A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF TALAZOPARIB WITH ENZALUTAMIDE IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER
Phase: PHASE3
Conditions: mCRPC
Sponsor: Pfizer

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TALAPRO-2
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
OF TALAZOPARIB WITH ENZALUTAMIDE IN METASTATIC 
CASTRATION-RESISTANT PROSTATE CANCER 
Investigational Product Number:
PF-06944076
Investigational Product Name:
Talazoparib
United States (US) Investigational New 
Drug (IND) Number:
129,642
European Clinical Trials Database 
(EudraCT) Number:
2017-003295-31
Protocol Number:
C3441021
Phase:
3
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 8
17 June 2021
The primary purpose of this amendment is to update 
the analysis trigger of IA1 (futility analysis only) for 
the DDR-deficient cohort and to introduce a second 
interim analysis for efficacy for the DDR-deficient 
cohort (section 9.1).  
Additional changes/clarifications have been done 
throughout the protocol:
-
In the statistical methods added an IA for futility 
in the DDR-deficient population at the final 
rPFS analysis for all comers and updated the 
definition of PFS2 Extended window of 
obtaining consent from 28 to 42 days from 
randomization in table 1 and added information 
about contact cards. Specified that serum folate 
will need to be measured (not RBC folate).
Reiterated that bone disease must be assessed 
only by bone scan.
-
In table 3, scans frequency per SOC will be 
accepted for patients on follow up cancer 
therapy
-
Section 1.3.2 provided a safety update from the 
phase 2 study of talazoparib in DDR-deficient
patients with mCRPC
-
Updated section 5.6.3
-
Section 5.9 added statement that COVID-19 
vaccines are allowed and clarified that any 
anticoagulant allowed per local enzalutamide 
prescribing information can be used in lieu of 
rivaroxaban and apixaban
-
Updated Sections 9.1 and 9.8.1 (introduction of 
IAs)
-
Section 9.5 added language to clarify the 
potential for early PK unblinding

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-
Appendices 2, 3, 4 and 5 removed due to 
copyrightsOther clarifications done throughout 
the protocol
Amendment 7
18 September 
2020
The primary purpose of this amendment is to 
introduce an extension cohort to ensure at least 
113 mCRPC patients are randomized in China. The 
additional patients randomized in the extension 
cohort will not be included in the analysis of the
primary or secondary study endpoints. Data from 
the China cohort will be analyzed separately per 
local regulatory requirement (see Appendix 10).
Amendment 6
26 February 2020
The primary purpose of the amendment is to 
introduce the use of liquid biopsies to assess the 
patient’s tumor DDR status at pre-screening or 
screening.  Concordance of DDR testing results 
between liquid and tumor tissue biopsies has been 
added as exploratory endpoint.  Both samples must 
be provided prior to randomization (Table 1, 
Table 5, Sections 3, 4, 5.1, 6.1, 6.2, 7.1).
In addition, the following changes or clarifications 
were introduced:

Table 3: collection of skeletal events should 
continue in long term follow up.  This was 
added to align with the text in Section 6.5 of the 
prior protocol version.

In the study design (Section 3) removed 
redundant information and clarified that all 
randomized patients can receive surgery or 
palliative radiotherapy after radiographic 
progression (not only patients from France).

Inclusion criteria 4 and 5 were updated to reflect 
the introduction of liquid biopsies in the study, 
the PSA progression definition at study entry 
was clarified in criterion 8, legal guardian was 
removed from criterion 15 since not applicable 
for this patient population.  Clarified in 
exclusion criterion 1 that the patient may have 
received first generation anti-androgens in the 

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CRPC settings; in exclusion criterion 5 clarified 
that no washout period is required for prior 
abiraterone administered for treatment of 
castration sensitive disease.  Also updated that 
>10 mg/day prednisone (or equivalent dose of 
other steroids) will be considered exclusionary 
and removed language regarding 5-alpha 
reductase inhibitor (use during study treatment is 
discussed in Section 5.9).  Provided more 
information regarding eligibility based on prior 
cancer diagnoses and added reference to 
Appendix 9 which include a guidance on how to 
enter all the variables into the MDRD equation 
in exclusion criteria 16 and 11, respectively.

