Clinical trial NCT03148795
Conditions: Prostate Cancer
Sponsor: Pfizer
Start date: 2017-07-04; Completion date: 2023-03-31
Enrollment: 128 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this international, phase 2, open-label, response rate study of talazoparib is to assess the efficacy and safety of talazoparib in men with DNA repair defects metastatic castration-resistant prostate cancer (CRPC) who previously received taxane-based chemotherapy and progressed on at least 1 novel hormonal agent (enzalutamide and/or abiraterone acetate/prednisone).

Detailed description:

Arms: arm 1: Talazoparib 1 mg daily
Interventions: intervention 1: Talazoparib
Intervention descriptions: intervention 1: 1 mg daily

Protocol documents:
SAP_002.pdf: 







































































































Prot_000.pdf: 
Talazoparib
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TALAPRO-1: A PHASE 2, OPEN-LABEL, RESPONSE RATE STUDY OF 
TALAZOPARIB IN MEN WITH DNA REPAIR DEFECTS AND METASTATIC 
CASTRATION-RESISTANT PROSTATE CANCER WHO PREVIOUSLY
RECEIVED TAXANE-BASED CHEMOTHERAPY AND PROGRESSED ON AT 
LEAST 1 NOVEL HORMONAL AGENT (ENZALUTAMIDE AND/OR 
ABIRATERONE ACETATE/PREDNISONE)
Investigational Product Number:
PF-06944076
Investigational Product Name:
Talazoparib
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2016-002036-32
Protocol Number:
C3441006 (MDV3800-06)
Phase:
2a
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
Amendment #4
15-Nov-2018
Rationale: The primary purpose of Protocol 
Amendment 4 is to address updated information 
reported in the August 2018 version of the 
Talazoparib Investigator’s Brochure. In addition, 
guidance for talazoparib dose modifications due to 
adverse events was updated to align with the Risk 
Management Committee (RMC) 
recommendations and the proposed regional 
labels. Changes included:

Extension of the time required, for 
contraceptive use and for patients to refrain 
from sperm donation, from 105 days to 
4 months.

Clarification/changes regarding prior and 
concomitant medications.

Clarifications to responses to adverse events, 
including talazoparib dose modifications.

Updated safety and efficacy data from clinical 
studies in patients that have taken talazoparib.

Updated pharmacokinetics data.

Update to the benefits and risks assessment.

The section pertaining to medication errors 
was updated to address talazoparib overdose.
In addition, the following major changes were 
made:

References to the protocol number were 
updated to reflect the change in sponsorship 
from Medivation to Pfizer. 

Given that the protocol is following a 
modified RECIST1.1./PCWG3 criteria to 
assess ORR, time to response, radiographic 
PFS, and duration of response, the term 
“modified RECIST1.1/PCWG3” has been 
introduced in the protocol.


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
Addition of secondary endpoint measure: 
“Proportion of patients with baseline CTC 
counts <5 who show increased CTC counts 
post-baseline”.

Clarification to indicate that patients enrolled 
in prior versions of the protocol, regardless of 
the type of DDR mutation or presence of 
measurable disease, will follow the same 
schedule of activities and discontinuation 
criteria as described in the current version of 
the protocol.

Clarification to indicate that for prior 
historical data reporting DDR+ mutation that 
may be considered for patient eligibility, if
sufficient residual DNA is available at 
Foundation Medicine, this could be used to 
confirm eligibility, noting that if eligibility for 
enrollment is established based either on prior 
results or residual DNA testing, available 
archival or de novo tumor tissue also should 
be submitted prior to Day 1.

The name of the Foundation Medicine test
used to determine DDR positivity is  now 
noted as FoundationOne CDx™ (formerly,  
FoundationOne®).

Clarification that central laboratory safety 
assessments are to be done at every scheduled 
visit, as well as unplanned, at the 
investigator’s discretion, or to monitor adverse 
events or decide dosing modifications, noting 
that local safety lab assessments may also be 
performed but should not replace central 
assessments. All data from local labs are to be 
entered in the appropriate CRF.

Clarification regarding PSA collection.

Clarification regarding assessment of 
radiographic imaging with details added to the 
criteria to document disease progression.


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
Adverse Event (AE) and Serious Adverse 
Event (SAE):

Noted that AEs and SAEs will be followed 
until respective event or its sequelae 
resolves or stabilizes to a level acceptable 
to the investigator and the sponsor concurs 
with that assessment.

Clarified the timeframe to record research 
related injuries.

Data Analysis/Statistical Methods:

Definition of the DDR Deficient 
Measurable Disease population; removal 
of ITT population.

Updates include additional details 
regarding study secondary efficacy 
analyses, interim analysis and sample size 
definition.

Data Handling and Record Keeping:

To address data protection, included text 
that describes measures to be taken to 
ensure protection of personal data.

Added to the Reference section: 

Litton JK et al, Talazoparib in Patients 
with Advanced Breast Cancer and a 
Germline BRCA Mutation. N Engl J Med. 
2018 Aug 3;379(8):753-763.

Lorente D et al, Circulating tumour cell 
increase as a biomarker of disease 
progression in metastatic castration-
resistant prostate cancer patients with low 
baseline CTC counts. Ann Oncol. 2018 
Jul 1;29(7):1554-1560.

Modified Appendix 6. Country Specific 
Amendment: France. Dose modification 
tables for France (Table 8: Dose 
Modification due to an Adverse Event and 
Table 9: Criteria For Temporary 


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Withholding of Study Drug in Association 
with Liver Test Abnormalities) were 
removed given that for Amendment 4, the 
dose modification guidance was updated 
to align as per RMC recommendations and 
proposed regional labels.

Added Appendix 7 to address a request 
from the German Ethics Committee 
regarding the enrollment in clinical studies 
of persons who have been housed in an 
institution following a regulatory or 
judicial order.
Additional changes were administrative or minor 
clarifications/corrections.
Amendment #3
15-Feb-2018
Administrative changes/clarifications:
Rationale- The protocol has been updated with the 
following administrative changes/clarifications: 
A clarification was added to the footnote for 
Table 2, and in Section 6.2.3, indicating that the 
peripheral blood sample should be submitted only 
if the sample was not already submitted at 
prescreening.
Table 3, footnote 1 and Section 6.3.3: a 
clarification was added stating that unplanned 
sample collection or assessments can be done to 
account for any insufficient, inadequate, or missed 
sample or assessments.
Table 3, noted an unscheduled PK collection.  
The following typographical errors were
corrected: In Section 5.10, Table 12 (as in 
Table 12. Instructions for Use of Concomitant 
Therapies) should be listed instead of Table 4.
In Section 6.3.2, the word electronic was included 
in error.
In Section 6.3.3, Table 3 (referring to 
Unscheduled Visit Procedures) should be listed 
instead of Table 13.


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In Section 7.1.2, Table 14 (as in Table 14. 
Confirmatory Imaging Requirements for Soft 
Tissue per RECIST 1.1 and Bone per PCWG3) 
should be listed, not Table 13.
In Section 7.5, removed Table 4.
In Section 8.1.3 changed “Patient Withdrawal”  to 
“Permanent Treatment Discontinuation”
In Section 8.4.4, removed ‘Lack of Efficacy’ since 
this study is not testing a marketed product.
In Section 9.8, Tables 17 and 18 (as in Table 17. 
Response Rates and Exact 95% CI for 60 Patients;
Table 18. Response Rates and Exact 95% CI for 
100 Patients) should be noted, not Table 1 and 
Table 2.
Added to the Reference section: Brookmeyer R, 
Crowley JJ. A confidence interval for median 
survival time. Biometrics. 1982 Mar; 38(1):29-41.
Amendment #2
20-Dec-2017
Rationale: The protocol has been updated with the 
following: 
Major changes included the following:

Amended to include a minimum of 
100 patients with measurable soft tissue 
disease and DNA damage repair (DDR) 
deficiencies (as assessed using a panel of 
13 genes where deficiency is likely to 
sensitize to poly (ADP-ribose) polymerase 
(PARP) inhibitor therapy);

Eliminated Cohort B, a cohort that had 
included subjects with DDR deficiencies 
assessed using an expanded DDR gene panel 
of genes where deficiency may sensitize to 
PARP inhibitor therapy. The cohort was 
eliminated given that not enough patients with 
rarer DDR mutations would have been 
projected to be enrolled to permit robust 
assessment of Overall Objective Response 
rates for those rarer genes.


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Addition of secondary endpoint measures:
•
Proportion of patients with a CTC count of 
1 or more (detectable) per 7.5 mL of blood at 
study entry that decreased to 
CTC=0 (undetectable) per 7.5 mL of blood 
anytime on study;
•
PRO Analyses (1) Time to deterioration of 
pain will be measured.  (2)Longitudinal mixed 
effect-model analyses to assess change from 
baseline in pain symptoms and general health 
status.
 
Removal of ctRNA analysis.
Inclusion/Exclusion Criteria were modified:
•
Patients must have measurable soft tissue 
disease per RECIST1.1;
•
Allows historical Foundation Medicine tissue 
biopsy data (with sponsor approval) to be 
included for eligibility assessment;
•
Patients whose only evidence of metastasis is 
measurable soft tissue disease below the aortic
bifurcation will be acceptable. Neither bone 
metastases on bone scan nor non-measurable 
soft tissue disease alone will qualify a patient.
•
Modified the exclusion criteria regarding:
•
Prior platinum-based chemotherapy;
•
Treatment with any cytotoxic or 
investigational drug(s) before and/or 
during study participation;
•
Entry threshold for albumin.
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Adverse event reporting:
•
Updated to align with the current Pfizer 
protocol template including safety template 
language; for prescreening, added text 
regarding research-related injury and 
clarification regarding AE reporting;
•
Following amendment 2 approval, 
investigators need not report overdose as an 
SAE if there is no accompanying sign or 
symptom meeting the definition of SAE.
Study Procedure:
•
Data base recording of local lab PSA 
measurements;
•
Clarified that talazoparib dose may not exceed 
0.75 mg for patients with moderate renal 
impairment.
Data Analysis:
•
Intent-to-treat (ITT) population is defined as 
all enrolled patients who receive any amount 
of study drug and have measurable soft tissue 
disease.
Additional changes were administrative and 
required as per the Pfizer protocol template.
Amendment #1
31-Mar-2017
The protocol was updated with the following 
major changes:
•
No longer require that all patients with CRPC 
to enroll with measurable disease at screening 
(per RECIST 1.1).
 
 
•
Added analyses of best overall response rate, 
time to objective response, duration of 
response, and radiographic progression free 
survival (PFS) based on investigator 
assessment to allow comparison with central 
review assessment. 
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Increased the frequency of clinical laboratory tests 
after week 25 from every 12 weeks to every 
8 weeks for increased patient safety and 
consistency across talazoparib studies. 
Clarified that the sponsor will obtain approval 
from the appropriate regulatory authority for any 
substantial amendments to the protocol prior to 
implementation. 
•
Added results of a talazoparib embryo-fetal 
development study in rats. 
•
Added guidance for dose modification of 
talazoparib and updates talazoparib product 
information for increased patient safety and 
consistency across talazoparib studies.
Additional changes were administrative or minor 
corrections.
Original protocol
01-Jun-2016
N/A
These amendments incorporate 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...................................................................................................................14
LIST OF FIGURES .................................................................................................................15
APPENDICES .........................................................................................................................15
PROTOCOL SUMMARY.......................................................................................................16
SCHEDULE OF ACTIVITIES................................................................................................23
1. INTRODUCTION ...............................................................................................................31
1.1. Overview and Mechanism of Action.......................................................................31
1.1.1. Overview.....................................................................................................31
1.1.2. Mechanism of Action/Indication................................................................31
1.2. Background and Rationale ......................................................................................32
1.2.1. Prostate Cancer ...........................................................................................32
1.2.2. PARP Inhibition..........................................................................................33
1.2.3. PARP Inhibitors as a Potential Targeted Therapeutic in Metastatic 
CRPC ...............................................................................................................34
1.2.4. Clinical Data Supporting PARP Inhibition as a Potential Targeted 
Therapeutic in Metastatic CRPC .....................................................................36
1.3. Summary of Relevant Clinical Experience With Talazoparib................................36
1.3.1. Efficacy.......................................................................................................36
1.3.2. Safety..........................................................................................................37
1.3.3. Pharmacokinetics........................................................................................38
1.4. Summary of Relevant Nonclinical Experience With Talazoparib..........................39
1.4.1. Nonclinical Pharmacology of Talazoparib.................................................39
1.4.2. Nonclinical PK and Metabolism.................................................................40
1.4.3. Nonclinical Toxicology ..............................................................................41
1.5. Talazoparib Benefits and Risks Assessment...........................................................42
1.6. Rationale for Talazoparib Dose...............................................................................43
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................43
3. STUDY DESIGN.................................................................................................................45
3.1. Overall Study Design and Plan: Description...........................................................45
3.2. Study Schematic......................................................................................................47
3.3. Blinding...................................................................................................................48
3.4. Duration of Study....................................................................................................48


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3.5. Discussion of Study Design and Rationale for Dose Selection ..............................48
4. PATIENT ELIGIBILITY CRITERIA.................................................................................50
4.1. Inclusion Criteria.....................................................................................................50
4.2. Exclusion Criteria....................................................................................................52
4.3. Lifestyle Requirements ...........................................................................................54
4.3.1. Contraception..............................................................................................54
4.4. Sponsor’s Qualified Medical Personnel..................................................................56
5. STUDY TREATMENTS.....................................................................................................56
5.1. Allocation to Treatment ..........................................................................................56
5.2. Talazoparib Product Characteristics........................................................................57
5.3. Packaging of Talazoparib........................................................................................57
5.4. Storage of Talazoparib ............................................................................................57
5.5. Directions for Administration of Talazoparib.........................................................57
5.6. Dose Modifications .................................................................................................57
5.6.1. Dose Modifications Due to Adverse Events...............................................57
5.7. Treatment Compliance ............................................................................................60
5.8. Investigational Product Storage ..............................................................................60
5.9. Investigational Product Accountability...................................................................61
5.9.1. Destruction of Investigational Product Supplies ........................................62
5.10. Concomitant Treatment(s).....................................................................................62
5.11. Potential Interactions Between the Test Product and Concomitant 
Medication.................................................................................................................63
5.12. Rescue/Salvage Medication ..................................................................................63
6. STUDY PROCEDURES .....................................................................................................64
6.1. Prescreening (optional)............................................................................................64
6.2. Screening Period .....................................................................................................64
6.2.1. Informed Consent .......................................................................................65
6.2.2. Screening Identification Numbers..............................................................65
6.2.3. Screening Procedures..................................................................................65
6.3. Treatment Period.....................................................................................................66
6.3.1. Treatment Period Visit Windows ...............................................................66
6.3.2. Treatment Period Procedures......................................................................66


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6.3.3. Unscheduled Visit Procedures....................................................................67
6.4. Permanent Treatment Discontinuation....................................................................67
6.5. Safety Follow-up.....................................................................................................69
6.6. Long Term Follow up .............................................................................................69
6.7. Lost to Follow up ....................................................................................................70
7. ASSESSMENTS..................................................................................................................70
7.1. Assessment of Efficacy ...........................................................................................70
7.1.1. Assessment of Primary Efficacy Endpoint: ORR.......................................70
7.1.2. Assessment of Radiographic Response and Progression............................71
7.2. Assessments of Secondary Efficacy Endpoints ......................................................72
7.2.1. Assessment of PSA.....................................................................................72
7.2.2. Assessment of Survival...............................................................................73
7.2.3. Assessment of Circulating Tumor Cells.....................................................73
7.2.4. Assessment of Patient Reported Pain .........................................................73
7.2.5. Assessment of Patient-Reported General Health Status.............................74
7.3. Assessments of Safety.............................................................................................74
7.3.1. Clinical Laboratory Tests ...........................................................................74
7.3.2. Physical Examinations, Vital Signs, and ECGs..........................................75
7.4. Pharmacokinetic Assessments.................................................................................76
7.7. Assessment of ECOG Performance Status..............................................................78
8. ADVERSE EVENT REPORTING......................................................................................79
8.1. Requirements...........................................................................................................79
8.1.1. Additional Details On Recording Adverse Events on the CRF..................80
8.1.2. Eliciting Adverse Event Information..........................................................80
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Permanent Treatment Discontinuation Section)..............................................80
8.1.4. Time Period for Collecting AE/SAE Information......................................80
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................81
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................81
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8.1.5. Causality Assessment .................................................................................81
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................82
8.2. Definitions...............................................................................................................82
8.2.1. Adverse Events...........................................................................................82
8.2.2. Abnormal Test Findings .............................................................................83
8.2.3. Serious Adverse Events ..............................................................................83
8.2.4. Hospitalization............................................................................................84
8.3. Severity Assessment................................................................................................85
8.4. Special Situations ....................................................................................................86
8.4.1. Protocol-Specified Serious Adverse Events...............................................86
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................86
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................87
8.4.3.1. Exposure During Pregnancy......................................................88
8.4.3.2. Exposure During Breastfeeding ................................................89
8.4.3.3. Occupational Exposure .............................................................89
8.4.4. Medication Errors .......................................................................................89
8.4.4.1. Medication Errors......................................................................90
8.4.5. Reporting AEs and/or Research-Related Injuries for Patients Who 
Sign the Molecular Prescreening Consent .......................................................91
8.4.5.1. Adverse Events..........................................................................91
8.4.5.2. Research-Related Injuries..........................................................91
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................92
9.1. Statistical and Analysis Plans..................................................................................92
9.2. Analysis Populations...............................................................................................92
9.3. Efficacy Analyses....................................................................................................93
9.3.1. Primary Efficacy Analyses .........................................................................93
9.3.2. Secondary Efficacy Analyses .....................................................................93
9.3.2.1. Time to Objective Response .....................................................93
9.3.2.2. Duration of Response................................................................93
9.3.2.3. Proportion of Patients With PSA Response 50%....................94
9.3.2.4. CTC Count Conversion Rate.....................................................94
9.3.2.5. Time to PSA Progression ..........................................................94


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9.3.2.6. Radiographic PFS......................................................................95
9.3.2.7. Overall Survival ........................................................................95
9.3.2.8. Patient Reported Pain................................................................95
9.3.2.9. Patient-Reported General Health Status (and Health 
Index).................................................................................................95
9.4. Safety Analyses.......................................................................................................96
9.5. Pharmacokinetic Analyses ......................................................................................96
9.7. Determination of Sample Size.................................................................................97
9.8. Interim Analysis ......................................................................................................97
9.9. Data Monitoring Committee ...................................................................................98
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................98
11. DATA HANDLING AND RECORD KEEPING .............................................................98
11.1. Case Report Forms/Electronic Data Record .........................................................98
11.2. Data Protection......................................................................................................99
11.3. Record Retention...................................................................................................99
12. ETHICS............................................................................................................................100
12.1. Institutional Review Board/Ethics Committee....................................................100
12.2. Ethical Conduct of the Study ..............................................................................100
12.3. Patient Information and Consent.........................................................................100
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................101
13. DEFINITION OF END OF TRIAL.................................................................................101
13.1. End of Trial in a Member State...........................................................................101
13.2. End of Trial in All Other Participating Countries...............................................102
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................102
15. PUBLICATION OF STUDY RESULTS........................................................................102
15.1. Communication of Results by Pfizer ..................................................................102
15.2. Publications by Investigators ..............................................................................103
16. REFERENCES ................................................................................................................104
LIST OF TABLES
Table 1.
Study Schedule of Activities: Prescreening (Optional)........................................24
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Table 2.
Study Schedule of Activities: Screening ..............................................................25
Table 3.
Study Schedule of Activities: Treatment*............................................................26
Table 4.
Study Schedule of Activities: Long Term Follow-Up..........................................30
Table 5.
Key Efficacy Results of Phase 2 and 3 Studies in Metastatic CRPC After 
Chemotherapy (Primarily Docetaxel)...................................................................33
Table 6.
Objectives and Endpoints for Study .....................................................................44
Table 7.
Predicted Talazoparib Mean Exposure at Steady-State........................................50
Table 8.
Talazoparib Dose Modifications Due to Adverse Events.....................................58
Table 9.
Instructions for Use of Concomitant Therapies....................................................63
Table 10.
Primary Reasons for Permanent Treatment Discontinuation ...............................68
Table 11.
Confirmatory Imaging Requirements for Soft Tissue per RECIST 1.1 and 
Bone per PCWG3 .................................................................................................71
Table 12.
Criteria for Evidence of Radiographic Progression..............................................72
Table 13.
ECOG Performance Status ...................................................................................78
Table 14.
Response Rates and Exact 95% CI for 100 Patients.............................................97
Table 15.
Response Rates and Exact 95% CI for 60 Patients...............................................97
LIST OF FIGURES
Figure 1.
Dual Cytotoxic Mechanisms of PARP Inhibitors.................................................31
Figure 2.
Study Schematic ...................................................................................................48
Figure 3.
Talazoparib Dose Reduction for Toxicity ............................................................60
APPENDICES
Appendix 1. Abbreviations....................................................................................................108
Appendix 2. Brief Pain Inventory Short Form.......................................................................111
Appendix 3. European Quality of Life- 5 Dimensions- 5 Levels Health Questionnaire.......113
Appendix 4. Pain Log ............................................................................................................116
Appendix 5. Analgesic Log ...................................................................................................117
Appendix 6. Country-Specific Amendment: France .............................................................122
Appendix 7. Country-Specific Documentation: Germany.....................................................123


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PROTOCOL SUMMARY
Overview
Talazoparib (also known as PF-06944076, MDV3800) is being investigated for the treatment 
of metastatic castration-resistant prostate cancer (mCRPC) with DNA damage repair 
deficiencies in men whose disease has previously progressed on novel hormonal therapy
(NHT: enzalutamide and/or abiraterone acetate) for the treatment of mCRPC and who were
previously treated with taxane-based chemotherapy for metastatic disease. 
Background and Rationale
Castration-resistant prostate cancer represents a lethal transition in the progression of prostate 
cancer, with most patients ultimately succumbing to the disease.  Prior to the recent approval 
of novel hormonal therapies (NHT) (enzalutamide, abiraterone acetate/prednisone), the only 
approved therapies for metastatic CRPC were docetaxel, cabazitaxel and sipeleucel-T.  The 
approval of NHTs in metastatic CRPC previously treated with docetaxel (De Bono et al, 
2011; Scher et al, 2012) represented a therapeutic advance for these patients.
Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) and PARP2 play 
important roles in DNA repair (Schreiber et al, 2006; Curtin, 2005).  Inhibition of PARP 
catalytic activity results in synthetic lethality whereby persistent single-strand DNA breaks 
lead to irreparable double-strand DNA breaks in cells with defective homologous 
recombination mechanisms.  Moreover, PARP inhibitors also trap the PARP enzyme on 
DNA to a variable extent, including that of tumor cells, thereby preventing DNA replication 
and transcription.  Talazoparib is a potent, orally bioavailable, small molecule PARP 
inhibitor in development for the treatment of a variety of human cancers.  Single-agent 
treatment with talazoparib demonstrates potent antitumor effects in tissue culture studies, 
mouse tumor xenograft models, and in Phase 1 studies in patients with solid tumors.  
Talazoparib has also been shown to enhance the cytotoxic effects of DNA-damaging 
chemotherapy.  Talazoparib in preclinical models demonstrates potent cytotoxic effects from 
PARP trapping.
Proof of concept that a PARP inhibitor may treat advanced metastatic CRPC with DNA 
damage repair deficiency was established in a Phase 2 study (TOPARP-A) with olaparib, 
which enrolled men heavily pre-treated with taxane-based chemotherapy and NHT (Mateo et 
al, 2015).  Thus, the current study was designed given the results of TOPARP-A for the 
treatment of late stage metastatic CRPC for which there are no approved treatments tested in 
the target population of this study.
Objectives 
Primary Objective: 

To evaluate the efficacy of single agent talazoparib in DNA damage repair (DDR) 
+ metastatic CRPC, as measured by best objective response rate (ORR).


