development was determined to be 1 mg QD.  Data from 
this study at 1 mg/day demonstrated objective responses or clinical benefit (CR, PR, or stable 


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disease 24 weeks) in patients with breast, ovarian/peritoneal, pancreatic cancer, SCLC, and 
Ewing sarcoma.  The dose level of 1 mg QD was selected for the randomized Phase 3 study 
673-301 in patients with BRCA 1/2 mutations and locally advanced or metastatic breast 
cancer. 
Recommended Phase 2 Dose 
For this present study, the dose level of talazoparib 1 mg orally (PO) QD in combination with 
avelumab 800 mg IV Q2W was selected following evaluation of 12 patients after 1 cycle of 
treatment in the Phase 1b portion of Study B9991025, a Phase 1b/2 study in patients with 
advanced solid tumors. As of the 18 May 2018 data cutoff date, the most frequently reported 
TEAEs were anemia (8 patients, 66.7%), neutropenia (7 patients, 58.3%), and chills and 
thrombocytopenia (both 5 patients, 41.7%). The most frequently reported Grade 3 TEAEs 
were thrombocytopenia (4 patients, 33.3%), anemia (3 patients 25.0%), and neutropenia 
(2 patients, 16.7%); a  serious AE (SAE) of anemia was reported in 1 patient (8.3%). There 
were no Grade 4 TEAEs. No AEs leading to treatment discontinuation of any of the study 
drugs was reported. Seven (7) patients (58.3%) experienced AEs that led to interruption of 
avelumab [thrombocytopenia (5 patients, 41.7%), anemia and neutropenia (both 2 patients, 
16.7%); chills and fatigue (both 1 patient, 8.3%), and restlessness (1 patient, 8.3%)] and eight 
(8) patients (66.7%) experienced AEs that led to interruption of talazoparib 
[thrombocytopenia (5 patients, 41.7%), anemia and neutropenia (both 3 patients, 25%), and 
fatigue (1 patient, 8.3%)]. Three (3) patients (25.0%) experienced TEAEs which led to 
talazoparib dose reduction and were declared to be DLTs: thrombocytopenia led to 
talazoparib dose reduction to 0.75 mg QD; of these, one patient required further dose 
reduction to 0.5 mg QD. A third patient experienced thrombocytopenia and anemia together, 
leading to a talazoparib dose reduction to 0.75 mg. As the frequency of the TEAEs were 
generally consistent with the frequency of TEAEs following administration of the single 
agents and were determined to be generally manageable, the Recommended Phase 2 Dose 
(RP2D) for talazoparib in combination with avelumab at 800 mg IV Q2W was established at 
1 mg PO QD. The starting dose of talazoparib for patients with moderate renal impairment 
(CLCR = 30-59 mL/min) will be 0.75 mg PO QD to account for the lower talazoparib 
clearance.
Although no PK drug-drug interaction is expected between avelumab and talazoparib, 
concentration-time data will be measured on this study for both avelumab and talazoparib 
following coadministration at single dose and at steady state, and will be compared with 
historical PK data for avelumab and talazoparib as single agents.
1.2.6. Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
The benefit-risk relationship has been carefully considered in the planning of this trial.  
Avelumab demonstrated clinical activity in patients with advanced solid tumors, including 
NSCLC (first-line and second-line or higher), breast cancer, CRPC, UC and ovarian cancer
in the expansion cohorts of the ongoing Phase 1 Study EMR 100070-001, as described in 


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Section 1.2.1 and Table 3. The clinical safety data available to date with single-agent 
avelumab in patients with advanced solid tumors suggest an acceptable safety profile, as 
described in Section 1.2.1.  Most of the observed adverse events were either in line with 
those expected in patients with advanced solid tumors or with similar class effects of mAbs 
blocking the PD-1/PD-L1 axis.  Infusion-related reactions, including hypersensitivity and 
irAEs/autoimmune disorders have been identified as important risks for avelumab.  
Respective risk mitigation measures have been implemented in all ongoing clinical studies 
with avelumab, including this clinical trial protocol.  These include guidelines for treatment 
interruption and discontinuation in case of irAEs, as well as mandatory pre-treatment with an 
antihistamine and acetaminophen prior to the first 4 avelumab infusions (Cycles 1-2) and as 
clinically indicated thereafter.
Talazoparib has also demonstrated single-agent clinical activity in patients with advanced 
solid tumors with DNA repair pathway abnormalities, particularly those associated with 
BRCA 1/2 and PTEN dysfunction, including breast cancer, ovarian/peritoneal cancer, and 
pancreatic cancer in the Phase 1 Study PRP-001, as described in Section 1.2.2.  Also, in an 
ongoing Phase 3, open-label, randomized, parallel-group study, (N=431, randomized 2:1 on 
talazoparib vs chemotherapy) in patients with locally advanced or metastatic breast cancer 
with germline BRCA 1/2 mutations, talazoparib monotherapy demonstrated longer PFS and 
better ORR than standard of care chemotherapy (median PFS: 8.6 months vs 5.6 months, 
HR: 0.54, 95% CI: 0.41- 0.71, p<0.0001; ORR: 62.6% vs 27.2%; odds ratio: 4.99, 95% 
CI: 2.9-8.8, p<0.0001; per RECIST 1.1, confirmation of CR/PR was not required).24
The clinical safety profile of talazoparib supports its use as both a single agent and in 
combination with cancer therapies.  The most common TEAEs associated with single-agent 
talazoparib administration (>20%) were myelosuppression (eg, anemia, thrombocytopenia, 
neutropenia), gastrointestinal toxicity (eg, nausea, diarrhea, vomiting), and fatigue with 
severe and serious adverse events mostly associated with myelosuppression.  These adverse 
events were primarily Grade 1 or 2 severity and typically resolved with temporary dose 
interruptions or reductions.23  In the EMBRACA study, the most common AEs observed with 
talazoparib (>20%, all grade) were anemia (52.8%), fatigue (50.3%), nausea (48.6%), 
neutropenia (34.6%), headache (32.5%), thrombocytopenia (26.9%), alopecia (25.2%), 
vomiting (24.8%), diarrhea (22%), constipation (22%), decreased appetite (21.3%), and back 
pain (21%).  The incidence of serious AEs was 31.8% in the talazoparib arm and 29.4% in 
the chemotherapy arm.  Discontinuations due to AEs occurred in 7.7% of patients in the 
talazoparib arm and 9.5% of patients in the chemotherapy arm.24Preliminary safety data from 
B9991025 with talazoparib combined with avelumab has been found to be generally 
consistent with the safety profiles from the single agents.  The avelumab plus talazoparib 
combination is anticipated to improve the anti-tumor activity of each drug when given as 
single-agent, while maintaining the manageable safety profiles of avelumab and talazoparib 
administered as single agents.  
The expected low incidence of overlapping severe toxicities, and the anticipated enhanced 
anti-tumor activity, the projected benefit-risk relationship of avelumab given in combination 
with talazoparib is expected to be favorable for investigation in this population of patients 
with advanced solid tumors with BRCA 1/2 or ATM gene defects.


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1.2.7. Rationale for Biomarker Assessments and Prospective Patient Selection
The combination of avelumab and talazoparib is predicated on the ability of talazoparib to 
promote DNA damage, which leads to increased inflammation, immune priming and tumor 
immunogenicity, and on the ability of avelumab to overcome PD-L1 mediated inhibition of 
any anti-tumor immune response resulting from this priming event.  Based on this 
mechanism of action, the combination of avelumab and talazoparib is expected to be 
optimally effective in patients that have greater sensitivity to talazoparib-mediated DNA 
damage.  This study will enroll patients expected to have such increased sensitivity, based on 
historic evidence of germline or somatic defects in BRCA1, BRCA2 or ATM, which have 
been associated in a number of studies with increased sensitivity to PARP inhibitors.43,44,54
In order to allow for confirmation of historic BRCA 1/2 and ATM test results, all patients 
entering the study are required to provide tumor tissue, in the form of a minimum of 
15 slides, for central testing. 
A number of assessments will also be undertaken in tumor tissue in order to understand the 
immune context of patient tumors, which will likely also be a key contributing factor in 
response to the combination of talazoparib and avelumab.  One key assessment of interest is 
PD-L1 expression by tumor and/or immune cell types in the tumor, measured by 
immunohistochemistry.  While initial studies have not indicated a relationship between 
PD-L1 expression and response to PARP inhibitor combinations with anti-PD-1/PD-L1 
antibodies, these studies were small in nature and PD-L1 has shown utility as a potential 
predictive marker across multiple tumor types treated with anti-PD-1/PD-L1 antibodies.25,55  
 
 
 
 To enable the 
above mentioned biomarker assessments, the provision of a pretreatment tumor tissue sample 
is mandatory (see Section 7.4.1.1); also, tumor tissue is requested for patients who undergo 
tumor biopsy or resection as part of routine clinical care during the study period, and every 
effort should be made to obtain end of treatment biopsies (see Section 7.4.1.2).
Given the limited ability to assess tumor tissue-based biomarkers longitudinally, a number of 
biomarkers will also be measured in peripheral blood at a number of time points.  Circulating 
tumor (ct)DNA will be collected from all patients at baseline, and will be used to correlate 
the presence defects in BRCA 1/2 and ATM in ctDNA with those in tissue, in order to 
determine the feasibility of a blood based biopsy approach for future patient selection.  In 
addition ctDNA samples collected during and at the end of treatment will be used to assess 
changes in the presence of such defects, and defects in other genes, which may inform the 
mechanism and timing of resistance to therapy.  
 
 
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In the event that clinical benefit is not observed or is transient, an understanding of the 
mechanisms of resistance may help guide optimal patient selection for future development of 
the combination.  For these reasons, tumor biopsies performed at the End of Treatment visit 
or in the event of permanent treatment discontinuation due to disease progression, are 
requested from patients, unless clinically contraindicated.  If the sponsor considers sufficient 
data have been obtained to confirm possible causes for lack of clinical benefit, collection of 
tumor tissue from End of Treatment tumor biopsies may be discontinued.
 
 
 
 
 
 
 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective:
Primary Endpoint:
•
To evaluate ORR of avelumab in combination with 
talazoparib, in patients with locally advanced or 
metastatic solid tumors harboring BRCA1, BRCA2 or 
ATM defect.
•
Confirmed OR in patients with locally advanced or 
metastatic solid tumors with BRCA 1/2 or ATM 
defect, as assessed by Blinded Independent Central 
Review (BICR), using RECIST v1.1 (Appendix 3) 
and, in patients with mCRPC, RECIST v1.1 and 
PCWG3 (bone) (Appendix 4).
Secondary Objectives:
Secondary Endpoints:
•
To assess the overall safety and tolerability of 
avelumab in combination with talazoparib.
•
To characterize the PK of avelumab and talazoparib 
when given in combination.
•
To evaluate the immunogenicity of avelumab when 
given in combination with talazoparib.
•
To assess other measures of the anti-tumor activity of 
avelumab in combination with talazoparib.
•
To assess the correlation of anti-tumor activity of 
avelumab in combination with talazoparib with PD-L1 
expression in baseline tumor tissue.
•
Adverse Events as characterized by type, severity (as 
graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI
CTCAE] v.4.03), timing, seriousness, and 
relationship to study therapy.
•
Laboratory abnormalities as characterized by type, 
severity (as graded by NCI CTCAE v.4.03) and 
timing.
•
PK parameters including: pre-dose/trough 
concentrations (Ctrough) for avelumab and talazoparib,  
post-dose concentrations for talazoparib, and 
maximum concentrations (Cmax) for avelumab.
•
Avelumab anti-drug antibody (ADA) levels and 
neutralizing antibodies (Nab) against avelumab.
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•
To assess the correlation of anti-tumor activity and 
emergence of resistance with defects in a panel of key 
oncogenes, including BRCA1/2 and ATM, and TMB 
in circulating tumor DNA (ctDNA) and tumor tissue 
at baseline, during treatment and at the end of 
treatment.
•
Confirmed OR as assessed by the investigator, using 
RECIST v1.1 (Appendix 3) and, in patients with 
mCRPC, RECIST v1.1 and PCWG3 (Appendix 4).
•
Time to event endpoints: Endpoints as assessed by 
BICR and as assessed by the investigator, using 
RECIST v1.1 (Appendix 3) and in patients with 
mCRPC, RECIST v1.1 and PCWG3 (Appendix 4), 
including time to tumor response (TTR), duration of 
response (DR), and progression free survival (PFS).  
Additional time-to-event endpoints include overall 
survival (OS) for all patients and time to 
prostate-specific antigen (PSA) progression 
(≥25% increase) for mCRPC patients. 
•
PSA response ≥50% decrease and CTC count 
conversion for patients with mCRPC.
•
Cancer antigen (CA)-125 response ≥50% decrease 
for patients with ovarian cancer.
•
PD-L1 expression level in baseline tumor tissue.
•
Presence of defects in a panel of key oncogenes, 
including BRCA 1/2 and ATM, and TMB in ctDNA 
and tumor tissue at baseline, during treatment, and at 
the end of treatment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 2b, open-label, multi-center, non-randomized study of avelumab in 
combination with talazoparib in adult patients with locally advanced (primary or recurrent) or 
metastatic solid tumors with a pathogenic or likely pathogenic germline or loss-of-function 
somatic BRCA1 or BRCA2, or ATM gene defect, as determined by local assessment and 
classification, who have received at least 1 line of SOC treatment for locally advanced or 
metastatic disease unless prior treatment requirements are otherwise specified.  Two cohorts 
will be enrolled in parallel:

Cohort 1 will enroll up to approximately 150 patients with locally advanced or 
metastatic solid tumors with one or more defects in the BRCA1 or BRCA2 genes;

Cohort 2 will enroll up to approximately 50 patients with locally advanced or 
metastatic solid tumors with one or more defects in the ATM gene.
Note: in the event that a patient has concomitant defects in more than 1 of the three 
genes (BRCA1 or BRCA2 or ATM), they will be enrolled in Cohort 1. 
Patients will continue on the study treatment until disease progression or withdrawal from 
study treatment for other reasons.  See Section 6.3 for reasons for withdrawal from the study 
treatment or the study follow-up.
4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team.  To confirm that participants meet critical eligibility criteria, sites 
may be asked to complete a Patient Enrollment Verification Form for review and 
confirmation by the sponsor prior to enrollment. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Pathogenic or likely pathogenic germline or somatic gene defect as determined by 
local assessment and classification:

One or more BRCA1 or BRCA2 gene defect (Cohort 1);


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
ATM gene defect in the absence of concurrent BRCA 1/2 defect (Cohort 2).
Note: in the event that a patient has concomitant defects in more than 1 of the 
three genes (BRCA1 or BRCA2 or ATM), they will be enrolled in Cohort 1. 
The presence of gene defects must have been determined by local assessment and 
classification using a test of either germline or tumor DNA which was performed in a 
CAP/CLIA-certified (or comparable local or regional certification) laboratory. 
2. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid 
tumors that are not amenable for treatment with curative intent, as follows:
a.
Recurrent Epithelial Ovarian Cancer:

Patients must have received at least 1 but no more than 5 total prior cytotoxic 
chemotherapy regimens, including at least 1 course of platinum-based 
therapy; 

Patients must not have progressed during or within 1 month after the last dose 
of the most recent platinum-based chemotherapy;

Platinum sensitivity requirements:

If previously treated with 2 prior cytotoxic chemotherapy regimens, 
patients must have had disease progression within 6 months after the last 
dose of platinum-based chemotherapy, also termed “platinum-resistant 
recurrent disease”;

If previously treated with >2 prior cytotoxic chemotherapy regimens, 
platinum-sensitive recurrent disease is allowed.

Any treatment regimen that began with cytotoxic chemotherapy and continued 
with another regimen for maintenance therapy following best response to 
initial cytotoxic regimen will count as one line of prior therapy.
b. TNBC (defined as ER- and PgR-negative [IHC nuclear staining <5%] and 
HER2-negative [IHC 0, 1+, or 2+ and/or ISH non-amplified with ratio less than 
2.0]) or hormone-receptor-positive (HR+), HER2-negative breast cancer:

Have been previously treated with no more than 3 prior chemotherapy 
regimens for locally advanced or metastatic breast cancer; 

There is no limit on the number of prior endocrine therapies or targeted 
anti-cancer therapies such as mammalian target of rapamycin (mTOR) or 
cyclin-dependent kinase (CDK)4/6 inhibitors, or vascular endothelial growth 
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
Previous neo-adjuvant/adjuvant treatment counts as 1 line of prior 
chemotherapy if disease progression occurred while on treatment or within 
6 months after the last treatment dose;

Patients must have received treatment with a taxane- or 
anthracycline-containing chemotherapy regimen in the neo-adjuvant, 
adjuvant, or advanced setting, unless deemed unsuitable for these treatments;

Patients that have previously been treated with platinum-based chemotherapy 
in the neo-adjuvant/adjuvant setting must not have had disease progression 
while on treatment or within 6 months after the last dose of platinum-based 
chemotherapy;

Patients that have previously been treated with platinum-based chemotherapy 
in the advanced/metastatic setting must not have had disease progression 
within 6 months of initiation of a platinum-containing regimen;

Patients with HR+ breast cancer must have received at least 1 prior endocrine 
therapy (adjuvant or metastatic), unless deemed not suitable for endocrine 
therapy.
c.
Metastatic castration-resistant prostate cancer (mCRPC) without small cell 
features:

Patients with disease spread limited to regional pelvic lymph nodes (below the 
aortic bifurcation) are not eligible unless bone metastasis is present on bone 
scan; 

Progressed on at least 1 line of second-generation anti-androgen therapy 
(enzalutamide and/or abiraterone acetate/prednisone) for treatment of 
mCRPC;

Have received no more than 2 prior chemotherapy regimens for mCRPC.  
Patients may have received radium-223, which does not count for a line of 
prior chemotherapy regimen; 

Serum testosterone 1.73 nmol/L (50 ng/dL);

Bilateral orchiectomy or ongoing androgen deprivation therapy with a 
gonadotropin-releasing hormone (GnRH) agonist/antagonist (surgical or 
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
Progressive disease at enrollment defined as 1 or more of the following 
3 criteria:

A minimum of 3 consecutive rising PSA values with an interval of at least
1 week between determinations.  The screening PSA value must be 
2 g/L (2 ng/mL) if qualifying solely by PSA progression;

Disease progression as defined by RECIST v1.1;

Bone disease progression defined by Prostate Cancer Working Group 3 
(PCWG3) with 2 or more new metastatic lesions on bone scan (confirm 
ambiguous results by other imaging modalities).
d. Metastatic ductal adenocarcinoma of the pancreas:

Have been previously treated with at least 1 but no more than 2 prior cytotoxic 
chemotherapy regimens (including at least one of the following: 
FOLFIRINOX or a gemcitabine-containing regimen) unless deemed 
unsuitable or patient declined these therapies;

Patients must not have had disease progression within 6 months of initiation 
of a platinum-containing regimen.
e.
Any other advanced solid tumor:

Have received at least 1 prior SOC regimen, if it exists, as appropriate for the 
respective tumor type unless deemed unsuitable, or declined these therapies;

Patients must not have had disease progression within 6 months of initiation 
of a platinum-containing regimen;

Patients with NSCLC harboring B-Raf proto-oncogene (BRAF)V600 mutations 
or ALK and c-Ros oncogene 1 (ROS1) translocations/rearrangements must 
have received the appropriate targeted therapy as approved by the relevant 
health care authority.  Patients with activating EGFR mutations are not 
eligible; non-squamous cell histologies require testing if EGFR status is 
unknown.
3. Availability of a fresh or recent tumor tissue sample from a diagnostic biopsy/surgery 
or a metastatic tumor biopsy; the sample must have been obtained within 24 months 
prior to study enrollment.  When only bone disease is present, an archival tumor 
tissue sample obtained within 5 years prior to study enrollment may be accepted for 
non-prostate cancer patients and a fresh bone biopsy may be accepted for prostate 
cancer patients only). (See Section 7.4.1 for details). 
4. Have progressive disease at study enrollment as defined by RECIST v1.1 (except for 
mCRPC, who must meet criterion 2c above).


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5. Must have measurable disease by RECIST v1.1 with at least 1 measurable lesion that 
has not been previously irradiated (patients with mCRPC may have only 
non-measurable disease).
6. Age 18 years (except in Japan, where patients must be 20 years old).
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. 
8. Adequate bone marrow function (without hematopoietic growth factor or transfusion 
support within 14 days prior to study enrollment), including:
a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L.
b. Platelets 100,000/mm3 or 100 x 109/L.
c.
Hemoglobin 9 g/dL (5.6 mmol/L).
9. Adequate renal function defined by an estimated creatinine clearance 30 mL/min 
according to the Cockcroft-Gault formula as:

CLCR={[(140–age) × weight)]/(72 x SCR)} × 0.85 (if female), where CLCR
(creatinine clearance) is measured in mL/min, age is expressed in years, weight in 
kilograms (kg), and SCR (serum creatinine) in mg/dL;

Or as measured by 24h urine assessment.
NOTE: Patients with moderate renal impairment (30-59 mL/min) will receive a 
reduced starting dose for talazoparib (See Section 5.4.2). 
10. Adequate liver function, including:
a.
Total serum bilirubin 1.5 × the upper limit of normal range (ULN); 
b. Aspartate and Alanine aminotransferase (AST and ALT) 2.5 x ULN.
11. Female patients of childbearing potential must have negative serum pregnancy or 
urine pregnancy test at screening. 
Women in the following categories are not considered to be women of child-bearing 
potential (WOCBP):
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;


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
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause 
other than the above, (eg, mullerian agenesis, androgen insensitivity), 
investigator discretion should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, 
or medical history interview.  The method of documentation should be 
recorded in the participant’s medical record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as age 60 years or older or no menses 
for 12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required 
to use one of the nonestrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
12. Evidence of a personally signed and dated informed consent document indicating that
the patient has been informed of all pertinent aspects of the study. 
13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Prior treatment with a PARP inhibitor.
2. Prior immunotherapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 
antibody.
3. Prior anti-cancer therapy within 2 weeks prior to study enrollment or prior radiation 
therapy within 2 weeks prior to study enrollment.  Prior palliative radiotherapy to 
metastatic lesion(s) is permitted, provided it has been completed at least 2 days prior 
to study enrollment and no clinically significant toxicities are expected (eg, mucositis, 
esophagitis).
4. Major surgery within 4 weeks prior to study enrollment.


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5. Current use of immunosuppressive medication at the time of study enrollment, 
EXCEPT for the following permitted steroids:
a.
Intranasal, inhaled, topical steroids, eye drops or local steroid injection 
(eg, intra-articular injection);
b. Systemic corticosteroids at physiological doses 10 mg/day of prednisone or 
equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg, computed 
tomography [CT] scan premedication).
6. Known prior severe hypersensitivity to investigational products or any component in 
their formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (National Cancer Institute Common Terminology Criteria for Adverse 
Events [NCI CTCAE] v4.03 Grade 3).
7. Known history of immune-mediated colitis, inflammatory bowel disease, 
pneumonitis, pulmonary fibrosis.
8. Active or prior autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or hypo-
or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
9. Prior organ transplantation including allogenic stem-cell transplantation.
10. Administration of live attenuated vaccines within 4 weeks of study enrollment.
11. Diagnosis of myelodysplastic syndrome (MDS).
12. Known symptomatic brain metastases requiring steroids.  Patients with previously 
diagnosed brain metastases are eligible if they have completed their treatment and 
have recovered from the acute effects of radiation therapy or surgery prior to study 
enrollment, have discontinued corticosteroid treatment for these metastases for at 
least 4 weeks, and are neurologically stable.
13. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study entry and/or during study participation.
14. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, 
alopecia and sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a 
safety risk, based on investigator's judgment, are acceptable. 
15. Known history of testing positive for human immunodeficiency virus (HIV) or 
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16. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
17. Active infection requiring systemic therapy.  Minor infections, eg, periodontal or 
urinary tract infection (UTI) infection, which may be treated with short term oral 
antibiotics are allowed.
18. Clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke (<6 months prior to study enrollment), myocardial infarction 
(<6 months prior to study enrollment), unstable angina, congestive heart failure 
(New York Heart Association Classification Class II), or a serious cardiac 
arrhythmia requiring medication.
19. Current or anticipated use of strong P-gp inhibitors within 7 days prior to enrollment, 
or anticipated use during the study. For a list of strong P-gp inhibitors, refer to
Section 5.7.10.
20. Inability to swallow capsules, known intolerance to talazoparib or its excipients, 
known malabsorption syndrome, or other condition that may impair absorption of 
talazoparib.
21. Bisphosphonate or denosumab dosage that was not stable (ie, not the same) for at 
least 2 weeks before study enrollment for patients receiving these therapies.
22. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
23. Diagnosis of any other malignancy within 2 years prior to study enrollment, except 
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of 
the breast, bladder, or cervix, or low-grade (Gleason 6) prostate cancer on 
surveillance without any plans for treatment intervention (eg, surgery, radiation, or 
castration), or other early-stage low-risk cancers.
24. Pregnant female patients, breastfeeding female patients, and female patients of 
childbearing potential who are unwilling or unable to use a method of highly effective
contraception as outlined in this protocol during treatment and for at least 30 days 
after the last dose of avelumab and for at least 7 months after the last dose of 
talazoparib; fertile male patients with female partners of reproductive potential or 
pregnant partners, unwilling to use a condom (even after vasectomy) during treatment
and for at least 4 months after the last dose of talazoparib. 


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25. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
4.3. Lifestyle Requirements
In this study, all patients will receive avelumab for which the teratogenic risk is currently 
unknown, in combination with talazoparib, which has been associated with genotoxic and 
teratogenic risk.  
All female patients who are of childbearing potential, who are, in the opinion of the 
investigator, sexually active and at risk for pregnancy   must agree to use highly effective 
contraception, preferably with low user dependency, during treatment and for at least 30 days 
after the last dose of avelumab and at least 7 months after the last dose of talazoparib.
Fertile male patients with female partners of reproductive potential or pregnant partners, 
must agree to use a condom (even after vasectomy) during treatment and for at least 
4 months after the last dose of talazoparib. Female partners of reproductive potential should 
use an additional highly effective contraceptive method for at least 4 months after the 
patient’s last dose of talazoparib.  
The investigator or his or her designee, in consultation with the patient, will confirm that the 
patient has selected an appropriate method of contraception for the individual patient and 
his/her partner from the list of permitted contraception methods (see below) and will confirm
that the patient has been instructed in their consistent and correct use.  At time points 
indicated in the Schedule of Activities, the investigator or designee will inform the patient of 
the need to use highly effective contraception consistently and correctly and document the 
conversation, and the patient’s affirmation, in the patient’s chart (patients need to affirm their 
consistent and correct use of at least 1 of the selected methods of contraception).  In addition, 
the investigator or designee will instruct the patient to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the patient or 
partner. 
CONTRACEPTIVES ALLOWED DURING THE TRIAL INCLUDE:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.