In Sections 3, 4.3, 5.1, 6.1 and 7.1 and Table 1 
added that if results from liquid and tumor tissue 
sample are available prior to randomization and 
results are not concordant for the presence of the 
selected DDR mutation(s), positive DDR results 
will be used for eligibility and stratification
regardless of the tissue used to generate the data.

Updated and clarified reportability of AE and 
research related injury during prescreening 
(Table 1 and Section 8). 

Removed the collection of the patient medical 
history at prescreening to avoid collecting data 
not required for analyses for patients that may 
not be randomized into the study (Table 1 and 
Section 6.1).

Instructions were provided in Table 8 for the 
management of symptomatic Grade 1 and 
2 anemia (eg, fatigue) to ensure the investigator 
will be able to manage the patient quality of life 
while on treatment.

B12, reticulocyte count, erythropoietin, folate 
(introduced in protocol amendment 2 to explore 
the mechanism of talazoparib induced anemia) 
and assessment of bicarbonate (or CO2) are no 

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longer required if not available at the site 
laboratory (Table 12 footnote). 

Scans can be done per standard of care at the 
institution if patient is continuing study 
treatment after determination of progression by 
investigator and BICR (Table 2 footnote and 
Section 6.3).

Table 11: text updated to align with text in 
Section 8.4.2.

Section 8.4.4.1 included as medication error the 
lack of study drugs withholding per criteria 
provided in the protocol.

Section 9.3.2 added planned analyses of 
objective response and PSA progression.

Provided clarifications for biomarker samples 
collected in China in Section 7.5.1.

Clarifications were added throughout the 
protocol considering the questions received from 
the sites (eg, in Section 6).
Amendment 5
28 Oct 2019
Changes at this time are specific for South Africa:
Optional HIV testing using the ELISA test may be 
conducted for subjects of unknown HIV status per 
investigator discretion.  Subjects will be asked to 
sign an HIV consent form and be given pre and post 
test counseling at the site.  (Added to Table 1, 
Section 6.2, Section 7.9 and Table 12).
Amendment 4
22 July 2019
The primary purpose of this amendment was to 
increase the patient size.  N in Part 2 increased from 
860 to 1018; Cohort 1 updated from 560 to 750; 
Cohort 2 updated from 300 to 268.  The estimation
of overlap of patients with DDR deficiency updated 
from ~85-140 to 112.  
An exploratory endpoint was added to correlate to 
the previously listed exploratory objective.

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Clarification of the recording of AEs and Research 
Related Injuries if a de novo tumor biopsy is 
obtained at a prescreening visit (also in 
Sections 8.1.4 and 8.1.5).
Schedule of Activities: clarified when reticulocyte 
count, erythropoietin, folate, and B12 are to be 
collected; clarified when measurement of height is 
required for patients in Part 2; added an additional 
PSA at Week 53 so subsequent PSA required tests 
and site visits are on the same 8 week schedule; 
deleted optional repeat tumor biopsy at Safety 
Follow-Up visit or End of Treatment (also in 
Section 6.3); instructions for CTC sample specific 
for patients enrolled in China added; clarification of 
requirements for radiographic imaging if a patient 
continues on study treatment after disease 
progression documented radiographically but the 
patient is clinically benefiting (also in Section 6.3); 
clarified that the electronic Patient Reported 
Outcomes are to be completed remotely if telephone 
visits are being conducted (also in Section 6.5).  
Sections 1.3.1 and 1.6.1 updated information 
regarding talazoparib added.
Section 1.5.1.5 clarification that the SmPC is the 
reference document for enzalutamide.
Number of study sites updated from 200 to 270.
Inclusion Criteria: (#8) definition of PSA 
progression updated to align with PCWG3 
guidelines; (#9) clarification that the use of 
bisphosphonate or denosumab is allowed during the 
study but is not mandatory.
Exclusion Criteria: (#1) clarification that ADT in the 
castration resistant prostate cancer disease state is 
not exclusionary; (#3) clarification that patients who 
have previously received enzalutamide be excluded 
from the study.  (This would be enzalutamide 
treatment at any time – including the CSPC disease 
state); (#4) clarification of the exclusionary time 