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Secondary Objectives: 
•
To evaluate efficacy with respect to the following parameters:
•
Time to objective response;
•
Duration of response;
•
Proportion of patients with prostate-specific antigen (PSA) decrease ≥50%;
•
Proportion of patients with conversion of circulating tumor cell (CTC) count;
•
Time to PSA progression;
•
Radiographic progression-free survival (PFS);
•
Overall survival.
•
To evaluate the safety of talazoparib in this patient population.
•
To evaluate the following patient-reported outcomes:
•
Time to deterioration in pain as assessed by the Brief Pain Inventory Short Form 
(BPI-SF);
•
Change from baseline in pain per BPI-SF;
•
Change from baseline in general health status as assessed by the European Quality of 
Life 5-Domain 5-Level Scale (EQ-5D-5L).
•
To evaluate the pharmacokinetics (PK) of talazoparib.
 
 
STUDY DESIGN
This is an international, phase 2, open-label, soft tissue response rate study of talazoparib 
(also known as PF-06944076, MDV3800, BMN 673), a poly (ADP-ribose) polymerase 
(PARP) inhibitor in development for treatment of cancer.  PARP inhibition has been shown 
to produce clinical responses in metastatic castration-resistant prostate cancer (mCRPC), 
particularly in patients with DNA damage repair deficiencies.  PARP inhibitors are thought 
to induce cell toxicity by inhibiting PARP catalytic activity as well as by trapping 
PARP-DNA complexes, which prevent DNA repair, replication, and transcription.  
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Nonclinical studies have shown that talazoparib has potent cytotoxic effects via both 
mechanisms, with greater cell toxicity from PARP trapping.  In this study, a minimum of 
100 men with measurable soft tissue disease and progressive metastatic CRPC with DNA 
damage repair deficiencies likely to sensitize to PARP inhibition will be studied.  Patients
will be evaluated for genomic deficiencies in DNA damage repair genes as assessed by a 
gene mutation biomarker panel where relevant mutations are likely to sensitize to PARP 
inhibition. 
Eligible patients must have previously received 1 to 2 chemotherapy regimens including at 
least 1 taxane-based regimen for treatment of metastatic prostate cancer, and progressed on at 
least 1 line of novel hormonal therapy (enzalutamide and/or abiraterone acetate/prednisone) 
for treatment of metastatic CRPC.  Patients will be evaluated at prescreening (optional) or 
screening for DNA damage repair deficiencies as assessed by a gene mutation biomarker 
panel.  Approximately 100 patients with DNA damage repair deficiencies as assessed by a 
panel of genes likely to sensitize to PARP inhibition will be enrolled.
Newly enrolled patients will have measurable soft tissue disease per Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1).  Patients must consent to submit 
sufficient tumor tissue (de novo tumor biopsy or archival tissue) to be centrally assessed for 
mutations in selected genes associated with DNA damage repair (DDR) deficiencies using 
the FoundationOne CDx™(Foundation Medicine) panel. Previous identification of DNA 
repair deficiencies likely to sensitize to PARP inhibition, may be considered with sponsor 
approval.
 
Patients enrolled in prior versions of the protocol, regardless of the type of DDR mutation or 
the presence of measurable disease, will follow the same schedule of activities and 
discontinuation criteria as described in the current amendment.
Study periods include prescreening (optional), screening, treatment, safety follow-up, and 
long-term follow-up.  Safety follow-up after permanent discontinuation of study drug 
treatment will occur approximately 28 days after the last dose of study drug or before 
initiation of a new antineoplastic or investigational therapy, whichever occurs first.  
Long-term follow-up will occur (usually every 8-12 weeks) after safety follow-up.  
Radiographic imaging should continue during long-term follow-up for patients who 
discontinue study drug for any reason other than radiographic progression determined by 
independent central review, withdrawal of consent for follow-up, or death.
Study Treatments
Patients will receive talazoparib, 1 mg daily by mouth, with continued androgen deprivation 
(gonadotropin-releasing hormone [GnRH] therapy or bilateral orchiectomy).  Talazoparib 
will be administered until radiographic progression is determined by independent central 
review, or unacceptable toxicity, or withdrawal of consent, or death. In addition, talazoparib 
can continue to be administered upon disease progression only if, in the opinion of the 
investigator the patient is clinically benefitting, no new concurrent systemic therapy is 
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started, and the sponsor is notified. For patients with moderate renal impairment (estimated 
glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m2 as per central laboratory) at 
screening, the starting dose will be 0.75 mg/day.  Study drug should not be discontinued 
based solely on PSA or CTC count increases.
Statistical Methods
The primary objective of the study is to evaluate the efficacy of single agent talazoparib in 
DDR+ mCRPC, as measured by best objective response rate (ORR).  An objective response 
is defined as a best overall response of complete response (CR) or partial response (PR) per 
RECIST 1.1.  Response must be confirmed by a follow-up radiographic assessment at least 
4 weeks later with a repeated computed tomography (CT) or magnetic resonance imaging 
(MRI) and with no evidence of confirmed bone disease progression per Prostate Cancer 
Working Group 3 (PCWG3) criteria on repeat bone scan at least 6 weeks later by 
independent central review. 
Efficacy Analyses
The statistical methods and analyses for this study will be described in detail in the statistical 
analysis plan.  
DDR Deficient Measurable Disease population is defined as all enrolled patients who have 
measurable soft tissue disease at screening by independent central review (ICR), have DDR 
deficiencies likely to sensitize to PARP inhibitor therapy and receive at least one dose of 
talazoparib. The DDR Deficient Measurable Disease population will be used for all baseline 
characteristics summaries and efficacy analyses. 
Three analyses are planned, including an initial safety/efficacy analysis followed by two 
efficacy analyses.  The initial safety/efficacy analysis will be performed after 20 patients with 
measurable soft tissue disease and DDR deficiencies likely to sensitize to PARP inhibitor 
therapy have received the study drug for at least 8 weeks.  Efficacy analyses of the primary 
endpoint will also be performed when 60 and 100 patients have complete at least 6 months of 
study treatment or are no longer being followed (ie, have withdrawn consent, discontinued 
from the study, died, or are otherwise lost to follow-up). All safety analyses will be 
performed using the safety population, defined as all patients who receive any amount of 
study drug.
Summaries and listings of efficacy and baseline data for patients that were enrolled under 
previous protocol versions and who are not part of the DDR Deficient Measurable Disease 
population will be described in the statistical analysis plan. 
All patient-reported outcome (PRO) analyses will be conducted on the PRO population, 
defined as all patients from the DDR Deficient Measurable Disease population who have 
completed a baseline and at least one post-baseline PRO assessment prior to the end of study 
treatment.


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The PK population is defined as all patients from the safety analysis set who have at least 
1 reportable drug concentration data point.  The CTC evaluable population is defined as all
patients with a baseline CTC assessment and at least 1 postbaseline CTC assessment from the 
DDR Deficient Measurable Disease population. 
 
 
Primary Efficacy Endpoint: 
•
Best ORR: The proportion of patients with a best overall soft tissue response of CR or 
PR per RECIST 1.1 by independent central review.  Soft tissue responses must 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 on 
repeat bone scan at least 6 weeks later per PCWG3 criteria by independent central 
review.
Secondary Efficacy Endpoints: 
•
Time to objective response: The time from first dose of talazoparib 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 best 
overall response of CR or PR per RECIST 1.1 by independent central review.  The 
response must be confirmed at least 4 weeks later with a repeated CT/MRI.
•
Duration of response: The time from the first objective evidence of soft tissue 
response (subsequently confirmed) per RECIST 1.1 by independent central review 
and no evidence of confirmed bone disease progression per 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 
per RECIST 1.1 by independent central review or bone disease progression per 
PCWG3 by independent central review.
•
Proportion of patients with PSA response ≥50%: The proportion of patients with 
confirmed PSA decline ≥50% compared to baseline.
•
Proportion of patients with conversion of CTC count: The proportion of patients with 
a CTC count ≥5 CTC per 7.5 mL of blood at study entry that decreases to <5 CTC per 
7.5 mL of blood any time on study.
•
Proportion of patients with a CTC count of 1 or more (detectable) per 7.5 mL of 
blood at study entry that decreases to CTC=0 (undetectable) per 7.5 mL of blood any
time on study (Scher et al, 2017).
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•
Proportion of patients with baseline CTC counts <5 who show increased CTC counts 
post-baseline (Lorente et al, 2018).
•
Time to PSA progression: The time from first dose of talazoparib to the date that a 
≥25% increase in PSA with an absolute increase of ≥2 μg/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.
•
Radiographic PFS: The time from first dose of talazoparib to radiographic 
progression in soft tissue per RECIST 1.1 by independent central review, in bone per 
PCWG3 by independent central review, or death due to any cause, whichever occurs 
first.
•
Overall survival: Defined as the time from first dose of talazoparib to death due to 
any cause. 
Analyses of best ORR, time to objective response, duration of response, and radiographic 
PFS will also be evaluated based on assessment by the investigator.  The statistical methods 
and analyses are described in detail in the statistical analysis plan.
PRO Analyses
•
Time to deterioration of pain (≥2-point increase from baseline, using question 3 of the 
BPI-SF), will be measured.  In order to adequately measure pain, it is equally 
important to adequately track analgesic use to ensure that the pain palliation observed 
is not the result of an increase in analgesic use but rather the effect of the antitumor 
treatment being studied.  After Day 1, pain and analgesic assessments will be
completed for each of 7 consecutive days before study visits; pain score averages 
during the period of reporting will be calculated.  Analgesic data (from the analgesic 
log) will be mapped to the World Health Organization (WHO) analgesic usage score 
and used concurrently to define pain progression with the BPI SF (Basch E et al, 
2013).
•
Longitudinal mixed effect-model analyses will be used to assess change from 
baseline in patient reported pain (assessed by BPI-SF) and general health status 
(assessed by EQ-5D-5L).
PK Analyses 
PK data collections will include predose sampling at Day 1 (baseline sample, drawn prior to 
patient’s taking his first dose of talazoparib) and predose samples at weeks 5, 9, and 13, and 
postdose sampling at Day 1 and week 5.  PK data analyses will include descriptive summary 
statistics of the predose trough and postdose plasma concentrations for talazoparib by study 
visit.  In addition, the PK data from this study may be used to develop a population PK 
model.
 
 
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Safety Analyses
The safety of talazoparib will be evaluated by analysis of the incidence of serious and 
nonserious adverse events, severity of adverse events, incidence of dose modifications and of 
permanent treatment discontinuation due to adverse events, and incidence of new clinically 
significant changes in clinical laboratory values and vital signs.  Treatment-emergent safety 
data will be collected from the first dose of study drug treatment through 28 days after the 
last dose (ie, permanent discontinuation) of study drug or before initiation of new 
antineoplastic or investigational therapy, whichever occurs first.  Adverse events will be 
coded to preferred term and system organ class using the Medical Dictionary for Regulatory 
Activities (MedDRA) and classified by severity using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03.  The number and 
percentage of patients with adverse events will be presented by MedDRA system organ class 
and preferred term, relationship to study drug, and severity.  Descriptive statistics will be 
used.  Laboratory values will be classified by severity using the CTCAE.  Laboratory shift 
tables of baseline to maximum post baseline results to each subsequent visit will be produced 
as appropriate.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 on 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.
Study Schedule of Activities: Prescreening (Optional)
General Activities
Comments
Prescreening may be performed any time before consent is 
signed for the screening period. 
Prescreening informed consent 
Use the prescreening consent form.  Obtain consent any time 
before performing any prescreening procedures. 
Screening number
Obtain screening number from the interactive response 
technology (IRT) system.
Adverse Event (AE) and research related injuries
Record in the Case Report Form (CRF) as described in
Section 8.4.5.
Pretreatment adverse events review
Refer to Section 8.4.5 for guidance on the reporting of 
adverse events or research-related injuries during the 
prescreening phase of the study. 
For all patients: Submit fresh or adequate archival tumor 
tissue.  Alternatively, prior results from Foundation 
Medicine may be considered for eligibility with sponsor 
approval.
If patient genomically qualifies based on prior tumor 
testing submit adequate archival or fresh tissue if 
available.
Submit tissue from a de novo biopsy of a safely accessible 
tumor lesion, or archival tumor tissue, for prospective central 
laboratory enrollment testing. 
Test results from prior tumor testing identifying DNA repair 
deficiencies likely to sensitize to PARP inhibition may be 
considered for eligibility. If sufficient residual DNA is 
available at Foundation Medicine this could be used to 
confirm a patient’s eligibility for enrollment.
Note that if eligibility for enrollment is established based on 
either prior results or residual DNA testing, available 
archival or de novo tumor tissue also should be submitted 
prior to Day 1 to support concordance analyses and 
additional molecular profiling, unless prohibited by local 
regulations or ethics committee (EC) decision.
Note: biopsies of the brain, lung/mediastinum, pancreas, or 
endoscopic procedures extending beyond the esophagus, 
stomach, or bowel may not be performed for the sole purpose 
of determining study eligibility.
Demographics
Prior Anti-Cancer Therapies
Medical History- Prostate Cancer 
For all patients, including those who by central laboratory 
assessment are not found to be genomically eligible:
•
Obtain patient demographics using the Patient 
Demographics screening CRF;
•
Obtain patient prior cancer treatment history using 
the Prior Cancer Therapy CRF;
•
Obtain patient prior medical history for prostate 
cancer using the Medical Prostate History CRF.
 
 
 
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Table 2.
Study Schedule of Activities: Screening
Study Day 
Window
Comments
General Activities
Screening activities may be repeated any time during the screening period if clinically indicated.
Informed consent
Informed consent may be obtained greater than 28 days before Day 1/enrollment; however consent must be 
obtained before performing any study-specific procedures.  Ensure the consent (signed and dated) is the 
current version of the form approved by the ethics committee and sponsor. 
Screening number
Obtain screening number from the IRT system after informed consent is signed, if not obtained at 
pre-screening.
Demographics;* Prior Therapy;* Medical History*
-28 to -1
Demographics;
Prior Anti-Cancer Therapies;
Medical History- Prostate Cancer.
Eligibility criteria 
-28 to -1
Enrollment authorization form 
-28 to -1
Complete, sign, and fax or email the form with requested items to sponsor or designee at least 2 business 
days before enrollment (day 1).  Patient may proceed to day 1 when sponsor or designee approves by signed 
form or email correspondence.
12-Lead electrocardiogram
-28 to -1
Local. 
Vital signs
-28 to -1
Measure blood pressure, heart rate, and temperature.
ECOG performance status
-28 to -1
Eastern Cooperative Oncology Group. 
Physical examination, weight, height
-28 to -1
Assess systems (eg, general appearance, head, eyes, ears, nose, mouth, skin, heart, lungs, lymph nodes, 
gastrointestinal, genitourinary, neurologic, and skeletal). 
Pretreatment adverse events review
-28 to -1
Report serious and nonserious adverse event information from time of signed informed consent.
Prior and concomitant medications
-28 to -1
Submit fresh or adequate archival tumor tissue.  
Alternatively, prior results from Foundation 
Medicine may be considered for eligibility with 
sponsor approval.
If patient genomically qualifies based on prior 
tumor testing, submit adequate archival or fresh
tissue if available.  
Any time 
before -1
(Refer to
Table 1)
If not obtained at the prescreening visit: submit tissue from a de novo biopsy of a safely accessible tumor 
lesion, or archival tumor tissue, for prospective central laboratory enrollment testing, 
Test results from prior tumor testing identifying DNA repair deficiencies likely to sensitize to PARP 
inhibition may be considered for eligibility. If sufficient residual DNA is available at Foundation Medicine 
this could be used to confirm a patient’s eligibility for enrollment.
Note that if eligibility for enrollment is established based on either prior results or residual DNA testing,
available archival or de novo tumor tissue also should be submitted prior to Day 1, to support concordance 
analyses and additional molecular profiling, unless prohibited by local regulations or ethics committee (EC) 
decision.
Note: biopsies of the brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the 
esophagus, stomach, or bowel may not be performed for the sole purpose of determining study eligibility.
 
 
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Laboratory Evaluations
Refer to the central laboratory instruction manual for sample processing and for estimated turnaround time 
for results.  All laboratory evaluations will be tested centrally except where noted.
Serum chemistry, hematology
-28 to -1
Testosterone, PSA
-28 to -1
Up to 2 or 3 local prostate-specific antigen measurements (PSA) will be used to determine eligibility, 
including local PSA values that may have been obtained prior to the patient signing the study ICD and 
greater than 28 days before Day 1. PSA measurements must be consecutive and at least 1 week apart.
The third PSA may, or may not, be the central lab screening PSA. If the screening central lab PSA is lower 
than local lab PSA #2, then a third local lab PSA may be submitted instead.
A central PSA assessment will be done at screening for all patients.
Screening PSA (as per central laboratory) must be ≥2 ng/mL for patients qualifying based only on PSA 
progression.  Refer to Section 7.2.1.
Radiographic Assessments
May use scans obtained as part of standard of care before consent was signed and within 42 days before day 
1 if scans were performed per the specific study requirements (per imaging manual).
CT of chest; CT or MRI of abdomen and pelvis
-42 to -1
Computed tomography or magnetic resonance imaging.
Whole-body radionuclide bone scan
-42 to -1
*Demographics, Prior Anti-Cancer Therapies and Medical History- Prostate Cancer will not be required for patients that have these data recorded at the prescreening visit.
Table 3.
Study Schedule of Activities: Treatment*
Study Period or Visit
Treatment
Unsched[1]
Safety FU[2]
Study Week
1**
3
5
7
9
13
17
21
25+[3]
Varies
Varies
Window (Days)[4]
na
±3 (±7 for scans)
na
-3 to +10
Enrollment ID number
X
General Activities
Vital signs[5]
X
X
X
X
X
X
X
X
X
X
X
Physical exam, weight[6]
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
X
BPI-SF, EQ-5D-5L[7]
X
X
X
X
X
X
X
X
X
X
X
Pain Log[19]
X
X
X
X
X
X
X
X
X
X
Analgesic Log[20]
X
X
X
X
X
X
X
X
X
X
Adverse events review[8]
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Study drug dispensing[9]
X[7]
X
X
X
X
X
X
X (optional)
Study drug accountability
X
X
X
X
X
X
X (optional)
Central Lab Evaluations[10]
Serum chemistry, hematology[3][11]
X
X
X
X
X
X
X
X
X
X
X
Prostate-specific antigen[21]
X
X
X
X
X
X
X
X
Blood sample for PK[12]
X
X
X
X
X


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Table 3.
Study Schedule of Activities: Treatment*
Study Period or Visit
Treatment
Unsched[1]
Safety FU[2]
Study Week
1**
3
5
7
9
13
17
21
25+[3]
Varies
Varies
Window (Days)[4]
na
±3 (±7 for scans)
na
-3 to +10
Blood sample for CTC enumeration[13]
X
X
X
X
X
Blood sample to be stored for reflex testing 
for viral hepatitis 
X
Contraception check[22]
X
X
X
X
X
X
X
X
X
X
Radiographic Assessments[18]
CT of chest, CT or MRI of abdomen and 
pelvis
X
X
X
X[1]
Bone scan 
X
X
X
X[1]
*Patients enrolled as per prior versions of the protocol will follow the same schedule of activities and treatment/study discontinuation criteria.
**Includes Day 1, defined as the day subject receives his first dose of talazoparib.
1.
Unscheduled visits/assessments can be done anytime necessary to assess or follow up adverse events, at the patient’s request, or per investigator decision, or 
to account for any insufficient, inadequate, or missed sample or assessments. Perform imaging if disease progression is suspected. Data are to be entered in 
the appropriate CRF. If medically required, additional ECGs will be done with results entered in the CRF; clinically significant findings will be captured as 
adverse events.  
2.
Approximately 28 days after permanent treatment discontinuation of study drug or before initiation of a new antineoplastic or investigational therapy 
whichever occurs first.  Phone patients for adverse event follow-up if they do not come to the clinic.
3.
Visits repeat every 12 weeks while on study drug. Hematology and serum chemistry assessments will be completed every 8 weeks by the central laboratory 
while on study drug.
4.
Drug supply must be taken into account when scheduling visits during windows.  Visit procedures may be split across the window to allow for drug resupply 
and completion of study procedures.
5.
Measure blood pressure, heart rate, and temperature.
6.
Assess systems (eg, general appearance, head, eyes, ears, nose, mouth, skin, heart, lungs, lymph nodes, gastrointestinal, genitourinary, neurologic, and 
skeletal) per standard of care at the study site or as clinically indicated by symptoms.  Measure weight.
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7.
Have the patient complete the questionnaires and collect blood samples before the first dose of study drug on day 1.  These assessments will be performed:
•
At baseline (Day 1);
•
Every 2 weeks (prior to Study Week 9) weeks 9, 13, 17, 21 through Week 25, or radiographic progression, whichever is earlier;
•
Every 12 weeks after Week 25 until radiographic progression when no such progression had been previously documented;
•
During unscheduled visit(s) when no radiographic progression had been previously documented;
•
During safety follow up;
•
And at end of trial when study results are determined.
8.
Collect serious and nonserious adverse event information from the time of signed informed consent for main screening through 28 days after the last dose of 
study drug (see Section 8 for details).  Report any diagnosis of MDS or AML as an SAE any time after the first dose of talazoparib (Section 8.1.4.1 and 
Section 8.2.3).  AEs and SAEs will be followed until the event or its sequelae resolves or stabilizes at a level acceptable to the investigator and the sponsor 
concurs with that assessment.
9.
Instruct patient to self-administer talazoparib.  The first dose is taken in the clinic; record the exact time of dose.
10. Refer to the central laboratory instruction manual for sample processing and for estimated turnaround time for laboratory results.
11. Central laboratory assessments (safety) are to be done at every scheduled visit, as well as unplanned, at the investigator’s discretion, or to monitor adverse 
events or decide dosing modifications, noting that local safety assessments may also be performed but should not replace central lab assessments. Every
effort should be taken to collect samples for central laboratory safety assessments even if unplanned. If serum chemistry and hematology laboratory tests 
were also done locally due to logistical issues, results from local laboratory assessments are to be entered in the appropriate CRF. 
12. Collect blood samples for talazoparib PK at predose and 2 hours postdose in Week 1 (Day 1) and in Week 5, and predose in Weeks 9 and 13.  Additional PK 
samples could be taken based on discretion of investigators, eg, adverse events.  The actual time of the sample collection and the most recent dosing time 
before and after each collection will be recorded on the CRF.
13. Blood sample for CTC enumeration.  Collect a minimum of 10 mL of whole blood at indicated visits.  CTC samples must be shipped on day of collection
and at room temperature. See Section 7.5 and Central Laboratory Manual. 
 