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5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

oral;

intravaginal;

transdermal;

injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation:

oral;

injectable.
3. Sexual abstinence:
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study portal.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 


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the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council for Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational products are avelumab and talazoparib.
5.1. Allocation to Treatment
All patients will be assigned to receive a fixed dose of avelumab 800 mg Q2W intravenously 
and oral talazoparib at 1 mg QD or 0.75 mg QD for patients with moderate renal impairment.
Assignment of patient number, patient enrollment, and allocation of study treatment will be 
managed by an Interactive Response Technology (IRT) system.  At the time that a patient has 
signed informed consent and entered screening, the site should contact the IRT system to 
obtain the patient identification number.  Once a patient has met all eligibility criteria, the 
site then contacts the IRT system to enroll the patient and to obtain the study treatment 
allocation information. Study treatment must be initiated preferably on the day of 
enrollment, but no later than 3 days after enrollment.
At the time of enrollment, site personnel (study coordinator or specified designee) will be 
required to enter into or select information from the IRT system including but not limited to 
the user’s identification (ID) and password, the protocol number, the patient number, and the 
date of birth of the patient.  The IRT system will then provide a treatment assignment and 
dispensable unit (DU) or vial number.  The IRT system will also provide a confirmation 
report containing the patient number and DU or vial number assigned.  The confirmation 
report must be stored in the site’s files. 
There is a 24-hour-a-day, 365-days-a-year IRT helpdesk available for any questions or 
issues.  The study-specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system.
5.2. Patient Compliance
The information related to each trial drug administration will be recorded in the case report 
form (CRF) as detailed below.  The investigator will make sure that the information entered 
into the CRF regarding drug administration is accurate for each patient.  Any reason for 
noncompliance should be documented.


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5.2.1. Avelumab Patient Compliance
All doses of avelumab will be administered at the investigator site by well-trained medical 
staff.  The total dose and start and stop times of the avelumab infusion, including infusion 
rate as well as start and stop times of any interruptions to infusions and/or changes in rate of 
infusion, will be recorded in the patients’ medical records.  The vials of avelumab that are
assigned and prepared for patients will be recorded in the pharmacy records.  These records 
will all be available for sponsor representatives to verify compliance. 
The site will complete the required dosage Preparation Record located in the Investigational 
Product manual (IP manual) for avelumab.  The use of the supplied Preparation Record is 
preferred, but it does not preclude the use of an existing appropriate clinical site 
documentation system.  The existing clinical site's documentation system should capture all 
pertinent/required information on the preparation of the avelumab dose, including date of 
preparation, patient identification number, total dose and volume prepared, date and time of 
expiry, and the initials of clinical site personnel preparing and approving the infusion.  This 
may be used in place of the Preparation Record after approval from the sponsor and/or 
designee. Noncompliance is defined as a patient missing >1 infusion of avelumab within a 
given cycle for non-medical reasons.  If 1 infusion is missed and the interval between the 
subsequent infusion and the last administered treatment is longer than 4 weeks for 
non-medical reasons, this would also be considered as noncompliance.
5.2.2. Talazoparib Patient Compliance
Patients will be required to return all unused talazoparib capsules every cycle.  The number 
of capsules returned by the patient should be counted, documented, and recorded by site 
personnel in the patient’s medical record and reconciled with the patient’s dosing diary to 
support the talazoparib accountability process.  Study site personnel must make reasonable 
efforts to obtain study drug packaging and any unused capsules from patients who do not 
routinely return them at study site visits.  Unreturned capsules will be considered to have 
been taken unless reported otherwise by the patient.
Additionally, a patient dosing diary will be provided to the patients to aid in patient 
compliance with the dosing instructions.  The diary will be maintained by the patient to 
include missed or changed talazoparib doses.  The time of talazoparib dose administration 
and the total dose of talazoparib taken each day will be recorded in the dosing diary.  Patients 
will be required to return the completed patient dosing diary for talazoparib on Day 1 of 
every cycle for timely review by site personnel and discussion of missed doses and/or 
compliance issues to ensure accurate data entry for the Dosing CRF. 
On days when the patient’s talazoparib dose is given at the clinic due to scheduled PK 
sample collection, the time of talazoparib dose administration and the total dose of 
talazoparib taken will be recorded in the patient’s dosing records that are included in the 
medical chart.
Patients will be considered out of compliance if ≥20% of the expected monthly doses are 
missed within a given cycle for non-medical reasons.  


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5.3. Investigational Product Supplies 
Avelumab and talazoparib will both be supplied for the study by Pfizer Global Clinical 
Supply, Worldwide Research and Development.  Drug supplies will be shipped to the study 
sites with a Drug Shipment and Proof of Receipt form.  This form will be completed, filed, 
and the shipment confirmed as directed on the bottom of the Drug Shipment and Proof of 
Receipt form.  The investigator shall take responsibility for and shall take all steps to 
maintain appropriate records and ensure appropriate supply, storage, handling, distribution, 
and usage of investigational products in accordance with the protocol and any applicable 
laws and regulations.
5.3.1. Dosage Forms and Packaging
Packaging and labeling for all study drugs will be in accordance with applicable local 
regulatory requirements and applicable Good Manufacturing Guidelines (GMP) guidelines.  
The information on each study drug will be in accordance with approved submission 
documents.
5.3.1.1. Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  It is 
presented at a concentration of 20 mg/mL in 10-mL glass vials closed with a rubber stopper 
and sealed with an aluminum polypropylene flip-off seal.  Each vial is intended for single use 
only. 
Avelumab will be packed in boxes each containing 1 vial. 
Avelumab will be shipped and must be stored under refrigerated conditions (2C to 8C) that 
are monitored with temperature control monitoring devices.
5.3.1.2. Talazoparib
Talazoparib will be provided as capsules for oral administration.  The 0.25 mg (opaque 
white, size 4) and 1.0 mg (opaque pale-pink, size 4) capsules will be supplied in separate 
bottles and labeled according to local regulatory requirements.  Talazoparib is packaged in 
induction sealed, high-density polyethylene bottles with child-resistant caps with 30 capsules 
of a single strength per bottle.  Storage temperature is 15C to 30C.  Schedule of patient 
visits must take into account number of talazoparib capsules dispensed, to ensure that patient 
has sufficient quantity of drug supply. 
5.3.2. Preparation and Dispensing
Investigational products must not be used for any purpose other than the trial.  The 
administration of study treatment to patients who have not been enrolled into the trial is not 
covered by the trial insurance.


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5.3.2.1. Avelumab
See the IP manual for instructions on how to prepare avelumab for administration.  
Investigational products should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance.
For administration in this trial, 4 vials of avelumab drug product must be diluted with 
0.9% saline solution (sodium chloride).  Detailed information on infusion bags and medical 
devices to be used for the preparation of the dilutions and subsequent administration will be 
provided in the Investigational Product Manual.
Any spills that occur should be cleaned up using the facility’s standard cleanup procedures 
for biologic products.
Any unused portion of the avelumab solution should be discarded in biohazard waste 
disposal with final disposal by accepted local and national standards of incineration.
5.3.2.2. Talazoparib
Talazoparib should be dispensed on the Day 1 Visit of every cycle.  A qualified staff member 
will dispense the investigational product in the bottles provided, in quantities of 30 capsules 
per bottle.  The patient/caregiver should be instructed to maintain the product in the bottle 
provided throughout the course of dosing, keep the investigational product away from 
children, and return the bottle to the site on the Day 1 Visit of every cycle.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the dispensing, handling, and safe 
disposal of talazoparib.  Talazoparib is considered a cytotoxic and clastogenic agent; 
precautions regarding appropriate secure storage and handling must be used by healthcare 
professionals, including personal protective clothing, disposable gloves, and equipment.76  
Patients should be advised that oral anti-cancer agents are toxic substances and that other 
caregivers should always use gloves when handling the capsules.
5.4. Administration
5.4.1. Combination Therapy Administration
On Days 1 and 15 of each cycle, when both avelumab and talazoparib are administered at the 
investigator site, the following must occur in the order specified:
1. All required tests and assessments will be performed, as per the Section 7 and blood 
will be drawn for PK and ADA assessments (when scheduled);
2. Avelumab premedication, as described below in Section 5.4.3, and talazoparib will be 
administered to the patient in any order chosen by the qualified site personnel;
3. Avelumab infusion will start within 30-60 minutes after the avelumab premedication 
was administered and after dosing with talazoparib;


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4. Blood will be drawn for PK assessments (when scheduled) immediately at the end of 
the avelumab infusion and the patient will remain in the clinic for observation for at 
least 30 minutes after the avelumab infusion.
Treatment with avelumab and talazoparib will continue until disease progression is 
confirmed by the investigator (except where treatment is allowed beyond progression, as per 
Section 5.4.7), patient refusal, unacceptable toxicity, or until the study is terminated by the 
sponsor, whichever occurs first. 
The investigational products and the required premedications are discussed in the following 
subsections, in the order of their administration.
5.4.2. Talazoparib Administration
Talazoparib 1 mg will be taken QD orally, starting on Cycle 1 Day 1 (C1D1), and treatment 
should continue until End of Treatment. 
For patients with moderate renal impairment (CLCR = 30-59 mL/min), the talazoparib starting 
dose should be reduced to 0.75 mg QD. Measurement of CLCR will be repeated for patients 
whose degree of renal impairment changes between screening and enrollment, if this change 
is suspected to be due to the hydration status of the patient, to determine the exact starting 
dose of talazoparib before initiation of study treatment.  
On Days 1 and 15 of each cycle, when the patient returns to the clinic for avelumab 
administration, the daily dose of talazoparib should not be taken prior to the study visit and 
will be taken at the clinic after all procedures/assessments have been completed and before 
the avelumab infusion.
Patients should self-administer talazoparib orally QD, with or without food.  The capsules 
should be swallowed whole with a glass of water without chewing, dissolving, or opening 
them prior to swallowing. 
Patients should be instructed to take talazoparib at approximately the same time each day and 
to not take more than the prescribed dose at any time.
If a patient forgets his/her daily dose of talazoparib at the time typically taken, but 
remembers this on the same day, within 12 hours of the usual dose time, the dose may be 
taken at that time. Any dose that is missed (not taken within 12 hours of the intended time) 
should be skipped and should not be replaced or made up on a subsequent day. Patients 
should not make up vomited doses; dosing should resume on the next calendar day unless 
otherwise instructed.
Patients should complete the Dosing Diary after taking each dose.  If the patient misses a day 
of treatment or takes a dose different than was prescribed, the reason for the missed dose or 
different dose must be recorded in the Dosing Diary.  The Dosing Diary should be returned 
to the site at every cycle.


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5.4.3. Avelumab Premedication
In order to mitigate infusion-related reactions, patients have to be premedicated with an 
antihistamine and with paracetamol (acetaminophen) prior to the first 4 infusions of 
avelumab.  Premedication should be administered for subsequent avelumab doses based upon 
clinical judgment and presence/severity of prior infusion reactions.
When avelumab and talazoparib are administered on the same day, premedications may be 
given either prior to talazoparib, at the same time as talazoparib, or after talazoparib.  
However, the avelumab infusion will not start until after talazoparib and at least 30 minutes 
after the avelumab premedication was administered.
5.4.4. Avelumab Administration
Avelumab will be administered at 800 mg as a 1-hour IV infusion starting 30-60 minutes 
after the mandatory premedication was administered, as per Section 5.4.3, at the investigator
site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle.  Investigator sites 
should make every effort to target the timing of the avelumab infusion to be as close to 
1 hour as possible.  The exact duration of infusion should be recorded in both the source
documents and the CRFs.  Additionally, the start and stop times of any interruptions to 
infusion and/or changes in rate of avelumab infusion will also need to be recorded in source 
documents. After Cycle 1, avelumab may be administered up to 3 days before or after the 
scheduled treatment day of each cycle for administrative reasons.
5.4.4.1. Special Precautions for Avelumab Administration
As with all mAb therapies, there is a risk of allergic reactions, including anaphylactic shock.  
Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for anaphylaxis, 
such as the ability to implement immediate resuscitation measures. 
If a hypersensitivity reaction occurs, the patient must be treated according to the best 
available medical practice. 
Symptoms of avelumab infusion-related reactions include, but are not limited to, fever, chills, 
flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. 
Management of avelumab infusion-related reactions is described in Table 6.  Patients should 
be instructed to immediately report to the investigator any delayed reactions that may occur 
after they leave the clinic.
5.4.5. Food Requirements
Both investigational products may be administered without regard to food.
5.4.6. Recommended Dose Modifications
Every effort should be made to administer each investigational product at the planned dose 
and schedule. 


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In the event of significant toxicity, dosing may be interrupted, delayed and/or reduced, only 
as described for each investigational product.  In the event of multiple toxicities, 
treatment/dose modifications should be based on the worst toxicity observed.  Patients are to 
be instructed to notify investigators at the first occurrence of any adverse symptom.
Treatment/dose modifications may occur independently for each investigational product in 
the combination based on the observed toxicity and the general guidance, as follows: 

Avelumab: No dose reductions are permitted in this study, but the next infusion may 
be omitted based on persisting toxicity.

Talazoparib: Dose modifications (dose interruptions, or dose reductions) may be 
implemented to manage toxicities.
See Section 5.4.6.3 for details regarding the specific protocol-permitted modifications for 
each investigational product.
All dose modifications must be clearly documented in the patient's medical chart and in the 
CRF. 
In addition to dose modifications, investigators are encouraged to employ best supportive 
care according to local institutional clinical practices.
5.4.6.1. Dosing Interruptions 
Guidelines for study treatment modifications for patients experiencing adverse events are 
provided in Sections 5.4.6.3, 5.4.6.4, and 5.4.6.5. 
Doses of either investigational product that were omitted for toxicity are not replaced within 
the same cycle.  The need for a dose reduction for talazoparib at the time of treatment 
resumption should be based on the criteria defined in Section 5.4.6.3. 
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the investigator. 
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) for >7 consecutive days, treatment resumption will be decided in 
consultation with the sponsor.
5.4.6.2. Dose Reductions of Talazoparib
Following dosing interruption due to toxicity at any time in the study, the talazoparib dose 
may need to be reduced, based on the worst toxicity reported, when treatment is resumed.  
Dose reduction should be made in accordance with the guidance provided in Section 5.4.6.3.  
Dose reduction of talazoparib by 1 dose level at a time will be allowed depending on the 
starting dose and type and severity of toxicity encountered (see Table 4 below for the 
available dose levels).
The talazoparib starting dose level for the present study is 1 mg QD.  


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Doses less than 0.5 mg are not permitted.  Patients unable to tolerate 0.5 mg QD, will be 
permanently discontinued from the talazoparib, but may continue on single agent avelumab.  
Available dose levels for dose reductions are listed below.
Table 4.
Dose Levels for Dose Reductions of Talazoparib
Dose Level
Talazoparib Dose 
(Oral)
D0
1 mg QD
D-1
0.75 mg QD
D-2
0.5 mg QD a
a Talazoparib dose de-escalation below 0.5 mg QD is not allowed.
D = dose; QD = once daily
Once a dose has been reduced due to toxicity for a given patient, all subsequent cycles should 
be administered at that dose level, unless further dose reduction is required.  Intra-patient 
dose re-escalation is not allowed.
If a dose reduction is required, the patient may need to return to the clinic to receive new 
drug supply prior to the next scheduled visit since dosage strengths of the capsules may be 
different.  Site personnel must ensure the patients are instructed how to take the reduced dose 
and that the patients have the correct dosage strength for the reduced dose. 
Recommended dose reductions for talazoparib are described in Section 5.4.6.3.
5.4.6.3. Study Treatment Modifications for Avelumab and Talazoparib Drug-Related 
Toxicity (excluding infusion-related reactions and immune-related adverse events)
Recommended avelumab and talazoparib treatment modifications in case of investigational 
product related toxicity are shown in Table 5.  The specific guidelines are applicable in cases 
which can be attributed to one of the investigational products.  The instructions should be 
followed in the column regarding the investigational product that toxicity is attributed to.  In 
cases where an AE is possibly related to both investigational products, the guidelines in both 
columns for both investigational products should be followed.  Patients who stop avelumab 
or talazoparib for unacceptable toxicity may continue treatment with the investigational 
product that is not considered to be responsible for the toxicity observed.
Avelumab infusion-related reactions should be managed according to guidelines in 
Section 5.4.6.4. 
For patients receiving avelumab, either as a single agent or in combination with talazoparib, 
any AE suspected to be immune-related should be managed according to the guidance for 
management of irAEs in Section 5.4.6.5.


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Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related 
AEs)
Talazoparib
Avelumab
Hematologic toxicities

Grade 1 and Grade 2

No requirement for dose 
interruption or dose reduction.

Continue as per schedule.

Anemia Grade 3
(hemoglobin <8 g/dL)

Hold talazoparib and monitor 
weekly until resolve to baseline. 

Talazoparib may be reduced by 
1 dose level, per Section 5.4.6.2. 

Permanently discontinue if 
persists for >4 weeks without 
recovery to baseline.  Refer to 
hematologist for evaluation 
including assessment of possible 
MDS/AML.

Hold avelumab.

Re-initiate avelumab once 
toxicity Grade 1 (hemoglobin 
>10 g/dL) or baseline.

Permanently discontinue 
avelumab if toxicity does not 
resolve to Grade 1 or baseline 
within 12 weeks or if the same 
Grade 3 toxicity recurs (if 
talazoparib had already been 
discontinued and recurrent 
event occurs on avelumab 
only).

Neutropenia Grade 3
(ANC <1000/L)

Hold talazoparib and monitor 
weekly until ANC 1500/L.

Resume talazoparib based on the 
following recovery times:

1 week: No change;

>1 week: Talazoparib may be 
reduced by 1 dose level, per 
Section 5.4.6.2.

Permanently discontinue 
talazoparib if persists for 
>4 weeks without recovery to 
ANC 1500/L.  Refer to 
hematologist for evaluation 
including assessment of possible 
MDS/AML.

Hold avelumab.

Re-initiate avelumab once 
toxicity Grade 1 (ANC 
1500/L) or baseline.

Permanently discontinue 
avelumab if toxicity does not 
resolve to Grade 1 or baseline 
within 12 weeks or if the same 
Grade 3 toxicity recurs (if 
talazoparib had already been 
discontinued and recurrent 
event occurs on avelumab 
only).

Thrombocytopenia
Grade 3 (platelets 
<50,000/L)

Hold talazoparib and monitor 
weekly until platelets 
75,000/L.

Resume talazoparib based on the 
following recovery times:

1 week: No change;

>1 week: Talazoparib may be 
reduced by 1 dose level, per 
Section 5.4.6.2.

Permanently discontinue 
talazoparib if persists for 
>4 weeks without recovery to 
platelets 75,000/L.  Refer to 
hematologist for evaluation 
including assessment of possible 
MDS/AML.

Hold avelumab.

Re-initiate avelumab once 
toxicity Grade 1 or baseline.

Permanently discontinue 
avelumab if toxicity does not 
resolve to Grade 1 or baseline 
within 12 weeks or if the same 
Grade 3 toxicity recurs (if 
talazoparib had already been 
discontinued and recurrent 
event occurs on avelumab 
only).


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Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related 
AEs)
Talazoparib
Avelumab
Non-hematologic toxicities
Grade 1 

No requirement for dose 
interruption or dose reduction. 

Continue as per schedule.

For suspected immune-related 
toxicities due to avelumab 
follow guidance in 
Section 5.4.6.5.
Grade 2

For suspected immune-related 
toxicities due to avelumab that 
require avelumab delay or 
discontinuation as per 
Section 5.4.6.5, talazoparib 
should also be placed on hold 
until toxicity is Grade 1 or 
baseline.

Continue as per schedule.

For suspected immune-related 
toxicities due to avelumab 
follow guidance in 
Section 5.4.6.5.


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Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related 
AEs)
Talazoparib
Avelumab
Grade 3 

Hold talazoparib.

Resume talazoparib reduced by 
1 dose level, per Section 5.4.6.2 if 
toxicity resolves to Grade 1 or 
baseline within 4 weeks.

Exceptions are:
Nausea, vomiting, or diarrhea 
lasting 72 hours; fatigue 
lasting <5 days; hypertension 
controlled with medical 
therapy; increase in indirect 
bilirubin indicative of 
Gilbert’s syndrome; serum 
lipase or amylase lasting 
7 consecutive days without 
clinical signs or symptoms of 
pancreatitis; endocrinopathies 
controlled with hormonal 
therapy; laboratory values 
that do not have any clinical 
correlate.

If the same Grade 3 toxicity 
recurs, reduce by 1 dose level.

Permanently discontinue if 
toxicity does not improve to 
Grade 1 or baseline within 4 
weeks.

Exceptions are:
Laboratory values that do not 
have any clinical correlate.

Permanently discontinue if 
Grade 3 liver test abnormality.  
Rechallenge may be considered 
once toxicity is Grade 1 or 
baseline, if an alternative cause 
for the abnormal liver tests (ALT, 
AST, total bilirubin) is identified. 

For suspected immune-related 
toxicities due to avelumab that 
require avelumab delay or 
discontinuation as per 
Section 5.4.6.5, talazoparib 
should also be placed on hold 
until toxicity is Grade 1 or 
baseline.

Hold avelumab.

Resume once toxicity is 
Grade 1 or baseline.

Permanently discontinue if 
toxicities does not resolve to 
Grade 1 or baseline within 
12 weeks or if the same 
Grade 3 toxicity recurs.

Exceptions are:
Laboratory values that do 
not have any clinical 
correlate.

For suspected immune-related 
toxicities follow guidance in 
Section 5.4.6.5.


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Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related 
AEs)
Talazoparib
Avelumab
Grade 4

Permanently discontinue 
talazoparib

Exceptions are:
Laboratory values that do not 
have any clinical correlate

Permanently discontinue 
avelumab

Exceptions are:
Laboratory values that do 
not have any clinical 
correlate. 

For suspected immune-related 
toxicities follow guidance in 
Section 5.4.6.5.
Abbreviations: AML=Acute Myeloid Leukemia; ANC=Absolute Neutrophil Count; MDS=Myelodysplastic 
Syndrome.
5.4.6.4. Treatment Modifications for Infusion-Related Reactions Associated with 
Avelumab
Recommended treatment modifications in case of avelumab infusion-related reactions are 
shown in Table 6.
Table 6.
Treatment Modification for Symptoms of Infusion-related Reactions 
Associated with Avelumab
NCI CTCAE Severity Grade
Treatment Modification
Grade 1 – mild

Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.

Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2 – moderate

Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, NSAIDs, 
narcotics, IV fluids; prophylactic medications 
indicated for 24 hours.

Temporarily discontinue avelumab infusion.

Resume avelumab infusion at 50% of previous 
rate once infusion-related reaction has resolved 
or decreased to at least Grade 1 in severity, and 
monitor closely for any worsening.a
Grade 3 or Grade 4 – severe or life-threatening

Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae.

Grade 4: Life-threatening consequences; urgent 
intervention indicated.

Stop the avelumab infusion immediately and 
disconnect infusion tubing from the patient.

Patients have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment.
a.
If avelumab infusion rate has been decreased by 50% due to an infusion reaction, it must remain 
decreased for the next scheduled infusion.  If no infusion reaction is observed at the next scheduled 
infusion, the infusion rate may be returned to baseline at subsequent infusions.
Abbreviations: NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs=nonsteroidal anti-inflammatory drugs; IV=intravenous.


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If, in the event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated above (including reducing the infusion rate by 
50%), the investigator may consider treatment with corticosteroids, and the infusion should 
not be resumed.  At the next dose, the investigator may consider the addition of H2 blocker 
antihistamines (eg, famotidine or ranitidine), meperidine, or ibuprofen to the mandatory 
premedication.  Prophylactic corticosteroids are not permitted.
5.4.6.5. Immune-Related Adverse Events Toxicity Management
For patients receiving avelumab, either as a single agent or in combination with talazoparib, 
any AE suspected to be immune-related (ie, an irAE) should be managed according to the 
guidance for management of irAEs (see Table 7) below. 
Treatment of irAEs is mainly dependent on severity (NCI CTCAE grade):

Grades 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring;

Grades 1 to 2 (persistent): manage similar to Grades 3 to 4 AE; 

Grades 3 to 4: treat with high dose corticosteroids; if suspected to be related to 
avelumab, talazoparib should be withhold until toxicity resolves to Grade 1 or 
baseline.
For Grade 3 immune-related toxicities suspected to be related to avelumab, talazoparib 
should be withheld until toxicity resolves to Grade 1 or baseline.
Table 7.
Management of Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of 
Diarrhea/Colitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1

Diarrhea: <4 stools/day 
over Baseline.

Colitis: asymptomatic.

Continue avelumab therapy.

Symptomatic treatment 
(eg, loperamide).

Close monitoring for worsening 
symptoms.

Educate patient to report 
worsening immediately.

If worsens, treat as Grade 2, 3 or 
4.
Grade 2 

Diarrhea: 4 to 6 stools 
per day over Baseline; 
IV fluids indicated
<24 hours; not 
interfering with ADL.

Colitis: abdominal pain; 
blood in stool.

Withhold avelumab therapy.

Symptomatic treatment.

If improves to Grade 1, resume 
avelumab therapy.

If persists >5-7 days or recurs, 
treat as Grade 3 or 4.


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Table 7.
Management of Immune-Related Adverse Events
Grade 3 to 4

Diarrhea (Grade 3):
7 stools per day over 
Baseline; incontinence; 
IV fluids 24 h; 
interfering with ADL.

Colitis (Grade 3):
severe abdominal pain, 
medical intervention 
indicated, peritoneal 
signs.

Grade 4:
life-threatening, 
perforation.

Withhold avelumab for Grade 3.

Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3.

1.0 - 2.0 mg/kg/day prednisone 
IV or equivalent.

Add prophylactic antibiotics for 
opportunistic infections.

Consider lower endoscopy.

If improves, continue steroids 
until Grade 1, then taper over at 
least 1 month; resume avelumab 
therapy following steroids taper 
(for initial Grade 3).

If worsens, persists >3 to 5 days, 
or recurs after improvement, add 
infliximab 5 mg/kg (if no 
contraindication).  
Note: infliximab should not be 
used in cases of perforation or 
sepsis
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1 to 2
Covering 30% body surface 
area.

Continue avelumab therapy.

Symptomatic therapy (for example, 
antihistamines, topical steroids).

If Grade 2 persists >1 to 
2 weeks or recurs, withhold 
avelumab therapy.

Consider skin biopsy.

Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent.  
Once improving, taper 
steroids over at least 
1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume avelumab therapy 
following steroids taper.

If worsens, treat as 
Grade 3 to 4.
Grade 3 to 4

Grade 3: Covering 
>30% body surface area.

Grade 4: Life 
threatening
consequences.

Withhold avelumab for Grade 3.

Permanently discontinue for Grade 4 
or recurrent Grade 3.

Consider skin biopsy.

Dermatology consult.

1.0 - 2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections.

If improves to Grade 1, 
taper steroids over at least 
1 month; resume avelumab 
therapy following steroids 
taper (for initial Grade 3).


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Table 7.
Management of Immune-Related Adverse Events
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only.

Consider withholding avelumab
therapy.

Monitor for symptoms every 
2 - 3 days.

Consider Pulmonary and Infectious 
Disease consults.

Re-assess at least every 
3 weeks.

If worsens, treat as Grade 2 
or Grade 3 to 4.
Grade 2
Mild to moderate new 
symptoms 

Withhold avelumab therapy.

Pulmonary and Infectious Disease 
consults.

Monitor symptoms daily; consider 
hospitalization.

1.0 - 2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections.

Consider bronchoscopy, lung biopsy.

Re-assess every 1 to 3 days.

When symptoms return to 
Grade 1, taper steroids over 
at least 1 month, and then 
resume avelumab  therapy 
following steroids taper.

If not improving after 
2 weeks or worsening, treat 
as Grade 3 to 4.
Grade 3 to 4

Grade 3: Severe new 
symptoms; 
New/worsening
hypoxia.

Grade 4:
Life-threatening.

Permanently discontinue avelumab 
therapy.

Hospitalize.

Pulmonary and Infectious Disease 
consults.

1.0 - 2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections.

Consider bronchoscopy, lung biopsy.