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period of prior treatment with platinum base 
chemotherapy; (#5) clarification of cytotoxic 
chemotherapy; (#6) clarification of time period for 
previous investigational agents; (#7) clarification of 
previous opioid treatment; (#8) clarification of 
exclusionary medications; (#9) additional 
information regarding palliative localized radiation 
being exclusionary; (#16) clarification of exclusion 
due to cancer history.
Randomization criteria updated for clarification.
Section 5.5.1 clarified that study treatment should 
be administered in the morning of each day until PK 
testing is completed for each patient.
Section 5.6.2 clarified study treatment as talazoparib 
or talazoparib/placebo to refer to both treatment in 
Part 1 and in Part 2.
Table 8 anemia reference updated to specific 
laboratory value, not grade of AE.
Section 5.9 prohibited and allowable concomitant 
medications clarified.
Section 6.2 added information regarding biopsy to 
the screening visit as previously omitted in error.  
This information was previously included in the 
pre-screening section but not in the Screening 
section and it is permitted per the protocol to have 
these tests performed at the screening visit if the 
pre-screening visit was not done.
Section 7.5 clarification of biomarkers are being 
collected on all tested patients.
Section 7.5.1 added to clarify allowable tests per 
China regulatory agency.
Table 12 added urea as allowable where BUN is not 
collected; footnote c clarified that bicarbonate is not 
collected in Japan.
Section 9.1 sample size determination updated to 
reflect changes in analysis.

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Table 13 updated to reflect updated sample size 
population and analysis.
Section 9.8.1 updated to reflect the updated analyses 
from updated patient enrollment numbers.
Minor typographical changes have been made 
throughout the document for clarification.
Amendment 3
12 March 2019
Changes at this time specific for France:
Study design: 

Updated to clarify allowable additional 
treatment, following consultation with Sponsor 
medical monitor, if a patient remains on study 
drug following radiographic progression.

Updated discontinuation of study treatment(s) 
requirements for patients who met progressive 
disease eligibility criterion for the study solely 
per PSA progression, and PSA continues to rise 
while on treatment.
Amendment 2
30 October 2018
The primary purpose of Protocol Amendment 2 was 
to allow the inclusion of patients without DNA 
Damage Repair (DDR) deficiencies as well as those 
with unknown mutation status. 
The study design for Part 2 was updated to begin 
enrollment with all-comers (DDR-deficient and non 
DDR-deficient and unknown DDR status).  Once 
enrollment is completed in this cohort, enrollment 
will continue but will be restricted to a second 
cohort of patients with DDR deficiencies (Cohort 2).
The talazoparib dose in combination with 
enzalutamide to be used in the randomized portion 
of the study (Part 2) is specified in Protocol 
Amendment 2 based on assessment of preliminary 
safety and PK data from Part 1.

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A high-level summary of changes made to the 
protocol specific by section is as follows:

Title updated to remove reference to DDR 
deficiency.

Overview and Background and Rationale 
updated with data from 2018 talazoparib IB. 

Part 2 Primary Objectives and Endpoints, 
Sample Size, Randomization Stratification, 
per updated study design.

Schedule of Activities updated to reflect 
different visit schedule, patient contraception 
requirements and use added to screening, 
allowance of specific local laboratory 
evaluations, additional CTC collection at 
screening, and an additional PK sample at 
Weeks 3 and 17.

Inclusion criteria #4 updated per Study 
Design update and eligibility of patients with 
or without DDR deficiencies.

Inclusion #13, #14, and exclusion #18 
updated to clarify required use and length of 
time for condom, contraception use, and 
sperm donation; not allowed to 4 months for 
patients that in the opinion of the 
investigator are capable of ejaculating. 

Exclusion #1 updated to clarify exclusionary 
prior systemic cancer treatment.