 
 
 
 
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18. Radiographic imaging should be performed until radiographic progression is determined by independent central review. Soft tissue lesions will be followed 
only by RECIST 1.1 and bone lesions will be followed only by PCWG3 (modified RECIST1.1/PCWG3). Of note, soft tissue component of lytic or mixed 
bone lesions will be followed by RECIST 1.1; all other bone lesions will be followed by PCWG3. Tumor lesion assessments and overall assessment by 
RECIST 1.1 performed by the site will be entered in the CRF. Bone lesion assessments performed by the site will be entered in the CRF using the separate 
PCWG3 CRF pages. 
19. Assessed via BPI-SF question 3 and recorded for each of the 7 consecutive days prior to each clinic visit after the Day 1 visit.
20. Use of any and all analgesics for prostate cancer pain is to be recorded for the 7 consecutive days prior to each clinic visit after the Day 1 visit.
21. Collect samples for analysis of PSA until determination of radiographic progression. Upon PSA progression or response, confirmation by a second 
consecutive value, at least 21 days later, is required.
22. Any time prior to dosing, document in the patient chart if patient is biologically capable of fathering a child or of exposing a fetus or partner via ejaculate. If 
capable, instruct the patient to use a condom to avoid pregnancy and/or fetal/partner exposure and instruct the patient to not donate sperm, for up to 4 months 
after talazoparib discontinuation. Only for these patients, investigators need to verify at every visit that the patient is following instructions provided as per
Section 4.3. Investigators must document the conversation with the patient and, as applicable, confirm condom and contraception use or note changes in 
patient chart as per the schedule of activities.
BPI-SF, Brief Pain Inventory Short Form; CT, computed tomography; CTC, circulating tumor cells; 
 ECOG, Eastern Cooperative Oncology 
Group; EQ-5D-5L, European Quality of Life 5-Domain 5-Level Scale; exam, examination; FU, follow-up; ID, identification; lab, laboratory; MRI, magnetic resonance imaging; 
na, not applicable; PK, pharmacokinetics; unsched, unscheduled.
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Table 4.
Study Schedule of Activities: Long Term Follow-Up
Study Period or Visit
Long-Term Follow-Up
Long-term follow-up begins after safety follow-up; visits repeat every 8*- 12 weeks from the 
date of last dose until the patient dies, withdraws consent for follow-up, or the study is 
terminated.  
Study Week
Every 8- 12*
Window (Days)
±7
General Activities
New antineoplastic therapy 
X
Record all subsequent treatment information for patients starting any new antineoplastic therapies
(approved or investigational).  
Diagnosis of 
myelodysplastic syndrome 
(MDS) or acute myeloid 
leukemia (AML)
X
Record date of diagnosis of MDS or AML.  Any diagnosis of MDS or AML will be reported as an 
SAE (Section 8.2.3).  Provide tissue samples and any other supporting data used to enable the 
diagnosis of MDS or AML for central review if requested.  
Survival status
X
Obtain survival status by any means including telephone, during a patient’s clinic visit, chart review, 
or by communicating with an individual (eg, family, friend, referring health care provider) who is 
knowledgeable of the patient’s survival status.  If allowed by local laws and regulations, survival 
status may be obtained from public records for patients withdrawing consent from the study or for 
patients lost to follow-up.
Radiographic imaging
X
Only for patients who permanently discontinue study drug for any reason other than radiographic 
progression determined by independent central review when the patient has not withdrawn consent 
for follow-up.  
*Every 8 weeks through week 25, then every 12 weeks thereafter.


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1. INTRODUCTION
1.1. Overview and Mechanism of Action
1.1.1. Overview
Talazoparib (also known as PF-06944076, MDV3800) is being investigated for the treatment 
of metastatic castration-resistant prostate cancer (mCRPC) with DNA damage repair 
deficiencies in men whose disease has previously progressed on novel hormonal therapy 
(NHT: enzalutamide and/or abiraterone acetate) given for the treatment of mCRPC and who 
were previously treated with taxane-based chemotherapy for metastatic disease.
1.1.2. Mechanism of Action/Indication
Talazoparib is a potent, orally bioavailable, small molecule poly (adenosine diphosphate 
[ADP]-ribose) polymerase (PARP) inhibitor in development for the treatment of a variety of 
human cancers.  PARP inhibitors including talazoparib exert cytotoxic effects via 
2 mechanisms: (1) inhibition of PARP1 and PARP2 catalytic activity, and (2) PARP 
trapping, a process in which PARP protein bound to a PARP inhibitor does not readily 
dissociate from DNA, thereby preventing DNA repair, replication, and transcription (Murai 
et al, 2012).
Figure 1.
Dual Cytotoxic Mechanisms of PARP Inhibitors
Source: Adapted from Reference 1
PARP = poly (adenosine diphosphate-ribose) polymerase.
Inhibition of PARP catalytic activity (upper pathway) interferes with the repair of single-strand breaks, leading 
to replication fork damage that requires homologous recombination DNA repair for cell survival.  Trapping of 
PARP–DNA complexes with PARP inhibitor (lower pathway; PARP inhibitor represented by ) also leads to 
replication fork damage with more DNA repair processes required for cell survival.
Single-agent treatment with talazoparib has demonstrated potent antitumor effects in tissue 
culture studies, mouse tumor xenograft models, and in Phase 1 studies in patients with solid 
tumors.  Talazoparib has also been shown to enhance the cytotoxic effects of DNA-damaging 
chemotherapy, including temozolomide and irinotecan, in both in vitro and in vivo 
preclinical models.


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1.2. Background and Rationale
1.2.1. Prostate Cancer
Prostate cancer is the second leading cause of cancer death in men.  The American Cancer 
Society estimates that up to 180,890 men in the United States (US) will be diagnosed with 
prostate cancer and approximately 26,120 will die of the disease in 2016 (American Cancer 
Society, 2016).  In Europe in 2012, prostate cancer was the third most common cancer site, 
with an estimated 416,700 new cases and 92,200 deaths (Ferlay et al, 2013).
The androgen receptor signaling axis, the principal driver of prostate cancer growth, has long 
been targeted by castration.  However, a proportion of tumors progress despite castrate levels 
of testosterone, at which point the disease is considered castration-resistant.  
Castration-resistant prostate cancer (CRPC) represents a lethal transition in the progression 
of prostate cancer, with most patients ultimately succumbing to the disease.  Molecular 
profiling studies have revealed that the androgen receptor remains functional in a majority of 
progressing tumors.  Rationally designed therapies targeting the androgen receptor signaling 
pathway (Donovan et al, 2010) include enzalutamide, a novel androgen receptor antagonist 
that is active in the presence of androgen receptor overexpression (Tran et al, 2009), and 
abiraterone acetate/prednisone (de Bono et al, 2011), an inhibitor of 17,20-lyase (an 
androgen biosynthetic enzyme overexpressed in CRPC) (Stanbrough et al, 2006; 
Holzbeierlein et al, 2004).  Prior to the recent approval of novel hormonal therapies (NHT) 
(enzalutamide, abiraterone acetate/prednisone), the only approved therapies for metastatic 
CRPC were docetaxel, cabazitaxel and sipeleucel-T.  The approval of NHTs in metastatic 
CRPC previously treated with docetaxel (De Bono et al, 2011; Scher et al, 2012) represented 
a therapeutic advance for these patients. 
Clinical experience with these therapies validated findings that the androgen receptor 
remains active despite androgen deprivation in men with CRPC, but resistance to these 
second-generation agents invariably occurs.  Median survival remains low (approximately 
15-18 months) for men with metastatic CRPC who had previously received docetaxel in 
studies of enzalutamide and abiraterone acetate/prednisone (Scher et al, 2012; de Bono et al, 
2011).  Furthermore, in the COMET-1 study of men with metastatic CRPC who had 
previously received both docetaxel and novel hormonal therapy, the median survival for 
those who received cabozantinib or prednisone was even lower at 11.0 months and 
9.8 months, respectively (Smith et al, 2015).  No approved therapy has been tested in the 
target population of this study, as all currently approved treatments for symptomatic 
metastatic CRPC (including soft tissue disease) after docetaxel-based chemotherapy were 
tested in patients who had not received novel hormonal therapy.  Thus, the target population 
in this study has an unmet medical need deserving of potentially promising experimental 
therapies.
The key efficacy results of phase 2 and 3 studies in metastatic CRPC after chemotherapy 
(primarily docetaxel) are presented in Table 5.


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Table 5.
Key Efficacy Results of Phase 2 and 3 Studies in Metastatic CRPC After 
Chemotherapy (Primarily Docetaxel)
Study
Prior Novel 
Hormonal 
Therapy
Treatment vs 
Comparator
ORR
Radiographic PFS 
(HR; median)
Overall Survival 
(HR; median)
SPARC 
No
Satraplatin vs 
placebo 
(background 
prednisone)
8% vs 0.7%
HR = 0.67
11 vs 10 wk
HR = 0.98
61 vs 61 wk
CRPC2; 
AFFIRM 
No
Enzalutamide vs 
placebo
29% vs 4% 
HR = 0.40
8.3 vs 2.9 mo
HR = 0.63
18.4 vs 13.6 mo 
COU-AA-301
No
Abiraterone vs 
placebo 
(background 
prednisone)
14% vs 3%  
HR = 0.67
5.6 vs 3.6 mo
HR = 0.65
14.8 vs 10.9 mo
EFC6193; 
TROPIC 
No
Cabazitaxel vs 
mitoxantrone 
(background 
prednisone)
14% vs 4%
HR = 0.74
2.8 vs 1.4 mo
HR = 0.70
15.1 vs 12.7 mo
COMET-1
Yes
Cabozantinib vs 
prednisone
Not reported
HR = 0.50
5.5 vs 2.8 mo
HR = 0.90
11.0 vs 9.8 mo
(NS)
TOPARP-A
Yes
Olaparib (no 
comparator)
71% (5 of 7) 
in BM+ 
subgroup[1,2]
HR = 0.24
9.8 vs 2.7 mo
(BM+ vs -)
HR = 0.47
13.8 vs 7.5 mo 
(BM+ vs -)
Abbreviations: 
SPARC: Satraplatin and Prednisone Against Refractory Prostate Cancer; TROPIC: Phase III trial of cabazitaxel 
for the treatment of metastatic castration-resistant prostate cancer; COMET-1: Carvedilol Or Metoprolol 
European Trial;
TOPARP-A: Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer, part A.
Source: Sternberg et al, 2009; Scher et al, 2012; de Bono et al, 2011; de Bono et al, 2010; Smith et al, 2015; 
Mateo et al, 2015,  Novel hormonal therapy is defined as enzalutamide and/or abiraterone acetate/prednisone 
after chemotherapy.
1.
All 7 patients with BRCA2 loss responded; 5 of 7 biomarker-positive patients with measurable disease had an 
objective response in soft tissue.
2.
Response rates of 88% vs 6% for BM+ vs BM– were based on a composite endpoint and not solely on soft tissue 
responses as for all other studies. 
BM+ vs -, biomarker positive versus negative; CRPC, castration-resistant prostate cancer; HR, hazard ratio; mo, 
months; NS, not significant; ORR, objective response rate; PFS, progression-free survival; vs, versus; wk, 
weeks.
1.2.2. PARP Inhibition
PARP1 and PARP2 play important roles in DNA repair (Schreiber et al, 2006; Curtin NJ.  
2005).  Following DNA damage, PARP1 and PARP2 bind to single-stranded DNA breaks, 
cleave nicotinamide adenine dinucleotide, and attach multiple ADP-ribose units to 
chromatin- associated proteins, including histones and PARP1 itself (Gibson & Kraus, 2012; 
Schreiber et al, 2002; Amé et al, 1999; Johansson 1999).  The outcome is a highly negatively 
charged protein, which leads to the unwinding of the DNA strands and recruitment of 
proteins to repair the damaged DNA through the base-excision repair process.  When 
PARP1 and PARP2 are inhibited, single-strand DNA breaks persist, resulting in stalled 


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replication forks and conversion of single-strand breaks into double-strand breaks.  These 
breaks must be repaired by homologous recombination or nonhomologous end joining or 
they may become lethal.  Thus, inhibition of PARP catalytic activity results in synthetic 
lethality as defects in homologous recombination DNA repair prevent double strand breaks 
from being repaired, thereby killing the cell, including cancer cells. 
In addition, PARP inhibitors bind to PARP-DNA complexes trapping them, thereby 
inhibiting DNA repair, replication, and transcription, with associated cytotoxic effects on 
cancer cells.  Although other PARP inhibitors possess both activities, in vitro studies 
demonstrated that talazoparib is a more potent PARP trapper than other PARP inhibitors in 
clinical development (Hopkins et al, 2015; Murai et al, 2014).
1.2.3. PARP Inhibitors as a Potential Targeted Therapeutic in Metastatic CRPC
Proof of concept that PARP inhibition may treat prostate cancer with DNA damage repair 
deficiency was established in a Phase 2 study (TOPARP-A) with the PARP inhibitor olaparib
(Mateo et al, 2015).  In the TOPARP-A study, 50 patients with metastatic CRPC were treated 
with the PARP inhibitor olaparib (400 mg orally twice daily).  All had been previously 
treated with docetaxel, 98% with abiraterone or enzalutamide, and 58% with cabazitaxel.  
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2; 
disease progression per Prostate Cancer Working Group 2 (PCWG2) and/or Response 
Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1); 5 or more circulating tumor 
cells (CTC) per 7.5 mL of blood; and consented to a fresh tumor biopsy.  No prior exposure 
to platinum, cyclophosphamide, mitoxantrone, or other PARP inhibitors was permitted.  
Forty-nine patients were evaluable for response based on a composite endpoint of objective 
response according to RECIST 1.1, a reduction of at least 50% in prostate-specific antigen 
(PSA), or a confirmed reduction in CTC counts from 5 or more cells per 7.5 mL of blood to 
less than 5 cells per 7.5 mL of blood in patients with an identified homozygous deletion 
and/or putative deleterious mutation in DNA repair genes.  Sixteen of 49 evaluable patients 
(33%) had a response and the median duration of treatment was 40 weeks for responding 
patients.  Treatment with olaparib led to a response based on the composite endpoint 
definition in 14 of 16 patients (88%) with identified genomic deficiencies associated with 
DNA damage repair.  On the other hand, only 2 responses (6%) were seen in 33 patients 
without such genomic deficiencies. 
Of the 32 evaluable patients (65% of the 49 evaluable patients) who had measurable disease 
at baseline per RECIST 1.1, 7 patients had DNA damage repair deficiencies and 5 of those 
7 (71%) had a partial response (PR) per RECIST 1.1.  Patients with DNA damage repair 
deficiencies had longer median radiographic progression-free survival (PFS) 
(9.8 vs 2.7 months) and median overall survival (13.8 vs 7.5 months) compared with patients 
without DNA damage repair deficiencies. 
In an integrated analysis of somatic and germline mutation status in tumor biopsies from 
150 patients with metastatic CRPC, 22.7% of cases had mutations in DNA repair genes 
associated with sensitivity to a PARP inhibitor, including BRCA2, BRCA1, CDK12, 
FANCA, RAD51B, RAD51C, MLH1, MSH2, and ATM.  Loss of BRCA2 was observed in 
12.7% of cases (approximately 90% of these were biallelic loss), and 8% harbored a germline 


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alteration.  Another clinical targeted sequencing analysis of prostate cancer identified similar 
frequencies of somatic and germline alterations in DNA damage repair genes BRCA2, 
BRCA1, and ATM (Abida et al, 2015). 
PARP1 and PARP2 play important roles in DNA repair (Schreiber et al, 2006; Curtin, 2005).  
Following DNA damage, PARP1 and PARP2 bind to single-stranded DNA breaks, cleave 
nicotinamide adenine dinucleotide (NAD+), and attach multiple ADP-ribose units to the 
target protein, including itself (Gibson & Kraus, 2012; Schreiber et al, 2002; Amé et al, 
1999; Johansson, 1999).  The outcome is a highly negatively charged protein, which leads to 
the unwinding of the DNA strands and recruitment of proteins to repair the damaged DNA 
through the base-excision repair process.  When PARP1 and PARP2 are inhibited, 
single-strand DNA breaks persist, resulting in stalled replication forks and conversion of 
single-strand breaks into double-strand breaks.  These breaks must be repaired by 
homologous recombination or nonhomologous end joining or they may become lethal.
Talazoparib (also known as PF-06944076, MDV3800, BMN 673) is a potent, orally 
bioavailable, small molecule poly(ADP-ribose) polymerase (PARP) inhibitor in development 
for the treatment of a variety of human cancers.  PARP inhibitors including talazoparib exert 
cytotoxic effects via 2 mechanisms: inhibition of PARP1 and PARP2 catalytic activity and 
PARP trapping, a process in which PARP protein bound to a PARP inhibitor does not readily 
dissociate from DNA, preventing DNA repair, replication, and transcription (Murai et al, 
2012).  Inhibition of PARP catalytic activity contributes to the process of synthetic lethality, 
as it results in persistent single-strand breaks that require homologous recombination DNA 
repair for survival.  Stabilized PARP-DNA complexes (ie, trapped) inhibit DNA repair, 
replication, and transcription, and are more cytotoxic than unrepaired single-strand breaks 
because they do not readily dissociate.  Although other PARP inhibitors possess both 
activities, in vitro studies demonstrated that talazoparib has greater PARP trapping activity 
than other PARP inhibitors in clinical development (Hopkins et al, 2015; Murai et al, 2014).  
PARP inhibition exhibits an enhanced cytotoxic effect in cancers with DNA damage repair 
deficiencies.  The majority of responses in the TOPARP-A study of the PARP1 and 
PARP2 inhibitor olaparib in metastatic CRPC (Mateo et al, 2015, described in Section 1.2)
were observed in men with known DNA damage repair deficiencies.  In this phase 2 study of
olaparib monotherapy, 16 of 49 evaluable patients with metastatic CRPC (33%) had 
mutations and/or deletions in genes involved in homologous recombination or other DNA 
repair pathways.  Of the 16 patients (33%) who responded to treatment with olaparib, 
14 (88%) had mutations in DNA repair genes.  These data suggest that PARP inhibition may 
be a useful strategy for the treatment of tumors in men with metastatic CRPC, especially 
those harboring DNA repair pathway deficiencies.  In an integrated analysis of somatic and 
germline mutation status in tumor biopsies from 150 patients with metastatic CRPC, 
22.7% of cases had mutations in DNA repair genes associated with sensitivity to a PARP 
inhibitor, including BRCA2, BRCA1, CDK12, FANCA, RAD51B, RAD51C, MLH1, and 
ATM (Robinson et al, 2015).  Loss of BRCA2 was observed in 12.7% of cases 
(approximately 90% of these were biallelic loss), and 8% harbored a germline alteration in 
BRCA2, BRCA1, or ATM.  Another clinical targeted sequencing analysis of prostate cancer 
identified similar frequencies of somatic and germline alterations in DNA damage repair 
genes BRCA2, BRCA1, and ATM (Abida et al, 2015).