If improves to Grade 1, 
taper steroids over at least 
1 month.

If not improving after 
48 hours or worsening, add 
additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, 
IV immunoglobulin, or 
mycophenolate mofetil).
Hepatic irAEs
Grade of Liver Test 
Elevation
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1

Grade 1 AST or ALT 
>ULN to 3.0 x ULN.

and/or Total bilirubin 
>ULN to 1.5 x ULN.

Continue avelumab therapy.

Continue liver function 
monitoring.

If worsens, treat as Grade 2 
or 3 to 4.
Grade 2

AST or ALT >3.0 to
5 x ULN.

and/or total bilirubin
>1.5 to 3 x ULN.

Withhold avelumab therapy.

Increase frequency of monitoring to 
every 3 days.

If returns to Grade 1, 
resume routine monitoring; 
resume avelumab therapy.

If elevation persists >5 to 
7 days or worsens, treat as 
Grade 3 to 4.


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Table 7.
Management of Immune-Related Adverse Events
Grade 3 to 4

AST or ALT >5 x ULN.

and/or total bilirubin 
>3 x ULN.

Permanently discontinue avelumab 
therapy.

Increase frequency of monitoring to 
every 1 to 2 days.

1.0 - 2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections.

Consult gastroenterologist/ 
hepatologist.

Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted.

If returns to Grade 1, taper 
steroids over at least 1 
month.

If does not improve in >3 to 
5 days, worsens or rebounds, 
add mycophenolate mofetil 
1 gram (g) twice daily.

If no response within an 
additional 3 to 5 days, 
consider other 
immunosuppressants per 
local guidelines.
Renal irAEs
Grade of Creatinine 
Increased (NCI-CTCAE 
v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased 
>ULN to 1.5 x ULN.

Continue avelumab therapy.

Continue renal function 
monitoring.

If worsens, treat as Grade 2 to 
3 or 4.
Grade 2 to 3
Creatinine increased 
>1.5 and 6 x ULN.

Withhold avelumab therapy.

Increase frequency of monitoring to 
every 3 days.

Add prophylactic antibiotics for 
opportunistic infections.

Consider renal biopsy.

1.0-2.0 mg/kg/day prednisone or 
equivalent.

If returns to Grade 1, taper 
steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper.

If worsens, treat as Grade 4.
Grade 4
Creatinine increased 
>6 x ULN.

Permanently discontinue avelumab 
therapy.

Monitor creatinine daily.

Add prophylactic antibiotics for 
opportunistic infections.

Consider renal biopsy.

Nephrology consultation.

If returns to Grade 1, taper 
steroids over at least 1 month.


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Table 7.
Management of Immune-Related Adverse Events
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management

New onset of cardiac 
signs or symptoms.

and / or new laboratory 
cardiac biomarker 
elevations (eg, troponin, 
CK-MB, BNP).

or cardiac imaging 
abnormalities suggestive 
of myocarditis.

Withhold avelumab therapy.

Hospitalize.

In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and arrhythmia 
management.

Cardiology consult to establish 
etiology and rule-out 
immune-mediated myocarditis.

Guideline based supportive treatment 
as per cardiology consult.*

Consider myocardial biopsy if 
recommended per cardiology consult.

If symptoms improve and 
immune-mediated etiology is 
ruled out, re-start avelumab 
therapy.

If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology 
consult, manage as 
immune-mediated 
myocarditis.
Immune-mediated 
myocarditis.

Permanently discontinue avelumab.

Guideline based supportive treatment 
as appropriate as per cardiology 
consult.*

1.0-2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections.

Once improving, taper 
steroids over at least 1 
month.

If no improvement or 
worsening, consider 
additional 
immunosuppressants 
(eg, azathioprine, 
cyclosporine A).
*Local guidelines, or eg, ESC or AHA guidelines 
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I 
diabetes mellitus).

Continue avelumab therapy.

Endocrinology consult if needed.

Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.

Rule-out secondary endocrinopathies 
(ie, hypopituitarism / hypophysitis).

Continue hormone 
replacement/suppression 
and monitoring of endocrine 
function as appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I 
diabetes mellitus).

Withhold avelumab therapy.

Consider hospitalization.

Endocrinology consult.

Start thyroid hormone replacement 
therapy (for hypothyroidism), 

Resume avelumab once 
symptoms and/or laboratory 
tests improve to Grade 1 
(with or without hormone 
replacement/suppression).


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Table 7.
Management of Immune-Related Adverse Events
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.

Rule-out secondary endocrinopathies 
(ie, hypopituitarism / hypophysitis).

Continue hormone 
replacement/suppression 
and monitoring of endocrine 
function as appropriate.

Hypopituitarism.

Hypophysitis 
(secondary 
endocrinopathies).
If secondary thyroid and/or adrenal 
insufficiency is confirmed (ie, subnormal 
serum FT4 with inappropriately low TSH 
and/or low serum cortisol with 
inappropriately low ACTH):

Refer to endocrinologist for dynamic 
testing as indicated and measurement 
of other hormones (FSH, LH, 
GH/IGF-1, PRL, testosterone in men, 
estrogens in women).

Hormone replacement/suppressive 
therapy as appropriate.

Perform pituitary MRI and visual 
field examination as indicated.
If hypophysitis confirmed:

Continue avelumab if mild symptoms 
with normal MRI.  Repeat the MRI in 
1 month.

Withhold avelumab if moderate, 
severe or life-threatening symptoms 
of hypophysitis and/or abnormal 
MRI.

Consider hospitalization.  Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed by 
corticosteroids taper during at least 
1 month.

Add prophylactic antibiotics for 
opportunistic infections.

Resume avelumab once 
symptoms and hormone 
tests improve to Grade 1 
(with or without hormone 
replacement).

In addition, for hypophysitis 
with abnormal MRI, resume 
avelumab only once 
shrinkage of the pituitary 
gland on MRI/CT scan is 
documented.

Continue hormone 
replacement/suppression
therapy as appropriate.
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 
clinical signs or symptoms 
suggestive of a potential 
irAE.

Withhold avelumab therapy pending 
clinical investigation.

If irAE is ruled out, manage 
as appropriate according to 
the diagnosis and consider 
re-starting avelumab 
therapy.

If irAE is confirmed, treat as 
Grade 2 or 3 irAE.


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Table 7.
Management of Immune-Related Adverse Events
Grade 2 irAE or first 
occurrence of Grade 3 
irAE.

Withhold avelumab therapy.

1.0 - 2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections.

Specialty consult as appropriate.

If improves to Grade 1, 
taper steroids over at least 
1 month and resume 
avelumab therapy following 
steroids taper.
Recurrence of same 
Grade 3 irAEs.

Permanently discontinue avelumab 
therapy.

1.0 - 2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections.

Specialty consult as appropriate.

If improves to Grade 1, 
taper steroids over at least 
1 month.
Grade 4.

Permanently discontinue avelumab 
therapy.

1.0 - 2.0 mg/kg/day prednisone or 
equivalent and/or other 
immunosuppressant as needed.

Add prophylactic antibiotics for 
opportunistic infections.

Specialty consult.

If improves to Grade 1, 
taper steroids over at least 
1 month.
Requirement for 10 mg 
per day or greater 
prednisone or equivalent 
for more than 12 weeks 
for reasons other than 
hormonal replacement for 
adrenal insufficiency.
Persistent Grade 2 or 3 
irAE lasting 12 weeks or 
longer.

Permanently discontinue avelumab 
therapy.

Specialty consult.
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine 
kinase MB; CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; 
IGF-1=insulin-like growth factor 1; irAE=immune-related adverse event; IV=intravenous; LH=luteinizing 
hormone; MRI=magnetic resonance imaging; NCI-CTCAE=National Cancer Institute-Common 
Terminology Criteria for Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; 
ULN=upper limit of normal.
5.4.7. Treatment After Initial Evidence of Radiological Disease Progression
Immunotherapeutic agents such as avelumab, may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 


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If radiologic imaging shows disease progression, after discussion between the sponsor and 
investigator, patients may continue to receive investigational products at the investigator’s 
discretion if the following criteria are met: 

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression; 

No decline in ECOG performance status; 

Absence of rapid progression of disease by radiographic imaging; 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.
Before continuation of treatment, the patient must be re-consented via informed consent 
addendum and informed that in order to continue receiving the investigational products on 
study, the patient may be foregoing approved therapy with possible clinical benefit(s).
If the patient is subsequently found to have further disease progression at a subsequent tumor 
assessment, either radiologically according to Response Evaluation Criteria in Solid Tumors 
(RECIST v 1.1) or clinically, then treatment with investigational products should be 
permanently discontinued.
5.5. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements. 
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD, which is the IB, will be superseded by the storage 
conditions stated on the product labels.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure it is maintained in working order.


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Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions as described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined under the 
labeled storage conditions and not used until Pfizer provides permission to use the 
investigational product.  It will not be considered a protocol deviation if Pfizer approves the 
use of the investigational product after the temperature excursion.  Use of the investigational 
product prior to Pfizer approval will be considered a protocol deviation. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the investigational products are briefly out of the temperature range described in the labeling 
are not considered excursions.
Specific details regarding information the site should report for each excursion will be 
provided to the site in the Investigational Product Manual.
5.5.1. Avelumab Storage
Avelumab must be stored in the refrigerator at 2–8C (36–46F).  Do not freeze.  Protect 
from light.  Do not shake vigorously.  See the Investigational Product Manual for storage 
conditions of avelumab once diluted.
5.5.2. Talazoparib Storage
Talazoparib is stored at room temperature (15C–30C; 59F–86F) or per approved local 
label. 
Site staff will instruct patients on the proper storage requirements for take home 
investigational product, as talazoparib will be self-administered at home by patients.
5.6. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
All unused talazoparib must be returned to the investigator or designated investigative site 
personnel by each patient on Day 1 of every cycle and at the end of the trial in order to 
perform and document drug accountability.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.


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5.7. Concomitant Treatment
Concomitant treatment considered necessary for the patient’s well-being (ie, antiemetics, 
analgesics, megestrol acetate for anorexia) may be given at discretion of the treating 
physician.
All concomitant medications and treatments, including herbal supplements, supportive care 
drugs (eg, antiemetic treatment and prophylaxis), drugs used to treat adverse events or 
chronic diseases, blood products, and nondrug interventions (eg, paracentesis) will be 
recorded from 28 days prior to the start of study treatment (ie, the screening period) and up to 
90 days after the last dose of investigational product (ie, the Short Term Follow-Up 
Day 90 Visit).  If a patient begins a new anti-cancer therapy, reporting of concomitant 
medications should end at the time the new treatment is started. 
5.7.1. Supportive Care
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines and as deemed necessary by the treating investigator.
5.7.2. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors may be used to treat 
treatment-emergent neutropenia as indicated by the current American Society of Clinical 
Oncology (ASCO) guidelines.78
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines.  Erythropoietin or darbepoetin may be used at 
the investigator’s discretion for the supportive treatment of anemia.
Patients who enter the study on stable doses of erythropoietin or darbepoetin may continue 
this treatment, and patients may start either drug during the study at the discretion of the 
treating physician.
5.7.3. Anti-Diarrheal, Anti-Emetic Therapy
Primary prophylaxis of diarrhea, nausea and vomiting is permitted at the investigator’s 
discretion.  The choice of the prophylactic drug, as well as the duration of treatment, is up to 
the investigator and assuming the drug is not included in the Prohibited Concomitant 
Medications and Therapies section.

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.

Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 


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5.7.4. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered, as needed, assuming the drug is not 
included in the Prohibited Concomitant Medications and Treatments section (Section 5.7.10). 
5.7.5. Corticosteroids
Data indicate that corticosteroids have an adverse effect on T-cell function and that they 
inhibit and damage lymphocytes.79  Furthermore, as with all immunotherapies intended to 
augment cell-mediated immunity, there is a risk that concomitant immunosuppressives, such 
as steroids, will counteract the intended benefit of avelumab.  However, studies with 
anti-CTLA4 compounds indicate that short-term use of steroids can be employed without 
compromising clinical outcomes.81  Therefore, the use of steroids during this trial is restricted 
as follows while on avelumab treatment: 

Treatment of infusion-related reactions and irAEs, according to the modalities 
indicated in Section 5.4.6.4 and Section 5.4.6.5.

Steroid replacement for adrenal insufficiency at physiologic doses equivalent to 
10 mg prednisone daily is acceptable.

Prophylactic use prior to CT or magnetic resonance imaging (MRI). 

Intranasal, inhaled topical steroids, eye drops, or local steroid injection 
(eg, intra-articular injection) are allowed.
See Section 5.7.10 Prohibited Concomitant Medications for information detailing specific 
prohibited uses of corticosteroids.
5.7.6. Bisphosphonates or Denosumab 
Bisphosphonate or denosumab treatment is allowed and it will be given as per local practice.  
The need to initiate treatment with bisphosphonate or denosumab or to increase the dose of 
these therapies while on study treatment (for patients who started bisphosphonate or 
denosumab therapy >2 weeks before study enrollment), may be considered as a symptom of 
disease progression that should be confirmed radiologically.
5.7.7. Androgen Deprivation Therapy for Patients with CRPC
Patients with CRPC must receive androgen deprivation therapy with a GnRH 
agonist/antagonist or bilateral orchiectomy (medical or surgical castration).


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5.7.8. Concomitant Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and administration of investigational products
required to minimize the risk of impaired wound healing and bleeding has not been 
determined.  Stopping investigational products temporarily is recommended in case of a 
surgical procedure.  Postoperatively, the decision to reinitiate treatment with investigational 
products should be based on a clinical assessment of satisfactory wound healing and recovery 
from surgery.
5.7.9. Concomitant Radiotherapy
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions and 
other sites of disease if considered medically necessary by the treating physician, provided 
that the bony lesions and/or other sites of disease to be irradiated were present at the time of 
the screening tumor assessments and the investigator clearly indicates that the need for
palliative radiotherapy is not indicative of disease progression.  All attempts should be made 
to rule out disease progression in the event of increased localized pain. 
Study treatment should be withheld for the entire duration of palliative radiotherapy and can 
be restarted upon recovery from any radiotherapy-related toxicities, but no sooner than 
48 hours after radiotherapy completion.
5.7.10. Prohibited Concomitant Medications and Therapies
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Any anti-cancer systemic chemotherapy or biological therapy, including vitamins that 
are used as anti-cancer treatments, other than avelumab and talazoparib.

Immunotherapy not specified in this protocol. 

Radiation therapy (with the exception noted above in Section 5.7.8).

Any investigational agents other than avelumab and talazoparib.

Any vaccination for the prevention of infectious disease while on avelumab 
treatment, except for administration of inactivated vaccines. 

Herbal remedies with immunostimulating properties (eg, mistletoe extract) or known 
to potentially interfere with major organ function (eg, hypericin).

Prophylactic use of corticosteroids to prevent acute infusion-related reactions. 


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
Immunosuppressive drugs (ie, systemic corticosteroids) while on avelumab treatment, 
unless otherwise indicated for the treatment of irAEs or listed as an exception in 
Section 5.7.5. The following list of strong P-gp inhibitors that result in ≥2-fold 
increase in the AUC ratio of an in vivo probe P-gp substrate are prohibited: 
amiodarone, carvedilol, clarithromycin, cobicistat, dronedarone, erythromycin, 
glecaprevir, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, pibrentasvir, 
propafenone, quinidine, ranolazine, ritonavir, saquinavir, sofosbuvir, telaprevir, 
tipranavir, valspodar, velpatasvir, verapamil, and voxilaprevir. This list will be 
updated annually and reflected in the Talazoparib Investigator Brochure.

Caution and monitoring for potential increased adverse reactions should be used upon 
concomitant use of the following transporter inhibitors with talazoparib: atorvastatin, 
azithromycin, conivaptan, curcumin, cyclosporine, diltiazem, diosmin, eliglustat, 
elacridar [GF120918], eltrombopag, felodipine, flibanserin, fluvoxamine, piperine, 
quercetin, and schisandra chinensis extract. This list will be updated annually and 
reflected in the talazoparib Investigator Brochure.
If there is a clinical indication for one of the medications or vaccinations specifically 
prohibited during the trial, discontinuation from study treatment may be required.  The 
investigator should consult with the sponsor about individual cases.
There are no prohibited therapies during the Short-Term and Long-Term Follow-up Phases.
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see the Schedule of Activities and Section 7.
All screening activities must take place within 28 days prior to enrollment into the study, 
unless otherwise noted.
6.2. Treatment Period
For the treatment period procedures, see the Schedule of Activities and Section 7.  For the 
treatment period, where multiple procedures are scheduled at the same nominal time point(s) 
relative to dosing, the following prioritization of events should be adhered to:

Pharmacokinetic blood specimens – obtain at the scheduled time.

Blood pressure/pulse rate –obtain prior to blood specimen collection and prior to 
dose.

Clinical safety laboratory tests – must be performed pre-dose.

Other procedures – All other procedures should be performed as close as possible to 
the scheduled time, but may be obtained before or after blood specimen collection, 
unless sampling is determined by the study personnel to potentially impact the results. 


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6.3. Patient Withdrawal/End of Treatment
For the End of Treatment Visit procedures, see Schedule of Activities and Section 7.
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also 
Section 8.1.3) or behavioral reasons, or the inability of the patient to comply with the 
protocol-required schedule of study visits or procedures at a given study site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression.  However, patients with disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to 
continue study treatment, provided that the treating physician has determined that the 
benefit/risk for doing so is favorable (see Section 5.4.7 for details and exceptions); 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to one of the two 
investigational products, the investigator may continue treatment with the other 
investigational product;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.


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6.3.1. Withdrawal of Consent
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  If the patient withdraws from the study, and also withdraws consent for disclosure 
of future information, no further evaluations should be performed, and no additional data 
should be collected.  The sponsor may retain and continue to use any data collected before 
such withdrawal of consent. Patients should notify the investigator in writing of the decision 
to withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF page.  
In the event that vital status (whether the patient is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
6.3.2. Lost to Follow-up
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient and report their ongoing status.  This includes follow-up with persons authorized by 
the patient.  All attempts to contact the patient and information received during contact 
attempts must be documented in the patient’s medical record.  In any circumstance, every 
effort should be made to document patient outcome, if possible.  The investigator should 
inquire about the reason for withdrawal, request that the patient return all unused talazoparib, 
request that the patient return for a final visit, if applicable, and follow-up with the patient 
regarding any unresolved AEs. 
Lost to follow-up is defined by the inability to reach the patient after a minimum of 
2 documented phone calls, faxes, or e-mails as well as lack of response by the patient to 
1 registered mail letter.  If it is determined that the patient has died, the site will use locally 
permissible methods to obtain the date and cause of death.  The site staff and representative 
will consult publicly available sources, such as public health registries and databases, in 
order to obtain updated contact information.  If, after all attempts, the patient remains lost to 
follow-up, then the last-known-alive date as determined by the investigator should be 
reported and documented in the patient’s medical records.
6.4. Short-Term Follow-up Visits
For Short Term Follow-Up procedures, see Schedule of Activities (Table 1) and Section 7.  
All patients will be followed for safety every 30 days through 90 days after the last dose of 
study treatment or until the start of new anti-cancer treatment whichever occurs first.
Patients with ongoing treatment-related toxicity following discontinuation of study treatment 
will be followed at least every 4 weeks until resolution or determination, in the clinical 
judgment of the investigator, that no further improvement is expected.


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If the patient has withdrawn from study treatment for a reason other than disease progression, 
the patient should continue to undergo tumor assessments during the Short Term Follow-Up 
period as if they were still on therapy, regardless if they start on a new anti-cancer therapy.  
See the Schedule of Activities (Table 1) for the frequency of tumor assessments during 
Short-Term Follow-Up.
6.5. Long-Term Follow-up Visits 
After patients complete the Short Term Follow-Up period (90 days after the last dose of 
investigational product), patients will be followed for survival, independently of time of 
disease progression, and subsequent anti-cancer therapies every 12 weeks (14 days) until 
death, lost to follow-up, patient withdrawal of consent, or study discontinued by the sponsor, 
whichever comes first.  Contraception checks will be performed as applicable and for the 
duration described in Section 4.3. For Long Term Follow-Up procedures, see the Schedule 
of Activities (Table 1).  These visits may be conducted in-clinic or by remote contact (eg, 
telephone).
If the patient has withdrawn from study treatment for a reason other than disease progression, 
the patient should continue to undergo tumor assessments during the Long Term Follow-Up 
period as if they were still on therapy, regardless if they start on a new anti-cancer therapy.  
In these cases, survival status will be collected at the time of the scheduled tumor 
assessments, which may be more or less frequent than the Long-Term Follow-Up visits (See 
Schedule of Activities, Table 1) for timing of tumor assessments in Long-Term Follow-Up 
Visits).
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study.
7.1. Safety Assessments
Safety assessments will include, but are not limited to, collection of AEs, serious adverse 
events (SAEs), vital signs, physical examination, 12-lead electrocardiogram (ECG), and 
laboratory assessments, including pregnancy tests, and verification of concomitant 
treatments.  See the following sections regarding the specific safety assessments.


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7.1.1. Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL human chorionic gonadotropin (hCG) and must be performed by a certified 
laboratory.  For female patients of childbearing potential, 2 negative pregnancy tests are 
required before receiving study treatment (1 negative pregnancy test at screening and one at 
the baseline (Cycle 1 Day 1) visit immediately before study treatment administration).
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and the second negative pregnancy result will then be required at the baseline 
(Cycle 1 Day 1) visit before the subject may receive the study treatment. Pregnancy tests 
(serum or urine) will also be repeated on Day 1 of every cycle prior to dosing of either study 
drug during the active treatment period and at the End of Treatment visit to confirm that the 
patient has not become pregnant during the study.  Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed and when potential pregnancy is otherwise suspected, 
and may be repeated if requested by institutional review boards (IRBs)/ethics committees 
(ECs) or if required by local regulations.  In the case of a positive confirmed pregnancy, the 
patient will be withdrawn from administration of investigational products but may remain in 
the study only for Short-Term Follow-up and Long-Term Follow-up (see Sections 8.4.3 and 
8.4.4 for required pregnancy follow-up and safety reporting requirements and the Schedule of 
Activities (Table 1) for Short-Term and Long-Term Follow-Up procedures).
7.1.2. Contraception Check
Male patients who are able to father children and female patients who are of childbearing 
potential, who are, in the opinion of the investigator, sexually active and at risk for pregnancy 
with their partner(s), will need to affirm that they meet the criteria for correct use of 
contraception.  The investigator or his or her designee will discuss with the patient the need 
to use highly effective contraception consistently and correctly and document such 
conversation in the patient’s chart.  In addition, the investigator or his or her designee will 
instruct the patient to call immediately if one or both selected contraception methods are 
discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner 
(Section 4.3).
7.1.3. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by NCI 
CTCAE v 4.03), timing, seriousness, and relatedness. 
7.1.4. Laboratory Safety Assessments
Blood samples and urine samples for safety laboratory assessments will be collected at the 
time points described in the Schedule of Activities and analyzed at local laboratories.  The 
required safety laboratory tests are listed in Table 8.  Required safety laboratory tests 
including at a minimum: hematology (hemoglobin, platelets, and white blood cells), and 
chemistry (ALT, AST, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, 
sodium, potassium, and glucose) must be reviewed prior to study drug administration on 
Days 1 and 15 of each treatment cycle. 


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Table 8.
Required Safety Laboratory Tests 
Hematology
Chemistry 
Coagulationa
Urinalysisa
(Dispstick is 
acceptable) 
Pregnancy Test
Hemoglobin
ALT
INR 
Urine dipstick for 
urine protein: If 
positive collect a 
microscopic (Reflex 
Testing)
For female patients of 
childbearing 
potential, serum or 
urine with a 
sensitivity of at least 
25 mIU/mL
Platelets
AST
PTT or aPTT
WBC
Alkaline Phosphatase
Absolute Neutrophils
Sodium
Absolute Lymphocytes
Potassium
Absolute Monocytes
Magnesium
Urine dipstick for 
urine blood: If 
positive collect a 
microscopic (Reflex 
Testing)
Absolute Eosinophils
Chloride
Absolute Basophils
Total Calcium
Total Bilirubinb
Thyroid Function 
Tests:
BUN or Urea
TSH, Free T4
Creatinine
Uric Acid
Glucose (non-fasted)
Other Tests:
Albumin
ACTH
Phosphorus or 
Phosphate
HBV surface antigen
Total Protein
Anti-HCV antibody
Amylase
If Anti-HCV antibody 
test positive, then HCV 
RNA
Gamma Glutamyl 
Transferase (GGT)
Testosterone (at 
screening only for 
CRPC patients)
Creatine Kinase
C-reactive Protein 
(CRP)
Lactate Dehydrogenase 
(LDH)
Lipase
Abbreviations used in the table: ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, CRPC=castration-resistant prostate cancer, 
GGT=gamma-glutamyltransferase, HBV=hepatitis B virus, HCV=hepatitis C virus, INR=international normalized ratio, 
LDH=lactate dehydrogenase,  PTT=partial thromboplastin time, aPTT=activated partial thromboplastin time, 
RNA=ribonucleic acid, TSH=thyroid-stimulating hormone, WBC=white blood cell.
a Required at screening then to be performed as clinically indicated.
b For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, creatine
kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, INR international normalized ratio, 
alkaline phosphatase, total bile acids and acetaminophen drug and/or protein adduct levels.
7.1.5. Physical Examinations and Vital Signs
Patients will have full physical examination at screening.  Subsequent visits will include 
major body systems (focused and/or as clinically indicated), vital signs, assessment of ECOG 
performance status (see Appendix 2), weight and height (height will be measured at 
screening only) at the time points described in Schedule of Activities (Table 1).


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Vital signs, to include blood pressure, pulse rate and temperature will be also recorded at the 
time points described in the Schedule of Activities (Table 1).  Vitals signs should be taken 
prior to administration of any investigational products at the visit. 
7.1.6. (12-Lead) Electrocardiograms
A standard 12 lead (with a 10 second rhythm strip) tracing will be used for all ECG 
assessments.
All patients require a single ECG measurement at baseline.  Thereafter, on treatment ECGs 
will be performed as clinically indicated. 
Clinically significant findings seen on subsequent ECGs should be recorded as adverse 
events.  In case of QTc >500 msec, a subsequent ECG should be repeated to verify the result.  
If ECG is confirmed >500 msec, local guidelines (eg, Repeat ECGs, review by cardiologist) 
should be followed.
7.2. Pharmacokinetics Assessments
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, the exact time of the sample collection will always be noted on the CRF.  
For samples where nominal time coincides with end of infusion, a sample collected within 
10 minutes post end of infusion will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF).  If a scheduled blood sample collection cannot be completed for any reason, the 
missed sample time may be re-scheduled with agreement of clinical investigators, patient and 
sponsor.  PK sampling schedule may be modified based on emerging PK data.
PK samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures (SOPs).
Details regarding the collection, processing, storage and shipping of the PK blood samples 
will be provided to the investigator site prior to initiation of the trial.  The samples must be 
processed and shipped as indicated to maintain sample integrity.  Any deviations from the 
processing steps (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulted in compromised sample integrity, will be considered a protocol deviation.
 