Exclusion #5 updated to clarify prednisone 
>10 mg/day is exclusionary.

Exclusion #16 deleted time periods for 
history of MDS or AML.

Exclusion #21 added per enzalutamide safety 
language.

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
Contraception language updated per 
2018 talazoparib IB. 

Information regarding talazoparib overdose 
added per 2018 talazoparib IB.

Added information regarding 
talazoparib/placebo continuing if 
enzalutamide is permanently discontinued 
and enzalutamide continuing if 
talazoparib/placebo is permanently 
discontinued.

Timeframe to allow anemia to resolve prior 
to talazoparib/placebo discontinuation 
updated from 4 to 8 weeks.

End of treatment requirements clarified.

Efficacy assessments (Part 2) per updated 
study design.

Clarified non DDR deficiency and unknown 
DDR status.

Data Analysis and Statistical Methods 
(Part 2) per updated study design.

General Data Protection Regulation (GDPR) 
language added.

Other administrative and/or editorial changes 
were also incorporated to improve overall 
document clarity and accuracy.
Typographical corrections made throughout the 
document.
Amendment 1
30 March 2018
Title of Study updated to reflect the deletion of 
abiraterone treatment arm.
Study Design:

Deleted the abiraterone treatment arm from both 
Part 1 and Part 2.

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
Sample size of patients in both study parts 
adjusted accordingly (Part 1 to 12; 
Part 2 to 340).

Clarification provided to explain how Part 1 
safety data from targeted safety events and PK 
analysis will be assessed for confirmation of the 
starting talazoparib daily dose in Part 2; 
tolerability added to evaluation in Part 1.
Schedule of Activities and Study Procedures:

Separated optional Prescreen visit activities and 
Screen activities.

Clarification that if a prescreen visit is done 
collection of demography, history of prostate 
cancer, and prior cancer therapy is to be 
completed at this visit.

Visit windows 3 days, and treatment is to be 
started within 3 days after randomization per 
SOA footnote ‘e’.

Deleted the single item questionnaire on identity 
of treatment received.

Clarified that tumor tissue (de novo or archival) 
is to be done at Prescreen or Screen visit; not 
Day 1 visit.

Added the option of taking PSA lab test at an 
unscheduled visit.

PK collection in Part 2 deleted from Weeks 1 
and 17, and added to unscheduled visit to ease 
patient burden.

CTC and ctDNA analyses deleted from Week 5 
and unscheduled, and added to safety follow-up 
visit.

Footnote clarified to indicate study visits 
following Week 25 while still on study drug are 

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to occur every 60 days for accurate drug 
dispensing.

Footnote to clarify 2 x 20 ml blood samples are 
to be collected for DNA analysis prior to first 
dose of study drug.

Upon PSA response (decline) or progression a 
consecutive confirmation lab value is required at 
least 21 days later.
Safety and Efficacy data of talazoparib updated with 
most recent information.
Rationale for enzalutamide dose added.
Objectives:

Part 1: added an additional exploratory objective 
“to explore correlations between 
talazoparib/enzalutamide exposure and 
biomarker, efficacy and safety outcome 
parameters, if data allow”.

Part 2: deleted exploratory objective “to explore 
whether talazoparib in combination with NHT 
induces a high degree of PSA response”.
Endpoints:

Part 2: Included details of Patient Reported 
Outcome assessment measurements.
Study Schematic updated to reflect amended study 
design. 
Subject Eligibility.
Inclusion Criteria:

Clarification regarding type of confirmed 
adenocarcinoma of the prostate without small 
cell or signet cell features.

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
Allow historic genomic testing of tumor tissue 
showing DDR positivity on selected genes 
following sponsor approval.

Clarification allowing patients who are on 
prophylactic opioid therapy for pain related to 
their prostate cancer diagnosis as long as no pain 
related to prostate cancer has been reported in 
the 28 days prior to enrollment (Part 1) or 
randomization (Part 2).

Clarification of the purpose of the saliva sample 
collection.

Relative time point for previous medications 
clarified as enrollment (Part 1) or randomization 
(Part 2).