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1.2.4. Clinical Data Supporting PARP Inhibition as a Potential Targeted Therapeutic in 
Metastatic CRPC
In the TOPARP-A study (Mateo et al, 2015), 50 patients with metastatic CRPC were treated 
with the PARP inhibitor olaparib (400 mg orally twice daily).  All had been previously 
treated with docetaxel, 98% with abiraterone or enzalutamide, and 58% with cabazitaxel.  
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2; 
disease progression per Prostate Cancer Working Group 2 (PCWG2) and/or Response 
Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1); 5 or more circulating tumor 
cells (CTC) per 7.5 mL of blood; and consented to a fresh tumor biopsy.  No prior exposure 
to platinum, cyclophosphamide, mitoxantrone, or other PARP inhibitors was permitted.  
Forty-nine patients were evaluable for response based on a composite endpoint of objective 
response according to RECIST 1.1, a reduction of at least 50% in prostate-specific antigen
(PSA), or a confirmed reduction in CTC counts from 5 or more cells per 7.5 mL of blood to 
less than 5 cells per 7.5 mL of blood in patients with an identified homozygous deletion 
and/or putative deleterious mutation in DNA repair genes.  Sixteen of 49 evaluable patients 
(33%) had a response and the median duration of treatment was 40 weeks for responding 
patients.  Treatment with olaparib led to a response based on the composite endpoint 
definition in 14 of 16 patients (88%) with identified genomic deficiencies associated with 
DNA damage repair.  Of the 32 evaluable patients (65% of 49) who had measurable disease 
at baseline per RECIST 1.1, 7 patients had DNA damage repair deficiencies and 5 of those 
7 (71%) had a partial response (PR) per RECIST 1.1.  Tumor regression in bone was 
documented on whole-body magnetic resonance imaging (MRI) in a patient with an ATM 
defect.  Patients with DNA damage repair deficiencies had longer median radiographic 
progression-free survival (PFS) (9.8 vs 2.7 months) and median overall survival (13.8 vs 
7.5 months) compared with patients without DNA damage repair deficiencies.  The median 
duration of olaparib treatment for all patients was 12 weeks.  Grade 3 and 4 adverse events 
included anemia (20% of patients), fatigue (12%), leukopenia (6%), thrombocytopenia (4%), 
and neutropenia (4%).  At least 1 dose reduction was required in 13 patients (26%), primarily 
due to anemia; 3 patients (6%) discontinued due to adverse events.
1.3. Summary of Relevant Clinical Experience With Talazoparib 
As of 31 Jan 2018, talazoparib has been evaluated in approximately 659 patients and 
18 healthy volunteers in both company-sponsored and investigator-sponsored studies in 
hematologic malignancies and solid tumors at doses up to 2 mg/day.  Results from 
company-sponsored studies are summarized in the following sections. 
1.3.1. Efficacy 
A phase 1 clinical study supports the efficacy of talazoparib monotherapy at 1 mg once daily. 
PRP-001 is a phase 1, open-label, safety, pharmacokinetics (PK), and dose-escalation 
(0.025-1.1 mg/day) and expansion (1 mg/day) study of talazoparib monotherapy in 
110 patients with advanced or recurrent solid tumors with DNA repair deficiencies.  As of 
the data cutoff date of 01 Sep 2016, data cutoff date for the primary analysis, objective 
responses (complete response [CR] or PR) per RECIST 1.1 were observed in 7 of 14 patients 
(50%) with breast cancer and 5 of 12 patients (41.7%) with ovarian/primary peritoneal cancer 


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with deleterious germline BRCA mutations treated at 1 mg/day; clinical benefit (CR, PR, or 
stable disease ≥24 weeks) was observed in 12 of 14 patients (85.7%) and 8 of 12 patients 
(66.7%), respectively.
Study 673-201 (ABRAZO) is a Phase 2, 2-stage, 2-cohort study of talazoparib in patients 
with germline BRCA mutation and locally advanced and/or metastatic breast cancer.  As of 
December 2016, the confirmed objective response rate (CRs and PRs) was 20.8% for cohort 
1 (95% confidence interval [CI]: 10.47, 34.99), including 2 CRs (4.2%), and 37.1% for 
cohort 2 (95% CI: 21.47, 55.08) per independent central radiology assessment.  The objective 
response rate across both cohorts was 27.7% (95% CI: 18.45, 38.62), demonstrating 
clinically meaningful responses in this population with a poor prognosis and a high unmet 
medical need. 
Activity of talazoparib in women with germline BRCA 1/2 mutation and locally advanced 
breast cancer has been confirmed in a phase 3 study (EMBRACA, Litton et al, 2018) 
comparing the safety and efficacy of 1 mg/day talazoparib versus physician’s-choice of 
chemotherapy (PCT) which included capecitabine, eribulin, gemcitabine, or vinorelbine.  The 
median progression-free survival was 8.6 months for patients treated with talazoparib, vs 
5.6 months for patients treated with physician’s-choice chemotherapy
(HR = 0.542, P <.0001).
Additional and updated information on the clinical efficacy of talazoparib is provided in the 
talazoparib investigator’s brochure. 
1.3.2. Safety 
Aggregate safety data from 5 open-label studies, including 1 randomized, company-
sponsored clinical study (PRP-001, 673-201, 673-301, MDV3800-13, and MDV3880-15: 
N = 502 patients) evaluating talazoparib monotherapy in solid tumors at the proposed dose of 
1 mg/day provide the basis for the reported treatment-emergent adverse events (TEAEs).  All 
causality TEAEs reported in ≥20% of patients administered single-agent talazoparib 
1 mg/day are related to myelosuppression (anemia, neutropenia), GI toxicity (nausea, 
diarrhea, vomiting, constipation, and decreased appetite), fatigue, headache, and alopecia. 
Grade 3 or 4 TEAEs in ≥5% of patients were associated with myelosuppression.  
Study drug-related TEAEs occurring in ≥20% of patients in the talazoparib 1 mg/day
population were anemia (45.8%), fatigue (36.1%), nausea (32.5%), neutropenia (21.9%), and
alopecia (20.1%). Grade 3 or 4 drug-related TEAEs occurring in ≥5% of patients were
anemia (34.1%), neutropenia (13.9%), thrombocytopenia (10.6%), and platelet count
decreased (5.4%).
A total of 23 of 502 (4.6 %) patients in the talazoparib 1 mg/day population had a TEAE that 
led to death, 8 deaths were associated with the malignancy under study (including 1 subject 
whose death was also associated with pneumonia); 2 deaths were associated with dyspnea; 
2 with general physical health deterioration; 3 with disease progression; and 1 each with lung 
infection, cerebral hemorrhage, cerebrovascular accident, fatigue (event term later changed to 


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failure to thrive), liver disorder, neurological symptom, respiratory failure, and 
veno-occlusive liver disease.  Of these, only veno-occlusive liver disease was assessed as 
related to study drug by the investigator.  
Serious adverse events (SAEs) occurred in 164 of 502 patients (32.7%) in the talazoparib 
1 mg/day population.  SAEs occurring in ≥2% of patients were anemia (5.2%) and dyspnea 
(2.2%) and pleural effusion (2.2%).  Forty-seven patients had SAEs considered related to 
study drug.  Study drug-related SAEs occurring in ≥1% of patents were anemia (4.6%), 
thrombocytopenia (1.2%) and platelet count decreased (1.2%).
Twenty (20) of 502 patients (4.0%) in the talazoparib 1 mg/day population discontinued
study drug due to a TEAE. The events that led to study drug discontinuation were anemia
(3 patients), increased alanine aminotransferase (ALT, 2 patients), and accidental overdose,
increased aspartate aminotransferase (AST), bradycardia, 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).
Among the 502 patients in the Talazoparib 1 mg/day population, 63.9% had a TEAE that led
to dose reduction and 61.2% had a TEAE that led to dosing interruption. The most common
TEAEs that led to dose reduction or interruption were associated with myelosuppression.
In the EMBRACA trial, the adverse events observed with talazoparib were consistent with 
findings from previous trials. The most common adverse events (AEs) observed with 
talazoparib (any grade in at least 15% of patients) 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%), back pain (21%) and dyspnea (17.5%). The incidence of SAEs was 31.8% in the 
talazoparib arm and 29.4% in the PCT chemotherapy arm. Discontinuations due to AEs 
occurred in 7.7% of patients in the talazoparib arm and 9.5% of patients in the PCT 
chemotherapy arm.
For additional important safety information from other talazoparib studies, please consult the 
current talazoparib investigator’s brochure.
1.3.3. Pharmacokinetics 
Talazoparib plasma exposure was dose proportional in the dose range of 0.025 mg to 2 mg 
once a day 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 Tmax
ranged from 0.5 to 2.0 hours across studies. Administration of a single 0.5 mg dose of 
talazoparib to healthy subjects with food (a high-fat, high-calorie meal) had no impact on the 
area under the plasma concentration time curve (AUC) while reduced the 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 overall exposure for the typical targeted anti-cancer therapies.  
Therefore, talazoparib can be taken without regard of food.


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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 
significantly greater than total body water (42 L), indicating that talazoparib 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 
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.
Talazoparib was eliminated slowly with a mean terminal plasma half-life (t½) of 89.8 hours. 
Talazoparib accumulated after 1 mg once a day dosing with a median accumulation ratio 
ranging from 2.33 to 5.15, consistent with its t½. Population PK analysis showed that 
talazoparib 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 to 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.  For patients with moderate renal impairment, the recommended dose 
of talazoparib is 0.75 mg once a day.
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 5.10.
Additional information on the clinical PK of talazoparib is provided in the talazoparib 
investigator’s brochure.
1.4. Summary of Relevant Nonclinical Experience With Talazoparib 
1.4.1. Nonclinical Pharmacology of Talazoparib 
The cytotoxic activity of talazoparib was demonstrated in cell culture, and antitumor effects 
were demonstrated in mouse xenograft models. 
In cell-free enzyme assays, talazoparib inhibited PARP1 and PARP2 catalytic activity with 
inhibitory constant (Ki) values of 1.2 nM and 0.87 nM, respectively (Wang et al, 2016).  
Talazoparib was approximately 3.4- to 8.3-fold more potent than other PARP inhibitors in 
clinical development (veliparib, rucaparib, olaparib) in inhibiting PARP1 catalytic activity 
(Shen et al, 2013).  In addition, talazoparib was approximately 40-fold more potent than 
olaparib in stimulating the formation of stable PARP1-DNA complexes (Murai et al, 2014).


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In tissue culture studies, talazoparib was cytotoxic to cancer cell lines harboring gene 
mutations that compromise DNA repair pathways, including MX-1 (BRCA1-mutant) and 
MDA-MB-468 (PTEN-mutant) mammary cancer cells, LNCaP (PTEN- and ATM-mutant) 
and PC-3 (PTEN-mutant) prostate cancer cells, and HCT-116 (MLH-1-mutant) colorectal 
tumor cells.  Additional information on the nonclinical pharmacology of talazoparib is 
provided in the talazoparib investigator’s brochure.
1.4.2. Nonclinical PK and Metabolism 
PK studies in rats and dogs show that talazoparib oral bioavailability was >43% in rats and 
>51% in dogs.  A Good Laboratory Practice (GLP) study in dogs demonstrated that the 
capsule formulation used in clinical studies is approximately 2-fold more bioavailable than 
the suspension formulation used in nonclinical studies.  In general, talazoparib displays 
greater than or approximately dose-proportional increases in exposure in rats and dogs with
no evidence of sex differences.
Studies of [14C]-talazoparib in rats and dogs indicate rapid absorption, wide distribution 
(greater than total body water), and nearly complete elimination of drug substance (>90%) by 
7 days.  Fecal elimination was the main route of elimination in both species, and renal 
excretion was moderate (21-26%).  In a study in rats, [14C]-talazoparib was widely 
distributed, reaching maximum levels 1 to 4 hours postdose.  Excluding the gastrointestinal 
tract, the highest radioactivity levels were observed in liver and kidney (and the eye uveal 
tract in albino rats).  Tissue radioactivity levels were greater than blood levels in the target 
organs of talazoparib toxicity (bone marrow, spleen, and thymus) through 7 days.  Metabolic 
profiling of plasma, urine, and feces samples indicated that [14C]-talazoparib is largely 
cleared via excretion of unchanged parent drug and metabolized to a minor extent via 
oxidation and dehydrogenation.
In vitro metabolism studies in rat, dog, and human hepatic microsomes demonstrated that 
[14C]-talazoparib has high metabolic stability (>90%) over 2 hours.  A minimal extent or a 
lack of metabolism for [14C]-talazoparib was observed in the presence of freshly isolated 
mouse, rat, dog, and human hepatocytes or cryopreserved human hepatocytes.  Talazoparib 
does not appear to be a substrate of any major cytochrome P450 (CYP450) metabolizing 
enzyme.
Mean binding to human plasma proteins is 78.7%; therefore, it is unlikely that talazoparib 
will demonstrate clinically significant drug-drug interactions related to displacement from 
plasma protein binding sites.  At therapeutic exposures, talazoparib does not markedly induce 
or inhibit CYP450 enzymes.  Therefore, it is unlikely that talazoparib will demonstrate 
clinically significant CYP450 inhibition- or induction-based drug-drug interactions when 
coadministered with corresponding substrates.  Talazoparib is not a substrate of metabolizing 
CYP450 enzymes.  At therapeutic exposures, talazoparib does not markedly induce or inhibit 
any transporters.  Therefore, it is unlikely that talazoparib will demonstrate clinically 
significant drug transporter inhibition-based drug–drug interactions when coadministered 
with corresponding substrates.
Additional information on the nonclinical PK and drug metabolism of talazoparib is provided 
in the investigator’s brochure.


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1.4.3. Nonclinical Toxicology
Safety pharmacology, single- and repeat-dose toxicity, genotoxicity, embryo-fetal 
development, and in vitro phototoxicity studies were conducted to evaluate the nonclinical 
toxicology profile of talazoparib.  Repeat-dose toxicity/toxicokinetic studies were conducted 
with talazoparib utilizing the intended oral route of administration in mice, rats, and dogs.  A 
repeat-dose study with talazoparib was conducted in BALB/c nude mice to select doses and 
exposures for the mouse xenograft studies.
Five-day, 28-day, and 13-week repeat-dose GLP toxicity and toxicokinetic studies with 
28-day recovery periods were conducted in the rat and dog.  The major findings are as 
follows:

Dose-dependent pancytopenia with bone marrow hypocellularity and depletion of 
lymphoid tissue in multiple organs was observed and considered possibly due to 
exaggerated pharmacology of talazoparib based on the higher (relative to baseline) 
poly(ADP-ribose) (index of PARP1/2 activity) tissue levels in these organs.  The 
hematologic findings were partially reversible and may be readily monitored in the 
clinic.  The toxicities that resulted in mortality in dogs (0.1 mg/kg/day) and some rats
(1 mg/kg/day) occurred at AUC0-24 exposures that were >0.8- and 4-fold higher,
respectively, than the exposure at the recommended human dose of 1 mg/day.  The 
toxicities were mainly due to septicemia that resulted from the severe bone marrow 
and lymphoid depletion.

A dose-dependent increased incidence of gastrointestinal tract findings of 
apoptosis/necrosis in the stomach and duodenum was observed.  Additional findings 
at higher doses included reversible villous atrophy and increased apoptosis 
throughout the gastrointestinal tract, most notably in the small intestine.  
Gastrointestinal tract toxicities of enteropathy and villous atrophy caused mortality in 
rats at 3.0 mg/kg/day.  Exposures at 3.0 mg/kg/day are significantly higher than the 
exposures at the recommended human dose.

Additional findings at the high dose (≥1 mg/kg/day) in the 5-day GLP study in rats 
included focal necrotic changes in the ovarian follicular atresia and hepatocyte 
necrosis of the liver.  These findings were not observed in the 28-day or 13-week 
repeat-dose studies in rats.

Atrophy and/or degenerative changes in testes and epididymis and effects on the 
seminiferous tubules were observed in rats and dogs; the severity correlated with both 
dose and duration of treatment.
There were no talazoparib-related effects on respiratory or central nervous system parameters 
after a single oral administration to rats (safety pharmacology studies), or on cardiovascular 
parameters and electrocardiogram (ECG) evaluations after a repeat-dose oral administration 
in dogs (repeat-dose toxicity studies).  Talazoparib had no effect on ophthalmologic 
endpoints in rats or dogs in repeat-dose toxicity studies.  Talazoparib was not mutagenic in a 
bacterial reverse mutation assay, but consistent with the genomic instability of its primary 


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pharmacology, was clastogenic in an in vitro chromosomal aberration assay and an in vivo 
micronucleus assay, indicating the potential for genotoxicity in humans.  Talazoparib caused 
fetal malformations, structural variations, and death in an embryo-fetal development study in 
rats.  Based on an in vitro 3T3 neutral red uptake assay, which results in a high incidence of 
false positives, talazoparib is potentially phototoxic in humans.  In conclusion, the main 
nonclinical toxicologic findings were early hematologic changes and subsequent bone 
marrow and lymphoid organ depletion; focal atrophy and degeneration of testes, epididymis, 
and seminiferous tubules; and dose-dependent apoptosis/necrosis in the gastrointestinal tract 
and liver after repeat-dose talazoparib.  These findings are consistent with the exaggerated 
pharmacology of talazoparib and its tissue exposure pattern.  
Additional information on the toxicology of talazoparib is provided in the talazoparib 
investigator’s brochure.
1.5. Talazoparib Benefits and Risks Assessment 
The doses of talazoparib in this protocol are supported by nonclinical studies and 
phase 1-3 studies in patients with advanced malignancies.  Adverse drug reactions with 
talazoparib include myelosuppression, gastrointestinal toxicity, fatigue, and alopecia.  
Hepatotoxicity, second primary nonhematologic malignancies and pneumonitis are adverse 
events of special interest per the investigator’s brochure. Seven AEs of second primary 
nonhematologic malignancies were reported in 6 patients (squamous cell carcinoma of skin 
[2 patients], and basal cell carcinoma, glioblastoma multiforme, intraductal proliferative 
breast lesion, neoplasm skin, and ovarian neoplasm [1 patient each, respectively]). These 
second primary malignancies were mostly skin malignancies. In general, latency to 
diagnosis of the malignancy was relatively short, making a relationship with talazoparib 
unlikely. Diagnoses of myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) 
have been reported in patients who received poly(adenosine diphosphate [ADP] ribose) 
polymerase (PARP) inhibitors. Overall, MDS/AML has been reported in 2 (1 MDS and 
1 AML case) out of 561 solid tumor patients treated with talazoparib in clinical studies.
The activity of talazoparib as monotherapy and in combination with other agents is being 
evaluated in multiple indications.  Recent results from the EMBRACA study (Litton et al, 
2018) a phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician's choice of 
therapy (PCT) in patients with advanced breast cancer and a germline BRCA mutation,
demonstrated that single-agent talazoparib at 1 mg/day significantly prolonged progression-
free survival in HER2-negative advanced breast cancer patients with a germline BRCA
1/2 mutation compared to PCT. Data from the study indicate that talazoparib was generally 
well tolerated with minimal non-hematologic toxicity and few AEs associated with treatment 
discontinuations.
The benefit-risk profile of talazoparib in prostate cancer patients is not yet characterized.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure.


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1.6. Rationale for Talazoparib Dose
Talazoparib has demonstrated efficacy at a dose of 1 mg/day. Talazoparib 1 mg/day orally 
will be administered until radiographic progression is determined by independent central 
review, unacceptable toxicity, withdrawal of consent, or death.  In addition, talazoparib can 
continue to be administered upon disease progression only if, in the opinion of the 
investigator the patient is clinically benefitting, no new concurrent systemic therapy is 
started, and the sponsor is notified.  For patients with moderate renal impairment (estimated 
glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m2 as per central laboratory) at 
screening, the starting dose will be 0.75 mg/day.  Study drug should not be discontinued 
based solely on PSA or CTC count increases.
2. STUDY OBJECTIVES AND ENDPOINTS
Study objectives and corresponding endpoints are provided in Table 6, below.


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Table 6.
Objectives and Endpoints for Study
Primary Objective(s):
Primary Endpoint(s):
To evaluate the efficacy, of single agent talazoparib in 
DDR+ mCRPC as measured by best objective response 
rate (ORR).
Best ORR: The proportion of patients with a best overall soft 
tissue response of CR or PR per RECIST 1.1 by independent 
central review.  Soft tissue responses must 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 on repeat bone scan at least 6 weeks later 
per PCWG3 criteria by independent central review.
Secondary Objective(s):
Secondary Endpoint(s):
To evaluate efficacy with respect to the following 
parameters:

Time to objective response;

Duration of response;

Proportion of patients with prostate-specific 
antigen (PSA) decrease ≥50%;

Proportion of patients with conversion of 
circulating tumor cell (CTC) count;

Time to PSA progression;

Radiographic progression-free survival (PFS);

Overall survival.
Time to objective response: The time from first dose of 
talazoparib 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 best overall response of CR or PR per 
RECIST 1.1 by independent central review.  The response 
must be confirmed at least 4 weeks later with a repeated 
CT/MRI.
Duration of response: The time from the first objective 
evidence of soft tissue response (subsequently confirmed) per 
RECIST 1.1 by independent central review and no evidence of 
confirmed bone disease progression per 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 per 
RECIST 1.1 by independent central review or bone disease 
progression per PCWG3 by independent central review.
Proportion of patients with PSA response ≥50%: The 
proportion of patients with confirmed PSA decline 
≥50% compared to baseline.
For CTC counts:

The proportion of patients with conversion of CTC count: 
The proportion of patients with a CTC count ≥5 CTC per 
7.5 mL of blood at study entry that decreases to <5 CTC 
per 7.5 mL of blood any time on study. 

The proportion of patients with a CTC count of 1 or more 
per 7.5 mL of blood at study entry that decreased to 
CTC=0 per 7.5 mL of blood any time on study.