 
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7.2.1. Blood for PK Analysis of Avelumab
Blood samples (3.5 mL whole blood at each time point) will be collected for PK analysis of 
avelumab, as outlined in the Schedule of Activities (Table 2).  Pre-dose avelumab PK 
samples will be collected within 1 hour prior to taking talazoparib dose.  The post-dose 
avelumab PK samples should be taken within 10 minutes after the avelumab infusion ends, 
Blood for PK samples will be drawn from the contralateral arm of the drug infusion.  Please 
refer to the Laboratory Manual for instructions for specific details on collection tubes, 
processing and shipping.
7.2.2. Blood for PK Analysis of Talazoparib
Blood samples (3 mL whole blood at each time point) will be collected for PK analysis of 
talazoparib as outlined in the Schedule of Activities (Table 2).  Pre-dose talazoparib PK 
samples will be collected within 1 hour prior to taking talazoparib dose.  The post-dose 
talazoparib PK samples should be taken within 10 minutes after the avelumab infusion ends, 
corresponding to approximately 2 hours after talazoparib dosing.  Please refer to the 
Laboratory Manual for instructions for specific details on collection tubes, processing and 
shipping.
7.3. Immunogenicity Assessments
Blood samples (3.5 mL whole blood) will be collected for assessment of avelumab 
Anti-Drug Antibodies (ADAs), as outlined in the Schedule of Activities (Table 2).  Predose 
ADA samples will be collected within 2 hours prior to talazoparib dosing.  Please refer to the 
Laboratory Manual for instructions for specific details on collection tubes, processing and
shipping. 
For all patients, blood for ADA samples will be drawn from the contralateral arm of the 
avelumab infusion.
Immunogenicity blood samples will be assayed for ADA using a validated assay in 
compliance with Pfizer standard operating procedures.  The sample analysis will follow a 
tiered approach of screening, confirmation, and titer determination.  Samples tested positive 
for ADA may be further analyzed for Nab using a validated assay in compliance with Pfizer 
standard operating procedures.  Additional details regarding the collection, processing, 
storage, and shipping of the blood samples will be provided in the Laboratory Manual to 
maintain sample integrity.  Any deviations from the processing steps (eg, sample collection 
and processing steps, interim storage or shipping conditions), including any actions taken, 
must be documented and reported to the sponsor.  On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any deviation 
from the specified sample handling procedure resulted in compromised sample integrity, will 
be considered a protocol deviation.
 
 
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7.4. Biomarker and Pharmacodynamic Assessments
The key objectives of the biomarker analyses that will be performed in this study are to:
•
Centrally confirm BRCA1, BRCA2 and ATM gene defects;
•
Assess the utility of ctDNA as an alternative to tissue based testing for selection of 
patients with BRCA1, BRCA2 and ATM defects;
•
Investigate candidate biomarkers in baseline tissue, ctDNA and blood that may have 
predictive value in identifying those patients, within the eligible population for this 
study, who are most likely to benefit from treatment with the combination of 
avelumab and talazoparib;
•
Investigate candidate biomarkers in on treatment and post treatment tissue and blood 
samples that will help to confirm the mechanism of action and/or resistance for the 
combination. 
Candidate biomarkers to be investigated include, but may not be limited to:
•
PD-L1 expression on tumor and infiltrating immune cells measured by 
immunohistochemistry (IHC);
•
Tumor mutational burden and loss of heterozygosity;
•
Presence of mutations in key oncogenes;
Information about PD-L1 expression will be collected at Screening, as part of patient’s 
cancer history, for all patients with prior available results. 
7.4.1. Tumor Tissue Samples
7.4.1.1. Pretreatment Tumor Tissue Samples
All patients must provide formalin-fixed paraffin-embedded (FFPE) tumor tissue as outlined 
in one of the options below. Availability of tumor tissue sample must be confirmed during 
screening prior to enrollment, and sample must be sent within 28 days after enrollment.
C
C
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C
C
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C
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Note that in all cases where slides are provided, positively-charged glass slides should be 
used and the slides generated should contain tumor tissue sections that are 4-5 microns thick 
and the slides should not be stained or baked.  All tumor tissue sections provided should 
ideally measure 5×5 mm and must contain 40% or greater tumor nuclei.
Where local or regional regulations prevent submission of FFPE tissue blocks, the requisite 
number of slides indicated below generated from the indicated block may be provided.
Option 1
For patients whose 
local BRCA/ATM test 
was conducted on a 
tissue sample collected 
24 months prior to 
enrollment, where the 
sample is still available 
and sufficient to 
provide at least 
20 slides
The following tissue should be provided from the same sample 
used to derive the historic test result that supported study 
eligibility:

An original (not recut) H&E slide together with a block 
containing sufficient tumor tissue to generate at least 20, but 
preferably 25 slides.

Where an older archive block (ie, collected >24 months prior 
to enrollment) is also available, this block should also be 
submitted if it contains sufficient tumor tissue to generate at 
least 10 slides.
Option 2
For patients whose 
local BRCA/ATM test 
was conducted on a 
tissue sample collected 
24 months prior to 
enrollment, where the 
sample is still available 
and sufficient to 
provide at least 15, but 
less than 20 slides.
OR
For patients whose 
local BRCA/ATM test 
was conducted on a 
tissue sample collected 
>24 months prior to 
enrollment, where the 
sample is still available 
and sufficient to 
provide at least 
15 slides.
The following tissue should be provided from the same sample 
used to derive the historic test result that supported study 
eligibility:

An original (not recut) H&E slide together with a block 
containing sufficient tumor tissue to generate at least 
15 slides.

An additional block should also be submitted, from a second 
sample collected 24 months prior to enrollment, containing 
sufficient tumor tissue to generate at least 5, but preferably 
10 slides.

Where an older archive block (ie, collected >24 months prior 
to enrollment) is also available, this block should also be 
submitted if it contains sufficient tumor tissue to generate at 
least 10 slides.


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Option 3
For patients whose 
local BRCA/ATM test 
was conducted on a 
tissue sample that is no 
longer available, or is 
insufficient to provide 
at least 15 slides.
OR
For patients whose 
local BRCA/ATM test 
was conducted on 
germline DNA.
The following tissue should be provided from a tissue sample 
collected 24 months prior to enrollment:

An original (not recut) H&E slide together with a block 
containing sufficient tumor tissue to generate at least 20, but 
preferably 25 slides.

Where an older archive block (ie, collected >24 months prior 
to enrollment) is also available, this block should also be 
submitted if it contains sufficient tumor tissue to generate at 
least 10 slides.
In all instances above, when no tissue sample collected within 24 months prior to study 
enrollment is available, a core biopsy from a locally recurrent or metastatic tumor site (that is 
not the only RECIST v1.1 target lesion) must be performed during screening to provide a 
FFPE tumor tissue block or the required number of slides specified above.  The biopsy is to 
be performed using a minimum 18 gauge needle, in order to maximize the quality and value 
of obtained tissue.  A minimum of 3 separate cores are requested for each biopsy procedure.  
Tissue derived from cytologic sampling cannot be submitted.
For non-prostate cancer patients, if a tissue sample collected within 24 months from study 
enrollment is not available, and no lesion that can be biopsied outside of bone is present, 
tumor tissue collected within 5 years prior to study enrollment may be provided. 
For prostate cancer patients, if a tissue sample collected within 24 months from study 
enrollment is not available, and no lesion that can be biopsied outside of bone is present, then 
fresh bone biopsies are acceptable. In other instances, tissue from bone biopsies should not 
be submitted. 
See the Laboratory Manual for additional details on the handling of tissue samples including 
processing, storage, and shipment. 
7.4.1.2. On Treatment and End of Treatment Tissue Samples
In addition to the pre-treatment tumor tissue described above, tumor tissue is requested 
(optional) for those patients who undergo a biopsy or tumor resection as part of routine 
clinical care at any time during the treatment period.  In addition, every effort should be 
made to perform a tumor biopsy at the time of RECIST v1.1 confirmed disease progression 
(for all patients except mCRPC) or PCWG3 confirmed disease progression (for mCRPC 
patients only) if a patient discontinues study treatment due to disease progression, except in 
instances where the procedure, as performed in the clinical research setting, poses an 
unacceptable risk to the patient.  A 14-day window is permitted.


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These samples will be used to assess one or more of the biomarkers listed above in 
Section 7.4, with the aim of determining mechanisms of response and resistance to treatment.
See the Laboratory Manual for additional details on the handling of all tissue samples 
including processing, storage, and shipment.
7.4.2. Peripheral Blood Samples
As described in the Schedule of Activities, the following blood samples and subsequent 
analyses will be conducted:  
 
•
Blood sample (20 mL whole blood for processing to plasma) will be collected before, 
during and at the end of treatment, for isolation of circulating tumor DNA (ctDNA).  
This sample will be used to analyze genetic biomarkers, including defects in 
BRCA 1/2 and ATM and TMB that may relate to response to resistance to treatment;
 
 
 
•
A single blood sample (4 mL whole blood) will be collected before treatment and 
processed to generate genomic DNA.  DNA will be used to assess potential 
epigenetic or genetic biomarkers that may relate to response to treatment, including 
the presence of germline defects in BRCA1, BRCA2 and ATM.
 
 
 
 
 
 
 
C
C
I
C
C
I
C
C
I
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7.6. Tumor Response Assessment
Tumor response assessments are dependent upon the patient’s tumor type.  All tumor types, 
except mCRPC, will perform tumor assessments, as per the requirements described in this 
section.  For tumor response assessments that are unique for patients with mCRPC, see 
Section 7.6.1.
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen and pelvis CT or MRI scans.  Baseline Brain CT or MRI scan is required for 
all patients at baseline (Screening); patients with stable brain metastases present at baseline 
(Screening) will continue to have brain CT or MRI scans performed at each tumor 
assessment.  Otherwise, brain CT or MRI imaging is required only when clinically indicated
if new brain metastases are suspected. 
Bone scans (preferred method) or 18-fluorodeoxyglucose positron emission tomography 
(18F- FDG-PET)/CT or MRI is required for all patients at baseline (Screening).  If bone 
metastases are present at baseline (screening), then repeat bone imaging is required every 
16 weeks for the first 52 weeks of study treatment and every 24 weeks thereafter.  Otherwise, 
bone imaging is required only if new bone metastases are suspected.  Bone imaging is also 
required at the time of confirmation of CR for patients who have bone metastases. 
CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons.  The same imaging technique used to characterize each identified and 
reported lesion at baseline (Screening) will be employed in the following tumor assessments. 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline (Screening), during treatment every 8 weeks for 52 weeks from the start of the study 
treatment, and then every 16 weeks thereafter until documented confirmed disease 
progression by BICR assessment regardless of initiation of subsequent anti-cancer therapy, as 
specified in the Schedule of Activities (Table 1).  In addition, radiological tumor assessments 
will also be conducted whenever disease progression is suspected (eg, symptomatic 
deterioration), and at the time of withdrawal from treatment (if not done in the previous 
4 weeks and the prior response is other than confirmed PD).  
Timing of disease assessment should follow calendar days and should not be adjusted for 
delays in cycle starts.  
In case CR or PR is observed, tumor assessments must be confirmed on repeated imaging at 
least 4 weeks after initial documentation.  The allowable time window for tumor assessments 
is 7 days.  
Assessment of response will be made using RECIST v1.1 (see Appendix 3) as assessed by 
BICR and investigator.  Measurable or evaluable lesions that have been previously irradiated 
will not be considered target lesions unless progression of such lesions has been observed 
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Details of treatment after initial evidence of radiological disease progression are provided in 
Section 5.4.7.
Expedited Blinded Independent Central Review for Disease Progression
Since the primary endpoint of the study is OR based on BICR assessment (CR or PR per 
RECIST v1.1 from the first dose of study treatment until disease progression), expedited 
BICR review will be performed for investigator-assessed disease progression. Upon 
investigator-assessed disease progression, all radiographic images collected for a patient 
from screening onwards will be submitted to the BICR for expedited review. See the Study 
Manual for process details. Every effort should be made to keep the patient on study 
treatment until the BICR has completed the radiographic image review, unless 
contraindicated by the investigator.
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.  
Management of incidental findings 
An incidental finding is one unknown to the patient that has potential health or reproductive 
importance, which is discovered unexpectedly in the course of a research study, but is 
unrelated to the purpose and beyond the aims of the study.  Radiographic images will be 
reviewed by a central review facility. 
The purpose of this review is to evaluate images for BICR.  Central image review is not a 
complete medical review of the subject and no incidental findings will be shared with the 
principal investigator, site staff, or the patient.  All safety reviews will be the sole 
responsibility of site staff. 
7.6.1. mCRPC Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging is categorized 
as soft tissue (including nodes, viscera and prostate/prostate bed [primary site]) or bone.  Soft 
tissue imaging may include CT scans of the chest, abdomen and pelvis or MRIs of the 
abdomen and pelvis.  Bone imaging must be whole body radionuclide bone scan 
(scintigraphy).  Bone scans and brain CT or MRI scans are required for all patients at 
baseline (Screening).  Patients with stable brain metastases present at baseline (Screening) 
will continue to have brain CT or MRI scans performed at each tumor assessment.  
Otherwise, brain CT or MRI imaging is required only when clinically indicated if new brain 
metastases are suspected. 
CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons.  The same imaging technique used to characterize each identified and 
reported lesion at baseline (Screening) will be employed in the following tumor assessments. 


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Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline (Screening), during treatment every 8 weeks for 24 weeks from the start of the study 
treatment, and then every 12 weeks thereafter until disease progression regardless of 
initiation of subsequent anti-cancer therapy, as specified in the Schedule of Activities
(Table 1), whenever disease progression is suspected (eg, symptomatic deterioration), and at 
the time of withdrawal from treatment (if not done in the previous 4 weeks and the prior 
response is other than confirmed PD).  Timing of disease assessment should follow calendar 
days and should not be adjusted for delays in cycle starts. 
Assessment of response will be made using RECIST v1.1 (see Appendix 3).  The investigator 
will assess response of soft tissue disease by RECIST v1.1.  Bone disease will not be 
considered as non-target lesions assessed by RECIST v1.1, but will be assessed for 
progressive disease by PCWG3.64  The documentation required for the determination of 
radiographic progression is shown in Appendix 4. 
An objective response is defined as a best overall response of CR or PR per RECIST v1.1 
and must be confirmed on repeated imaging at least 4 weeks after initial documentation.  
Disease progression in bone disease must be confirmed at least 6 weeks later, as per PCWG3.  
The allowable time window for tumor assessments is 7 days.  See Appendix 4 for the 
timing of confirmatory imaging requirements.
Other requirements for tumor assessment management that are not unique to mCRPC, 
including BICR expedited review and treatment after initial evidence of radiological disease 
progression, are  to be followed as per Section 7.6. 
7.7. Blood Tests for Tumor Markers and Circulating Tumor Cells
7.7.1. CA-125 for Patients with Ovarian Cancer
For patients with ovarian cancer, blood will be collected at the time points described in the 
Schedule of Activities (Table 1) and analyzed at local laboratories for cancer antigen 
125 (CA-125) testing.
7.7.2. Prostate-Specific Antigen for Patients with mCRPC
For patients with mCRPC, blood will be collected at the time points described in the 
Schedule of Activities (Table 1) and analyzed at local laboratories for prostate-specific 
antigen (PSA).
7.7.3. Circulating Tumor Cells (CTCs) for Patients with mCRPC
For patients with mCRPC, blood will be collected at the time points described in the 
Schedule of Activities (Table 1) and analyzed at the central laboratory to allow quantitation 
of CTCs. 


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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer Safety 
Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the investigational 
product under study during 
pregnancy or breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), except 
occupational exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of suspected causal relationship to the 
investigational product(s) will be reported as described in the following paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
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For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient 
Withdrawal/End of Treatment section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.


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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 90 calendar days after the last administration of the investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, the recording period for non-serious AEs ends 
at the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 


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investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);


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
Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);


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
Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 


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8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede total bilirubin (TBili) 
elevations (>2 × ULN) by several days or weeks.  The increase in TBili typically occurs 
while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same lab sample).  In rare instances, by the time TBili elevations are 
detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller);

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.


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The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered and assessed by radiological methods 
as indicated. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. All cases demonstrated on repeat testing as meeting the 
laboratory criteria of AST/ALT and TBili elevation defined above should be considered 
potential DILI (Hy’s law) cases if no other reason for the liver function test (LFT) 
abnormalities has yet been found.  Such potential DILI (Hy’s law) cases are to be reported as 
SAEs, irrespective of availability of all the results of the investigations performed to 
determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.4. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;


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
An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 


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Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.
8.4.4.1. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.4.2. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.5. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer Safety 
Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.5.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving patient exposure to the investigational product;


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
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
This section describes the data analysis and statistical methods for each of the cohorts 
evaluated in this study and are further detailed in a statistical analysis plan (SAP), which will 
be maintained by the sponsor. The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Analysis Sets 
9.1.1. Full Analysis Set
The full analysis set includes all enrolled patients who receive at least 1 dose of study 
treatment.  Patients will be classified according to the cohort assigned at enrollment.
9.1.2. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least 1 dose of study 
treatment.  In this non-randomized study, the full analysis set and the safety analysis set are 
identical.
9.1.3. Pharmacokinetics Analysis Sets
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least 1 concentration above the lower limit of quantitation (LLQ) for 
avelumab or talazoparib.
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least 1 of the PK parameters of interest for avelumab or talazoparib.
9.1.4. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least 1 ADA/Nab sample collected for avelumab.


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9.1.5. Biomarker Analysis Sets
The biomarker analysis set includes all patients in the safety analysis set who have at least 
1 screening biomarker assessment.  Analysis sets will be defined separately for blood-based 
and tumor tissue-based biomarkers. 
 
 
9.2. Sample Size Determination
The primary endpoint is confirmed OR in patients with locally advanced or metastatic solid 
tumors with BRCA 1/2 or ATM defect, as assessed by BICR using RECIST v1.1 and, in 
patients with mCRPC, RECIST v1.1 and PCWG3. 
Up to approximately 150 patients will be enrolled in Cohort 1 and 50 patients in Cohort 2.  
Thus, a total of approximately 200 patients will be enrolled. 
With 150 and 50 treated patients in Cohort 1 and Cohort 2, respectively, ORR can be 
estimated with a maximum standard error of 0.041 and 0.071, respectively.  Assuming a beta 
(0.5, 0.5) prior:
•
Cohort 1: if 66 responders (out of 150 patients, ORR of 44%) are observed, the 
posterior probability of a true ORR ≥40% (considered a clinically relevant effect) will 
be ≥0.80 (0.841);
•
Cohort 2: if 23 responders (out of 50 patients, ORR of 46%) are observed, the 
posterior probability of a true ORR ≥40% (considered a clinically relevant effect) will 
be ≥0.80 (0.807).
Table 9 provides the exact 95% confidence intervals for ORR based on different observed 
number of responders in a given tumor type cohort. 
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Table 9.
Sample Size and Exact 95% Confidence Intervals for ORR
N per Cohort
Number of Responders
Observed ORR
Exact 95% CI for ORR
50
20
40%
26.4% - 54.8%
23
46%
31.8% - 60.7%
25
50%
35.5% - 64.5%
27
54%
39.3% - 68.2%
28
56%
41.3% - 70.0%
30
60%
45.2% - 73.6%
32
64%
49.2% - 77.1%
35
70%
55.4% - 82.1%
150
60
40%
32.1% - 48.3%
66
44%
35.9% - 52.3%
75
50%
41.7% - 58.3%
83
55%
47.0% - 63.4%
90
60%
51.7% - 67.9%
98
65%
57.1% - 72.9%
105
70%
62.0% - 77.2%
CI=confidence interval; ORR=objective response rate.
9.3. Efficacy Analysis
All efficacy analyses will be performed based on the full analysis set, separately by cohort 
and for both cohorts combined.
9.3.1. Analysis of the Primary Endpoint
The primary endpoint is confirmed OR by BICR assessment. 

For patients with solid tumors, except mCRPC: 
Objective response (OR) is defined as a CR or PR per RECIST v1.1 from the first dose of 
study treatment until disease progression or death due to any cause.  Both CR and PR must 
be confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.  ORR is defined as the proportion of patients with a confirmed CR or 
PR according to RECIST v1.1.  Confirmed responses are those that persist on repeat tumor 
assessments for at least 4 weeks after initial documentation or response.  Otherwise, the 
patient will be counted as a non-responder in the assessment of ORR.  Additionally, patients 
with inadequate data for tumor assessment (eg, no baseline assessment or no follow-up 
assessments) will be considered as non-responders in the assessment of ORR.  The 2-sided 
exact 95% CIs for ORR will be calculated.

For patients with mCRPC: 
Objective response (OR) is defined as the proportion of patients with a best overall soft tissue 
response of CR or PR per RECIST v1.1 from the first dose of study treatment until disease 
progression or death due to any cause.  Soft tissue responses will be confirmed by a 
follow-up radiographic assessment at least 4 weeks later with a repeated CT or MRI with no 
evidence of confirmed bone disease progression per PCWG3 criteria.  The radiographic 
assessment of soft tissue disease will use RECIST v1.1 (see Appendix 3), and bone disease 
will be evaluated per PCWG3 (see Appendix 4).


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9.3.2. Analysis of the Secondary Endpoints
Objective response (OR) based on investigator assessment will also be summarized as 
described in Section 9.3.1.  The secondary endpoints TTR, DR, and PFS will be summarized 
separately based on BICR assessments and based on investigator assessment.
For patients with solid tumors, except mCRPC:

TTR is defined for patients with confirmed objective response (CR or PR) as the time 
from the first dose of study treatment to the first documentation of objective tumor 
response;

DR is defined for patients with confirmed objective response (CR or PR) as the time 
from the first documentation of objective tumor response to the first documentation of 
objective tumor progression or to death due to any cause, whichever occurs first.  
Censoring for DR will follow that described below for PFS;

PFS is defined as the time from the first dose of study treatment to the date of disease 
progression by RECIST v1.1 or death due to any cause, whichever occurs first.  PFS 
data will be censored on the date of the last adequate tumor assessment for patients 
who do not have an event (PD or death), for patients who start new anti-cancer 
treatment prior to an event, or for patients with an event after 2 or more missing 
tumor assessments.  Patients who do not have a baseline tumor assessment or who do 
not have any post-baseline tumor assessments will be censored on the date of first 
dose of study treatment unless death occurred on or before the time of the second 
planned tumor assessment in which case the death will be considered an event;

OS is defined as the time from the first dose of study treatment to the date of death.  
Patients without an event (death) will be censored at the date of last contact;

TTR will be summarized using simple descriptive statistics (eg, median and range).  
DR, PFS, and OS will be analyzed using Kaplan-Meier methods and descriptive 
statistics.  Point estimates will be presented with 95% CIs.  In addition, progression 
date, death date, date of first response, and last tumor assessment date will be listed, 
along with Best Overall Response (BOR), TTR, DR, PFS and OS.
For patients with mCRPC:

TTR is defined as the time from the first dose of study treatment to the first objective 
evidence of soft tissue response with no evidence of confirmed bone disease 
progression on bone scan per PCWG3.  Soft tissue response is defined as a BOR of 
CR or PR per RECIST v1.1.  The response must be confirmed at least 4 weeks later 
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
DR is defined for patients with confirmed objective response (CR or PR) as the time 
from the first objective evidence of soft tissue response (subsequently confirmed) per 
RECIST v1.1 and no evidence of confirmed bone disease progression by PCWG3 to 
the first subsequent objective evidence of radiographic progression or death due to 
any cause, whichever occurs first.  Radiographic progression is defined as soft tissue 
progression evaluated per RECIST v1.1 or bone disease progression evaluated per 
PCWG3 (see Appendix 4); 

PFS is defined as the time from the first dose of study treatment to documentation of 
radiographic progression in soft tissue evaluated per RECIST v1.1, in bone evaluated 
per PCWG3, or death, whichever occurs first (see Appendix 4).  Details associated 
with censoring will be presented in the SAP;

PSA response is defined as the proportion of patients with confirmed PSA decline 
50% compared to baseline.  PSA response will be calculated as a decline from 
baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50%.  A PSA 
response must be confirmed by a second consecutive value at least 3 weeks later.  The 
proportion of patients with confirmed PSA decline 50% compared with baseline will 
be calculated along with 95% Cis; 

Time to PSA progression is defined as the time from the first dose to the date that a 
25% increase in PSA with an absolute increase of 2 g/L (2 ng/mL) above the 
nadir (or baseline for patients with no PSA decline) is documented, confirmed by a 
second consecutive PSA value obtained 3 weeks (21 days) later.  Details associated 
with censoring will be presented in the SAP;

OS is defined as the time from the first dose of study treatment to the date of death.  
Patients without an event (death) will be censored at the date of last contact;

TTR will be summarized using simple descriptive statistics (eg, median and range).  
DR, PFS, time to PSA progression and OS will be analyzed using Kaplan Meier 
methods and descriptive statistics.  Point estimates will be presented with 95% Cis;

CTC count conversion is defined as a decrease in CTC count from 5 CTC per 
7.5 mL of blood at baseline to <5 CTC per 7.5 mL of blood anytime on study. CTC0, 
defined as a decrease in CTC count from 1 CTC per 7.5 mL to an undetectable level 
anytime on study, will also be reported.  The proportion of patients with CTC count 
conversion and CTC0 will be calculated along with 95% CIs.
For patients with ovarian cancer:

CA-125 response is defined as at least a 50% reduction in CA-125 levels from 
baseline.  The response must be confirmed and maintained for at least 28 days.  The 
proportion of patients with CA-125 response will be calculated along with 2-sided 
exact 95% CIs. 


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9.4. Analysis of Pharmacokinetics and Pharmacodynamics 
9.4.1. Analysis of Pharmacokinetics of Investigational Products
Pharmacokinetic data analyses will include pre-dose and post-dose sampling for serum 
avelumab and plasma talazoparib concentrations on Days 1 and 15 of Cycle 1 and on Day 1 
of Cycle 3 for both talazoparib and avelumab, and additionally on Day 1 of Cycles 6, 12, 18, 
and 24 for avelumab only.  PK data analyses will include descriptive summary statistics of 
the pre-dose/trough (Ctrough) concentrations for both investigational products and post-dose 
(for talazoparib) or maximum (Cmax) concentrations (for avelumab) for each cycle.  Other PK 
parameters may be determined if deemed appropriate.  Additional summary statistics will be 
presented for avelumab across all treatment groups by study phase as well as combined 
across both study phases.  For talazoparib, summary statistics will also be presented 
combined for all patients.  The summary data will be compared with the historical data of 
avelumab and talazoparib as single agents to assess the effect of avelumab on the PK of 
talazoparib and the effect of talazoparib on the PK of avelumab. 
The pre-dose/trough and post-dose/Cmax concentrations for avelumab and talazoparib will be 
plotted using box whisker plots by cycle and day within cycle for the subsets of data 
corresponding to the summary statistics described above.
9.4.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/Pharmacodynamic) Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies investigating 
avelumab and/or talazoparib to: 1) further assess the effect of talazoparib on the PK of 
avelumab and/or avelumab on the PK of talazoparib, and 2) explore any association between 
study drug exposure and biomarkers or significant safety endpoints.  If performed, the details 
of these analyses will be outlined in a separate pharmacometric analysis plan (PMAP).  The 
results of these analyses, if performed, may be reported separately.
9.4.3. Analysis of Biomarker Secondary 
 Endpoints
All analyses of biomarkers will be performed based on the biomarker analysis set, separately 
by cohort and pooled across cohorts.
Biomarker data will include baseline and on-treatment/end of treatment levels of and changes 
in biomarkers including, but not limited to, centrally assessed defects in BRCA1, BRCA2 
and ATM in tumor tissue and ctDNA, PD-L1 expression, and TMB in tumor tissue, TMB in 
ctDNA, germline defects in BRCA1, BRCA2 and ATM.  Tumor mutational burden (TMB), 
is defined as the total number of mutations in the tumor genome, or number of mutations per 
megabase of DNA if derived from targeted sequencing.
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate.  
Appropriate change from baseline measurements will be provided. 
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For discrete measurement biomarkers (eg, tumor marker status), frequencies and percentages 
of categorical biomarker measures will be determined at baseline and 
on-treatment/post-treatment time points, as appropriate; shift tables may also be provided.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Fisher’s exact test, Wilcoxon rank-sum test, Kaplan-Meier estimates, and 
linear regression as appropriate.  The statistical approaches will explore the correlations of 
biomarker results with pharmacokinetic parameters and measures of efficacy, such as tumor 
response and progression free survival.
9.4.4. Analysis of Immunogenicity Data of Avelumab
ADA/Nab data for avelumab will be listed and summarized. 
The percentage of patients with positive ADA and Nabs each will be summarized by cohort 
and, if deemed appropriate, combined across all cohorts.  For patients with positive ADA, the 
magnitude (titer), time of onset, and duration of ADA response will also be described, if data 
permit.  The effect of ADA on avelumab concentrations and pharmacokinetics may be 
evaluated, if data permit.
9.5. Safety Analysis
All safety analyses will be performed based on the safety analysis set separately by cohort 
and pooled across cohorts.
9.5.1. Adverse Events
AEs will be graded by the investigator according to the CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on TEAEs, those with initial onset or increasing in severity after the first dose of study 
treatment.  The number and percentage of patients who experienced any AE, SAE, 
treatment-related AE, and treatment-related SAE will be summarized according to worst 
toxicity grades.
9.5.2. Laboratory Test Abnormalities
The laboratory results will be graded according to the CTCAE v4.03 severity grade whenever 
applicable.  The number and percentage of patients who experienced laboratory test 
abnormalities will be summarized according to worst toxicity grade observed for each 
laboratory test.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done.
Shift tables will be provided to examine the distribution of laboratory toxicities.