Definition of PSA progression must be from 
3 consecutive assessments.

Increased the length of time for contraception 
use and sperm donation from 105 to 120 days.
Exclusion Criteria:

Previous cancer treatment initiated in the 
mCRPC state updated to be any prior systemic 
cancer treatment.

Clarification that patients whose only evidence 
of metastasis is adenopathy below the aortic 
bifurcation are excluded.

Prior platinum-based chemotherapy is only 
exclusionary if administered within the previous 
6 months.

Concomitant medications due to potential DDI 
with talazoparib updated.

Concomitant medications due to potential DDI 
with enzalutamide updated.

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
Exclusionary value for albumin updated to 
<2.8 g/dL.

Added an exclusionary criterion if patient is not 
willing to comply with protocol contraception 
requirements.
Stratification Factors for Randomization Criteria: 
Updated due to change in study design to 
(1) previous treatment with NHT for 
castration-sensitive prostate cancer or 
non-metastatic castration-resistant prostate cancer 
(M0 CRPC) (yes/no), and (2) previous treatment 
with taxane-based chemotherapy for 
castration-sensitive prostate cancer (yes/no).
PK analyses updated to clarify inclusion of 
enzalutamide N-desmethyl metabolite.
Breaking the Blind procedure updated per Pfizer 
SOP language.
Investigational Product Supplies updated with 
details of talazoparib and identical placebo, and 
enzalutamide.
Clarification that dispensing of study drugs in 
Part 1 will be performed manually by the sites.
Clarification that in Part 2 the starting dose of 
talazoparib in patients with moderate renal 
impairment will be determined based on the starting 
dose for patients with normal renal function for 
Part 2.
Instructions included if a patient forgets to take his 
daily dose of both blinded study drug and 
enzalutamide.
Concomitant Treatments: 

Updated with details of specific treatments 
allowed, prohibited, and information regarding 
the use of anticoagulants in the study.

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
Clarification added for the dose of enzalutamide 
to be reduced to 80 mg/day if strong cytochrome 
P450 2C8 inhibitors are administered.
Companion Diagnostics updated to clarify that de 
novo, archival or historical result (with Sponsor 
pre-approval) must be done by Foundation Medicine 
using the FoundationOnetest.
Details added regarding the study biomarkers and 
banked biospecimens.
Adverse Events:

Additional medical guidance for treatment of 
anemia, neutropenia, and thrombocytopenia 
included in Table 7.

The time period for collection of SAEs updated 
to 28 calendar days without regard of initiation 
of antineoplastic or investigational therapy.

Clarification of reporting of potential research 
related injury events following de novo tumor 
biopsy if performed at a prescreening visit.

Emphasis that all events of myelodysplastic 
syndrome or acute myeloid leukemia are to be 
reported as SAEs irrespective of time of 
diagnosis or investigators opinion of causality.

Update to version 4.03 of CTCAE for the 
investigator’s definitions of severity of adverse 
events.
Medication Errors updated to include:

Incorrect study drug dose taken by patient.

Approximately <80% of expected dosing.
Patient Reported Outcomes: 

Clarification throughout the document that 
Patient Reported Outcome assessments are only 

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to be completed by patients in Part 2 of the 
study.

Analyses of Patient Reported Outcomes 
detailed.
Data Analysis:

Part 2 Key Secondary Endpoints analyses 
detailed.