The proportion of patients with baseline CTC counts 
<5 who show increased CTC counts post-baseline.
Time to PSA progression: The time from first dose of 
talazoparib to the date that a ≥25% increase in PSA with an 
absolute increase of ≥2 μg/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. 
Radiographic PFS: The time from first dose of talazoparib to 
radiographic progression in soft tissue per RECIST 1.1 by 
independent central review, in bone per PCWG3 by 
independent central review, or death, due to any cause 
whichever occurs first. 
Overall survival: Defined as the time from first dose of 
talazoparib to death due to any cause. 


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Table 6.
Objectives and Endpoints for Study
To evaluate the safety of talazoparib in this patient 
population.
To evaluate the following patient-reported outcomes:
•
Time to deterioration in patient reported pain 
as assessed by the Brief Pain Inventory Short 
Form (BPI-SF);
•
Change from baseline in patient reported 
pain per BPI-SF;
•
Change from baseline in patient-reported 
outcome general health status as assessed by 
the European Quality of Life 5-Domain 
5-Level Scale (EQ-5D-5L).
To evaluate the pharmacokinetics (PK) of talazoparib.
Assessment of safety will include adverse events, incidence of 
dose modifications and of permanent treatment discontinuation 
due to adverse events, vital signs, and clinical laboratory tests.
Evaluate the following patient-reported outcomes:
•
Time to deterioration in patient reported pain as 
assessed by the Brief Pain Inventory Short Form 
(BPI-SF);
•
Change from baseline in patient reported pain per 
BPI-SF;
•
Change from baseline in patient-reported outcome 
general health status as assessed by the European 
Quality of Life 5-Domain 5-Level Scale 
(EQ-5D-5L).
Assessment of the pharmacokinetics of talazoparib will 
include pre-dose trough and post-dose plasma concentrations 
for talazoparib.
 
 
 
 
 
 
 
 
3. STUDY DESIGN
3.1. Overall Study Design and Plan: Description 
This is an international, phase 2, open-label, soft tissue response rate study of talazoparib, a 
PARP inhibitor in development for the treatment of cancer.  PARP inhibition has been shown 
to produce clinical responses in metastatic CRPC, particularly in patients with DNA damage 
repair deficiencies.  PARP inhibitors are thought to induce cell toxicity by inhibiting PARP 
catalytic activity as well as by trapping PARP-DNA complexes, which prevent DNA repair, 
replication, and transcription.  Nonclinical studies have shown that talazoparib has potent 
cytotoxic effects via both mechanisms, with greater cell toxicity from PARP trapping.
In this study, patients will be evaluated at prescreening (optional) or screening for DNA 
damage repair deficiencies as assessed by a gene mutation biomarker panel.  At least
100 men with measurable soft tissue disease (per RECIST1.1) and progressive metastatic 
CRPC and DNA damage repair deficiencies likely to sensitize to PARP inhibition will be 
enrolled.  Eligible patients must have previously received 1 to 2 chemotherapy regimens 
including at least 1 taxane-based regimen for treatment of metastatic prostate cancer, and 
progressed on at least 1 line of novel hormonal therapy (enzalutamide and/or abiraterone 
acetate/prednisone) for treatment of metastatic CRPC. 
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Patients must consent to submit sufficient tumor tissue (de novo tumor biopsy or archival 
tissue) for targeted next-generation sequencing to determine DNA damage repair gene 
deficiencies for eligibility. Previous identification of DNA repair deficiencies likely to 
sensitize to PARP inhibition, using the FoundationOne CDx™ test may be considered for 
eligibility (with sponsor approval). Biopsies of the brain, lung/mediastinum, pancreas, or 
endoscopic procedures extending beyond the esophagus, stomach, or bowel may not be 
performed for the sole purpose of determining study eligibility.
The primary efficacy endpoint is best ORR by modified RECIST1.1/PCWG3.  An objective 
response is defined as a best overall response of CR or PR per RECIST 1.1.  Responses must
be confirmed by a follow-up radiographic assessment at least 4 weeks later with a repeated 
computed tomography (CT)/MRI and with no evidence of confirmed bone disease 
progression on repeat bone scan at least 6 weeks later per PCWG3 criteria by independent 
central review. 
Talazoparib 1 mg/day orally will be administered until radiographic progression is 
determined by independent central review, unacceptable toxicity, withdrawal of consent, or 
death.  In addition, talazoparib can continue to be administered upon disease progression 
only if, in the opinion of the investigator the patient is clinically benefitting, no new 
concurrent systemic therapy is started, and the sponsor is notified. For patients with 
moderate renal impairment (estimated glomerular filtration rate [eGFR] 
30-59 mL/min/1.73 m2 per central laboratory) at screening, the starting dose will be 
0.75 mg/day.  Study drug should not be discontinued based solely on PSA or CTC count 
increases. 
Study periods include prescreening (optional), screening, treatment, safety follow-up, and 
long-term follow-up.  Safety follow-up after permanent discontinuation of study drug 
treatment will occur approximately 28 days after the last dose of study drug or before 
initiation of a new antineoplastic or investigational therapy, whichever occurs first. 
Long-term follow-up will occur every 8 (if study treatment discontinuation is prior to 
week 25) to 12 weeks (if study treatment discontinuation is at or beyond week 25) after 
safety follow-up.  Radiographic imaging should continue during long-term follow-up for 
patients who discontinue study drug for any reason other than radiographic progression 
determined per protocol, withdrawal of consent for follow-up, or death.  Survival status, new 
antineoplastic therapy(ies), and diagnosis of myelodysplastic syndrome and acute myeloid 
leukemia will be assessed until the study is terminated.
 
 
 
 
 
 
 
 
 
 
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Patient-reported outcomes will be assessed to determine time to deterioration in pain using 
the Brief Pain Inventory Short Form (BPI-SF) and general health status using the EQ-5D-5L 
health questionnaire.  These assessments will be performed:
•
At baseline (Day 1);
•
Every 2 weeks (prior to Study Week 9) , weeks 9, 13, 17, 21 through Week 25, or 
radiographic progression, whichever is earlier; 
•
Every 12 weeks after Week 25 until radiographic progression when no such 
progression had been previously documented;
•
During unscheduled visit(s) when no radiographic progression had been previously 
documented;
•
During safety follow up;
•
And at end of trial when study results are determined.
3.2. Study Schematic 
The study schematic is provided in Figure 2 (below).
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Figure 2.
Study Schematic
Key assessments: Bone scan, CT/MRI, PSA, PK, 
 CTC, patient-reported outcomes
Optional: Prescreening for tumor tissue analysis for eligibility purposes
3.3. Blinding
Talazoparib treatment will be open label.  All patients, study site personnel (including 
investigators), and sponsor staff and its representatives will be unblinded to treatment 
identity.
3.4. Duration of Study 
The primary endpoint analysis will be performed when the last enrolled patient who does not 
discontinue treatment prematurely, completes at least 6 months of study drug treatment, 
withdraws consent, discontinues from the study, or dies, whichever occurs first. 
3.5. Discussion of Study Design and Rationale for Dose Selection 
Treatment of men with metastatic CRPC previously treated with taxane-based chemotherapy 
and who progressed on novel hormonal therapy is an area of high unmet need.  No therapy is 
approved for this patient population, and National Comprehensive Cancer Network (NCCN) 
guidelines do not specifically address treatment in this late disease stage.  Study C3441006 
(MDV3800-06) is based on nonclinical studies supporting the sensitivity of prostate tumors 
with DNA damage repair deficiencies, which may sensitize to PARP inhibition, and clinical 
evidence demonstrating a high response rate to the PARP inhibitor, olaparib, in a 
genomically selected subset of men with metastatic CRPC (the TOPARP-A study, discussed 
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in Section 1.2).  Talazoparib has cytotoxic effects believed to be caused by inhibition of the 
catalytic activity of PARP-dependent DNA repair and suppression of DNA synthesis and 
transcription at sites of PARP trapping. 
This study will evaluate patients at prescreening (optional) or screening for DNA damage 
repair deficiencies as assessed using a biomarker panel of gene mutations.  The patients will 
be evaluated for gene mutations in a panel of genes that, when mutated, are likely to sensitize 
to PARP inhibition. 
The sample size requirement for patients with measurable soft tissue disease supports the 
primary endpoint of best ORR, which is a clinically relevant endpoint with precedent in 
oncology indications where high unmet need exists.  Cabazitaxel is a possible therapy 
indicated for these patients and its previous use is permitted.  Similarly, radium-233 is a 
possible therapy for patients with symptomatic bone metastatic CRPC without visceral 
metastases and its previous use is permitted. 
Mechanisms of resistance to PARP inhibition may be shared with DNA-damaging agents 
such as cyclophosphamide and or mitoxantrone; thus, these agents and prior treatment with a 
PARP inhibitor in an experimental setting are excluded to maximize the likelihood of 
treatment efficacy. Similarly, treatment with platinum-based therapies in the 6 months prior 
to screening, or progression on prior platinum-based therapy at any time in the past, will 
exclude participation.  Treatment with chemotherapy (eg, docetaxel, cabazitaxel) within 
28 days of Day 1 and on study is also prohibited given the heightened risk of 
myelosuppression.  A known diagnosis of myelodysplastic syndrome or acute myeloid 
leukemia and central laboratory hematology values below specified thresholds for 
hemoglobin, absolute neutrophil count, and platelet count at screening are also exclusionary 
given the predicted risk of dose-dependent myelosuppression.  Pulmonary function testing is 
not mandated given the rarity of pneumonitis reports with exposure to other PARP inhibitors.  
Current or anticipated use within 7 days prior to first dose of study drug or anticipated use 
during the study of strong P-gp inhibitors is exclusionary. For a list of strong P-gp inhibitors, 
refer to Section 5.11. 
C3441006 (MDV3800-06) will include an efficacy assessment schedule of every 8 weeks 
during the first 24 weeks based on the standard of care for the target patient population with 
progressive advanced disease.  Efficacy assessments will be every 12 weeks after the first 
24 weeks.  Additional safety precautions will include monitoring for potential hematologic 
toxicities by evaluating complete blood counts every 2 weeks through week 9, every 4 weeks 
through week 25, and then every 8 weeks thereafter during treatment.  Prolonged 
myelosuppression will be monitored closely and diagnoses of myelodysplastic syndrome and 
acute myeloid leukemia occurring during or after study drug treatment will be reported.  The 
potential for liver toxicity will be monitored by periodic transaminase testing with predefined 
dose modification and discontinuation criteria.  Finally, patients with moderate renal 
impairment will receive talazoparib at a lower starting dose as they are at risk of higher 
exposure due to decreased renal clearance. 


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Talazoparib 1 mg/day was determined to be the maximum tolerated dose (MTD) and 
recommended phase 2 monotherapy dose based on the results of the phase 1, dose-escalation 
study in patients with solid tumors, PRP-001.  Based on population PK analyses, talazoparib 
CL/F was estimated to be 37.1% lower in patients with moderate renal impairment than in 
those with normal renal function, resulting in higher exposure (Section 1.3.3).  Simulations 
were performed to predict the steady-state exposure (AUC) for a 0.75 mg/day dose in 
patients with moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) and for a 1 mg/day 
dose in patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2) (Table 7).  The 
predicted exposure at 0.75 mg/day for patients with moderate renal impairment is 
comparable to the exposure at 1 mg/day for patients with normal renal function as assessed 
by steady-state AUC.  Based on these data, the planned starting dose for patients with 
moderate renal impairment is 0.75 mg/day.  Patient with moderate renal impairment should 
remain on a reduced talazoparib dose throughout the study; dose escalation to a dose of 
1 mg/day is not permitted for those patients.
Table 7.
Predicted Talazoparib Mean Exposure at Steady-State
Renal Function 
Dose
(mg/day)
Steady-State AUC0-24 (ng•h/mL)
Mean (5th-95th Percentile)
Normal 
1
161 (136-188)
Moderate impairment
0.75
179 (163-196)
AUC0-24, area under the plasma concentration-time curve from time zero to the time 24 hours (dosing 
interval).  
4. PATIENT ELIGIBILITY CRITERIA
Selection of Study Population 
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 nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol.
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2.  The sponsor will not grant any eligibility waivers.
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
4.1. Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Patients must be at least 18 years of age, and there must be evidence of a personally 
signed and dated informed consent document indicating that the patient has been 
informed of all pertinent aspects of the study.


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2. Histologically or cytologically confirmed adenocarcinoma of the prostate without 
signet cell, or small cell features.  Histologic confirmation may be based on a de novo 
tumor biopsy obtained for purposes of screening.  Biopsies of the brain, 
lung/mediastinum, pancreas, or endoscopic procedures extending beyond the 
esophagus, stomach, or bowel may not be performed for the sole purpose of 
determining study eligibility.
3. Patients must have measurable soft tissue disease per RECIST 1.1.
4. DNA damage repair gene alterations likely to sensitize to PARP inhibition 
(DDR-positive) as determined by:

Prospective testing of de novo or archival tumor tissue (via central laboratory) or 
prior historical (with sponsor preapproval) testing of tumor tissue using the 
Foundation Medicine, FoundationOne CDx™NGS gene panel test;
(Available archival or de novo tumor tissue also should be submitted prior to
Day 1 to support concordance analyses and additional molecular profiling).
5. Unless prohibited by local regulations or ethics committee (EC) decision, consent to a 
saliva sample collection for retrospective sequencing of DDR genes used to assess 
patient eligibility based on tumor tissue, and to serve as a germline control in 
identifying tumor mutations.
6. Serum testosterone ≤1.73 nmol/L (50 ng/dL) at screening by central laboratory.
7. Bilateral orchiectomy or ongoing androgen deprivation therapy with a 
gonadotropin-releasing hormone (GnRH) agonist/antagonist (surgical or medical 
castration).
8. Progressive disease at study entry defined as 1 or more of the following 3 criteria:

A minimum of 3 rising PSA values with an interval of at least 1 week between 
determinations.  The screening central laboratory PSA value must be ≥2 μg/L 
(2 ng/mL) if qualifying solely by PSA progression. For additional guidance, refer 
to Section 7.2.1.

Soft tissue disease progression as defined by RECIST 1.1.

Bone disease progression defined by PCWG3 with 2 or more new metastatic 
lesions on bone scan.
9. Metastatic disease.  Patients whose only evidence of metastasis is measurable soft 
tissue disease below the aortic bifurcation will be acceptable. Neither bone 
metastases on bone scan nor non- measurable soft tissue disease alone will qualify a 
patient.


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10. Previous treatment with 1 or 2 chemotherapy regimens including at least 
1 taxane-based regimen for metastatic (non-castrate or castrate) prostate cancer.  
Patients may have received radium-223 and/or cabazitaxel, or were deemed 
unsuitable, declined, or did not have access to these therapies.
11. Documented disease progression (either radiographic or biochemical) on at least 
1 novel hormonal therapy (enzalutamide and/or abiraterone acetate/prednisone) for 
the treatment of metastatic CRPC, irrespective of prior NHT treatment for 
non-castrate prostate cancer or nonmetastatic (M0) CRPC.
12. Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks 
before day 1 for patients receiving these therapies.
13. ECOG performance status of 0 to 2.
14. Estimated life expectancy of ≥6 months as assessed by the investigator.
15. Able to swallow the study drug, have no known intolerance to study drugs or 
excipients, and comply with study requirements.
16. Must use a condom when having sex with a pregnant woman from the time of the 
first dose of study drug through 4 months after last dose of study drug.  A highly 
effective form of contraception (Section 4.3.1) must be used from the time of the first 
dose of study drug through 4 months after last dose of study drug when having sex 
with a non-pregnant female partner of childbearing potential.
17. Must agree not to donate sperm from the first dose of study drug to 4 months after the 
last dose of study drug.
18. Patients must be 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. Use of systemic chemotherapeutic (including but not limited to taxanes), hormonal, 
biologic, or radionuclide therapy for treatment of metastatic prostate cancer (other 
than approved bone-targeting agents and GnRH agonist/antagonist) or any other 
investigational agent within 4 weeks before day 1.
2. Prior treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone 
chemotherapy. Patients who discontinued prior platinum-based chemotherapy 
6 months prior to screening or whose disease previously progressed on 
platinum-based therapy at any time in the past are also excluded. 
3. Treatment with any concurrent cytotoxic chemotherapy or investigational drug(s) 
within 4 weeks before Day 1 and/or during study participation.


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4. Radiation therapy within 3 weeks (within 2 weeks, if single fraction of radiotherapy) 
before day 1. 
5. Major surgery within 2 weeks before day 1.
6. Clinically significant cardiovascular disease, including any of the following: 

Myocardial infarction or symptomatic cardiac ischemia within 6 months before 
screening;

Congestive heart failure New York Heart Association class III or IV;

History of clinically significant ventricular arrhythmias (eg, sustained ventricular 
tachycardia, ventricular fibrillation, torsade de pointes) within 1 year before 
screening;

History of Mobitz II second degree or third degree heart block unless a permanent 
pacemaker is in place;

Hypotension as indicated by systolic blood pressure <86 mm Hg at screening;

Bradycardia as indicated by a heart rate of <45 beats per minute on the screening 
electrocardiogram;

Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg 
or diastolic blood pressure >105 mm Hg at screening.
7. Significant organ dysfunction by central laboratory results as defined by any one of 
the following laboratory abnormalities:

Renal: eGFR <30 mL/min /1.73 m2 by the MDRD equation (Modification of Diet 
in Renal Disease [available via www.mdrd.com]).

Hepatic:

Total serum bilirubin >1.5 times the upper limit of normal (ULN) 
(>3 × ULN for patients with Gilbert syndrome or for whom indirect 
bilirubin concentrations suggest an extrahepatic source of elevation);

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥2.5 times ULN (if liver test abnormalities are due to hepatic metastasis, 
then AST or ALT ≥5 × ULN);

Albumin <2.8 g/dL.


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
Bone marrow reserve: absolute neutrophil count <1500/μL, platelets 
<100,000/μL, or hemoglobin <9 g/dL (NOTE: may not have received growth 
factors or blood transfusions within 14 days before obtaining the hematology 
values at screening per central laboratory).
8. Known or suspected brain metastasis or active leptomeningeal disease.
9. Symptomatic or impending spinal cord compression or cauda equina syndrome.
10. Prior diagnosis of myelodysplastic syndrome or acute myeloid leukemia.
11. History of another cancer within 3 years before enrollment with the exception of
nonmelanoma skin cancers, or American Joint Committee on Cancer stage 0 or stage 
1 cancer that has a remote probability of recurrence in the opinion of the investigator 
and the sponsor.
12. Gastrointestinal disorder affecting absorption.
13. Current or anticipated use within 7 days prior to first dose of study drug or anticipated 
use during the study of strong P-gp inhibitors. For a list of strong P-gp inhibitors, 
refer to Section 5.11.
14. Any other acute or chronic medical or psychiatric condition (concurrent disease, 
infection, or comorbidity) that interferes with ability to participate in the study, causes 
undue risk, or complicates the interpretation of data, in the opinion of the investigator 
or sponsor, 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. 
15. 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.
16. Fertile male subjects who are unwilling or unable to use a condom as well as a highly 
effective method of contraception as outlined in this protocol for the duration of the 
study and for at least 4 months after the last dose of investigational product.
4.3. Lifestyle Requirements
4.3.1. Contraception
All fertile male subjects who are, in the opinion of the investigator, sexually active, capable 
of ejaculation and/or at risk for pregnancy with their partner(s) must agree to use both a 
condom as well as a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 4 months after the last dose of 


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investigational product.  The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject and his partner from the permitted list of contraception methods (see 
below) and will confirm that the subject has been instructed in its consistent and correct use.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
All sexually active male subjects capable of ejaculating must agree to prevent potential 
transfer to and exposure of fetus/partner(s) to drug through ejaculate (even after vasectomy)
by using a condom consistently and correctly, beginning with the first dose of investigational 
product and continuing for at least 4 months after the last dose of investigational product.  
All fertile males must agree not to donate sperm from the first dose of study drug to 4 months
after the last dose of study drug.
If applicable, as indicated in the Schedule of Activities, the investigator or designee will 
inform the subject of the need to use highly effective contraception consistently and correctly 
and document the conversation and the subject’s affirmation in the subject’s chart (subjects 
need to affirm their consistent and correct use of at least 1 of the selected methods of 
contraception). If applicable, sperm donation and fetus/partner exposure should also be 
discussed as per schedule of activities. In addition, the investigator or designee will instruct 
the subject to call immediately if the selected contraception method is discontinued or if 
pregnancy or fetus/ partner exposure is known or suspected.


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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 team SharePoint site. 
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 product 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 
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
will be directed back to the investigator site.
5. STUDY TREATMENTS 
For the purposes of this study, and per International Conference on 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 product, or study drug, is talazoparib.  The sponsor will 
provide talazoparib capsules.
5.1. Allocation to Treatment
This is an open-label study in which all eligible subjects will receive talazoparib. The study 
will use an interactive response technology (IRT) system (interactive Web-based response 
system [IWRS]).  The site personnel (study coordinator or specified designee) will be 
required to enter or select information including but not limited to the user’s identification 
(ID) and password, the protocol number, and the subject number.  The site personnel will 
then be provided with a subject identification number, and dispensable unit (DU) or container 
number when investigational product is being supplied via the IRT system.  The IRT system 
will provide a confirmation report containing the subject number, and DU or container 
number assigned.  The confirmation report must be stored in the site’s files.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system.