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9.5.3. Electrocardiogram
Baseline ECG measurements will be summarized by cohort.  Interval measurements from 
clinically indicated on treatment ECGs will be included in the outlier analysis (categorical 
analysis) as individual values obtained at unscheduled time points. 
QT intervals will be corrected for heart rate (QTc) using standard correction factors [ie, 
Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, and QTc.
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval.
9.6. Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameters, and biomarkers.  Data will also be displayed 
graphically, where appropriate.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.8. Interim Analysis 
As this is an open-label study, the sponsor may conduct unblinded reviews of the data during 
the course of the study for the purpose of safety assessment, facilitating 
PK/Pharmacodynamic modeling, and/or to support clinical development.
An interim analysis will be performed to allow early termination of the cohorts for futility.  
Within each cohort, ORR based on confirmed PR or CR by BICR assessment will be 
estimated after at least 20 patients are treated and followed for 24 weeks, without holding 
patient enrollment in either cohort.  If based on the observed ORR, the probability of a true 
ORR ≥40% is ≤0.05 then the cohort will be stopped for futility.  For example if 4 or less 
responders are observed out of 20 patients treated in a cohort (ORR ≤20%) after the 
minimum follow-up specified above, then the cohort will be stopped for futility. 
9.9. Data Monitoring Committee 
This study will not use a data monitoring committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital or the physician patient chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 


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Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients. The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent document and any patient recruitment materials must be in compliance 
with ICH GCP, local regulatory requirements, and legal requirements, including applicable 
privacy laws.


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The informed consent document used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 Code of Federal Regulations (CFR) 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, 
where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the Informed Consent 
Document (ICD).
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab and/or talazoparib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 1 month.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
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www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (CSR synopses in which any data that could be used 
to identify individual patients has been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.


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If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Appendix 1. Abbreviations and Definitions of Terms
The following is a list of abbreviations that may be used in the protocol.
ACTH
Adrenocorticotropic Hormone
ADA
Anti-Drug Antibody
ADME
Absorption, Distribution, Metabolism, and Excretion
ADP
Adenosine Diphosphate
AE
Adverse Event
AIDS 
Acquired Immune Deficiency Syndrome
ALK
Anaplastic Lymphoma Kinase
ALT 
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
ATM
Ataxia-Telangiectasia Mutated
ATR
Ataxia-Telangiectasia and Rad3-Related
AUC
Area Under the Curve
BA
Biomarker Analysis
BBS
Biospecimen Banking System
BCRP
Breast Cancer Resistance Protein
BICR
Blinded Independent Central Review
BOR
Best Overall Response
BP
Blood Pressure
BRAF
B-Raf Proto-Oncogene, Serine/Threonine Kinase
BRCA
BReast CAncer Gene
BUN 
Blood Urea Nitrogen
C1D1
Cycle 1 Day 1
CA-125
Cancer Antigen 125
CDK
Cyclin-Dependent Kinase
CFR
Code of Federal Regulations
CI
Confidence Interval
CK
Creatine Kinase
CL
Clearance
CLCR
Creatinine Clearance
CL/F
Apparent Oral Clearance
Cmax
Maximum Plasma Concentration
CPK
Creatine Phosphokinase
Ctrough
Lowest (trough) Concentration 
CR
Complete Response
CRF
Case Report Form
CRP
C-Reactive Protein
CRPC
Castration-Resistant Prostate Cancer
CSA
Clinical Study Agreement
CSR
Clinical Study Report


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CT
Computed Tomography
CTA
Clinical Trial Application
CTC
Circulating Tumor Cell
CTCAE 
Common Terminology Criteria for Adverse Events
ctDNA
Circulating Tumor DNA
CV
Coefficient of Variation
CYP
Cytochrome P450
D
Dose
DC
Dendritic Cell
DDI
Drug-Drug Interaction
DDR
DNA Damage Repair
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DOR
Duration of response
DSB
Double Strand DNA Breaks
DU
Dispensable Unit
E
Escalation/Re-Escalation
EC
Ethics Committee 
ECG 
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure During Pregnancy
EDTA
Ethylene Diamene Tetra-acetic Acid
EGFR
Epidermal Growth Factor Receptor
EOT
End of Treatment
ER
Estrogen Receptor
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FANC
Fanconi Anemia Complementation
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin-Fixed Paraffin-Embedded 
FSH
Follicle Stimulating Hormone
gBRCAm
germline Breast Cancer Gene mutation
GC/GEJ
Gastric and Gastro-esophageal Cancers
GCIG
Gynecological Cancer Intergroup
GCP 
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GITR
Glucocorticoid Induced TNF Receptor
GnRH
Gonadotropin-Releasing Hormone
GMP
Good Manufacturing Procedure
GVHD
Graft Versus Host Disease
HA
Hyaluronic Acid
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus


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HER2
Human Epidermal Growth Factor Receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV 
Human Immunodeficiency Virus
HPV
Human Papilloma Virus
HR
Hormone Receptor
HR+
Hormone Receptor Positive
HRD
Homologous Recombination Deficiency
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
IASLC
International Association for the Study of Lung Cancer
ICD
Informed Consent Document
ICH
International Council for Harmonisation
ICOSL
Inducible Costimulator Ligand
ID
Identification
IDO
Indoleamine 2,3-Dioxygenase
IEC 
Independent Ethics Committee
IERC
Independent Endpoint Review Committee
IFN
Interferon
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL-2
Interleukin-2
IND
Investigational New Drug
INN
International Nonproprietary Name
INR 
International Normalized Ratio
IP
Investigational Product
IQR
Interquartile Range
irAE
Immune-Related Adverse Event
irCR
Immune-Related Complete Response
irOR
Immune-Related Objective Response
irPD
Immune-Related Progressive Disease
irPR
Immune-Related Partial Response
irSD
Immune-Related Stable Disease
IRB 
Institutional Review Board
irDR
Immune-Related Duration of Response
irORR
Immune-Related Objective Response Rate
IRR
Infusion-Related Reaction
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
K2EDTA
Dipotassium Ethylenediaminetetraacetic Acid
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLQ
Lower Limit of Quantitation
LOH
Loss of Heterozygosity
LSLV
Last Subject Last Visit


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mAb
Monoclonal Antibody
MAD
Maximum Administered Dose
mCRPC
metastatic Castration Resistant Prostate Cancer
M-CSF
Macrophage-Colony Stimulating Factor
MDS
Myelodysplastic Syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MCC
Merkel Cell Carcinoma
MHC
Major Histocompatibility Compex
mMCC
metastatic Merkel Cell Carcinoma
MRI 
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
mTOR
Mammalian Target of Rapamycin
mTPI
Modified Toxicity Probability Interval
NA
North America
N/A
Not Applicable
Nab
Neutralizing Antibody
NCI 
National Cancer Institute
NE
Not Estimable
NEMO
NF-κB essential modulator
NHL
Non-Hodgkin’s Lymphoma
NK
Natural Killer
NKG2DL
Natural Killer Group 2 Member D Ligand
NKT
Natural Killer T-cell
NSAIDs
Nonsteroidal Anti-inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
OC
Ovarian Cancer
OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PARP
Poly (ADP-Ribose) Polymerase
PBMC
Peripheral Blood Mononuclear Cell
PCD
Primary Completion Date
PCT
Physician’s Choice Therapy
PCWG3
Prostate Cancer Working Group 3
PD
Progressive Disease 
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PO
Orally
PET
Positron Emission Tomography
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PI
Principal Investigator
PK
Pharmacokinetics
PMAP
Pharmacometric analysis plan
PR
Partial Response


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PR
Progesterone Receptor
 
PS
Performance Status
PSA
Prostate-Specific Antigen
PT
Prothrombin Time
PTEN
Phosphatase and Tensin Homolog Gene
PTT
Partial Thromboplastin Time
Q2W
Every 2 Weeks
QD
Once Daily
RCC
Renal Cell Carcinoma
RE
Re-escalation
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
Ribonucleic Acid
ROS1
c-Ros Oncogene 1
RP2D
Recommended Phase 2 Combination Dose
S
Stay (at current dose)
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SOC
Summary of Changes
SOP
Standard Operating Procedure
SRSD
Single Reference Safety Document
STING
Stimulation of Interferon Genes
t1/2
Terminal Half-Life
TBili
Total Bilirubin
TCGA
The Cancer Genome Atlas
TDO
Tryptophan 2,3-Dioxygenase
TE
Target Engagement
TEAE
Treatment Emergent Adverse Event
TIL
Tumor Infiltrating Lymphocytes 
TKI
Tyrosine Kinase Inhibitor
Tmax
Time to Maximum Plasma Concentration
TNBC
Triple-Negative Breast Cancer
TO
Target Occupancy
TPS
Tumor Proportion Score
TSH
Thyroid Stimulating Hormone
TTR
Time-to-Tumor Response
UC
Urothelial Cancer
ULN 
Upper Limit of Normal
UPM
Unit Probability Mass
US
United States
USPI 
United States Package Insert
UTI
Urinary Tract Infection
CCI
CCI


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VEGF
Vascular Endothelial Growth Factor
V/F
Apparent Volume of Distribution
Vss/F
Apparent Steady-State Volume of Distribution
WBC 
White Blood Cell
WT
Wild Type
WHO
World Health Organization
WOCBP
Woman of Childbearing Potential


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Appendix 2. ECOG Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair
5
Dead
From: Oken MM, Creech RH, Tormey DC et al.  Toxicity and response criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol. 1982; 5: 649–655.83


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Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines
Adapted from E.A. Eisenhauer, et al.  New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247.84
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and <15 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to start of study treatment and all disease must be 
documented appropriately.  If baseline assessment is inadequate, subsequent statuses 
generally should be indeterminate. 
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed post-baseline. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
the lesion is considered to have disappeared, 0 mm should be recorded; otherwise if a 
lesion is determined to be present but too small to measure, the lesion status will 
indicate “too small to measure and judged to be less than 10 mm” and 5 mm will be 
used in the calculation of the sum of the diameters.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target Disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE (ie, Not Evaluable), 
PRESENT/NOT INCREASED, INCREASED.  Multiple non-target lesions in one organ may 
be recorded as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).


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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
should be discussed with the radiologist and the sponsor to determine if substitution is 
possible.  If not, subsequent objective statuses are not evaluable. 
Target Disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  All target lesions must be assessed. 

Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions 
must be assessed.  Stable can follow PR only in the rare case that the sum increases 
by less than 20% from the nadir (smallest sum of diameters consider baseline and all 
assessments prior to the time point under evaluation), but enough that a previously 
documented 30% decrease no longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Not evaluable (NE): Progression has not been documented, and 

one or more target lesions have not been assessed; or

assessment methods used were inconsistent with those used at baseline; or

one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure); or

one or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Non-target Disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels 
(if being followed).  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level (if 
being followed) above the normal limits. 


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
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

Not evaluable (NE): Progression has not been determined and one or more non-target 
lesion sites have not been assessed or assessment methods used were inconsistent 
with those used at baseline or one or more non-target lesions cannot be assessed 
(eg, poorly visible or unclear images) or one or more non-target lesions were excised 
or irradiated and have not reappeared or increased. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document PD even after discontinuation of study 
treatment. 
Determination of Tumor Response by RECIST
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  New lesions will also be recorded separately.  Determination of tumor response 
at each assessment based on target, non-target and new lesions is summarized in the 
following table.


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Objective Response Status at Each Assessment for Patients with Measurable 
Disease at Baseline
Target Lesions
Non-target Lesions
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD or 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
*Non-PD includes CR and Non-CR/Non-PD
** New lesions must be unequivocal 
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest sum 
on study).  For CR and PR, the patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  CR and PR must be confirmed 
by 2 measurements at least 4 weeks apart.  In the case of SD, follow up measurements must 
have met the SD criteria at least once after start of the treatment at a minimum interval of 
6 weeks.


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Appendix 4. Assessment of Radiographic Response and Progression in Patients with 
Metastatic CRPC
Radiographic imaging for patients with CRPC is categorized as soft tissue or bone.  Soft 
tissue imaging may include CT scans of the chest, abdomen and pelvis or MRIs of the 
abdomen and pelvis).  Bone imaging must be whole body radionuclide bone scan 
(scintigraphy).
The investigator will assess response of soft tissue disease by RECIST v1.1 (see 
Appendix 3).  However, bone disease will not be considered as non-target lesions assessed by 
RECIST v1.1.  An objective response is defined as a best overall response of CR or PR per 
RECIST v1.1 and must be confirmed on repeated imaging at least 4 weeks after initial 
documentation. 
Bone disease will be assessed for progressive disease only by PCWG3.64  The documentation 
required for the determination of radiographic progression is shown in the table below.
Criteria for Evidence of Radiographic Progression
Date 
Progression 
Detecteda
Criteria for Progression
Criteria to Confirm 
Progression
Criteria to Document Disease 
Progression on Confirmatory 
Scan
Week 8 
Bone lesions: 2 or more 
new lesions compared to 
screening bone scan by 
PCWG3
Timing: At least 6 weeks 
after progression identified 
or at Week 16 visitb  
2 or more new bone lesions on 
bone scan compared to Week 8 
scan
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression
Week 16 or 
later
Bone lesions: 2 or more 
new lesions on bone scan 
compared to Week 8 bone 
scan
Timing: At least 6 weeks 
after progression identified 
or at next imaging time 
pointb
Persistent or increase in 
number of bone lesions on 
bone scan compared to prior 
scanc
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression 
a
Progression detected by bone scan at an unscheduled visit either before Week 8 or between scheduled 
visits will require a confirmatory scan at least 6 weeks later and should follow confirmation criteria 
outlined in the table for the next scheduled scan. 
b Confirmation must occur at the next available scan. 
c
For confirmation, at least 2 of the lesions first identified as new must be present at the next available scan 
(confirmation scan).  
Disease progression in bone disease must be confirmed at least 6 weeks later, as per PCWG3.  
See table below for the timing of confirmatory imaging requirements.


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Confirmatory Imaging Requirements for Patients with mCRPC Based on 
RECIST v1.1 and PCWG3
Disease Site
Response
Progressiona
Soft tissue
Must be confirmed at least 
4 weeks later 
No confirmation required 
Bone
Not applicable
Must be confirmed at least 6 weeks 
later 
a
To inform permanent treatment discontinuation.
Radiographic PFS is defined as the time from enrollment to documentation of radiographic 
progression in soft tissue by investigator’ assessment according to RECIST v1.1, in bone by 
investigator’s assessment according to PCWG3, or death, whichever occurs first.


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SAP_001.pdf: 
Avelumab
B9991032 (MSB0010718C, MDV3800) Statistical Analysis Plan    
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A PHASE 2 STUDY TO EVALUATE SAFETY AND ANTI-TUMOR ACTIVITY OF 
AVELUMAB IN COMBINATION WITH TALAZOPARIB IN PATIENTS WITH 
BRCA OR ATM MUTANT TUMORS
JAVELIN BRCA/ATM
STATISTICAL ANALYSIS PLAN – B9991032
Compounds:
MSB0010718C
MDV3800, BMN 673
Compound Name:
Avelumab
Talazoparib
Version:
4.0
Date:
16-Dec-2021
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
APPENDICES ...........................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION ...............................................................................................................10
2.1. Study Objectives .....................................................................................................10
2.2. Study Design ...........................................................................................................11
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................12
3.1. Primary Endpoint ....................................................................................................12
3.2. Secondary Endpoints...............................................................................................12
3.2.1. Safety endpoints..........................................................................................12
3.2.2. Efficacy endpoints ......................................................................................12
3.2.3. Pharmacokinetic endpoints.........................................................................13
3.2.4. Immunogenicity endpoints .........................................................................14
3.2.5. Biomarker endpoints...................................................................................14
3.4. Baseline Variables...................................................................................................15
3.4.1. Study drug, study treatment and baseline definitions.................................15
3.4.2. Baseline characteristics...............................................................................16
3.5. Safety Endpoints .....................................................................................................16
3.5.1. Adverse events............................................................................................16
4. ANALYSIS SETS ...............................................................................................................17
4.1. Full Analysis Set .....................................................................................................17
4.2. Safety Analysis Set..................................................................................................17
4.3. Other Analysis Set...................................................................................................17
4.3.1. PK analysis sets ..........................................................................................17
4.3.2. Biomarker analysis set................................................................................17
4.3.3. Immunogenicity analysis set.......................................................................18
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................18
5.1. Hypotheses and Decision Rules ..............................................................................18
5.1.1. Hypotheses and sample size determination................................................18
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5.1.2. Decision rules .............................................................................................19
5.2. General Methods .....................................................................................................19
5.2.1. Data handling after the cut-off date............................................................20
5.2.2. Pooling of centers .......................................................................................20
5.2.3. Presentation of continuous and qualitative variables..................................20
5.2.4. Definition of study day...............................................................................20
5.2.5. Definition of start of new anti-cancer drug therapy....................................21
5.2.6. Definition of start of new anti-cancer therapy............................................21
5.2.7. Definition of on-treatment period...............................................................21
5.2.8. Standard derivations and reporting conventions.........................................21
5.2.9. Unscheduled visits......................................................................................22
5.2.10. Adequate baseline tumor assessment........................................................22
5.2.11. Adequate post-baseline tumor assessment................................................22
5.3. Methods to Manage Missing Data ..........................................................................22
5.3.1. Missing data................................................................................................22
5.3.1.1. Pharmacokinetic concentrations................................................23
5.3.1.2. Pharmacokinetic parameters .....................................................23
5.3.2. Handling of incomplete dates .....................................................................24
5.3.2.1. Disease history ..........................................................................24
5.3.2.2. Adverse events ..........................................................................24
5.3.2.3. Prior and concomitant medications...........................................24
5.3.2.4. Exposure....................................................................................25
5.3.3. Imputation rules for date of last contact and efficacy assessments ............25
5.3.3.1. Date of last contact....................................................................25
5.3.3.2. Death date..................................................................................26
5.3.3.3. Tumor assessments....................................................................26
5.3.3.4. Date of start of new anti-cancer therapy ...................................26
6. ANALYSES AND SUMMARIES ......................................................................................28
6.1. Primary Endpoints...................................................................................................28
6.1.1. Objective response as assessed by the BICR per RECIST v1.1.................28
6.1.1.1. Primary analysis ........................................................................28
6.2. Secondary Endpoint(s) ............................................................................................31
6.2.1. Safety endpoints..........................................................................................31


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6.2.2. Efficacy endpoints ......................................................................................31
6.2.2.1. Tumor shrinkage from baseline.................................................31
6.2.2.2. Duration of response .................................................................32
6.2.2.3. Time to response .......................................................................34
6.2.2.4. Progression-free survival...........................................................35
6.2.2.5. Overall Survival ........................................................................37
6.2.2.6. Time to PSA progression for patients with metastatic 
CRPC.................................................................................................38
6.2.2.7. PSA response for patients with metastatic CRPC.....................39
6.2.2.8. CTC count conversion and CTC0 for patients with 
metastatic CRPC................................................................................40
6.2.2.9. CA-125 response for patients with ovarian cancer ...................41
6.2.2.10. BICR vs Investigator Assessment...........................................41
6.2.3. Pharmacokinetic endpoints.........................................................................42
6.2.4. Population pharmacokinetic endpoints.......................................................43
6.2.5. Biomarker endpoints...................................................................................43
6.2.6. Endpoints for immunogenicity data of avelumab.......................................44
6.4. Subset Analyses.......................................................................................................48
6.4.1. Objective response and progression-free survival......................................48
6.4.2. PSA response for patients with metastatic CRPC ......................................49
6.4.3. CTC count conversion for patients with metastatic CRPC ........................49
6.5. Baseline and Other Summaries and Analyses.........................................................49
6.5.1. Baseline summaries ....................................................................................49
6.5.1.1. Demographic characteristics .....................................................49
6.5.1.2. Medical history..........................................................................50
6.5.1.3. Disease characteristics...............................................................50
6.5.1.4. Prior anti-cancer therapies.........................................................51
6.5.2. Study conduct and patient disposition........................................................52
6.5.2.1. Patient disposition .....................................................................52
6.5.2.2. Protocol deviations....................................................................53
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6.5.3. Study treatment compliance and exposure .................................................53
6.5.3.1. Exposure to avelumab ...............................................................54
6.5.3.2. Exposure to talazoparib.............................................................55
6.5.3.3. Dose reductions.........................................................................56
6.5.3.4. Dose interruptions .....................................................................56
6.5.3.5. Dose delays ...............................................................................56
6.5.3.6. Infusion rate reductions.............................................................57
6.5.3.7. Infusion interruptions ................................................................57
6.5.4. Concomitant medications and non-drug treatments ...................................57
6.5.5. Subsequent anti-cancer therapies................................................................58
6.6. Safety Summaries and Analyses .............................................................................58
6.6.1. Adverse events............................................................................................58
6.6.1.1. All adverse events .....................................................................59
6.6.1.2. Adverse events leading to dose reduction.................................60
6.6.1.3. Adverse events leading to discontinuation of study 
treatment............................................................................................60
6.6.2. Deaths .........................................................................................................61
6.6.3. Serious adverse events................................................................................61
6.6.4. Other significant adverse events.................................................................61
6.6.5. Laboratory data...........................................................................................62
6.6.5.1. Hematology and chemistry parameters.....................................62
6.6.5.2. Other laboratory parameters......................................................64
6.6.6. Electrocardiogram.......................................................................................64
7. INTERIM ANALYSES.......................................................................................................64
7.1. Introduction .............................................................................................................64
7.2. Interim Analyses and Summaries............................................................................65
8. REFERENCES ....................................................................................................................66
9. APPENDICES .....................................................................................................................68
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................7
Table 2.
PK Parameters to be Determined for Avelumab and Talazoparib ...........14
Table 3.
Biomarker Definition and Determination.................................................14


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Table 4.
Sample Size and Exact 95% Confidence Intervals for ORR....................19
Table 5. 
Criteria for Evidence of Radiographic Progression for Patients with 
mCRPC.....................................................................................................33
Table 6.
Outcome and Event Dates for DR Analyses.............................................33
Table 7. 
DR Censoring Reasons and Hierarchy .....................................................34
Table 8.
Outcome and Event Dates for PFS Analyses ...........................................36
Table 9.
PFS Censoring Reasons and Hierarchy....................................................37
Table 10.
OS Censoring Reasons and Hierarchy......................................................38
Table 11.
Outcome and event dates for Time to PSA progression analysis.............39
Table 12.
Possible BOR Outcomes for Investigator vs BICR..................................41
Table 13. 
Patients Characterized Based on Anti-Drug Antibody Results 
(ADA Status) ............................................................................................45
Table 14. 
Patients Characterized Based on Neutralizing Antibody Results 
(nAb Status)..............................................................................................46
Table 15.
Case Definition for irAEs .........................................................................68
Table 16.
Case Definition for IRRs – IV Study Drugs Administered Alone Or 
In Combination With Non-IV Study Drugs..............................................70
APPENDICES
Appendix 1. Immune-Related Adverse Events........................................................................68
Appendix 2. Infusion Related Reactions .................................................................................70
Appendix 3. Abbreviations and Definitions of Terms.............................................................71


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B9991032 is based on the protocol amendment
1 dated 15NOV2018.  
Table 1.
Summary of Major Changes in SAP Amendments
Version
Version 
Date
Summary of Changes
4
16-Nov-2021
The following changes were implemented:
•
Section 2. “Introduction” – The definition of the primary analysis cutoff 
date was modified to allow longer patient follow-up.
•
Section 6.2.5. “Biomarker endpoints” – Alternative categories for TMB 
were added grouping the categories medium and high. 
 
 
 
  
 
 
•
Section 6.4.1. “Objective response and progression-free survival” - Subset 
analyses by BRCA-dependent status and by BRCA-associated status were 
added.
•
Section 6.6.1.1. “All adverse events” and Section 6.6.1.3. “Adverse events 
leading to interruption of study treatment” - The summary tables and listing 
of TEAEs leading to interruption of each study drug (avelumab, 
talazoparib) were deleted.
•
Section 6.6.1.1. “All adverse events” and Section 6.6.1.3. “Adverse events 
leading to discontinuation of study treatment” - The summary tables of 
TEAEs leading to permanent discontinuation of each study drug 
(avelumab, talazoparib) were deleted.
•
Section 6.6.4. “Other significant adverse events” - The summary tables of 
irAEs leading to discontinuation of each study drug (avelumab, 
talazoparib), any, and all drugs and the summary tables of IRRs leading to 
discontinuation of avelumab, and time related to first onset of an IRR were 
deleted.
•
Section 6.6.5.1. “Hematology and chemistry parameters” - The shift 
tables for the parameters with NCI-CTCAE grades available and the 
eDISH plot were deleted. The Hy’s Law criteria for the listing was 
corrected,
•
Section 6.6.6. “Vital signs” - The vital sign summaries by visit were 
deleted.
3 
09-Sep-2020
The following changes were implemented:
•
Section 3.4.2. “Baseline characteristics”, Section 5.2.8. “Standard 
derivations and reporting conventions”, Section 6.5.1.1. “Demographic 
characteristics” – the summary of physical measurements (BMI, height and
weight) was deleted.
•
Section 4.3.2. “Biomarker analysis set” – the biomarker analysis set will 
include blood-based and tumor tissue-based biomarkers.
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•
Section 6.2.2.2. “Duration of response” - the listing of duration of response 
time was deleted.
•
Section 6.2.2.4. “Progression-free survival” - the summary of time of 
follow-up for PFS was simplified.
•
Section 6.2.2.5. “Overall survival” - the summary of time of follow-up for 
OS was simplified.
•
Section 6.2.2.7. “PSA response for patients with metastatic CRPC” – the 
plot of the change in PSA value from baseline was added.
•
Section 6.2.2.10. “BICR vs Investigator Assessment” - the concordance 
analysis of BOR outcomes for investigator vs BICR was added.
•
Section 6.4.1. “Objective response and progression-free survival” - subset 
analysis of duration of response were removed. The Kaplan-Meier plot for 
PFS by subset (if meaningful) and the subset analysis of patients with 
measurable disease at baseline based on BICR/investigator assessment
were added.
•
Section 6.5.1.3. “Disease characteristics” - the summary of substance use 
was deleted.
•
Section 6.5.1.4. “Prior anti-cancer therapies”, Section 6.5.5. “Subsequent 
anti-cancer therapies” - the listings of anti-cancer radiation therapy and 
anti-cancer surgeries were deleted.
•
Section 6.5.1.4. “Prior anti-cancer therapies” – the summary of prior anti-
cancer therapies by class was deleted.
•
Section 6.5.4. “Concomitant medications and non-drug treatments” - the
summaries of prior medications and pre-medications and the listings of 
prior medications, concomitant medications, pre-medications and non-drug 
treatments were deleted.
•
Section 6.6.1.3. “Adverse events leading to interruption of study treatment”
- the listing of all AEs leading to interruption of study treatment was added.
•
Section 6.6.5.1. “Hematology and chemistry parameters” - the summary of 
laboratory parameters by CTCAE grade table was replaced by the summary 
of newly occurring or worsening laboratory abnormalities.
•
Section 6.6.5.2. “Other laboratory parameters” - the listing of laboratory 
results with CTCAE grading was added.
•
Section 6.6.8. “ECOG performance status” - the ECOG shift table was 
deleted.
2
04-Feb-2020
The following changes in the SAP were implemented in accordance to protocol 
amendment 1.
 