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5.2. Talazoparib Product Characteristics
Talazoparib is provided as the 4-methylbenzenesulfonate (tosylate) salt and has the chemical 
name (8S,9R) 5-fluoro-8-(4-fluorophenyl)-2,7,8,9-tetrahydro-9-(1-methyl-1H-1,2,4-triazol-5-
yl)-3H-pyrido[4,3,2-de]phthalazin-3-one.  The drug product is a capsule containing 
talazoparib tosylate and silicified microcrystalline cellulose.  The capsules for each dose 
strength will be provided in dose-specific colors.  Additional details will be provided in the 
pharmacy binder.
5.3. Packaging of Talazoparib 
Talazoparib study drug is packaged in induction sealed, high-density polyethylene bottles 
with child-resistant caps.
The label will vary depending on individual country requirements.  At minimum, each label 
typically provides the study protocol number, contents, directions for use and storage, 
clinical trial statement, sponsor name, batch/lot number, and product retest or expiration date.
5.4. Storage of Talazoparib 
The drug product should be stored safely and properly in accordance with the study drug 
label.  Specific details describing storage conditions may be found in the Investigational 
Product Manual.
5.5. Directions for Administration of Talazoparib 
The daily dose of talazoparib is 1 mg/day given orally at approximately the same time each 
day.  The starting and maximum dose will be 0.75 mg/day for patients with moderate renal 
impairment at screening (eGFR: 30-59 mL/min/1.73 m2 per central laboratory).
Patients should self-administer talazoparib orally once daily, with or without food.  The 
capsules should be swallowed whole with a glass of water without chewing, dissolving, or 
opening them.
Patients should not make up missed or vomited doses; dosing should resume on the next 
calendar day unless otherwise instructed.
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 (Goodin et al, 2011).  Patients 
should be advised that oral anticancer agents are toxic substances and that other caregivers 
(including family members) should always use gloves when handling the capsules.
Dose modifications due to adverse events are described below.
5.6. Dose Modifications
5.6.1. Dose Modifications Due to Adverse Events
Dose modifications for talazoparib due to adverse events are described in Table 8:


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Table 8.
Talazoparib Dose Modifications Due to Adverse Events
Toxicity
Management of Adverse Events [1]
Grade 1 or 2
No requirement for dose interruption or dose reduction.  
Selected hematologic 
grade 3 or 4 events
Grade 3 or 4 Anemia 
(hemoglobin 
<8.0 g/dL)
Hold talazoparib and implement supportive care per local guidelines. Monitor 
weekly until hemoglobin returns to 9.0 g/dL or better, then resume talazoparib at 
a reduced dose per Figure 3. 
If anemia with hemoglobin <8.0 g/dL recurs after dose reduction, hold 
talazoparib and implement supportive care per local guidelines. Monitor weekly 
until hemoglobin returns to 9.0 g/dL then resume talazoparib at a further reduced 
dose per Figure 3.
If anemia persists for >4 weeks without recovery of hemoglobin to at least 
9.0 g/dL despite supportive care measures at any dose level, discontinue 
talazoparib and consider referral to a hematologist.
Transfusions and other supportive measures are permitted to support management 
of hematological toxicities at any occurrence.
Grade 3 or 4 
Neutropenia 
(ANC <1000/µL)
Hold talazoparib and implement supportive care per local guidelines. Monitor 
weekly until ANC ≥1500/µL, then resume talazoparib at a reduced dose as per 
Figure 3. 
If neutropenia recurs after the dose reduction, hold talazoparib and implement 
supportive care per local guidelines.  Monitor weekly until ANC ≥1500/µL, then
resume talazoparib at a further reduced dose.
If neutropenia persists for >4 weeks without recovery to ≥1500/µL at any dose 
despite supportive care measures, discontinue talazoparib and consider referral to 
a hematologist. 
G-CSF and GM-CSF may be used at investigator’s discretion for the supportive 
treatment of neutropenia at any occurrence.
Grade 3 or 4 
Thrombocytopenia 
(platelets <50,000/µL)
Hold talazoparib and implement supportive care per local guidelines. Monitor 
weekly until platelets ≥50,000/µL then resume talazoparib at a reduced dose per 
Figure 3. 
If thrombocytopenia (<50,000/μL) recurs after one dose reduction, hold 
talazoparib and implement supportive care per local guidelines. Monitor weekly 
until platelets ≥75,000/µL, then resume talazoparib at a further reduced dose. 
If thrombocytopenia persists for >4 weeks without recovery to ≥50,000/μL 
despite supportive care measures, discontinue talazoparib and consider referral to 
a hematologist.
Thrombopoietin analogues and/or platelet transfusions may be used at 
investigator’s discretion for the supportive treatment of thrombocytopenia at any 
occurrence.


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Table 8.
Talazoparib Dose Modifications Due to Adverse Events
Toxicity
Management of Adverse Events [1]
Nonhematologic 
laboratory grade 
≥3 events, except 
abnormal liver tests[1]
Hold talazoparib as follows: 
For clinically significant Grade 3 laboratory abnormalities hold talazoparib until 
the laboratory abnormality resolves to Grade 2 (to baseline grade for creatinine 
increases).  Resume talazoparib at the same dose or reduce by 1 dose level per 
Figure 3. 
If Grade 3 laboratory abnormality recurs, hold talazoparib until the laboratory 
abnormality resolves to Grade 2 (to baseline grade for creatinine increases).
Reduce talazoparib one dose level per Figure 3.
For Grade 4 laboratory abnormalities, hold talazoparib.  Resume talazoparib 
when the laboratory abnormality resolves to Grade ≤2 (to baseline grade for 
creatinine increases) at a 1 dose level reduction per Figure 3. Talazoparib must 
be discontinued if a Grade 4 adverse event recurs after treatment resumes.
Implement supportive care per local guidelines.  Contact sponsor to discuss 
potential dose modification.
Talazoparib must be permanently discontinued for unresolved Grade 3 toxicity 
lasting longer than 14 days or for Grade 4 toxicity lasting longer than 3 days.  
Treatment may be resumed at a 1 dose level reduction if clear clinical benefit is 
observed, after discussion with the sponsor.  
Grade ≥3 abnormal 
liver tests
Subjects who develop abnormal liver tests (AST, ALT, total bilirubin [TBili]), 
signs or symptoms consistent with hepatitis during study treatment may meet the 
criteria for temporarily withholding or permanently discontinuing study drug 
talazoparib.
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities if any of the following occur:

Subjects who develop AST or ALT >5 x ULN (without TBili
>2 x ULN); OR

Subjects with baseline total bilirubin <1.5 x ULN who subsequently 
present with >3 x ULN; OR

Subjects with baseline total bilirubin >1.5 x ULN and <3 x ULN (eg, 
Gilberts) who subsequently present with bilirubin >5 x ULN.
If abnormalities resolve to baseline values within 2 weeks, there are no signs of 
drug induced liver injury (DILI), and none of the permanent discontinuation 
criteria are met, then upon discussion with the Sponsor, the investigator may 
re-challenge at a reduced dose level.
Criteria for Permanent Discontinuation of Study Drug in Association with Liver 
Test Abnormalities if any of the following occur:

Refer to Section 8.4.2 for potential DILI cases;

Subjects with AST/ALT >5 × ULN that persists for more than 7 days 
(AST/ALT >8 × ULN for subjects with hepatic involvement);

Subjects with AST/ALT >20 × ULN that persists for longer than 3 days.

Subjects with Tbili >3 × ULN that persists for longer than 7 days (>5 × 
ULN for subjects with Gilbert’s disease).


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Table 8.
Talazoparib Dose Modifications Due to Adverse Events
Toxicity
Management of Adverse Events [1]
Nonlaboratory grade 
≥3 events[1]
Hold talazoparib as follows: 
For clinically significant grade 3 adverse events, hold talazoparib until the 
adverse event resolves to grade ≤1 or baseline.  Resume talazoparib at the same 
dose or reduce by 1 dose level per Figure 3.
For clinically significant grade 4 adverse events, hold talazoparib until the 
adverse event resolves to grade ≤1 or baseline.  Resume talazoparib at a 1 dose 
level reduction per Figure 3. 
Implement supportive care per local guidelines.
Contact sponsor to discuss potential dose modification. 
Talazoparib must be permanently discontinued for unresolved grade 3 toxicity 
lasting longer than 4 weeks or for grade 4 toxicity lasting longer than 1 week.  
Treatment may be resumed at a 1 dose level reduction if clear clinical benefit is 
observed, after discussion with the sponsor.  Talazoparib must be discontinued if 
a grade 4 adverse event recurs after treatment resumes.
1. Talazoparib dose re-escalation may be allowed after the reduced dose is tolerated without recurrence of 
toxicities, and after discussion with the sponsor. AML, acute myeloid leukemia; ANC, absolute neutrophil 
count; MDS, myelodysplastic syndrome.  
The dose of talazoparib may be reduced incrementally as shown in Figure 3:
Figure 3.
Talazoparib Dose Reduction for Toxicity
0.75 mg/day
Moderate renal 
impairment
0.5 mg/day
0.25 mg/day
Normal/mild 
renal impairment
1 mg/day
0.75 mg/day
0.5 mg/day
0.25 mg/day
Dose re-escalation: Dose re-escalation may be allowed after toxicities resolve, the reduced 
dose has been tolerated, and after discussion with the sponsor. 
5.7. Treatment Compliance
Accountability for the study drug capsules will be performed to document compliance with 
the dosing regimens.  Patients will be asked to bring all used and unused study drug bottles to 
study visits for personnel to perform drug accountability prior to dispensing additional study 
drug.  Study site personnel must make reasonable efforts to obtain used and unused study 
drug bottles from patients who do not routinely return them at study site visits.  Unreturned 
capsules will be considered to have been taken.
5.8. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
talazoparib is stored in a secured area with controlled access under required storage 
conditions and in accordance with applicable regulatory requirements.


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Investigational products should be stored in their original containers and in accordance with 
the labels.
Any storage conditions stated in the talazoparib Investigator’s Brochure will be superseded 
by the storage conditions stated on the label.
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 non-working 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 they are maintained in working order.
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 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 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. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct patients on the proper storage requirements for take home 
investigational products. 
Refer to the Investigational Product Manual for additional guidance on storage conditions 
and actions to be taken when conditions are outside of the prespecified range.
5.9. Investigational Product Accountability 
The investigator 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.


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All bottles of study drug must be returned to the investigator by the patient at every visit and 
at the end-of-treatment visit.  Patients who do not return bottles at the end-of-treatment visit 
will be reminded to bring them at their next visit.
5.9.1. 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 investigator 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.
5.10. Concomitant Treatment(s)
Concomitant medications will be assessed at all clinic visits.  All concomitant medications, 
including over-the-counter and prescription medications, must be recorded on the appropriate 
case report form.  If the use of any medication during the study is due to an adverse event, 
the adverse event must be recorded on the adverse event case report form and in the patient’s 
source documents. All prior cancer treatments, other medications taken within 28 days 
before day 1, and any medications prescribed for chronic or intermittent use during the study 
or dose adjustments of these medications must be recorded on the case report form and in the 
patient’s source documents.
Required and prohibited medications are described in Table 9.  Supportive medications may 
be provided prophylactically or therapeutically per investigator discretion.  Concomitant use 
of steroids as hormonal treatment for prostate cancer is not allowed. Intranasal, inhaled, or 
topical corticosteroids are allowed. Palliative low dose treatment with corticosteroids (10 mg 
or less of prednisone or equivalent/day) to reduce pain and inflammation although allowed, if 
no alternative therapy is available, is discouraged; investigators are to document in the case 
report form (CRF) the reason why steroids were given. Higher doses of steroids should be 
avoided unless no other therapies are available. Deviation from these guidelines should 
occur only if absolutely necessary for the well-being of the patient, and the sponsor is to be 
notified to determine whether continued treatment with study drug is permitted.
Study drug must be permanently discontinued upon initiation of a prohibited antineoplastic 
or investigational therapy.  Patients who discontinue treatment due to initiation of such 
therapy will complete safety follow-up per Section 6.5 and will have long-term follow-up per 
Section 6.6.  Patients will use analgesic logs (Appendix 5) to document their use of any and 
all analgesics for prostate cancer pain beginning 7 days before a scheduled visit (or scheduled 
contact during the post-treatment follow-up periods).  Analgesics include but are not limited 
to opioids, and nonopioid analgesics, which include acetaminophen, aspirin, nonsteroidal 
anti-inflammatory drugs (NSAIDs), such as ibuprofen and ketorolac, and selective 
cyclooxygenase type 2 (COX-2) inhibitors, such as celecoxib and rofecoxib.


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Table 9.
Instructions for Use of Concomitant Therapies
Use Category
Medication or Treatment
Comment on Use
Required
Ongoing androgen deprivation 
therapy with a GnRH 
agonist/antagonist or bilateral 
orchiectomy (medical or surgical 
castration).
For the duration of the study.
Prohibited
Prior PARP inhibitor, 
cyclophosphamide, or mitoxantrone 
ever in the past; also, prior platinum
within the 6 months prior to 
screening or if there was ever prior 
disease progression on platinum.
Prior to screening and through safety 
follow-up.
Any systemic (eg,
chemotherapeutic, hormonal, 
biologic, radionuclide) 
antineoplastic therapy, and other 
investigational agents.
Within 4 weeks before day 1 through safety 
follow-up.
Radiation therapy.
Within 3 weeks (within 2 weeks, if single 
fraction) before day 1.
P-gp inhibitors (refer to 
Section 5.11).
For the duration of the study.
Used with 
caution
Transporter inhibitors (refer to 
Section 5.11).
For the duration of the study.
GnRH, gonadotropin-releasing hormone; PARP, poly(ADP-ribose) polymerase.
5.11. Potential Interactions Between the Test Product and Concomitant Medication

Strong P-gp inhibitors that result in ≥2-fold increase in the exposure of an in vivo 
probe P-gp substrate according to the University of Washington Drug-Drug 
Interaction database (https://www.druginteractioninfo.org/) are prohibited:
amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, 
erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, 
propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, 
verapamil and valspodar.

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.
The list of strong P-gp inhibitors and transporter inhibitors to be used with caution will be 
updated annually and reflected in the Investigator’s Brochure.
5.12. Rescue/Salvage Medication
New treatments for prostate cancer prior to the determination of radiographic progression by 
the independent blinded reviewers are strongly discouraged.


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6. STUDY PROCEDURES 
Study enrollment and procedures are summarized in the following subsections.  The study 
periods will include prescreening (optional), screening, treatment, safety follow-up, and 
long-term follow-up.  The timing of all study procedures is provided in the schedules of 
activities (Table 1, Table 2, Table 3, Table 4).  The interactive response system user manual 
contains the information needed for registering patient status (eg, assigning screening 
numbers, indicating screen failure, and end of treatment). 
6.1. Prescreening (optional)
Certain procedures or activities may be performed during a prescreening period defined as 
any time before a prospective study participant signs an informed consent form to be 
formally screened for study enrollment.  These include a biopsy procedure to obtain de novo
tumor tissue or the retrieval of archived tumor tissue for evaluation of a DNA damage repair 
deficiency as assessed using the FoundationOne CDx™(Foundation Medicine) gene 
mutation panel. 
 
 
A separate prescreening consent form must be signed if de novo or archival tissue and blood 
sample will be obtained and analyzed before the patient signs consent for the protocol 
screening period.  In addition, after the prescreening consent is signed, previously obtained 
(ie, historic) testing results from analysis of tumor tissue using the FoundationOne CDx™
test may be submitted.
Test results obtained using the FoundationOne CDx™ test identifying DNA repair 
deficiencies likely to sensitize to PARP inhibition may be considered for eligibility with 
sponsor approval. If sufficient residual DNA is available at Foundation Medicine, this could 
be used to confirm a patient’s eligibility for enrollment. Note that if eligibility for enrollment 
is established based either on historical results or residual DNA testing, available archival or 
de novo tumor tissue also should be submitted prior to Day 1.
Study site personnel must document the informed consent process for tissue and blood 
sampling in the patient’s clinical record.  After obtaining signed informed consent, study site 
personnel will access the interactive response system to assign a screening identification (ID) 
number for each potential study participant. In addition, the demographic data case report 
form (CRF), the Prior Anti-Cancer Therapies CRF and the Medical History- Prostate Cancer 
CRF should be completed at pre-screening if pre-screening is performed. For subjects for 
whom new tissue or blood sampling needs to be obtained and as applicable, AEs and/or 
research related injuries are to be reported as per Section 8.4.5.
Prescreening procedures are listed in the schedule of activities in Table 1.
6.2. Screening Period
The screening period will be from day -28 through day-1 for most procedures (Table 2).  For 
the purposes of this study, there will be no day 0. 
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6.2.1. Informed Consent 
Study site personnel must explain to potential study participants all aspects of the study, 
including all scheduled visits and activities.  Study site personnel must obtain signed and 
dated informed consent before any study-specific procedures are conducted unless the 
procedures are part of routine standard of care, and must document the informed consent 
process in the patient’s source documents.
6.2.2. Screening Identification Numbers 
After obtaining signed informed consent, study site personnel will access the interactive 
response system to assign a screening ID number (if not obtained previously during 
prescreening) for each potential study participant. 
For patients who provide informed consent and subsequently do not meet eligibility criteria 
or withdraw consent, study site personnel will document the screen failure or consent 
withdrawal in the patient’s source documents.  The documentation will include demographics
(which may have been assessed at pre-screening), and medical history for prostate cancer, 
prior treatment(s) for prostate cancer, the reason for screen failure, the eligibility criteria 
reviewed, and procedures performed and, as applicable, any AE/SAE that occurs during the 
active collection period (refer to Section 8.1.4) until the patient is determined to be a screen 
failure. 
6.2.3. Screening Procedures 
Screening procedures are listed in the schedule of activities in Table 2.  All procedures must 
be completed within 28 days before day 1 except as noted. 
Scans obtained within 42 days before day 1 as part of standard of care may be used for the 
screening radiographic assessment. 
De novo or archival tumor tissue for analysis of DNA damage repair deficiencies is required 
for enrollment (if not collected at prescreening) as assessed using the FoundationOne CDx™
(Foundation Medicine) gene mutation panel.  In addition, previously obtained (ie, historic) 
testing results from analysis of tumor tissue using the FoundationOne CDx™ test may be 
submitted with sponsor approval. Should a patient qualify based either on prior results or 
DNA available at Foundation Medicine, available de novo or archival tumor tissue should be 
submitted prior to Day 1 to support planned concordance analysis
 
 
The 
investigator will assess the eligibility of each patient.  All screening procedure results and 
relevant medical history must be available before eligibility can be determined.  All inclusion 
criteria must be met and none of the exclusion criteria may apply.
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After a patient is screened and the investigator determines the patient is eligible, study site 
personnel will complete an Enrollment Authorization Form and fax or email it to the sponsor 
or designee to approve the enrollment in writing. Eligibility will be determined as per the 
amendment approved at the site at the time the Enrollment Authorization Form is reviewed. 
No eligibility waivers will be granted.
6.3. Treatment Period 
6.3.1. Treatment Period Visit Windows 
All treatment period visits have a visit window of ±3 days (ie, 3 days before or after the 
given day), except the day 1 visit (start of study treatment).  The window for imaging 
assessments is ±7 days.
 
 
Study drug supplies must be taken into account when scheduling visits.  Procedures for a 
given visit may be split across the window to allow for drug resupply and completion of 
study procedures.
6.3.2. Treatment Period Procedures 
Specified study procedures will be performed at each clinic visit according to the schedule of 
activities (Table 3).
•
All patients will have clinic visits every 2 weeks for the first 8 weeks (through 
week 9), then every 4 weeks through week 25, and every 12 weeks thereafter.
•
Day 1 is the day of the first dose of study drug treatment (talazoparib).  
Questionnaires should be completed 
 
 
•
Safety assessment labs will be done by the central laboratory per schedule of 
assessment. In addition, every effort should be taken to send unscheduled samples to 
the central laboratory to monitor resolution of AE/SAE. Pretreatment serum 
chemistry and hematology laboratory tests may be performed at the local laboratory 
within 3 days before the scheduled times (every 2 weeks through week 9, then every 
4 weeks through week 25, and every 8 weeks thereafter).  The investigator must 
review the laboratory results before dosing.  Regardless of whether local laboratory 
testing is obtained for serum chemistry and hematology values, blood samples must 
be sent to the central laboratory for evaluation. Results from local laboratory 
assessments will be entered in the appropriate CRF.
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
Radiographic assessments will be obtained and submitted for independent central 
review (Section 7.1.2).

Patients will document their pain symptoms and their use of any and all analgesics for 
prostate cancer pain by completing both the pain log and an analgesic log during each 
of the 7 consecutive days preceding a scheduled visit after Day 1.

Any diagnosis of myelodysplastic syndrome (MDS) or AML will be reported as an 
SAE (Section 8.2.3).  If requested, provide tissue samples and other supporting data 
used to enable diagnosis for review by blinded independent reviewers.
Study visits and study drug treatment will continue until criteria for permanent study 
discontinuation are met (Section 6.4).  PSA progression or CTC count increases alone should 
not lead to study drug discontinuation.
6.3.3. Unscheduled Visit Procedures 
Unscheduled visits/assessments may be performed anytime to assess or follow up adverse 
events, to perform scans, or at the request of the patient or investigator or sponsor, or to 
account for any insufficient, inadequate, or missed sample or assessments.  The date and 
reason for the unscheduled visit must be recorded in the source documentation. 
A review of adverse events and changes to concomitant medications or treatments (including 
herbal therapies) occurring since the previous visit should be performed at unscheduled 
visits.  If an unscheduled visit is necessary to assess toxicity or for suspected disease 
progression, diagnostic tests may be performed based on investigator assessment as 
appropriate.  Imaging may be performed if appropriate for patients who are symptomatic or 
for whom radiographic progression or response is being determined. All radiographic 
assessments obtained (including unscheduled ones) will need to be submitted for independent 
central review. Unscheduled visits and visit procedures are listed in Table 3.  Other study 
procedures may be performed as clinically appropriate. 
6.4. Permanent Treatment Discontinuation
Treatment discontinuation is defined as permanent cessation of study drug treatment 
administration.  After permanent discontinuation, safety follow-up will occur per Section 6.5,
unless the patient withdraws consent for further follow-up. 
Temporary treatment interruption (eg, due to an adverse event) is not considered permanent 
discontinuation. 
The primary reasons for which patients permanently discontinue study treatment are listed in
Table 10.


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Patients may withdraw from treatment 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 Withdrawal From the Study Due to Adverse Events) 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. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.
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 investigational product(s), request that the patient return for a final visit, if 
applicable, and follow up with the patient regarding any unresolved adverse events (AEs).  If 
applicable, patients who return for a final visit will undergo safety and long term follow-up 
procedures as shown in Table 3 and Table 4.
Patients may withdraw from the study at any time at their own request.  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.
If allowed by local laws and regulations survival information will be collected using public 
records.
Table 10.
Primary Reasons for Permanent Treatment Discontinuation
Reason
Comment
Radiographic progression
Per RECIST 1.1 for soft tissue disease and per PCWG3 for 
bone disease.  Must be determined by independent central 
review and confirmed for bone disease progression.  Refer to 
Section 7.1.2.
Adverse event or intercurrent illness
Any intolerable adverse event that cannot be ameliorated by 
the use of adequate medical intervention or that in the opinion 
of the investigator or sponsor would lead to undue risk if 
study treatment were continued (eg, severe drug-induced liver 
injury [Section 8.4.2] or MDS/AML]).  Refer to Section 8.  
May or may not be related to disease progression. 
Administration of any systemic 
anticancer therapy
Refer to Section 5.10.
Patient decision
Patients may permanently discontinue treatment anytime for 
any reason.  Withdrawal of consent for study treatment should 
be distinguished from withdrawal of consent for further 
participation in the study, including follow-up.  This category 
should be selected if adverse event, disease progression, or 
administration of prohibited concomitant therapy does not 
apply.  Patients are strongly encouraged to continue in 
long-term follow-up as described in Section 6.6, even if they 
choose to permanently discontinue study drug treatment.  


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Table 10.
Primary Reasons for Permanent Treatment Discontinuation
Reason
Comment
Investigator decision
Protocol treatment may be discontinued if the investigator 
considers it is in the patient’s best interest.  This category 
should be selected if adverse event, disease progression, or 
administration of prohibited concomitant therapy does not 
apply and the patient preferred to continue treatment.
Major noncompliance with protocol
The sponsor or investigator may request permanent treatment 
discontinuation in the event of a major protocol deviation, 
lack of cooperation, or noncompliance.  
Lost to follow-up
Refer to Section 6.7.
Sponsor discontinuation of study
The sponsor reserves the right to terminate the study anytime 
for any reason as described in Section 14. The sponsor will 
terminate this study following completion of the study 
objectives, or earlier if deemed necessary.
6.5. Safety Follow-up
Patients will have safety follow-up after permanent discontinuation of study drug treatment.  
Safety follow-up should occur approximately 28 days after the last dose of study drug or 
before initiation of new antineoplastic or investigational therapy, whichever occurs first.  In 
the event that new antineoplastic or new investigational therapy is initiated before safety 
follow-up occurs (eg, a physician not associated with protocol C3441006 
(MDV3800-06) initiates the treatment, and study site personnel are not aware of the 
treatment until afterward), safety follow-up should be scheduled as soon as possible. 
Safety follow-up procedures are listed in Table 3.
If treatment is discontinued due to an adverse event or serious adverse event, the event(s) 
must be followed up as described in Table 3.
For patients who refuse to come to the clinic for safety follow-up, telephone contact must be 
attempted and documented to review for adverse events through approximately 28 days after 
the last dose of study drug or before initiation of new antineoplastic or new investigational 
therapy, whichever occurs first.  If the patient does not respond to telephone calls, the 
procedures for lost to follow-up in Section 6.7 should be followed.
6.6. Long Term Follow up
For long-term follow-up procedures see Table 4.  This period begins after safety follow-up 
and can be conducted by telephone unless imaging is required. Long-term follow-up begins 
after safety follow-up and continues until the patient dies, withdraws consent or, refuses 
follow up, or the study is terminated. Radiographic imaging should continue during long-
term follow-up for patients who discontinue study drug for any reason other than 
radiographic progression, determined by independent central review, when the patient has 
not withdrawn consent for follow-up.  All known follow-up anticancer therapies have to be 
entered in the CRF.  Potential cases of AML or MDS will be entered in the CRF and reported 
as SAEs in the sponsor safety database irrespective of investigator’s opinion of causality or 
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6.7. Lost to Follow up
Every reasonable effort must be made to contact any patient apparently lost to follow-up 
during the course of the study to complete study-related assessments and record outstanding 
data.  Following unsuccessful telephone contact, the following should occur: 

An effort to contact the patient by mail using a method that provides proof of receipt 
should be attempted;

Alternate contacts are permissible if the patient is not reachable (eg, primary care 
providers, referring physician, relatives);

Such efforts should be documented in the patient’s source documents.
If all efforts fail to establish contact, the patient will be considered lost to follow-up.
Survival information will be collected from public records if allowed by local laws and 
regulations.
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, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
CT scans/MRI/bone scans will be reviewed by independent radiologists (central review).  
The purpose of this review is to evaluate images for appropriate study endpoints.  Central
image review is not a complete medical review of the participant and no incidental findings 
will be shared with the principal investigator (PI), site staff, or the participant.  All safety 
reviews will be the sole responsibility of site staff. 
7.1. Assessment of Efficacy
7.1.1. Assessment of Primary Efficacy Endpoint: ORR 
The primary efficacy endpoint is best ORR and the assessment uses standard radiographic 
methods to evaluate response for soft tissue disease.


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7.1.2. Assessment of Radiographic Response and Progression 
Disease status will be assessed at regular intervals during the course of the study by CT 
(chest, abdomen, pelvis), which is the preferred method, or MRI (abdomen, pelvis) of soft 
tissue, and CT of the chest without contrast if the patient is allergic to CT contrast agents, 
and whole body radionuclide bone scan.  The radiographic assessment of soft tissue disease 
(including soft tissue components of lytic or mixed bone lesions) will use RECIST 1.1
(Eisenhauer et al, 2009), and bone disease will be evaluated per PCWG3 (Scher et al, 2016), 
with confirmatory imaging requirements shown in Table 11 (modified RECIST1.1/PCWG3).
The determinations for study endpoints will be made by independent central review.
However, investigator assessments will be collected in the CRF.
Table 11.
Confirmatory Imaging Requirements for Soft Tissue per RECIST 1.1 and 
Bone per PCWG3
Disease Site
Response
Progression
Soft tissue
Must be confirmed at least 
4 weeks later[1]
No confirmation required[1,2]
Bone
Not applicable
Must be confirmed at least 
6 weeks later[1,2]
1.
For analytic purposes. 
2.
To inform permanent treatment discontinuation. 
PCWG3, Prostate Cancer Working Group 3; RECIST 1 1, Response Evaluation Criteria in Solid Tumors, 
version 1.1.
An objective response is defined as a best overall response of CR or PR per RECIST 1.1 by 
independent central review. Responses must be confirmed by a follow-up CT or MRI at least 
4 weeks later and with no evidence of confirmed bone disease progression per Prostate 
Cancer Working Group 3 (PCWG3) criteria on repeat bone scan at least 6 weeks later by 
independent central review. 
Radiographic assessments will be every 8 weeks through the first 24 weeks, then every 
12 weeks thereafter.  Scans may be obtained sooner than scheduled if disease progression is 
clinically suspected (for example, PSA progression).  The study films (CT/MRI and bone 
scan) will be sent for independent central review. 
The documentation required for the determination of radiographic progression is shown in 
Table 12.


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Table 12.
Criteria for Evidence of Radiographic Progression
Date Progression 
Detected 
(Visit)[1]
Criteria for Progression
Criteria to Confirm 
Progression
Criteria to Document 
Disease Progression on 
Confirmatory Scan
Week 9
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 
17 visit.[2]  
Persistence of at least two 
of the lesions seen at 
week 9 AND 2 or more 
additional new bone lesions 
on bone scan compared to 
week 9 scan (2+2 rule).
Date of progression is the 
date of the first post 
treatment scan.
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST 1.1.
No confirmatory scan 
required for soft tissue 
disease progression.
No confirmatory scan 
required for soft tissue 
disease progression.
Week 17 or later
Bone lesions: 2 or more 
new lesions on bone scan 
compared to week 9 bone 
scan.
Timing: at least 6 weeks 
after progression 
identified or at next 
imaging time point.[2]
At least 2 of the lesions first 
identified as new compared 
to week 9 must be still 
present. Date of 
progression is the date of 
the scan that first 
documented 2 or more new 
lesions.
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST 1.1.
No confirmatory scan 
required for soft tissue 
disease progression.
No confirmatory scan 
required for soft tissue 
disease progression.
1.
Progression detected by bone scan at an unscheduled visit either before week 9 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. 
2.
Confirmation must occur at the next available scan. 
CT, computed tomography; MRI, magnetic resonance imaging; PCWG3, Prostate Cancer Working Group 3; 
RECIST 1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.
7.2. Assessments of Secondary Efficacy Endpoints
The secondary efficacy endpoints include time to objective response, duration of response, 
proportion of patients with PSA response ≥50%, proportion of patients with conversion of 
CTC count, time to PSA progression, radiographic PFS, overall survival.  The study 
assessments of efficacy for these endpoints will include standard radiographic and imaging 
methods to evaluate disease progression and response, PSA, survival status monitoring, pain 
and quality of life questionnaires, and CTC enumeration.
7.2.1. Assessment of PSA
Local laboratory PSA values will be used to determine eligibility for the study at screening 
(Table 2) including a minimum of 3 consecutive, rising PSA values with an interval of at 
least 1 week between determinations; values are to be recorded on the CRF.  The third PSA 
may or may not be the central lab screening PSA. (If the screening central lab PSA is lower 
than local lab PSA #2, then a third local lab PSA may be submitted instead if the PSA 
measurement is higher than the second local lab PSA.)


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A central PSA assessment will be done at screening for all patients.
The screening value must be ≥2 ng/mL as assessed at the central laboratory if qualifying 
solely based on PSA progression. During the study, PSA will be measured at the central 
laboratory according to the schedule of activities (Table 3).  PSA progression alone should 
not lead to study drug discontinuation, and study drug administration should continue 
regardless of PSA increases until radiographic progression is determined by independent 
central review. PSA progression or response, as determined by the central lab, must be 
confirmed at least 21 days later.
7.2.2. Assessment of Survival 
The survival status of each patient will be monitored during study treatment and after 
permanent treatment discontinuation for any reason. Survival status will be documented 
during long-term follow-up according to the schedule of activities (Table 4).  The date and 
cause of death will be recorded.  During the course of the study, the sponsor may request that 
a survival sweep be conducted to obtain an accurate number of deaths across the study.  The 
sponsor will provide instructions on these survival sweeps immediately before they 
commence as well as a timeline for contacting patients.
7.2.3. Assessment of Circulating Tumor Cells 
The assessment of CTCs will be performed by collecting blood samples according to the 
schedule of activities (Table 3). CTC count increases alone should not lead to study drug 
discontinuation.  Details on sample handling and shipping will be provided separately in a 
laboratory manual.
7.2.4. Assessment of Patient Reported Pain 
The assessment of pain will use the BPI-SF.  This questionnaire is a validated instrument that 
uses a self-reported scale assessing level of pain, its effect on activities of daily living, and 
analgesic medication use.  This study will use the short form containing 9 main questions 
related to pain.  The primary question (paraphrased) is “On a scale of 0 to 10, please rate 
your pain at its worst in the last 24 hours.” The questionnaire is provided in Appendix 2. It 
is important that patients are fluent in reading the language used in the questionnaire and that 
they complete it without influence of the investigator, study site staff, or anyone else.
Tracking analgesic use is particularly important to ensure that the delay in pain progression 
observed is truly the result of the treatment being studied rather than the result of an increase 
in analgesic use. After the Day 1 visit, pain (assessed using BPI-SF question 3, Appendix 4) 
and analgesic use (assessed using an analgesic log, Appendix 5) will be collected for each of 
7 consecutive days prior to study visits; the timing of collection is shown in Table 3 and 
described in Section 6.3.


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7.2.5. Assessment of Patient-Reported General Health Status
The assessment of this patient-reported outcome will use the EQ-5D-5L.  The EQ-5D-5L 
questionnaire is a standardized instrument that measures health-related quality of life for men 
with prostate cancer.  Patients will self-rate their current state of mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression by choosing 1 of 5 possible responses that 
record the level of severity (no problems, slight problems, moderate problems, severe 
problems, or extreme problems) within each dimension.  The questionnaire also includes a 
visual analog scale to self-rate general health state on a scale from “the worst health you can 
imagine” to “the best health you can imagine.” The EQ-5D-5L questionnaire is provided in 
Appendix 3.
On Day 1, patients will complete these questionnaires before the first dose of study drug.  At 
subsequent visits, patients will complete these questionnaires at the site before any other 
study activities and in the same order at each visit.  These questionnaires will be collected 
according to the schedule of assessments in Section 6.3.
7.3. Assessments of Safety
The assessment of safety will include adverse events, physical examinations, vital signs, and 
clinical laboratory tests.  AE will be graded using CTCAE version 4.03.  The procedures for 
the investigator assessment of adverse events are presented in detail in Section 8.  The 
procedures for clinical laboratory safety tests are presented in Section 7.3.1, and for physical 
examinations and vital signs in Section 7.3.2.
7.3.1. Clinical Laboratory Tests 
Routine clinical laboratory tests (hematology, serum chemistry) will be performed according 
to the schedules of activities by the central laboratory (Table 2, Table 3).  Central safety 
laboratory assessments may also be collected as unplanned, at the investigator’s discretion, or 
to monitor adverse events or determine if dosing modifications are required. Local safety 
laboratory assessments may also be performed but should not replace central lab 
assessments; results from local laboratory assessments are to be entered in the appropriate 
CRF. Every effort should be taken to collect samples for central laboratory safety 
assessments even if unplanned. Samples will be stored until the specified analyses are 
completed and then will be destroyed in accordance with standard laboratory practice and 
applicable local regulations.
A list of the required routine clinical laboratory tests and other evaluations is provided below.  
All samples for laboratory analysis must be collected, prepared, labeled, and shipped 
according to laboratory requirements. 
All clinical laboratory tests will be performed by the central laboratory specified in Form 
FDA 1572 Section 4 unless otherwise specified.  The central laboratory reference ranges will 
be used.  Eligibility at screening will be based on central laboratory assessments (preceding 
local laboratory PSA values will also be required if qualifying based solely on PSA 
progression).  The screening value must be ≥2 ng/mL as assessed at the central laboratory if 
qualifying solely based on PSA progression. 


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A local clinical laboratory may be used to evaluate serum chemistry and hematology within 
3 days before a scheduled visit.  The results of these local laboratory assessments may be 
used for dosing decisions.  However, samples must also be collected and sent to the central 
laboratory for testing. 
For all patients, a local clinical laboratory may be used to assess samples at unscheduled 
visits or for urgent care to evaluate an adverse event.  Central laboratory samples should also 
be obtained whenever possible during unscheduled visits. 
Central Laboratory Tests
Hematology
Chemistry
Additional
Hematocrit 
Hemoglobin
Mean corpuscular volume
Red blood cell count
Platelet count
White blood cell count with 
differential
Total neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Albumin 
Total protein 
Alkaline phosphatase 
ALT (alanine aminotransferase)
AST (aspartate aminotransferase)
Total bilirubin
Blood urea nitrogen
Creatinine
Glucose (nonfasting)
Bicarbonate
Calcium*
Chloride 
Magnesium
Phosphate
Potassium
Sodium
LDH (lactate dehydrogenase)
PSA (prostate-specific antigen)
Testosterone (screening only)
The laboratory manual for this study provides details regarding sample collection procedures, laboratory tests, 
and additional tests that may be required. *Central lab data include calcium and calcium albumin corrected.
7.3.2. Physical Examinations, Vital Signs, and ECGs
The investigator will perform physical examinations according to the schedules of activities 
(Table 2, Table 3).  Interval medical history will be reviewed as a part of physical 
examinations.  Physical examinations will include an assessment of systems (eg, general 
appearance, head, eyes, ears, nose, mouth, skin, heart, lungs, lymph nodes, gastrointestinal, 
genitourinary, neurologic, and skeletal) per standard of care at the study site or as clinically 
indicated by symptoms.  Weight will be measured at the time of the examination.  Height 
will be measured only at screening.  Vital sign measurements will include blood pressure, 
heart rate, and temperature. 
12-Lead ECGs will be obtained and read locally at screening.  Additional ECGs may be 
obtained as necessary per standard of care.


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7.4. Pharmacokinetic Assessments
Blood samples will be collected predose and postdose according to the schedules of activities 
(Table 3).  Additional PK blood samples may be collected from patients experiencing 
unexpected or serious adverse events, or adverse events that lead to discontinuation.  Plasma 
talazoparib concentrations will be measured using a validated method. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time AND collected prior to 
administration of the investigational product on that day (for pre-dose PK samples) will be 
considered protocol compliant.  Patients must be instructed to withhold their daily dose of 
study drugs on PK sampling days until the pre-dose PK sample collection has been 
completed.  The actual time of the sample collection and the most recent dosing time before 
and after each collection will be recorded on the CRF.  The date of missing dose should also 
be recorded in the CRF.
Samples will be collected, processed and shipped as described in the laboratory manual.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.7. Assessment of ECOG Performance Status
Assessment of ECOG performance status is required to assess patient functional status for 
study eligibility purposes and will be performed throughout the study according to the 
schedules of activities (Table 2, Table 3).  Scoring for the assessment is shown in Table 13.
Table 13.
ECOG Performance Status
Score
Description of Functional Status
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair
5
Dead
Source: Oken et al, 1982
ECOG, Eastern Cooperative Oncology Group.
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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 treatment group or 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.
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 
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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/legally acceptable representative.  In addition, each study 
patient/legally acceptable representative 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 Permanent 
Treatment Discontinuation 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 or treatment 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.
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 28 calendar days after the last administration of the investigational product.
A different reporting period applies only to patients who sign the molecular prescreening 
consent as described in Section 8.4.5.
For patients who are screen failures, the active collection period ends when screen failure 
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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 as of signing of the main informed consent document
(ICD) at screening.
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. All SAEs of myelodysplastic syndrome (MDS) or 
acute myeloid leukemia (AML) are to be reported to Pfizer Safety irrespective of 
investigator’s opinion of causality or time of diagnosis.
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 anticancer 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 anticancer 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 
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 
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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);

Exposure via breastfeeding;

Medication error;

Occupational exposure.


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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.
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 
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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 only 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, 
version 4.03) 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);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);


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
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
The investigator will use the following definitions of severity in accordance with the current 
CTCAE version (4.03) to describe the maximum intensity of the adverse event. 
GRADE
Clinical Description of Severity
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.


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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. 
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 aspartate aminotransferase (AST) and/or alanine 
aminotransferase (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);


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
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.  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. 
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 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
Although this study will be conducted exclusively in male patients, it is theoretically possible 
for female partners to be exposed to study drug during pregnancy. 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.


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8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (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;

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.


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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;

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.
8.4.3.2. Exposure During Breastfeeding
In female partners of study patients, 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.
8.4.3.3. 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.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.


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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
8.4.4.1. 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:

Overdose (any dose higher than the prescribed dose):
There is no specific treatment in the event of talazoparib overdose, and symptoms 
of overdose are not established. In the event of overdose, treatment with 
talazoparib should be stopped, and physicians should consider gastric 
decontamination, follow general supportive measures as per local guidelines, and 
treat symptomatically;

Lack of dose reduction as specified by the protocol;

Continuation of treatment although patient met discontinuation criteria;

Incorrect study drug dose taken by patient;

Patient did not take study medication, as prescribed, for 6 or more days 
(approximately <80%) within 4 weeks, unless dose was withheld due to an AE.

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 in 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 a medication dosing error, the sponsor (study clinician) 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.


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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4.5. Reporting AEs and/or Research-Related Injuries for Patients Who Sign the 
Molecular Prescreening Consent
This section is applicable only to those subjects for whom new tissue or blood sampling 
needs to be obtained at prescreening.  For these patients, there is an informed consent 
specifically for these procedures that is completely separate from the study informed consent. 
The investigator must obtain information adequate to determine the outcome of the AE and 
to assess whether it meets the criteria for classification as a research-related injury requiring 
immediate notification to Pfizer as described below.
8.4.5.1. Adverse Events 
Any AE that occurs from the time the patient undergoes a procedure to obtain de novo tissue 
or blood through and including 14 days upon completion of said procedure, must be 
recorded.  The investigator is required to assess whether the AE may be related to the 
patient’s participation in the study.
Record adverse events on the CRF from the time the patient undergoes a procedure to obtain 
tissue or blood through until 14 days after completion of said procedure.
8.4.5.2. Research-Related Injuries 
Should a patient, in the investigator’s opinion, suffer a medically important research-related 
injury caused by their participation in the study, the designated Pfizer clinician must be 
notified immediately.
A medically important research-related injury is any untoward medical occurrence 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.
Medical and scientific judgment is exercised in determining whether an injury 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 
outcomes listed in the definition above, the important medical event should be reported as a 
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An investigator may be requested by the designated Pfizer clinician to obtain specific 
additional follow-up information in an expedited fashion. In general, this will include a 
description of the injury in sufficient detail to allow for a complete medical assessment of the 
case and independent determination of possible causality. Information on other possible 
causes of the event, such as concomitant treatments, vaccines, and/or 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 or its designated representative.
Record research-related injuries on the CRF from the time the patient undergoes a procedure
until the patient is deemed a screen failure or until the end of the study.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and 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. Statistical and Analysis Plans
The statistical methods and analyses for this study will be described in detail in the statistical 
analysis plan.  Three analyses are planned, including an initial safety analysis/efficacy 
analysis followed by two efficacy analyses.  The initial safety/efficacy analysis will be 
performed after 20 patients with measurable soft tissue disease and DDR deficiencies likely 
to sensitize to PARP inhibitor therapy have received the study drug for at least 8 weeks.  
Efficacy analyses of the primary endpoint will also be performed when 60 and 100 patients 
have completed at least 6 months of study treatment or are no longer being followed (ie, have 
withdrawn consent, discontinued from the study, died, or are otherwise lost to follow-up).
9.2. Analysis Populations
The DDR Deficient Measurable Disease population is defined as all enrolled patients who 
have measurable soft tissue disease at screening by ICR, have DDR deficiencies likely to 
sensitize to PARP inhibitor therapy and receive at least one dose of talazoparib. The DDR 
Deficient Measurable Disease population will be used for all baseline characteristics 
summaries and efficacy analyses.
Summaries and listings of efficacy and baseline data for patients that were enrolled under 
previous protocol versions and who are not part of the DDR Deficient Measurable Disease 
population will be described in the statistical analysis plan.
The safety population is defined as all patients who receive at least one dose of talazoparib.  
The safety population will be used for all safety analyses.  
The PK population is defined as all patients from the safety analysis set who have at least 
1 reportable drug concentration data point.  