 
• Section 6.5.3.5. “Dose delays” - the window for dose delays was updated 
from 2 days to 3 days.
• Section 3.4.1. “Study drug, study treatment and baseline definitions” and 
Section 5.2. “General Methods” - the recommended Phase 2 dose (RP2D) for 
talazoparib when administered in combination with avelumab and the 
talazoparib starting dose for patients with moderate renal impairment were 
specified.
In addition, the following changes were implemented.
• Section 3.4.1. “Study drug, study treatment and baseline definitions” -
removed definition of baseline for ECG assessments as no summaries will be 
provided (ECGs are only collected post-treatment if clinically indicated).
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Section 3.5.1. and Section 6.6.1 “Adverse events” – updated definition of 
treatment-emergent adverse events to include only adverse events with onset 
dates during the on-treatment period.
Section 5.3.1.1. “Pharmacokinetic concentrations” and 5.3.1.2. 
“Pharmacokinetic parameters” - summary statistics at a particular time point 
will not be presented if less than 3 evaluable measurements are available 
(whereas in V1 of the SAP this referred to more than 50% of the data 
missing).  
Section 6.1.1. “Objective response as assessed by the BICR per RECIST 
v1.1” – added "No evidence of disease at baseline" as a possible reason for 
best overall response of NE as applicable, for example, to patients with 
mCRPC with no measurable disease and no non-target lesions at baseline.
Section 6.2.2.2. “Duration of response” – added details regarding censoring 
for duration of response since “no adequate baseline assessment” and “no 
adequate post-baseline assessment” which is used in censoring for PFS 
analyses is not applicable to analyses of duration of response for patients with 
objective response.
Section 6.2.3. “Pharmacokinetic endpoints” – removed requirements to 
present log-linear plots as only sparse samples are collected; clarified plots 
will display either mean or medians (but not both).
Section 6.2.5. “Biomarker endpoints” - The category "unknown" for BRCA 
and ATM mutations was added. The number and percentage of patients will 
also be reported based on the full analysis set to include the patients in the 
category "unknown". The summaries for DR, PFS and OS for each biomarker 
category were removed.
Section 6.2.6. “Endpoints for immunogenicity data of avelumab” –Kaplan-
Meier estimates for ADA response time/duration of response, summary of 
ADA titers, and summaries of PK, safety and efficacy by immunogenicity 
status were removed – such analyses will be performed only if the study 
results warrant further exploration of these data.
Section 6.4. “Subset Analyses” - subset analyses for efficacy endpoints will 
be performed only based on BICR assessment.  Removed subset analyses for 
the following variables based on clinical importance, redundancy and/or 
number of patients expected in a subgroup: visceral disease, history of central 
nervous system, baseline lactate dehydrogenase, triple negative breast cancer, 
hormone receptor positive, total Gleason score at diagnosis, and all subset 
analyses for patients with pancreatic cancer.
Section 6.5.1.3. “Disease characteristics” - The following disease 
characteristics will be summarized as categorical variables: tumor type, 
visceral disease, central nervous system metastasis, presence of liver 
metastasis in pancreatic cancer patients (all based on BICR assessment),
baseline lactate dehydrogenase and the total Gleason score at diagnosis.  Site 
of primary tumor will not be summarized as only collected in the eCRF for 
patients with UC. Time since initial diagnosis and time since diagnosis of 
local/regional recurrence of disease will not be summarized.
Section 6.5.3. “Study treatment compliance and exposure” - removed by-
cycle summaries.
Section 6.5.3.4. “Dose interruptions” – the reason for dose interruption was
removed from the analysis specifications.  
Section 6.6.1 “Adverse events” and subsections – the following summaries 
were removed: adverse events leading to dose reduction of avelumab 
(avelumab dose reduction is not allowed per protocol), adverse events related 
to avelumab and adverse events related to talazoparib (adverse events related 


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to either study drug will continue to be summarized), adverse events 
excluding serious adverse events, adverse events leading both dose reduction 
and interruption of avelumab or talazoparib.  
Section 6.6.5 “Laboratory data” and subsections – descriptive summaries by 
visit were removed as data will be summarized based on worst CTCAE grade 
or based on laboratory abnormalities.  
Section 6.6.6. “Electrocardiogram” – removed the analyses of ECGs that are 
not applicable to this study as ECGs are only collected when clinically 
indicated. 
Section for “Physical Examination” was removed as data not collected in the 
eCRF.
Appendix 1 “Immune-Related Adverse Events” - steps 3 and 4 of the 
algorithm will be checked concurrently. 
Redundant listings or listings that do not provide meaningful information were 
removed. Minor editorial and consistency changes throughout the document.
1
14-May-2018 
Not applicable (N/A)
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991032.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie,
pharmacokinetic [PK] data, immunogenicity data, biomarker data, and tumor assessment 
results by the Blinded Independent Central Review (BICR)). The primary analysis will 
include all data up to a cut-off date corresponding to at least 18 months after the last patient 
receives the first dose of study treatment.  The final analysis of the data will be performed 
after last patient last visit (LPLV). 
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes.
2.1. Study Objectives
Primary Objective

To evaluate objective response rate (ORR) of avelumab in combination with talazoparib, 
in patients with locally advanced or metastatic solid tumors harboring BRCA1, BRCA2 
or ATM defect.
Secondary Objectives

To assess the overall safety and tolerability of avelumab in combination with talazoparib;

To characterize the PK of avelumab and talazoparib when given in combination;

To evaluate the immunogenicity of avelumab when given in combination with 
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•
To assess other measures of the anti-tumor activity of avelumab in combination with 
talazoparib;
•
To assess the correlation of anti-tumor activity of avelumab in combination with 
talazoparib with PD-L1 expression in baseline tumor tissue;
•
To assess the correlation of anti-tumor activity and emergence of resistance with defects 
in a panel of key oncogenes, including BRCA1/2 and ATM, and tumor mutational burden 
(TMB) in circulating tumor DNA (ctDNA) and tumor tissue at baseline, during treatment 
and at the end of treatment.
 
 
 
 
 
 
 
2.2. Study Design
This is a Phase 2, open-label, multi-center, non-randomized study of avelumab in 
combination with talazoparib in adult patients with locally advanced (primary or recurrent) or 
metastatic solid tumors with a pathogenic or likely pathogenic germline or loss-of-function 
somatic BRCA1 or BRCA2, or ATM gene defect, as determined by local assessment and 
classification, who have received at least 1 line of standard of care treatment for locally 
advanced or metastatic disease unless prior treatment requirements are otherwise specified.  
Two cohorts will be enrolled in parallel:
•
Cohort 1 will enroll up to approximately 150 patients with locally advanced or metastatic 
solid tumors with one or more defects in the BRCA1 or BRCA2 genes;
•
Cohort 2 will enroll up to approximately 50 patients with locally advanced or metastatic 
solid tumors with one or more defects in the ATM gene.
Note: in the event that a patient has concomitant defects in more than 1 of the three genes 
(BRCA1 or BRCA2 or ATM), they will be enrolled in Cohort 1. 
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND
CONVENTIONS
3.1. Primary Endpoint

Confirmed objective response (OR) in patients with locally advanced or metastatic solid 
tumors with BRCA 1/2 or ATM defect, as assessed by BICR, using RECIST v1.1 and, in 
patients with metastatic castration-resistant prostate cancer (mCRPC), RECIST v1.1 and 
PCWG3 (bone).
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 for patients with solid tumors except mCRPC and, according to RECIST v1.1 (soft 
tissue) and PCWG3 (bone) for patients with mCRPC, from the date of first dose of study 
treatment until the date of the first documentation of progressive disease (PD). Both CR 
and PR must be confirmed by repeat assessments performed no less than 4 weeks after 
the criteria for response are first met.
3.2. Secondary Endpoints
3.2.1. Safety endpoints

Adverse Events as characterized by type, severity (as graded by National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03), timing, 
seriousness, and relationship to study treatments;
AEs will be graded by the investigator according to CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA)

Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v4.03) and timing.
3.2.2. Efficacy endpoints

Confirmed OR as assessed by the investigator, using RECIST v1.1 and, in patients with 
mCRPC, RECIST v1.1 and PCWG3;

Time to event endpoints: Endpoints as assessed by BICR and as assessed by the 
investigator, using RECIST v1.1 and in patients with mCRPC, RECIST v1.1 and 
PCWG3, including time to tumor response (TTR), duration of response (DR), and 
progression-free survival (PFS).  Additional time-to-event endpoints include overall 
survival (OS) for all patients and time to prostate-specific antigen (PSA) progression 
(25% increase) for patients with mCRPC;
TTR is defined, for patients with an OR who have solid tumors except mCRPC, as the 
time from the date of first dose of study treatment to the first documentation of objective 
response (CR or PR) which is subsequently confirmed. TTR is defined, for patients with 
an OR who have mCRPC, as the time from the date of first dose of study treatment to the 
first documentation of soft tissue objective response (CR or PR) which is subsequently 
confirmed, with no evidence of confirmed bone disease progression on bone scan per 
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DR is defined, for patients with OR who have solid tumors except mCRPC, as the time 
from the first documentation of objective response (CR or PR) to the date of first 
documentation of PD or death due to any cause.  
DR is defined, for patients with OR who have mCRPC, as the time from the first 
documentation of soft tissue objective response (CR or PR) per RECIST v1.1 and no 
evidence of confirmed bone disease progression by PCWG3 to the date of first 
documentation of PD by soft tissue evaluated per RECIST v1.1 or bone disease evaluated 
per PCWG3, or death due to any cause.  
For patients with solid tumors except mCRPC, PFS is defined as the time from the date 
of first dose of study treatment to the date of the first documentation of PD or death due 
to any cause, whichever occurs first. For patients with mCRPC, PFS is defined as the 
time from the date of first dose of study treatment to the date of the first documentation 
of radiographic progression in soft tissue evaluated per RECIST v1.1, in bone evaluated 
per PCWG3, or death due to any cause, whichever occurs first.
OS is defined as the time from the date of first dose of study treatment to the date of 
death due to any cause.
Time to PSA progression for patients with mCRPC is defined as the time from the date of 
first dose of study treatment to the date that a 25% increase in PSA with an absolute 
increase of 2 g/L (2 ng/mL) above the nadir (or baseline for patients with no PSA 
decline) is documented. PSA progression must be confirmed by a second, consecutive 
PSA assessment 3 weeks later. 

PSA response 50% decrease and circulating tumor cells (CTC) count conversion for 
patients with mCRPC;
PSA response is defined as PSA decline 50% compared to baseline. PSA response must 
be confirmed by a second, consecutive PSA assessment 3 weeks later.  
CTC count conversion is defined as a decrease in CTC count from ≥ 5 CTC per 7.5 mL 
of blood at baseline to < 5 CTC per 7.5 mL of blood on study. CTC0, defined as a 
decrease in CTC count from ≥ 1 CTC per 7.5 mL to an undetectable level on study, will 
also be reported.

Cancer antigen (CA)-125 response 50% decrease for patients with ovarian cancer.
CA-125 response is defined as ≥ 50% reduction in CA-125 levels from baseline.  CA-125 
response must be confirmed by a second, consecutive CA-125 value 4 weeks later.
3.2.3. Pharmacokinetic endpoints

PK parameters including: pre-dose/trough concentrations (Ctrough) for avelumab and 
talazoparib, post-dose concentrations for talazoparib, and maximum concentrations 
(Cmax) for avelumab.  


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Table 2.
PK Parameters to be Determined for Avelumab and Talazoparib
Parameter
Definition
Method of Determination
Cmax a
Maximum observed plasma concentration 
Observed directly from data
Tmax a
Time for Cmax
Observed directly from data as time of 
first occurrence
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
a For avelumab only
For avelumab, the actual time difference between avelumab end of infusion (EOI) 
captured in the eCRF and Tmax will also be reported.
For talazoparib, the post-dose concentration value and its actual time relative to 
talazoparib dose will be reported.
3.2.4. Immunogenicity endpoints
•
Avelumab anti-drug antibody (ADA) levels and neutralizing antibodies (nAb) against 
avelumab.
3.2.5. Biomarker endpoints
•
PD-L1 expression level in baseline tumor tissue.
•
Presence of defects in a panel of key oncogenes, including BRCA 1/2 and ATM, and 
TMB in ctDNA and tumor tissue at baseline, during treatment, and at the end of 
treatment.
Table 3.
Biomarker Definition and Determination
Parameter
Definition
Method of Determination
PD-L1 expression level 
in baseline tumor 
tissue
The number of PD-L1 positive cells and/or 
qualitative assessment of PD-L1 staining on 
tumor and inflammatory cells in regions of 
interest
Pathologist, assisted by 
image analysis.
Presence of defects in a 
panel of key oncogenes 
from tumor tissue, 
from germline DNA 
and from ctDNA  
Presence or absence of a deleterious or 
expected deleterious mutation in BRCA1, 
BRCA2 and ATM from tumor tissue 
(somatic defect), from germline DNA 
(germline defect), and from ctDNA.
Next generation sequencing 
followed by computational 
analysis.
Tumor mutational 
burden (TMB) from 
tumor tissue and from 
ctDNA
The total number of mutations in the tumor 
genome, or number of mutations per 
megabase of DNA if derived from targeted 
sequencing.
Next generation sequencing 
followed by computational 
analysis.
 
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3.4. Baseline Variables
3.4.1. Study drug, study treatment and baseline definitions
In this study, ‘study drug’ refers to avelumab or to talazoparib and ‘study treatment’ (or 
‘treatment group’) refers to one of the following:
•
Cohort 1: avelumab 800 mg IV Q2W plus talazoparib at the recommended Phase 2 dose 
(RP2D) in patients with locally advanced or metastatic solid tumors with one or more 
defects in the BRCA1 or BRCA2 genes;
•
Cohort 2: avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients with 
locally advanced or metastatic solid tumors with one or more defects in the ATM gene.
RP2D is the recommended Phase 2 dose for talazoparib when administered in combination 
with avelumab. RP2D for talazoparib was established at 1 mg PO QD. The starting dose of 
talazoparib for patients with moderate renal impairment (CLCR = 30-59 mL/min) will be 
0.75 mg PO QD to account for the lower talazoparib clearance.
Start and end dates of study treatment:
The date/time of first dose of study treatment in a combination group is the earliest date/time 
of the first non-zero dose date/time for the study drugs in the combination. 
The date/time of last dose of study treatment in a combination group is the latest date/time of 
the last non-zero dose date/time for the study drugs in the combination.
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Definition of baseline: 
Definition of baseline for immunogenicity analyses
The last available assessment prior to the start of treatment with avelumab is defined as 
‘baseline’ result or ‘baseline’ assessment.  If an assessment is planned to be performed prior 
to the first dose of avelumab in the protocol and the assessment is performed on the same day 
as the first dose of avelumab, it will be assumed that it was performed prior to avelumab 
administration, if assessment time point is not collected or is missing.
Definition of baseline for efficacy analyses and for safety analyses
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety and efficacy analyses.  If an assessment is planned 
to be performed prior to the first dose of study treatment in the protocol and the assessment is 
performed on the same day as the first dose of study treatment, it will be assumed that it was 
performed prior to study treatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
3.4.2. Baseline characteristics
Baseline characteristics (including demographics, disease history and prior anti-cancer 
therapies) are described in Section 6.5.1.  These baseline characteristics are not planned to be 
included as stratification variables or covariates in statistical models unless otherwise 
specified in Section 6. 
3.5. Safety Endpoints
3.5.1. Adverse events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –


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1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.
Adverse Events of Special Interest (AESIs)
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendix 1 and 
Appendix 2, respectively.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.
4.1. Full Analysis Set
The full analysis set (FAS) will include all patients who receive at least one dose of study 
drug.  Patients will be classified according to the study treatment actually received.  If a 
patient receives more than one treatment the patient will be classified according to the first
study treatment received. 
4.2. Safety Analysis Set
The safety analysis set will include all patients who receive at least one dose of study drug.  
Patients will be classified according to the study treatment actually received.  If a patient 
receives more than one study treatment, the patient will be classified according to the first
study treatment received. In this non-randomized study, the FAS and the safety analysis set 
are identical. 
4.3. Other Analysis Set
4.3.1. PK analysis sets
The PK concentration analysis sets (one unique set for each study drug used in the 
combination treatment) are a subset of the safety analysis set and will include patients who 
have at least one concentration measurement for avelumab or talazoparib. 
The PK parameter analysis sets (one unique set for each study drug used in the combination 
treatment) are a subset of the safety analysis set and will include patients who have at least 
one of the PK parameters of interest for avelumab or talazoparib.
4.3.2. Biomarker analysis set
The biomarker analysis set is a subset of the safety analysis set including patients who have 
at least one baseline biomarker assessment.  


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4.3.3. Immunogenicity analysis set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb sample result for avelumab.  
 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and sample size determination
Up to approximately 150 patients will be enrolled in Cohort 1 and 50 patients in Cohort 2.  
Thus, a total of approximately 200 patients will be enrolled. 
With 150 and 50 treated patients in Cohort 1 and Cohort 2, respectively, ORR can be 
estimated with a maximum standard error of 0.041 and 0.071, respectively.  Assuming a beta 
(0.5, 0.5) prior:
•
Cohort 1: if 66 responders (out of 150 patients, ORR of 44%) are observed, the posterior 
probability of a true ORR ≥40% (considered a clinically relevant effect) will be ≥0.80 
(0.841);
•
Cohort 2: if 23 responders (out of 50 patients, ORR of 46%) are observed, the posterior 
probability of a true ORR ≥40% (considered a clinically relevant effect) will be ≥0.80 
(0.807).
Table 4 provides the exact 95% confidence intervals (CIs) for ORR based on different 
observed number of responders in a given tumor type cohort.
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Table 4.
Sample Size and Exact 95% Confidence Intervals for ORR
N per Cohort
Number of Responders
Observed ORR
Exact 95% CI for ORR
50
20
40%
26.4% - 54.8%
23
46%
31.8% - 60.7%
25
50%
35.5% - 64.5%
27
54%
39.3% - 68.2%
28
56%
41.3% - 70.0%
30
60%
45.2% - 73.6%
32
64%
49.2% - 77.1%
35
70%
55.4% - 82.1%
150
60
40%
32.1% - 48.3%
66
44%
35.9% - 52.3%
75
50%
41.7% - 58.3%
83
55%
47.0% - 63.4%
90
60%
51.7% - 67.9%
98
65%
57.1% - 72.9%
105
70%
62.0% - 77.2%
CI=confidence interval; ORR=objective response rate.
5.1.2. Decision rules
An interim analysis will be performed to allow early termination of the cohorts for futility. 
Within each cohort, ORR based on confirmed PR or CR by BICR assessment will be 
estimated after at least 20 patients are treated and followed for 24 weeks, without holding 
patient enrollment in either cohort.
The decision rule is based on the observed ORR: if the probability of a true ORR 40% is 
≤0.05 then the cohort will be stopped for futility.  For example, if 4 or fewer responders are 
observed out of 20 patients treated in a cohort (ORR ≤20%) after the minimum follow-up 
specified above, then the cohort will be stopped for futility.
5.2. General Methods
As described in Section 3.4, in this study ‘treatment group’ refers to one of the following:

Cohort 1: avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients with 
locally advanced or metastatic solid tumors with one or more defects in the BRCA1 or 
BRCA2 genes;

Cohort 2: avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients with 
locally advanced or metastatic solid tumors with one or more defects in the ATM gene.
RP2D is the recommended Phase 2 dose for talazoparib when administered in combination 
with avelumab. RP2D for talazoparib was established at 1 mg PO QD. The starting dose of 
talazoparib for patients with moderate renal impairment (CLCR = 30-59 mL/min) will be 
0.75 mg PO QD to account for the lower talazoparib clearance.


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Baseline characteristics, disposition, efficacy data and PRO data will be summarized based 
on the FAS. Other data including safety data, exposure, and concomitant medications will be 
summarized based on the safety analysis set. 
All analyses will be summarized separately by treatment group and for both treatment groups 
combined unless otherwise specified; some analyses will be summarized for the appropriate 
cohort only (eg: Cohort 1 for BRCA analyses, Cohort 2 for ATM analysis, see Section 6.2.5; 
Cohort 1 for QLQ-OV28, QLQ-PR25, and QLQ-BR23, see Section 6.3.2).
5.2.1. Data handling after the cut-off date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients treated at each center.
5.2.3. Presentation of continuous and qualitative variables
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3). 
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore, counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified.
5.2.4. Definition of study day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start of study treatment + 1. 
The study day for assessments occurring prior to the first dose of study treatment (eg,
baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.


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5.2.5. Definition of start of new anti-cancer drug therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 
the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages.
5.2.6. Definition of start of new anti-cancer therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.1 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment amongst the following:

Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages

Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’ 

Surgery date recorded in ‘On-Study Anti-Cancer Surgery’, and ‘Follow-up Surgery’ 
eCRF pages when ‘Surgery Outcome’ = ‘Resected’ or ‘Partially Resected’.  
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.3.4 should be applied using ‘Follow-up Cancer Therapy’, 
‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘On-Study Anti-Cancer
Surgery’, and ‘Follow-up Surgery’ eCRF pages.
5.2.7. Definition of on-treatment period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard derivations and reporting conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.


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Demographics and physical measurements:

Age [years]: 
-
(date of given informed consent - date of birth + 1) / 365.25
-
In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth)
-
In case only year of birth is given: Age [years]: (year of given informed consent -
year of birth)
The integer part of the calculated age will be used for reporting purposes. 
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will generally be reported to one decimal 
place. The rounding will be performed to closest integer / first decimal using the common 
mid-point between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 
5, and 5.5 to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements and vital signs will include only data from scheduled visits (if such 
analyses are performed).
5.2.10. Adequate baseline tumor assessment
Adequate baseline is defined using the following criteria:

All baseline assessments must be within 28 days prior to and including the date of first 
dose of study treatment.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions assessment status at baseline for 
non-target lesions).
5.2.11. Adequate post-baseline tumor assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.1.1.1).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.


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In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’. 
5.3.1.1. Pharmacokinetic concentrations
Concentrations Below the Limit of Quantification
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables and 
figures. 
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
as anomalous by the clinical pharmacologist. If this is performed, a footnote or other 
documentation in the clinical study report (CSR) detailing the exclusions will be 
provided.
Summary statistics will not be presented at a particular time point if less than 3 evaluable 
measurements are available.  For analysis of pharmacokinetic concentrations, no values will 
be imputed for missing data.
5.3.1.2. Pharmacokinetic parameters
Actual sampling time will be used for the derivation of PK parameters.  If a PK parameter 
cannot be derived from a patient’s concentration data, the parameter will be coded as NC (ie, 
not calculated).  NC values will not be generated beyond the day that a patient discontinues.
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if less than 3 evaluable measurements are 
available.  For statistical analyses (ie, analysis of variance), PK parameters coded as NC will 
also be set to missing.
If an individual patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this will be footnoted in summary tables or flagged 
in the listings and will not be included in the calculation of summary statistics or statistical 
analyses.


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5.3.2. Handling of incomplete dates
5.3.2.1. Disease history
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows:

If the day is missing, it will be imputed to the 15th day of the month. 

If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st.

If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st. 

If the date is completely missing, no imputation will be performed.
5.3.2.2. Adverse events
Incomplete AE-related dates will be imputed as follows:

If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment.

If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015.

If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014.

In all other cases the missing onset day or missing onset month will be replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the date of cut-off outcome of AE is ongoing at cut-off. 
5.3.2.3. Prior and concomitant medications
Incomplete prior/concomitant medication dates will be imputed as follows:

If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment.

If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015. 


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
If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014.

In all other cases the missing medication day or missing medication month will be 
replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete medication stop date will not be imputed. 
5.3.2.4. Exposure
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows:

If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date

If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then 
imputed last dose date is:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date) 
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date)
= min (EOT date, death date), for all other cases.
5.3.3. Imputation rules for date of last contact and efficacy assessments
5.3.3.1. Date of last contact
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following:

All patient assessment dates (eg, blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments)

Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation

AE start and end dates

Last date of contact where “Subject Remains in Follow-up” or “Subject No Longer Being 
Followed for Survival” collected on the “Survival Follow-up” eCRF

Study drug start and end dates

Withdrawal of consent date


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
Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will not 
be applied to derive the last contact date.
5.3.3.2. Death date
Missing or partial death dates will be imputed based on the last contact date:

If the date is missing it will be imputed as the day after the date of last contact 

If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following:
-
Missing day:
1st day of the month and year of death
-
Missing day and month:
January 1st of the year of death
5.3.3.3. Tumor assessments
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year.
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates (eg,
X-ray, CT-scan).  
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment. If both a previous and following assessments are not available, this 
assessment will not be used for any calculations.
5.3.3.4. Date of start of new anti-cancer therapy
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment. If the imputation results in an end date prior to the imputed 
start date, then the imputed start date should be set to the end date.   


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
The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is
-
completely missing then it will be ignored in the imputations below
-
partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy
-
partially missing with only month and year available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy

For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below. 

If the start date of new anti-cancer therapy is completely or partially missing, then the 
imputed start date of new anti-cancer therapy is derived as follows:
-
Start date of new anti-cancer therapy is completely missing
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy]
-
Only year (YYYY) for start of anti-cancer therapy is available
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY; 
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = 01JANYYYY
-
Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available
IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND


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MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]);
ELSE IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = 01 MMM YYYY;
ELSE IF
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
THEN 
imputed start date = 01 MMM YYYY.
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology. 
6.1. Primary Endpoints
6.1.1. Objective response as assessed by the BICR per RECIST v1.1 
6.1.1.1. Primary analysis
The following analyses will be based on the FAS by treatment group and for both treatment 
group combined.  Assessment of response will be made using RECIST v1.1 for patients with 
solid tumors except mCRPC, and using RECIST v1.1 and PCWG35 for patients with 
mCRPC.  Assessments below refer to BICR assessment.  Similar analyses will be repeated 
using investigator assessment as secondary analysis.
Patients with solid tumors except mCRPC


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Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the date of first dose of study treatment until the first 
documentation of PD, according to the following rules. Only tumor assessments performed 
on or before the start date of any further anti-cancer therapies will be considered in the 
assessment of BOR.  Clinical deterioration will not be considered as documentation of
disease progression.

CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD

PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) at least 4 weeks apart and before first documentation of PD (and not qualifying for a 
CR) 

SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the date of first dose of study treatment and before 
first documentation of PD (and not qualifying for CR or PR).

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the date of first dose 
of study treatment and before first documentation of PD (and not qualifying for CR or 
PR).

PD = first documentation of PD ≤ 12 weeks after the date of first dose of study treatment
(and not qualifying for CR, PR, SD or non-CR/non-PD).  

NE:  all other cases.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met.
Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  ORR is the proportion of patients with OR in 
the analysis set.
Patients with mCRPC 
Best overall response (BOR) will be assessed based on reported overall soft tissue 
responses and bone scan assessment at different evaluation time points from the date of first 
dose of study treatment until the first documentation of PD, according to the following rules. 
Only assessments performed on or before the start date of any further anti-cancer therapies 


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will be considered in the assessment of BOR.  Clinical deterioration will not be considered as 
documentation of disease progression.

CR = at least two determinations of CR in soft tissue per RECIST v1.1 at least 4 weeks 
apart and before first documentation of PD (PD in soft tissue per RECIST v1.1 or in bone 
by PCWG3).

PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) in soft tissue per RECIST v1.1 at least 4 weeks apart and before first documentation 
of PD (in soft tissue per RECIST v1.1 or in bone by PCWG3), and not qualifying for a 
CR. 

SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the date of first dose of study treatment and before 
first documentation of PD (in soft tissue per RECIST v1.1 or in bone by PCWG3, and not 
qualifying for CR or PR). 

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the date of first dose 
of study treatment and before first documentation of PD (in soft tissue per RECIST v1.1 
or in bone by PCWG3 and not qualifying for CR or PR).

PD = first documentation of PD ≤ 12 weeks after the date of first dose of study treatment
(and not qualifying for CR, PR, SD or non-CR/non-PD).  

NE:  all other cases.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met.
Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have a post-baseline radiographic assessment of soft tissue or bone 
lesions due to early progression, who receive anti-cancer therapies other than the study 
treatments prior to reaching a CR or PR, or who die, progress, or drop out for any reason 
prior to reaching a CR or PR will be counted as non-responders in the assessment of OR. 
Each patient will have an objective response status (0: no OR; 1: OR).  ORR is the proportion 
of patients with OR in the analysis set.
ORR for all patients  
ORR by treatment group and for both treatment group combined will also be calculated along 
with the 2-sided 95% CI using the Clopper-Pearson method 2 (exact CI for a binomial 
proportion as computed by default by the FREQ procedure using the EXACT option). 


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The posterior probability of ORR 40% using the observed number of responders (patients 
with BOR of CR or PR) and the non-informative prior of (0.5, 0.5) will be provided.
In addition, the frequency (number and percentage) of patients with a confirmed BOR of CR, 
PR, SD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), PD, and NE will be tabulated. Patients with confirmed BOR of NE will be 
summarized by reason for having NE status. The following reasons will be used:

No baseline assessment 

No evidence of disease at baseline

No post-baseline assessments due to death 

No post-baseline assessments due to other reasons

All post-baseline assessments have overall response NE

New anti-cancer therapy started before first post-baseline assessment

SD of insufficient duration (<6 weeks after the date of first dose of study treatment 
without further evaluable tumor assessments)

PD too late (>12 weeks after the date of first dose of study treatment)
Special and rare cases where BOR is NE due to both SD of insufficient duration and late PD 
will be classified as ‘SD too early’ (ie, SD of insufficient duration).
6.2. Secondary Endpoint(s)
6.2.1. Safety endpoints
Refer to Section 6.6.
6.2.2. Efficacy endpoints
The following analyses will be based on the FAS by treatment group and for both treatment 
groups combined.  Assessment of response will be made using RECIST v1.11 for patients 
with solid tumors except mCRPC, and using RECIST v1.1 and PCWG3 for patients with 
mCRPC. Tumor-related endpoints will be analyzed separately based on BICR assessments 
and based on investigator assessment.  
6.2.2.1. Tumor shrinkage from baseline
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as:

((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100


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The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created by treatment group. 
These plots will display the best percentage change from baseline in the sum of the diameters
of all target lesions for each patient with measurable disease at baseline and at least one post-
baseline assessment.
6.2.2.2. Duration of response
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  
Patients with solid tumors except mCRPC: The documentation of PD is using RECIST 
v1.1.
If a patient has not had an event (PD or death), DR is censored at the date of last adequate 
tumor assessment. The censoring rules for DR are described in Table 6.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375
Patients with mCRPC: The documentation of PD is defined by either soft tissue progression 
using RECIST v1.1 or by bone disease using PCWG3, as described in Table 5.
If a patient has not had an event (PD or death), DR is censored at the date of last adequate 
tumor assessment. The censoring rules for DR are as described for PFS in Table 6.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375


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Table 5. 
Criteria for Evidence of Radiographic Progression for Patients with 
mCRPC
Date 
Progression 
Detecteda
Criteria for Progression
Criteria to Confirm 
Progression
Criteria to Document Disease 
Progression on Confirmatory 
Scan
Week 8 
Bone lesions: 2 or more 
new lesions compared to the 
baseline bone scan by 
PCWG3
Timing: At least 6 weeks 
after progression identified b  
Persistence of at least 2 lesions 
seen at week 8 AND 2 or more 
new bone lesions on bone scan 
compared to week 8 scan
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression
Week 16 or 
later
Bone lesions: 2 or more 
new lesions on bone scan 
compared to Week 8 bone 
scan
Timing: At least 6 weeks 
(or earlier, if no subsequent 
assessments performed) 
after progression identified b
Persistence of at least 2 of the 
lesions identified as new 
compared to week 8
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression 
a
Progression detected by bone scan at an unscheduled visit during the flare window should follow the 
confirmation criteria outlined for week 8.  Progression detected by bone scan at an unscheduled visit after 
the flare window should follow the confirmation criteria specified for week 16 or later.
b
Confirmation must occur at the next available scan. When 3 or more successive unconfirmed PD events 
exist that are less than 6 weeks apart, but the 1st and 3rd unconfirmed PD events are ≥6 weeks apart, the 
1st unconfirmed PD becomes the confirmed date of bone progression.
Table 6.
Outcome and Event Dates for DR Analyses
Scenario
Date of event/censoring
Outcome
PD or death 
-
After at most one missing or inadequate post-
baseline tumor assessment, OR
-
≤ 16 weeks after the date of first dose of 
study treatment
Date of PD or death
Event
PD or death 
-
After 2 or more missing or inadequate post-
baseline tumor assessments
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor 
assessments 
Censored
No PD and no death
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor 
assessments 
Censored
New anti-cancer therapy given prior to PD or death
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor 
assessments
Censored


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Scenario
Date of event/censoring
Outcome
a  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment.
Kaplan-Meier estimates4 (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median DR time with 2-sided 
95% CIs.  In particular, the DR rates at 4, 6, 8, 10 and 12 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)1 and the CIs for the survival function estimates at the time 
points defined above will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc LIFETEST)
with back transformation to a CI on the untransformed scale. The estimate of the standard 
error will be computed using Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 7 following the hierarchy shown.
Table 7. 
DR Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
Start of new anti-cancer therapy before event  
Start of new anti-cancer therapy
2 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of randomization
Event after 2 or more missing 
assessments a
3
No event and [withdrawal of consent date ≥ date of 
randomization] 
Withdrawal of consent
4
No event and lost to follow-up in any disposition page 
Lost to follow-up
5
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
6.2.2.3. Time to response
Time to response (TTR) is defined, for patients with OR, as the time from the date of first 
dose of study treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
Patients with solid tumors except mCRPC: The first documentation of objective response 
(CR or PR) is using RECIST v1.1.


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Patients with mCRPC: The first documentation of objective response is the first objective 
evidence of soft tissue response using RECIST v1.1 with no evidence of confirmed bone 
disease progression per PCWG3.
TTR (in months) = [first date of OR – the date of first dose of study treatment
+1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.2.4. Progression-free survival
Progression-Free Survival (PFS) is defined as the time from the date of first dose of study 
treatment to the date of the first documentation of PD or death due to any cause, whichever 
occurs first.   
Patients with solid tumors except mCRPC: 
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.  Patients who do not have an adequate baseline tumor assessment or who do not 
have an adequate post-baseline tumor assessment will be censored on the date of first dose of 
study treatment unless death occurred on or before the time of the second planned tumor 
assessment (ie ≤ 16 weeks after the date of first dose of study treatment) in which case the 
death will be considered an event. 
In this study, antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and every 8 weeks until PD regardless of initiation of subsequent 
anti-cancer therapy.  After 52 weeks from the date of first dose of study treatment, tumor 
assessments will be conducted less frequently, ie, at 16-week intervals.
Patients with mCRPC: 
Progression-Free Survival (PFS) is defined as the time from the date of first dose of study 
treatment to the date of the first documentation of PD as described in Table 8 or death due to 
any cause, whichever occurs first. 
In this study, antitumor activity in patients with mCRPC will be assessed through 
radiological tumor assessments conducted at screening, every 8 weeks (± 7 days) until PD 
regardless of initiation of subsequent anti-cancer therapy.  After 24 weeks from the date of 
first dose of study treatment, tumor assessments will be conducted less frequently, ie, at 12-
week intervals.
The censoring and event date options to be considered for the PFS analysis are presented in 
Table 8.  
PFS (months) = [date of event or censoring– date of first dose of study treatment 
+1]/30.4375


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Table 8.
Outcome and Event Dates for PFS Analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of first dose of study 
treatment a
Censored a
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 16 weeks after the date of first dose of 
study treatment
Date of PD or death
Event
PD or death 
-
After 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
No PD and no death
Date of last adequate tumor
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
New anti-cancer therapy given prior to PD or 
death
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a However if the patient dies ≤16 weeks after the date of first dose of study treatment and did not initiate new 
anti-cancer therapy, the death is an event with date on death date
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment
Kaplan-Meier estimates4 (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with 2-sided 
95% CIs.  In particular, the PFS rates at 4, 6, 8, 10, 12, 14, 16 and 18 months will be 
estimated with corresponding 2-sided 95% CIs.  The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982)1 and the CIs for the survival function 
estimates at the time points defined above will be derived using the log-log transformation 
according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc 
LIFETEST) with back transformation to a CI on the untransformed scale. The estimate of the 
standard error will be computed using Greenwood’s formula.  
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 9 following the hierarchy shown.


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Table 9.
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy before event
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/ date of first dose of study treatment
Event after missing assessments a
4
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [disposition page for any epoch after 
screening says patient will not continue into any 
subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A Kaplan-Meier plot for PFS follow-up duration will also be generated to assess the follow-
up time in the treatment groups reversing the PFS censoring and event indicators, including 
the median time of follow-up for PFS with 2-sided 95% CIs.
6.2.2.5. Overall Survival
Overall survival (OS) is defined as the time from the date of first dose of study treatment to 
the date of death due to any cause. Patients last known to be alive will be censored at date of 
last contact.
OS (months) = [date of death or censoring– date of first dose of study treatment 
+1]/30.4375
Kaplan-Meier estimates4 (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median OS time with 2-sided 
95% CIs.  In particular, the OS rates at 4, 6, 8, 10, 12, 14, 16, 18 and 24 months will be 
estimated with corresponding 2-sided 95% CIs.  The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982)1 and the CIs for the survival function 
estimates at the time points defined above will be derived using the log-log transformation 
according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc 
LIFETEST) with back transformation to a CI on the untransformed scale. The estimate of the 
standard error will be computed using Greenwood’s formula.  


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Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according to 
the categories in Table 10 following the hierarchy shown.
Table 10.
OS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment OR End of study (EOS) = Patient
refused further follow-up] 
Withdrawal of consent
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 14 weeks] 
Lost to follow-up
3
No event and none of the conditions in the prior hierarchy 
are met 
Alive
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for OS
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the OS censoring and event indicators, including the 
median time of follow-up for OS with 2-sided 95% CIs.  
6.2.2.6. Time to PSA progression for patients with metastatic CRPC 
Time to PSA progression for patients with mCRPC is defined as the time from the date of 
first dose of study treatment to the date that a 25% increase in PSA with an absolute 
increase of 2 g/L (2 ng/mL) above the nadir (or baseline for patients with no PSA decline) 
is documented. PSA progression must be confirmed by a second, consecutive PSA 
assessment 3 weeks later.
Time to PSA progression will be censored on the date of the last PSA assessment for patients 
who do not have an event (confirmed PSA progression), for patients who start a new anti-
cancer therapy prior to an event (see Section 5.2.6) or for patients with an event after 2 or 
more missing PSA assessments.  Patients who do not have a baseline PSA assessment or who 
do not have a post-baseline PSA assessment will be censored on the date of the first dose of 
study treatment. 
PSA assessments will be conducted at screening, every 4 weeks ± 2 days, and at the EOT.  
The censoring and event date options to be considered for the time to PSA progression 
analysis are presented in Table 11.
Time to PSA progression (months) = [date of PSA progression or censoring– date of 
first dose of study treatment +1]/30.4375


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Table 11.
Outcome and event dates for Time to PSA progression analysis 
Scenario
Date of event/censoring
Outcome
No PSA assessment at baseline
Date of first dose of study treatment
Censored 
PSA progression (subsequently 
confirmed), after at most one missing 
PSA assessment.
Date of first PSA progression 
Event
PSA progression (subsequently 
confirmed) after 2 or more missing 
PSA assessments 
Date of last PSA assessment 
documenting no PSA progression 
before new anti-cancer therapy is 
given or missed PSA assessments 
Censored
PSA progression not confirmed or no 
PSA progression
Date of last PSA assessment 
documenting no PSA progression 
before new anti-cancer therapy is 
given or missed PSA assessments
Censored
New anti-cancer therapy prior to 
confirmed PSA progression 
Date of last PSA assessment 
documenting no PSA progression 
before new anti-cancer therapy is 
given or missed PSA assessments
Censored
Kaplan-Meier estimates4 (product-limit estimates) will be presented together with a summary 
of associated statistics including the median time to PSA progression with 2-sided 95% CIs.  
In particular, the PSA progression rate at 4, 6, 8, 10, 12, 14, 16, and 18 months will be 
estimated with corresponding 2-sided 95% CIs. The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982)1 and the CIs for the survival function 
estimates at the time points defined above will be derived using the log-log transformation 
according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc 
LIFETEST). The estimate of the standard error will be computed using Greenwood’s 
formula.  
Frequency (number and percentage) of patients with an event and patients censored will be 
presented.  The time to PSA progression or censoring time will also be presented in a patient 
listing.
6.2.2.7. PSA response for patients with metastatic CRPC
PSA response is defined as PSA decline 50% compared to baseline. PSA response must be 
confirmed by a second, consecutive PSA assessment 3 weeks later.   
PSA response will be assessed based on PSA assessments at different evaluation time points 
from the date of first dose of study treatment until PSA progression. Only PSA assessments 
performed on or before the start of any further anti-cancer therapies will be considered in the 
assessment of PSA response.  

PSA response = at least 2 assessments, at least 3 weeks apart with ≥ 50% reduction in 
PSA level from baseline.

No PSA response = all other cases.


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Each patient will have a PSA response status (0: no PSA response; 1: PSA response).  PSA 
response rate is the proportion of patients with PSA response in the analysis set.
PSA response rate will be calculated along with the 2-sided 95% CI using the Clopper-
Pearson method (exact CI for a binomial proportion as computed by default by the FREQ 
procedure using the EXACT option).   
A spider plot of the percent change in PSA value from baseline per time point and a waterfall 
plot of the best percentage change in PSA value from baseline will be created. These plots
will display for each patient with a baseline assessment and at least one post-baseline 
assessment.
6.2.2.8. CTC count conversion and CTC0 for patients with metastatic CRPC
The following analyses will be based on the FAS separately by treatment group and for both 
treatment groups combined. 
CTC count conversion is defined as a decrease in CTC count from ≥ 5 CTC per 7.5 mL of 
blood at baseline to < 5 CTC per 7.5 mL of blood on study. Only the CTC count assessments 
performed on or before the start of any further anti-cancer therapies will be considered in the 
assessment of CTC count conversion. The analysis set will include all patients with CTC 
count ≥ 5 CTC per 7.5 mL at baseline. All other patients will be considered as non-evaluable. 
The patients in the analysis set will be counted as: 

CTC count conversion = one or more post-baseline assessment(s) of CTC count < 5 CTC 
per 7.5 mL 

No CTC count conversion = all other cases.
Patients with CTC count ≥ 5 CTC per 7.5 mL at baseline and who do not have a post-
baseline CTC count assessment will be counted as no CTC count conversion. Each patient in 
the analysis set will have a CTC count conversion status (0: no CTC count conversion; 1: 
CTC count conversion). The CTC count conversion rate is the proportion of patients with 
CTC count conversion rate in the analysis set.
A waterfall plot of maximum percent decrease in CTC count from baseline will be created 
for all patients with CTC count ≥ 5 CTC per 7.5 mL at baseline. The plot will display the 
best percentage change from baseline in CTC count for each patient with a baseline 
assessment and at least one post-baseline assessment.
CTC0 is defined as a decrease in CTC count from ≥ 1 CTC per 7.5 mL of blood at baseline 
to an undetectable level on study. Only the CTC count assessments performed on or before 
the start of any further anti-cancer therapies will be considered in the assessment of CTC0. 
The analysis set will include all patients with CTC count ≥ 1 CTC per 7.5 mL at baseline. All 
other patients will be considered as non-evaluable. The patients in the analysis set will be 
counted as: 

CTC0 = one or more post-baseline CTC count are at undetectable level(s)

No CTC0 = all other cases.


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Patients with CTC count ≥ 1 CTC per 7.5 mL at baseline and who do not have a post-
baseline CTC count assessment will be counted as no CTC0. Each patient in the analysis set 
will have a CTC0 status (0: no CTC0; 1: CTC0). The CTC0 rate is the proportion of patients 
with CTC0 in the analysis set.
The CTC count conversion rate and CTC0 rate by treatment group and for both treatment 
groups combined will be calculated along with the 2-sided 95% CI using the Clopper-
Pearson method (exact CI for a binomial proportion as computed by default by the FREQ 
procedure using the EXACT option).   
6.2.2.9. CA-125 response for patients with ovarian cancer 
CA-125 response is defined as ≥ 50% reduction in CA-125 levels from baseline.  CA-125 
response must be confirmed by a second, consecutive CA-125 value 4 weeks later.   
CA-125 response will be assessed based on the CA-125 values (ng/mL) collected at baseline
and at different time points from the date of first dose of study treatment until EOT, 
according to the following rule. Only CA-125 value collected on or before the start of any 
further anti-cancer therapies will be considered in the assessment of CA-125 response. 

CA-125 response = at least 2 consecutive assessments 4 weeks apart with ≥ 50% 
reduction in CA-125 level from baseline.

No CA-125 response = all other cases
Each patient will have a CA-125 response status (0: no CA-125 response; 1: CA-125 
response).  CA-125 response rate is the proportion of patients with CA-125 response in the 
analysis set.
CA-125 response rate will be calculated along with the 2-sided 95% CI using the Clopper-
Pearson method (exact CI for a binomial proportion as computed by default by the FREQ 
procedure using the EXACT option).    
A waterfall plot of maximum percent decrease in CA-125 value from baseline will be 
created. The plot will display the best percentage change from baseline in CA-125 value for 
each patient with a baseline assessment and at least one post-baseline assessment.
6.2.2.10. BICR vs Investigator Assessment
Table 12.
outlines the possible BOR outcomes by investigator and BICR. 
Table 12.
Possible BOR Outcomes for Investigator vs BICR
BOR
BICR Assessment
CR
PR
SD
Non-CR/ non-PD
PD
NE
Investigator 
Assessment
CR
n11
n12
n13
n14
n15
n16
PR
n21
n22
n23
n24
n25
n26
SD
n31
n32
n33
n34
n35
n36


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Non-CR/ non-PD
n41
n42
n43
n44
n45
n46
PD
n51
n52
n53
n54
n55
n56
NE
n61
n62
n63
n64
n65
n66
∑
ሺ݊௜௜ሻ
଺
௜ୀଵ
is the number of agreements on BOR between BICR and Investigator 
∑
൫݊௜௝൯
଺
௜,௝ୀଵ
for i ≠ j is the number of disagreements on BOR between BICR and Investigator 
N= ∑
൫݊௜௝൯
଺
௜,௝ୀଵ
The following measures of concordance will be calculated for each treatment group:
•
Concordance rate for BOR = ∑
ሺ݊௜௜ሻ
଺
௜ୀଵ
/ܰ
•
Concordance rate for response =  ሾ∑
൫݊௜௝൯൅∑
൫݊௜௝൯ሿ/ܰ
଺
௜,௝ୀଷ
ଶ
௜,௝ୀଵ
Concordance rates are calculated for the treatment groups combined.  
6.2.3. Pharmacokinetic endpoints
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
group and for both treatment groups combined.  
For this study, two PK samples (pre-dose and post-dose) are taken for each analyte in cycles 
with scheduled PK assessments.
For avelumab, the pre-dose and post-dose concentrations correspond to Ctrough and Cmax PK 
parameters, respectively. The actual time of the occurrence of avelumab Cmax will be reported 
as Tmax. The time difference between avelumab EOI and Tmax will also be reported. 
For talazoparib, the pre-dose and post-dose concentrations correspond to Ctrough PK 
parameter and the post-dose concentration, respectively. One table will be generated for the 
parameters, which will include concentrations labelled as “Pre-dose/Ctrough” and “Post-dose”. 
The post-dose talazoparib concentration and its actual time relative to talazoparib dose (ie, 
Actual Elapsed Time) will also be reported.
Pharmacokinetic parameters for avelumab and talazoparib will be taken from observed 
values or derived from plasma concentration-time data as described in Section 3.2.3.
Presentation of pharmacokinetic data will include:
•
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean
and its associated %CV and 95% CI) of plasma concentrations and pharmacokinetic 
parameters will be presented in tabular form by cycle, day, and nominal time. 
Additionally, similar descriptive statistics will also be generated for dose-normalized 
avelumab and talazoparib pharmacokinetic parameters, as appropriate.
•
Linear-linear plots of mean or median plasma concentrations by nominal time for 
avelumab and talazoparib will be presented for PK sampling days by cycle and study day. 


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
Pharmacokinetic parameters for avelumab and talazoparib will be listed and summarized
by cycle and study day using descriptive statistics (n, mean, SD, %CV, median, 
minimum, maximum, geometric mean, and its associated %CV, and 95% CI). For Tmax, 
the range (min, max) will also be provided. PK parameters with zero values will be 
excluded from the calculation of geometric means and its associated %CV. 

The trough concentrations for avelumab and talazoparib will be plotted using a box 
whisker plot by cycle and day in order to assess the attainment of steady state. Ctrough (and 
Cmax as deemed appropriate) for avelumab and talazoparib will be plotted using box-
whisker plots by treatment group and cycle and day within cycle for data corresponding 
to the summary statistics described above. Individual data points, the geometric mean,
and the median of the parameter in each treatment will be overlaid on the box plots. If a 
treatment group has limited evaluable PK data (n<4), matchstick plots showing changes 
in Ctrough and/or Cmax or post-dose concentration for each analyte in individual patients 
will then be generated. The geometric mean of the parameter in each treatment will be 
overlaid in the plots. Patients who have undergone intra-patient dose reduction or 
escalation will be excluded from the summary tables and figures.

Data from patients assigned a reduced talazoparib dose based on renal impairment status 
may be pooled with normal renal function patients receiving a 1 mg dose or may be 
presented separately at the discretion of the clinical pharmacologist.
6.2.4. Population pharmacokinetic endpoints
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab and/or talazoparib exposure and biomarkers or significant 
safety/efficacy endpoints. The results of these analyses, if performed, may be reported 
separately.
6.2.5. Biomarker endpoints
Secondary endpoints in the study are candidate predictive biomarkers in tumor tissue and in 
ctDNA including, but not limited to, centrally assessed PD-L1 expression, BRCA1/2, ATM 
and TMB. Defects in a panel of key oncogenes, including BRCA1, BRCA2, and ATM will 
also be assessed in germline DNA. 
Biomarker data will be analyzed based on the full analysis set or biomarker analysis sets, 
depending on the specific analysis, separately by treatment group and for both treatment 
groups combined, unless specified.
For PD-L1 expression level, patients may be classified as positive, negative, or some other 
category according to scoring algorithms and cut-offs established from external sources.  If 
no external standards exist, patients may be stratified using the median, quartiles, and tertiles. 
For example, patients may be categorized based on PD-L1 expression level ≥ 50%, < 50% 
and >0, equal to 0, or Unknown. The number and percentage of patients in each category will 
be tabulated. 


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For TMB, patients will be classified as high, medium, low, or Unknown, or alternatively as 
high, low, or unknown. The number and percentage of patients in each category, by sample 
source (tumor tissue, ctDNA) and by timepoint (baseline, and when available on-treatment, 
and at the end of treatment), will be tabulated.
Where sample numbers of a given tumor histology are sufficient to support such an analysis, 
TMB and PD-L1 may also be analyzed as described above but tabulated based on individual 
tumor histologies.
For defects in BRCA1 and BRCA2 by central laboratory analysis, patients will be classified 
as positive, negative or unknown. The number and percentage of patients in each category of 
BRCA 1 defect, BRCA 2 defect, BRCA 1 or BRCA 2 defect, by sample source 
(somatic/tumor tissue, germline DNA, ctDNA), and by timepoint (baseline, and on-
treatment/at the end of treatment as appropriate), will be presented for Cohort 1. 
For defects in ATM by central laboratory analysis, patients will be classified as positive,
negative or unknown. The number and percentage of patients in each category of ATM, by 
sample source (somatic/tumor tissue, germline DNA, ctDNA) and by timepoint (baseline, 
and on-treatment/at the end of treatment as appropriate) will be presented for Cohort 2.
The following analyses will be performed for each biomarker secondary endpoint.
BOR will be summarized for each category of the biomarkers following the methodology 
outlined in Section 6.1.1. The number of responders (patients with BOR of CR or PR) will be 
tabulated relative to biomarker classifications using a contingency table and a Fisher’s exact 
test will be performed.
 
 
 
6.2.6. Endpoints for immunogenicity data of avelumab 
All analyses described below are performed by treatment group and for both treatment 
groups combined. 
Blood samples for avelumab immunogenicity testing will be collected pre-dose on Day 1 and 
Day 15 of Cycle 1, on Day 1 of Cycle 3 and then on Day 1 of Cycle 6, 12, 18, and 24. All 
samples should be drawn within 2 hours before start of avelumab infusion.  Additional 
samples for anti-avelumab antibodies (and simultaneous PK draws for measurement of 
avelumab) will be collected at EOT visit. 
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb. Analyses 
of nAb data described in the following sections will only be conducted contingent upon assay and 
data availability at the time of reporting. 
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Patients will be characterized into different ADA categories based on the criteria defined in 
Table 13.    
Table 13.
Patients Characterized Based on Anti-Drug Antibody Results (ADA Status)
Category
Definition
Patients at Risk (Denominator for 
Incidence)
ADA never-positive 
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint)
Number of patients with at least one 
valid ADA result at any time point
ADA ever-positive 
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint)
Number of patients with at least one 
valid ADA result at any time point
Baseline ADA 
positive
A positive ADA result at baseline
Number of patients with valid baseline 
ADA result
Treatment-boosted 
ADA
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result
Treatment-induced 
ADA
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive post-baseline 
ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Transient ADA 
response
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Persistent ADA 
response
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
ADA: anti-drug antibody, NR = not reportable.
Patients will be characterized into different nAb categories based on the criteria in Table 14. 
For nAb, treatment-boosted is not applicable since no titer result is available.