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The PRO population is defined as all patients from the DDR Deficient Measurable Disease 
population who have completed a baseline and at least one post-baseline PRO assessment 
prior to the end of study treatment.  
The CTC evaluable population is defined as all patients with a baseline CTC assessment and 
at least 1 post-baseline CTC assessment from the DDR Deficient Measurable Disease 
population.
 
9.3. Efficacy Analyses 
9.3.1. Primary Efficacy Analyses
The primary study objective is to evaluate efficacy as measured by the primary endpoint best 
ORR.  The best ORR is defined as the proportion of patients with a best overall soft tissue 
response of CR or PR per RECIST 1.1 by independent central review.  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 on repeat bone 
scan at least 6 weeks later per PCWG3 criteria by independent central review.  ORR will be 
summarized along with the 95% CI using the Clopper-Pearson method (Clopper-Pearson; 
1934).  Analyses based on assessment by the investigator will also be performed.
9.3.2. Secondary Efficacy Analyses 
The following efficacy parameters will be evaluated.
9.3.2.1. Time to Objective Response 
The time from first dose of talazoparib to the first documented 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 best overall response of CR or PR per RECIST 
1.1 by independent central review.  The response must be confirmed at least 4 weeks later 
with a repeated CT/MRI.  Analyses will include the patients from the DDR Deficient 
Measurable Disease population who achieve a confirmed CR or PR without documentation 
of confirmed bone progression. Descriptive statistics (mean, standard deviation, median, 
minimum, maximum, and quartiles) will be provided.  Analyses based on assessment by the 
investigator will also be performed.
9.3.2.2. Duration of Response 
The duration of response is defined as the time from the first objective evidence of soft tissue 
response (subsequently confirmed) per RECIST 1.1 by independent central review and no 
evidence of confirmed bone disease progression per 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 per RECIST 1.1 by 
CCI


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independent central review or bone disease progression per PCWG3 by independent central 
review. Details on the conventions for censoring will be presented in the statistical analysis 
plan. Analyses will include the patients from the DDR Deficient Measurable Disease 
population who achieve a confirmed CR or PR without documentation of confirmed bone 
progression.  Duration of response will be estimated using the Kaplan-Meier method and 
95% CI for median time will be calculated using the Brookmeyer-Crowley method 
(Brookmeyer & Crowley, 1982).  Analyses based on assessment by the investigator will also 
be performed.
9.3.2.3. Proportion of Patients With PSA Response 50% 
PSA response will be calculated as a decline from baseline PSA (ng/mL) by at least 50% 
measured by central laboratory.  A PSA response must be confirmed by a second consecutive 
value at least 3 weeks later.  Patients without a baseline and at least one post baseline PSA 
assessment will not be analyzed for this endpoint. Only assessments performed from the date 
of first dose of study treatment until confirmed PSA progression or start of new anticancer 
treatment given after the first dose of study treatment will be considered. The proportion of 
patients in the DDR Deficient Measurable Disease population with confirmed PSA decline 
≥50% compared to baseline will be calculated along with the 95% CI using the
Clopper-Pearson method (Clopper-Pearson; 1934).
9.3.2.4. CTC Count Conversion Rate 
The CTC count conversion rate will be defined as the proportion of patients with a CTC 
count ≥5 CTC per 7.5 mL of blood at study entry that decreases to <5 CTC per 7.5 mL of 
blood anytime on study.  CTC counts <5 CTC per 7.5 mL of blood will be considered 
favorable and CTC counts ≥5 CTC per 7.5 mL of blood will be considered unfavorable.  The 
conversion rate will be calculated along with the 95% CI using the Clopper-Pearson method 
(Clopper-Pearson; 1934).  Patients with a CTC count <5 per 7.5 mL of blood at baseline are 
not analyzed for this conversion endpoint, though they are included in continuous summaries.
In addition, the proportion of patients with a CTC count of 1 or more (detectable) per 7.5 mL 
of blood at study entry that decreased to CTC=0 (undetectable) per 7.5 mL of blood any time 
on study will be assessed. The conversion rate will be calculated along with the 95% CI 
using the Clopper-Pearson method (Clopper-Pearson; 1934).  Patients with a CTC count of 
0 per 7.5 mL of blood at baseline are not analyzed for this conversion endpoint, though they 
are included in continuous summaries. The proportion of patients with baseline CTC counts 
<5 who show increased CTC counts post-baseline will also be assessed.
9.3.2.5. Time to PSA Progression 
The time to PSA progression is defined as the time from first dose of talazoparib to the date 
that a ≥25% increase in PSA with an absolute increase of ≥2 μg/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. Kaplan-Meier estimates will be 
presented together with a summary of associated statistics including the median and quartiles 
with two-sided 95% CIs.  Conventions for censoring will be presented in the statistical 
analysis plan. 


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9.3.2.6. Radiographic PFS 
Radiographic PFS is defined as the time from first dose of talazoparib to radiographic 
progression in soft tissue per RECIST 1.1 by independent central review, in bone per 
PCWG3 by independent central review, or death due to any cause, whichever occurs first.  
Details on the conventions for censoring PFS will be presented in the statistical analysis plan.  
Radiographic PFS will be estimated using the Kaplan-Meier method; the 95% CI for median 
time will be calculated using the Brookmeyer-Crowley method (Brookmeyer & Crowley, 
1982).  Analyses based on assessment by the investigator will also be performed. 
9.3.2.7. Overall Survival 
Overall survival is defined as the time from first dose of talazoparib to death due to any 
cause.  Details on the conventions for censoring will be presented in the statistical analysis 
plan.  Kaplan-Meier methods will be used to estimate overall survival.  The 95% CI for 
median overall survival time will be calculated using the Brookmeyer-Crowley method 
(Brookmeyer & Crowley, 1982). 
9.3.2.8. Patient Reported Pain
Pain assessed by the BPI-SF will be summarized using descriptive statistics by study visit.
Patient-reported outcomes assessments will be analyzed using the PRO population.  Missing 
items will be handled per the scoring manuals of each questionnaire administered. 
Deterioration in pain is defined as 2-point increase from baseline using question 3 of the 
BPI-SF.  Additional pain and analgesic assessments will be completed for 7 consecutive days 
before study visits.  Four or more completed daily pain reports at each reporting time period
are required for a patient to be considered evaluable.  Pain score averages during each 
reporting period will be calculated.
In order to adequately measure pain, it is equally important to adequately track analgesic use 
to ensure that the pain palliation observed is not the result of an increase in analgesic use but 
rather the effect of the antitumor treatment being studied.  Analgesic data (from the analgesic 
log) will be mapped to the WHO analgesic usage score and used concurrently to define pain 
progression with the BPI SF (Basch E et al, 2013).
Time to deterioration in pain will be summarized using the Kaplan-Meier method and will 
include the median and 95% CIs based on the Brookmeyer-Crowley method.  Longitudinal 
mixed effects model analyses will be used to assess change from baseline in pain symptoms.
9.3.2.9. Patient-Reported General Health Status (and Health Index)
A patient-reported general health status assessed by the EQ-5D-5L will be summarized using 
descriptive statistics.  Longitudinal mixed effects model analyses will be used to assess 
change from baseline in general health status. In addition, there will be a health status profile 
analysis consisting of a display of the number and percentage of patients in each of the 
5 response levels for each of the 5 dimensions at each visit.


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9.4. Safety Analyses
All safety analyses will be performed using the safety population, defined as all patients who 
receive any amount of any study drug.  Drug exposure will be summarized using descriptive 
statistics.  Treatment-emergent safety data will be collected from the first dose of study 
treatment through 28 days after the last dose (ie, permanent discontinuation) of study drug or 
before initiation of new antineoplastic or investigational therapy, whichever occurs first.  The 
safety of talazoparib will be evaluated by the analysis of incidence of serious and nonserious 
adverse events, severity of adverse events, incidence of dose modifications and of permanent 
treatment discontinuation due to adverse events, and incidence of new clinically significant 
changes in clinical laboratory values and vital signs.  Adverse events will be coded to 
preferred term and system organ class using the Medical Dictionary for Regulatory Activities 
(MedDRA) and classified by severity using the CTCAE, version 4.03.  The number and 
percentage of patients with adverse events will be presented by MedDRA system organ class 
and preferred term, relationship to study treatment, and severity.  Descriptive statistics will 
be used.  Laboratory values will be classified by severity using the CTCAE, version 4.03.  
Laboratory shift tables of baseline to maximum postbaseline results to each subsequent visit 
will be produced as appropriate.
9.5. Pharmacokinetic Analyses
PK data analyses will include descriptive summary statistics of the predose and postdose 
plasma concentrations of talazoparib by study visit.  In addition, the PK data from this study 
may be used to develop a population PK model.  
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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9.7. Determination of Sample Size
At least 100 patients will be enrolled with soft tissue measurable disease (per RECIST1.1) 
and alterations in DNA damage repair genes, determined at prescreening (optional) or 
screening by the gene mutation biomarker panels used for the assessment of tumor tissue 
DNA.

Patients with DNA damage repair deficiencies assessed using the gene mutation 
biomarker panels used for the assessment of a panel of genes likely to sensitize to 
PARP inhibition (N = 100).
With 100 patients the ORR can be estimated with a maximum standard error of 5.1%. A 
sample size of 100 patients is sufficient to demonstrate that if the observed best ORR is 
≥23%, the lower bound of the corresponding exact 2-sided 95% CI excludes 15.2%. 
Table 14 provides the response rates and exact 95% CI for 100 patients based on different 
scenarios.
Table 14.
Response Rates and Exact 95% CI for 100 Patients
Number of 
Responders
ORR point 
Estimate
Lower 95% CI of 
ORR
Upper 95% CI of 
ORR
23
23%
15.2%
32.5%
33
33%
23.9%
43.1%
43
43%
33.1%
53.3%
50
50%
39.8%
60.2%
9.8. Interim Analysis
The study is designed to have an initial analysis for safety and efficacy and an interim 
analysis for efficacy. The initial analysis will be performed after 20 patients from the DDR 
deficient measurable disease population receive study treatment for at least 8 weeks. The 
subsequent interim analysis will be performed when 60 patients form the DDR deficient 
measurable disease population complete at least 6 months of study treatment or are otherwise 
no longer being followed (ie, have, withdrawn consent, discontinued from the study, died, or 
are otherwise lost to follow-up).
An interim analysis with at least 60 patients is planned and if the observed best ORR is
≥23%, the lower bound of the corresponding exact 2-sided 95% CI would exclude <13%.
With 60 patients, the ORR can be estimated with a maximum standard error of 6.6%.  
Table 15 provides the exact binomial 95% CI for ORR for 60 patients based on different 
observed responses.
Table 15.
Response Rates and Exact 95% CI for 60 Patients
Number of 
Responders
ORR point 
Estimate
Lower 95% CI of 
ORR
Upper 95% CI of 
ORR
14
23.3%
13.4%
36%
20
33.3%
21.7%
46.7%
26
43.3%
30.6%
56.8%
30
50%
36.8%
63.2%


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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 dose-escalation 
decisions, facilitating pharmacokinetic (PK)/pharmacodynamic (PD) modeling, and/or to 
support clinical development. 
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.
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.


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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. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff has access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant specific numerical code.  Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred.  All other identifiable data transferred to the 
sponsor will be identified by this single, participant specific code.  The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity.  In case of data transfer, the sponsor 
will protect the confidentiality of participants’ personal data consistent with the clinical study 
agreement and applicable privacy laws.
11.3. 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 the ICH guidelines, according to local 
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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 an independent third party arranged by Pfizer.
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.


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The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents 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 must ensure that each study patients fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
Whenever consent is obtained from a patient’s legally acceptable representative or legal 
guardian, the patient’s assent (affirmative agreement) must subsequently be obtained when 
the patient has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a patient’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the patient’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study patient does not provide 
his or her own consent, the source documents must record why the patient did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the patient’s legally acceptable representative, the consent 
signer’s relationship to the study patient (eg, parent, spouse), and that the patient’s assent was 
obtained or waived.  If assent is obtained verbally, it must be documented in the source 
documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  The investigator 
will retain the original of each patient's signed consent document.
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 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.


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13.2. End of Trial in All Other Participating Countries 
End of trial in all [other] participating countries is defined as last patient last visit (LPLV).
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 
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) as quickly as is practical.  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 
which the study was conducted.
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.


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www.pfizer.com. 
Pfizer posts Public Disclosure Synopses (clinical study report 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.
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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Clopper, CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
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Curtin NJ. PARP inhibitors for cancer therapy. Expert Rev Mol Med. 2005 Mar 
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de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and 
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de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone 
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Donovan MJ, Osman I, Khan FM, Vengrenyuk Y, Capodieci P, Koscuiszka M, et al. 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
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Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et 
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Gibson BA, Kraus WL. New insights into the molecular and cellular functions of 
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Goodin S, Griffith N, Chen B, Chuk K, Daouphars M, Doreau C, et al. Safe handling of 
oral chemotherapeutic agents in clinical practice: recommendations from an 
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Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, et al. Gene 
expression analysis of human prostate carcinoma during hormonal therapy identifies 
androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004 
Jan;164(1):217-27.
16.
Hopkins TA, Shi Y, Rodriguez LE, Solomon LR, Donawho CK, DiGiammarino EL, et 
al. Mechanistic dissection of PARP1 trapping and the impact on in vivo tolerability and 
efficacy of PARP inhibitors. Mol Cancer Res. 2015 Nov; 13(11):1465-77. 
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International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
conduct, reporting, editing, and publication of scholarly work in medical journals 
[Internet]. 2015 Dec [cited 2017 Mar 20]. Available from: http://www.icmje.orgorgorg.
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Investigator’s Brochure, Talazoparib (PF-06944076) August 2018.
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Johansson M. A human poly(ADP-ribose) polymerase gene family (ADPRTL): cDNA 
cloning of two novel poly(ADP-ribose) polymerase homologues. Genomics. 1999 May 
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Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, Fehrenbacher L, 
Yerushalmi R, Mina LA, Martin M, Roché H, Im YH, Quek RGW, Markova D, Tudor 
IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in Patients with Advanced Breast 
Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763.
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Lorente D, Olmos D, Mateo J, Dolling D, Bianchini D, Seed G, Flohr P, Crespo M, 
Figueiredo I, Miranda S, Scher HI, Terstappen LWMM, de Bono JS. Circulating tumour 
cell increase as a biomarker of disease progression in metastatic castration-resistant 
prostate cancer patients with low baseline CTC counts. Ann Oncol. 2018 Jul 
1;29(7):1554-1560.
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Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair 
defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015 Oct 
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PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012 Nov 1;72(21):5588-
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trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 
2014 Feb;13(2):433-43.
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and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
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Integrative clinical genomics of advanced prostate cancer. Cell. 2015 May 
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survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 
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metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with a post-
treatment circulating tumor cell (CTC) of 0 vs CTC > 0: Post hoc analysis of COU-AA-
301. Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 5015-5015.
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Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and 
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Schreiber V, Amé JC, Dollé P, Schultz I, Rinaldi B, Fraulob V, et al. Poly(ADP-ribose) 
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an old molecule. Nat Rev Mol Cell Biol. 2006 Jul;7(7):517-28. 
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Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, et al. BMN 673, a 
novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with 
DNA repair deficiency. Clin Cancer Res. 2013 Sep 15;19(18):5003-15.
35.
Smith MR, de Bono JS, Sternberg CN, Le Moulec S, Oudard S, De Giorgi U, et al. 
Final analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in 
metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated 
with docetaxel (D) and abiraterone (A) and/or enzalutamide (E) [abstract]. J Clin Oncol. 
2015 Mar 1;33(7 Suppl):13. 
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Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, et al. Increased 
expression of genes converting adrenal androgens to testosterone in androgen-
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Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, et al. 
Multinational, double-blind, phase III study of prednisone and either satraplatin or 
placebo in patients with castrate-refractory prostate cancer progressing after prior 
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second-generation antiandrogen for treatment of advanced prostate cancer. Science. 
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Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE. Discovery and 
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inhibitor as an anticancer agent. J Med Chem. 2016 Jan 14;59(1):335-57.


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Appendix 1. Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ADP
adenosine disphosphate
AE
adverse event
ALT
alanine aminotransferase
AML
acute myeloid leukemia
AR
androgen receptor
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC 0-24
area under the plasma concentration-time curve from time zero to the time 
24 hours (dosing interval).  
BALB/c
Bagg Albino inbred research mouse strain c
BCRP
breast cancer resistant protein
BMN
BioMarin
BPI-SF
Brief Pain Inventory-Short Form
Cmax
maximum plasma concentration
Cmin
mean plasma trough concentration 
CI
confidence interval
CK
creatine kinase
CL/F
apparent oral clearance
COMET
Carvedilol Or Metoprolol European Trial
COX-2
cyclooxygenase-2
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CRPC
castration-resistant prostate cancer
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
computed tomography/clinical trial
CTA
clinical trial application
CTC
circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
CT SAE
Clinical trial serious adverse event
CYP
cytochrome 450
DDR
deoxyribonucleic acid damage repair
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dispensable unit
E-DMC
External Data Monitoring Committee
eGFR
estimated glomerular filtration rate
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EORTC
European Organisation for Research and Treatment of Cancer
CCI
CCI


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Abbreviation
Term
EQ-5D-5L
European Quality of Life 5-Dimension, 5-Level Scale
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GnRH
gonadotropin-releasing hormone
HBV
hepatitis B virus
HCP
health care professional
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNPC
hormone-naïve prostate cancer
HR
hazard ratio
HRD
homologous recombination deficiency
HRQL
health-related quality of life
IC50
half -maximal inhibitory concentration 
ICH
International Conference on Harmonisation
ICD
informed consent document
ICR
independent central review
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ITT
intent-to-treat
IUD
intrauterine device
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
K2EDTA
dipotassium ethylenediaminetetraacetic acid
Ki
inhibitory constant 
LFT
liver function test
LPLV
last patient last visit 
M0
nonmetastatic
M1
metastatic
mCRPC
Metastatic castration-resistant prostate cancer
MDRD
Modification of Diet in Renal Disease
MDS
myelodysplastic syndrome
MDV
Medivation
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
N/A
not applicable
NAD
nicotinamide adenine dinucleotide 
NASH
Nonalcoholic steatohepatitis 
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
next generation sequencing
NHT
novel hormonal therapy
NLCB
no longer clinically benefitting


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Abbreviation
Term
NSAIDS
Nonsteroidal anti-inflammatory drugs
ORR
Objective response rate
P-gp
P-glycoprotein
PARP
poly(adenosine diphosphate-ribose) polymerase
PCD
primary completion date
PCT
Physician’s choice chemotherapy
PCWG
Prostate Cancer Working Group
PD
pharmacodynamics(s)
PF
Pfizer
PFS
progression-free survival
PGx
pharmacogenomics(s)
PI
principal investigator
PID
patient identification
PK
pharmacokinetic
PR
partial response
PR-25
Quality of Life Questionnaire Prostate Cancer Module
PRO
patient-reported outcome
PSA
prostate-specific antigen
PT
prothrombin time
QoL
quality of life
QLQ-C30
Quality of Life Questionnaire
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCLC
Small cell lung cancer
SMQ
Standardized MedDRA Query
SOP
standard operating procedure
SRSD
single reference safety document
SSID
single subject identification
SUSAR
suspected unexpected serious adverse reaction
SPARC
Satraplatin and Prednisone Against Refractory Prostate Cancer;
TALAPRO
TALAzoparib PROstate
TBili
total bilirubin
TEAE
treatment-emergent adverse event
Tmax
Time to mean maximum plasma concentration
TOPARP-A
Trial of Olaparib in Patients With Advanced Castration Resistant Prostate 
Cancer, part A
ULN
upper limit of normal
US
United States
V/F
volume of distribution 
WHO
World Health Organization


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Appendix 6. Country-Specific Amendment: France
This appendix applies to study sites located in France. 
Institutional Review Board/Ethics Committee
Ethic Committee and health authority approval will be obtained for any substantial protocol 
amendments and informed consent revisions before implementing the changes.
GCP Training
Prior to enrollment of any subjects, the investigator and any sub-investigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer.  Any investigators who later join the study will 
complete the Pfizer GCP Training or equivalent before performing study-related duties.  For 
studies of applicable duration, the investigator and sub-investigators will complete Pfizer 
GCP Training or equivalent every three years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials.
Investigational Product
No subjects or third-party payers will be charged for investigational product.


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Appendix 7. Country-Specific Documentation: Germany
This appendix applies to study sites located in Germany.
Per German law, it is prohibited to enroll in clinical studies any persons who have been 
housed in an institution following a regulatory or judicial order. Consistent with the 
inclusion criterion 18 of the TALAPRO-1 protocol amendment 4 (“Patients must be willing 
and able to comply with scheduled visits, treatment plan, laboratory tests and other study 
procedures”) and in accordance with German law, institutionalized patients will not be able 
to participate in the TALAPRO-1 study.