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Table 14.
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status)
Category
Definition
Patients at Risk (Denominator for 
Incidence)
nAb never-positive 
No positive nAb results at any time point
(including no positive ADA results at any 
time point and no nAb results)
Number of patients with at least one 
valid ADA result at any time point
nAb ever-positive 
At least one positive nAb result at any time 
point
Number of patients with at least one 
valid ADA result at any time point
Baseline nAb 
positive
A positive nAb result at baseline
Number of patients with valid baseline 
ADA result
Treatment-induced 
nAb
Patient is not nAb positive at baseline and has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive post-
baseline ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
Transient nAb 
response
If patients with treatment-induced nAb have (a 
single positive nAb result or duration between 
first and last positive result <16 weeks) and 
nAb result at the last assessment is not 
positive.
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR)
Persistent nAb 
response
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
ADA = antidrug antibody, nAb = neutralizing antibody, NR = not reportable.
The number and percentage of patients in each ADA and nAb category will be summarized. 
In order to derive and interpret persistent and transient ADA responses, the ADA and nAb 
analyses described below will include patients with treatment-induced ADA or nAb, 
respectively.  
Time (weeks) to ADA response is defined as:
(Date of first positive ADA result – date of first dose of avelumab + 1)/7. 
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).  
Duration (weeks) of ADA response is defined as:
(Date of last positive ADA result – date of first positive ADA result + 1)/7. 
Duration of ADA response will be censored if: 

the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or

the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (EOT visit) is after the cut-off date. As data 


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permit, the analyses described above will be repeated for patients with treatment-induced 
nAb.
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result. 
Based on the results observed, additional analyses may be performed for ADA including PK, 
safety and/or efficacy relationships. 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
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6.4. Subset Analyses
6.4.1. Objective response and progression-free survival
OR and PFS (if meaningful) will also be summarized based on the FAS for patients in the 
following subsets and following the methodology outlined in Section 6.1.1 and in Section 
6.2.2.4 based on BICR assessment.
The subset analyses will be presented for each cohort and subset, and for both cohorts 
combined and subset when appropriate.  Subset analyses will be performed only if there are 
at least 10 patients in the associated cohort(s) and each subset. Subset analyses will be 
performed by tumor type. In addition, the following subset analyses will be performed.
For all patients and by tumor type:
•
ECOG: 0, ≥1
•
Number of prior anti-cancer drug therapy regimens: ≤ 2, ≥ 3 
•
PD-L1 status: Positive, Negative, Unknown
•
TMB: High, Medium, Low, Unknown
•
BRCA from local laboratory test: BRCA1, BRCA2, BRCA1 or BRCA2
•
Measurable disease at baseline based on BICR assessment: Yes
•
BRCA-dependent status: Yes, No
•
BRCA-associated status: Yes, No
The definition of the BRCA-dependent status and BRCA-associated status of tumor types 
will be based on clinical assessment, using the BRCA result from the local laboratory test.
In addition, for patients with breast cancer:
•
Received prior platinum treatment for locally advanced or metastatic disease: Yes, No
•
Number of prior anti-cancer drug therapy regimens for locally advanced or metastatic 
disease: 0, 1, ≥ 2 
•
Received prior cytotoxic chemotherapy for locally advanced or metastatic disease: Yes, 
No
For patients with ovarian cancer:
•
Number of prior platinum-based regimens:  ≤ 2, ≥ 3
•
Number of prior cytotoxic chemotherapy regimens:  ≤ 2, ≥ 3
•
Platinum status: sensitive, resistant
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For patients with mCRPC:

Measurable disease at baseline based on BICR assessment: Yes, No

Measurable disease at baseline based on investigator assessment: Yes, No

Received prior taxane-based regimen: Yes, No 
6.4.2. PSA response for patients with metastatic CRPC 
PSA response will be summarized based on the FAS for the subset of patients with mCRPC
with measurable disease at baseline based on BICR assessment and the subset of patients 
with mCRPC and no measurable disease at baseline based on BICR assessment, following 
the methodology outlined in Section 6.2.2.7 and the definition in Section 6.5.1.3. The subset 
analyses will be presented for each cohort and subset, and for both cohorts combined and 
subset when appropriate.
6.4.3. CTC count conversion for patients with metastatic CRPC 
CTC count conversion will be summarized based on the FAS for the subset of patients with 
mCRPC with measurable disease at baseline based on BICR assessment and the subset of 
patients with mCRPC and no measurable disease at baseline based on BICR assessment, 
following the methodology outlined in Section 6.2.2.8 and the definition in Section 6.5.1.3.
The subset analyses will be presented for each cohort and subset, and for both cohorts 
combined and subset when appropriate.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline summaries
The following analyses will be based on the FAS overall and separately by treatment group.
6.5.1.1. Demographic characteristics
Demographic characteristics will be summarized by treatment group using the following 
information from the ‘Screening/Baseline Visit’ eCRF pages.

Demographic characteristics 
-
Gender: Male, Female 
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Unknown
-
Ethnic origin: 

Hispanic or Latino 

Not Hispanic or Latino
-
Age (years): summary statistics 
-
Age categories: 

< 65 years, ≥ 65 years 

< 65, 65-<75, 75-<85, ≥ 85 years


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-
Pooled Geographical Region (as applicable): 

North America 

Europe

Asia

Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including > 10% of the overall 
treated population)
-
Geographic Region (as applicable):

North America

Latin America

Western Europe

Eastern Europe

Middle East

Australasia

Asia

Africa
-
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4 
Center codes will be used for the determination of the patient’s geographic region.
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity and ECOG 
performance status.
6.5.1.2. Medical history
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order.
6.5.1.3. Disease characteristics
Information on disease characteristics collected on ‘Primary Diagnosis’ and RECIST eCRF 
pages will be summarized overall and by treatment group. Summary statistics will be 
presented for the following.
From the ‘Primary Diagnosis’ eCRF page:


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
Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page)

Tumor type, derived from the primary diagnosis eCRF page based on clinical assessment
From the RECIST eCRF page:
Measurable disease (lesions) at baseline (Yes, No, No disease)
Involved tumor sites at baseline
From the BICR assessment:
Measurable disease (at least one target lesion in soft tissue by BICR assessment) at 
baseline (Yes, No, No disease)
Involved tumor sites at baseline
Visceral disease (yes, no)
Central nervous system metastasis at baseline (yes, no)
Presence of liver metastasis at baseline in pancreatic cancer patients (yes, no)
From the Gleason Score for Prostate Cancer:

Total Gleason score at diagnosis (≤ 7, ≥ 8)
From the Laboratory results:

Baseline lactate dehydrogenase (LDH): <threshold, ≥ threshold (threshold value will come 
from external information; if it is not the case, the median value will be selected as 
threshold)
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ eCRF page) and derived variables as above.
6.5.1.4. Prior anti-cancer therapies
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages.
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated:

Patients with at least one type of prior anti-cancer therapy

Patients with at least one prior anti-cancer drug therapy

Patients with at least one prior anti-cancer radiotherapy

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Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following:

At least one prior anti-cancer drug therapy

Number of prior anti-cancer drug therapy regimens: missing, 0, 1, 2, 3, ≥4

Intent of Drug Therapy: Neo-Adjuvant, Adjuvant, Advanced – Metastatic/Local regional 
Disease-Recurrence

Best response: CR, PR, SD, PD, Unknown, Not applicable. Best response is derived from 
the last treatment regimen.
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with breast cancer with the following:

At least one prior platinum-containing regimen

Number of prior platinum-containing regimens: missing, 1, 2, 3, ≥4
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with ovarian cancer with the following:

At least one prior platinum-containing regimen

Number of prior platinum-containing regimens: missing, 1, 2, 3, ≥4
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with mCRPC with the following:

At least one prior taxane-containing regimen

Number of prior taxane-containing regimens: missing, 1, 2, 3, ≥4
Prior anti-cancer drug therapies will be included in the listing that follow with a flag to 
identify prior therapies. These will include the patient identification number, and all the 
relevant collected data-fields on the corresponding eCRF pages.

Listing of anti-cancer drug therapies 
6.5.2. Study conduct and patient disposition
The following analyses will be performed based on the FAS overall and separately by
treatment group.
6.5.2.1. Patient disposition
The percentages below will be calculated based on the number of patients in the FAS.

Total number of patients screened overall

Number of patients who discontinued from the study prior to treatment with study drug 
overall and by the main reason for discontinuation

Number and percentage of treated patients in each of the analysis sets defined in Section 4


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
Number and percentage of patients with study drug ongoing (separately for each study 
drug administered in combination)

Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug (separately for each study drug administered in 
combination)

Number and percentage of patients who entered follow-up

Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation

Number and percentage of patients who entered long-term follow-up

Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation
In addition, the following will be summarized:

Number and percentage of treated patients overall, by region, country and center
In addition, a cross tabulation of patients who have discontinued/are ongoing treatment with 
avelumab vs patients who have discontinued/are ongoing treatment with talazoparib will also 
be provided. 
6.5.2.2. Protocol deviations
All protocol violations that impact the safety of the patients and/or the conduct of the study 
and/or its evaluation will be reported. These include:

Patients who are dosed on the study despite not satisfying the inclusion criteria

Patients who develop withdrawal criteria whilst on the study but are not withdrawn

Patients who receive the wrong treatment 

Patients who receive an excluded concomitant medication

Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study treatment compliance and exposure
The following analyses will be based on the safety analysis set by treatment group and for 
both treatment groups combined.
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.  


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For Cycle X, actual cycle start date for each patient is

the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the patient 
received study treatment on that visit (ie, any study drug with dose>0 at that visit)

the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit.
Actual cycle end date for each patient is, 

for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date 
– 1 day;

for the last cycle, actual cycle end date = actual cycle start date + 28 (in days) – 1 day
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7
When summarizing exposure for each study drug, only cycles from first dose of study
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.   
Exposure may be summarized as dose received (cumulative dose, actual dose intensity) and 
as dose received relative to intended dose (relative dose intensity [RDI]).  
The information that will be summarized depends on how the study drug is dosed (eg, 
infusion cyclical, oral daily). The formulae below should be applied to each study drug 
separately even when study drugs are administered in combination.
The derivations below are provided assuming 1 cycle = 4 weeks and for the following study 
drugs (administered alone or in combination):

Avelumab administered as a 1-hour IV infusion at a dose of 800 mg once every 2 weeks 
in 4-week cycles. 

Talazoparib administered orally QD PO at the RP2D (mg) for talazoparib when 
administered in combination with avelumab.
6.5.3.1. Exposure to avelumab 
The dose level for avelumab is calculated as actual dose administered (mg). 


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Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle with non-zero dose of study drug + 28 – 1
Duration of exposure to avelumab (weeks) = 
(last dose date of avelumab – first dose date of avelumab + 14)/7  
Cumulative dose (mg) is the sum of the actual doses of avelumab received.  
Actual Dose Intensity (DI)

Overall actual DI (mg/4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/4].  
Relative Dose Intensity (RDI)  

Intended DI (mg/4-week cycle) 
= [intended cumulative dose per cycle] / [intended number of 4-weeks in a cycle] 
= [2 × 800 (mg)] / [1 (4-week cycle)]  
= 1600 (mg/4-week cycle)

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                    
= 100 × [overall actual DI] / [1600 (mg/4-week cycle)] 
6.5.3.2. Exposure to talazoparib  
The dose level is calculated as actual dose administered (mg/day).  
Intended duration of treatment with talazoparib (weeks) = (end date – date of first dose 
of talazoparib +1)/7, 
where end date = date of last dose of talazoparib.
Duration of exposure to talazoparib (weeks) = 
(last dose date of talazoparib – first dose date of talazoparib + 1)/7  
Note: For talazoparib, the duration of exposure and the intended duration of treatment are the 
same.
Cumulative dose (mg) is the sum of the actual doses of talazoparib received in the study.  
Actual Dose Intensity (DI)

Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)]   
Relative Dose Intensity (RDI)  


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
RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of talazoparib to last dose of talazoparib]  
= 100 × [overall cumulative dose] / [7 × d × duration of exposure to talazoparib in weeks]
where d is the RP2D (mg) for talazoparib when administered in combination with avelumab.
6.5.3.3. Dose reductions 
Applicable to avelumab. Dose reduction is defined as actual non-zero dose < 90% of the 
planned dose. 
Applicable to talazoparib. Dose reduction is defined as a change to a non-zero dose level 
lower than that planned in the protocol.
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized. 
6.5.3.4. Dose interruptions
Applicable to talazoparib.  
An interruption is defined a 0 mg dose administered on one or more days for talazoparib. 
What follows defines how dose interruptions will be counted in the case of multiple dose 
interruptions.

If an interruption occurs consecutively for at least two days, then it will be counted only 
once (example: If the actual dose on days 1-3 is at the RP2D and actual dose on days 4-5 
is 0 mg, then the total number of dose interruptions is 1).

If an interruption occurs for more than one day but the days are not consecutive, ie there is 
at least one dosing day in between, then each dose interruption will be counted as a different 
occurrence (example: If the actual dose on days 1, 3 and 5, is at the RP2D and actual dose 
on days 2 and 4 is 0 mg, the total number of dose interruptions is 2). 
A dose interruption is not considered a dose reduction.
The number and percentage of patients with dose interruptions and the corresponding reasons 
will be summarized.
6.5.3.5. Dose delays 
Applicable to avelumab.
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses. 
For Cycle 1:
Dose Delay (days) = day of the first day of study drug -1


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After Cycle 1:
       Dose Delay for Dose x (days) 
       = Date of Dose x – Date of Dose (x-1) – Planned days between two consecutive doses
       = Date of Dose x – Date of dose (x-1) – 15
Dose delays will be grouped into the following categories: 

No delay 

1-3 days delay

4-6 days delay

7 or more days delay
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16 or 17, this is considered as 1-2 days delay.  
No delay and 1-3 days delay will also be summarized together. 
The number and percentage of patients with delayed study drug administration and maximum 
length of delay, ie, the worst case of delay if patients have multiple dose delays will be 
summarized. 
6.5.3.6. Infusion rate reductions
Applicable to avelumab.
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the eCRF as well as the frequency of patients 
with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% will be summarized.
6.5.3.7. Infusion interruptions
Applicable to avelumab.
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded).
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized.
6.5.4. Concomitant medications and non-drug treatments
The following analyses will be based on the safety analysis set by treatment group.
Concomitant medications are medications, other than study drugs, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 


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study drugs and pre-medications for study drug, which are started before the first dose of 
study treatment. 
Concomitant medications will be summarized from the ‘General Concomitant Medications’ 
eCRF page. 
Summary of concomitant medications will include the number and percentage of patients by 
Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred term. A patient 
will be counted only once within a given drug class and within a given drug name, even if 
he/she received the same medication at different times. If any concomitant medication is 
classified into multiple ATC classes, the medication will be summarized separately under 
each of these ATC classes. The summary tables will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used. In 
case any specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category. 
6.5.5. Subsequent anti-cancer therapies
The following analyses will be based on the FAS by treatment group.
Anti-cancer drug treatment will be provided in a data listing with data retrieved from 
‘Follow-up Cancer Therapy’ eCRF page. 
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Surgery’ eCRF pages. 
6.6. Safety Summaries and Analyses
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of
AEs and other safety parameters will be based on the safety analysis set by treatment group.  
6.6.1. Adverse events
TEAEs are those events with onset dates occurring during the on-treatment period as defined 
in Section 3.5.1.
All analyses described in what follows will be based on TEAEs (started during the on-
treatment period) if not otherwise specified. The AE listings will include all AEs (whether 
treatment-emergent or not). AEs outside the on-treatment period will be flagged in the 
listings.

Related Adverse Events: adverse events with relationship to study treatment (as recorded 
on the AE eCRF page, Relationship with study treatment = Related) reported by the 
investigator and those of unknown relationship (ie, no answer to the question ‘Relationship 
with study treatment’). Related AEs are those related to any study drug (ie, at least one of 
the study drugs).


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
Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).

Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction of 
study treatment (as recorded on the AE eCRF page, Action taken with study treatment = 
Dose reduced).

Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).  IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion.

Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).  

Adverse Events Leading to Death: adverse event leading to death (as recorded on the AE 
eCRF page, Outcome = Fatal, as well as AEs of Grade 5).

Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan [SRP] and finalized for analysis of the current study
data prior to DB lock)

Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs documented in the 
SRP and finalized for analysis of the current study data prior to DB lock.
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment group, primary SOC 
and PT in decreasing frequency based on the frequencies observed for the treatment groups 
combined. 
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity.
6.6.1.1. All adverse events
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the latest version of MedDRA PT as event category and MedDRA 
primary SOC body term as Body System category. 
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed. 
The following tables will be created: 


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
The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment group:
-
TEAEs
-
TEAEs, Grade ≥ 3
-
Related TEAEs
-
Related TEAEs, Grade ≥ 3
-
TEAEs leading to dose reduction of talazoparib
-
TEAEs leading to discontinuation of any study drug
-
TEAEs leading to discontinuation of all study drugs
-
Related TEAEs leading to discontinuation of any study drug
-
Related TEAEs leading to discontinuation of all study drugs
-
Serious TEAEs
-
Related Serious TEAEs 
-
TEAEs leading to death
-
Related TEAEs leading to death
-
irAEs
-
IRRs 

TEAEs by SOC and PT and worst grade

TEAEs related to any study drug by SOC and PT and worst grade

TEAEs leading to death by SOC and PT

Related TEAEs leading to death by SOC and PT
6.6.1.2. Adverse events leading to dose reduction
The frequency (number and percentage) of patients with each of the following will be presented 
for TEAEs leading to dose reduction of talazoparib by SOC, PT and treatment group.
6.6.1.3. Adverse events leading to discontinuation of study treatment
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of study treatment, by treatment 
group:

TEAEs leading to discontinuation of any study drug by SOC and PT

Related TEAEs leading to discontinuation of any study drug by SOC and PT

TEAEs leading to discontinuation of all study drugs by SOC and PT

Related TEAEs leading to discontinuation of all study drugs by SOC and PT


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The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’
eCRFs, by treatment group.  

All deaths 

Deaths within 30 days after last dose of study treatment

Reason for Death 
-
Disease progression
-
Study treatment toxicity
-
AE not related to study treatment
-
Unknown
-
Other.
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information:

AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5), 

Flag for death within 30 days of last dose of study treatment.
6.6.3. Serious adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group:

SAEs by SOC and PT

Related SAEs by SOC and PT
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period.
6.6.4. Other significant adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group:

irAEs leading to death, by Cluster and PT

irAEs, by Cluster and PT

irAEs, Grade ≥ 3, by Cluster and PT


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
Serious irAEs, by Cluster and PT
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group:

IRRs leading to death, by PT

IRRs, by PT

IRRs, Grade ≥ 3, by PT

Serious IRRs, by PT.
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.
6.6.5. Laboratory data
6.6.5.1. Hematology and chemistry parameters
Laboratory results will be classified according to the NCI-CTCAE criteria v4.03. Non-
numerical qualifiers (with the exception of fasting flags) will not be taken into consideration 
in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). 
Abnormalities classified according to NCI-CTCAE toxicity grading v4.03 will be described 
using the worst grade. For those parameters which are graded with two toxicities, the 
toxicities will be summarized separately. Low direction toxicity grades at baseline and post 
baseline will be set to 0 when the variables are derived for summarizing high direction 
toxicity, and vice versa.  
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows: 
Derived differential absolute count = (WBC count) × (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is
available) then Grade 1 will be attributed to as follows: 

Lymphocyte count decreased:  
-
derived absolute count does not meet Grade 2-4 criteria, and
-
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-
derived absolute count  ≥ 800/mm3

Neutrophil count decreased 
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count  ≥ 1500/mm3
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows
Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L])
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.   
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment group:

ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN

AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN

(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN

TBILI ≥ 2×ULN

Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN 

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or missing)
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 

In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI ≥ 2×ULN, concomitantly with an ALT≥ 3×ULN or AST ≥ 3×ULN and 
with an ALP ≤ 2×ULN or missing will be provided.


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Parameters with NCI-CTCAE grades available: 
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).
The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities during the on-treatment period will be summarized by worst grade on-
treatment (Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4)).
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE.
Parameters with NCI-CTCAE grades not available:Hematology and chemistry 
evaluations which cannot be graded per CTCAE criteria will be summarized as frequency 
(number and percentage) of patients with: 

shifts from baseline normal to at least one result above normal during on-treatment period 

shifts from baseline normal to at least one result below normal during on-treatment period
6.6.5.2. Other laboratory parameters
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range or with CTCAE grade ≥1 will also be flagged in the 
data listings, along with corresponding normal ranges.  A listing of CTCAE grading will also 
be generated for those laboratory tests.
6.6.6. Electrocardiogram
ECGs are collected only when clinically indicated. Patients with qualitative ECG 
abnormalities will be listed.
7. INTERIM ANALYSES
7.1. Introduction
An interim analysis will be performed to allow early termination of the cohorts for futility. 
Within each cohort, ORR based on confirmed PR or CR by BICR assessment will be 
estimated after at least 20 patients are treated and followed for 24 weeks, without holding 
patient enrollment in either cohort.  
If based on the observed ORR, the probability of a true ORR 40% is ≤0.05 then the cohort 
will be stopped for futility.  For example, if 4 or fewer responders are observed out of 20 
patients treated in a cohort (ORR ≤20%) after the minimum follow-up specified above, then 
the cohort will be stopped for futility.


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7.2. Interim Analyses and Summaries
At the interim analysis cutoff date in each cohort, OR analysis will be performed by the 
Sponsor. OR will be summarized by treatment group as described in Section 6.1.1.1. The 
interim analysis cutoff is defined as the date when at least 20 patients are treated and 
followed for 24 weeks. All tumor assessments available up to the analysis cutoff, including 
all patients in the FAS, will be included in the interim analysis.  


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8. REFERENCES
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
2.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413, 1934.
3.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience. 2002.  
4.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
5.
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer 
TM, Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath EI, 
Hussain M, Kelly WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin 
SF, Ryan CJ, Sartor O, Small EJ, Smith MR, Sternberg CN, Taplin ME, Wilding G, 
Nelson PS, Schwartz LH, Halabi S, Kantoff PW, Armstrong AJ; Prostate Cancer 
Clinical Trials Working Group. Trial Design and Objectives for Castration-Resistant 
Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials 
Working Group 3. Journal of Clinical Oncology 34:12, 1402-1418, 2016
 
 
 
 
 
 
 
 
 
 
 
C
C
I
C
C
I
C
C
I
C
C
I
CCI


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CCI
CCI


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9. APPENDICES
Appendix 1. Immune-Related Adverse Events
The MedDRA PTs and clusters for irAEs are defined in the SRP for avelumab.
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 15.  
Unless otherwise noted, this case definition is hierarchical, ie, each step is only checked for 
patients and events that have already met the prior step.  
Table 15.
Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list, then it is in for the next 
step
2
AE onset during 1st study drug 
administration or anytime thereafter through 
90 days after last dose of study treatment.
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
Steps 3 and 4 will be checked concurrently.  Step 5 
will be checked if the criteria in Step 4 is met, 
irrespective of whether the Criteria in Step 3 is met.
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs 
if A) OR B) OR C) below are met then the AE is in 
for the next step
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA, L04AB, 
L04AC, L04AD, L04AX, A07EA) and AE PT 
is in any of the irAE clusters.
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters associated 
with “Immune-mediated endocrinopathies”
C) conmed ATC code is A10A and AE PT is in 
the irAE cluster associated with “Immune-
mediated endocrinopathies: Type I Diabetes 
Mellitus”


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5
A) No clear etiology (other than immune 
mediated etiology)
B) Histopathology / biopsy consistent with 
immune-mediated event
Event is in if 
[Answer to 5B1 and 5B2 is YES (regardless 
of answer to 5A)]
OR
[Answer to 5B1 is YES AND answer to 
5B2 is NO AND answer to 5A is NO] 
OR
[Answer to 5B1 is NO AND answer to 5A 
is NO]
A) From the AE eCRF page.
Is the AE clearly related to an etiology other 
than immune-mediated etiology?    Yes / No
If answer is Yes, check all that apply:
Underlying malignancy / progressive disease.
Other medical conditions. 
Prior or concomitant medications / 
procedures.  
Other.  Specify.
B) From the AE eCRF page.
B1) Was there a pathology /histology 
evaluation performed to investigate the AE?  
Y/N
B2) If answer to the above is Yes, does the 
pathology/histology evaluation confirms an 
immune mediated mechanism for the AE?  Y/N
B3) If pathology / histology evaluation 
performed to investigate the AE, provide 
summary of relevant findings of the pathology 
/histology report.  (Free Text)
The data set associated with irAEs may be refined based on medical review.  The final data 
set including any changes based on medical review (eg, addition of cases that are not selected 
by the programmatic algorithm) will be the basis of the irAE analyses.


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Appendix 2. Infusion Related Reactions
For defining an AE as IRR, the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered. 

All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
infusion) and the event resolved with end date within 2 days after onset. 

All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
the infusion) or the day after the study drug infusion (irrespective of resolution date).
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab. 
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 16
and will be identified for IV drugs only.     
Table 16.
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs
Conditio
n
Selection criterion
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)] then AE is classified as an IRR
1
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list 
2

AE onset date = date of infusion of study drug AND

AE timing related to study drug (‘DURING’, ‘AFTER’) AND

AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND

AE end date – AE onset date ≤2 
3
PT is included in the ‘IRRs CORE’ list 
4A

AE onset date = date of infusion of study drug AND

AE timing related to study drug in (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion


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Appendix 3. Abbreviations and Definitions of Terms
The following is a list of abbreviations that may be used in the Statistical Analysis Plan.
ADA
Anti-Drug Antibody
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT 
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATM
Ataxia-Telangiectasia Mutated
AUC
Area Under the Curve
BICR
Blinded Independent Central Review
BOR
Best Overall Response
BRCA
BReast CAncer Gene
CA-125
Cancer Antigen 125
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
Ctrough
Lowest (trough) Concentration 
CR
Complete Response
CRF
Case Report Form
CSR
Clinical Study Report
CTC
Circulating Tumor Cell
CTCAE 
Common Terminology Criteria for Adverse Events
ctDNA
Circulating Tumor DNA
CV
Coefficient of Variation
DDR
DNA Damage Repair
DOR
Duration of response
ECG 
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOT
End of Treatment
irAE
Immune-Related Adverse Event
IV
Intravenous
mCRPC
metastatic Castration Resistant Prostate Cancer
MedDRA
Medical Dictionary for Regulatory Activities
N/A
Not Applicable
nAb
Neutralizing Antibody
NCI 
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PCWG3
Prostate Cancer Working Group 3
PD
Progressive Disease 
PD-L1
Programmed Death-Ligand 1
PFS
Progression-Free Survival
PR
Partial Response
CCI


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PSA
Prostate-Specific Antigen
Q2W
Every 2 Weeks
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
TBILI
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
Tmax
Time to Maximum Plasma Concentration
TTR
Time-to-Tumor Response
ULN 
Upper Limit of Normal
TMB
Tumor Mutational Burden 
CCI