Analysis of radiographic progression free 
survival updated to be based on the updated 
2 stratification factors.
Interim Analysis updated to be one interim analysis 
for futility.
Definition of End of Trial updated to indicate last 
patient last visit for all countries.
Original 
protocol
Final 28 
July-2017
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................23
LIST OF FIGURES .................................................................................................................23
PROTOCOL SUMMARY.......................................................................................................24
SCHEDULE OF ACTIVITIES................................................................................................37
1. INTRODUCTION ...............................................................................................................47
1.1. Overview and Mechanism of Action.......................................................................47
1.1.1. Overview.....................................................................................................47
1.1.2. Mechanism of Action/Indication................................................................47
1.2. Background and Rationale ......................................................................................48
1.2.1. Prostate Cancer ...........................................................................................48
1.2.2. PARP Inhibition..........................................................................................49
1.2.3. PARP Inhibitors as a Potential Targeted Therapy in mCRPC, 
Including in Androgen Pathway Manipulation................................................49
1.3. Summary of Relevant Clinical Experience with Talazoparib.................................51
1.3.1. Efficacy.......................................................................................................52
1.3.2. Safety..........................................................................................................53
1.3.3. Pharmacokinetics and Metabolism.............................................................54
1.3.3.1. Talazoparib................................................................................54
1.3.3.2. Enzalutamide.............................................................................55
1.3.3.3. Drug Drug Interactions between Talazoparib and 
Enzalutamide.....................................................................................56
1.4. Talazoparib Benefits and Risks Assessment...........................................................56
1.5. Enzalutamide Benefits and Risks Assessments ......................................................57
1.6. Rationale for Combination Treatment.....................................................................59
1.6.1. Rationale for Study Treatment Dose ..........................................................60
1.6.1.1. Talazoparib................................................................................60
1.6.1.2. Enzalutamide.............................................................................61
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................61
3. STUDY DESIGN.................................................................................................................65
3.1. Part 1: Open-Label Treatment.................................................................................70
3.2. Part 2: Double-Blind Treatment..............................................................................70
4. PATIENT ELIGIBILITY CRITERIA.................................................................................72

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4.1. Inclusion Criteria.....................................................................................................72
4.2. Exclusion Criteria....................................................................................................74
4.3. Randomization Criteria ...........................................................................................77
4.4. Lifestyle Requirements ...........................................................................................78
4.4.1. Contraception..............................................................................................78
4.5. Sponsor’s Qualified Medical Personnel..................................................................79
5. STUDY TREATMENTS.....................................................................................................79
5.1. Allocation to Treatment ..........................................................................................79
5.2. Breaking the Blind ..................................................................................................80
5.3. Patient Compliance .................................................................................................81
5.4. Investigational Product Supplies.............................................................................81
5.4.1. Dosage Forms and Packaging.....................................................................81
5.4.1.1. Talazoparib and Identical Placebo ............................................81
5.4.1.2. Enzalutamide.............................................................................81
5.4.2. Preparation and Dispensing........................................................................81
5.5. Administration.........................................................................................................82
5.5.1. Talazoparib or Blinded Therapy.................................................................82
5.5.1.1. Talazoparib Overdose ...............................................................83
5.5.2. Enzalutamide ..............................................................................................83
5.6. Dose Modifications .................................................................................................83
5.6.1. Part 1: Talazoparib Dose Determination ....................................................83
5.6.2. Study Treatment Dose Modification ..........................................................84
5.6.2.1. Dose Modifications for Talazoparib or 
Talazoparib/Placebo Due to Adverse Events ....................................84
5.6.2.2. Dose Modifications for Enzalutamide Due to Adverse 
Events ................................................................................................87
5.6.2.3. Talazoparib or Talazoparib/Placebo Dose Escalation Only
if Enzalutamide Permanently Discontinued ......................................87
5.6.3. Modifications Due to Abnormal Liver Tests (All Treatments)..................88
5.6.4. End of Treatment........................................................................................90
5.7. Investigational Product Storage ..............................................................................90
5.8. Investigational Product Accountability...................................................................91
5.8.1. Destruction of Investigational Product Supplies ........................................92

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5.9. Concomitant Treatment(s).......................................................................................92
5.10. Rescue/Salvage Medication ..................................................................................94
6. STUDY PROCEDURES .....................................................................................................94
6.1. Prescreening (optional)............................................................................................94
6.2. Screening.................................................................................................................95
6.3. Treatment Period (Part 1 and Part 2).......................................................................96
6.4. Safety Follow-up.....................................................................................................98
6.5. Long-Term Follow-up.............................................................................................98
6.6. Patient Withdrawal..................................................................................................99
7. ASSESSMENTS................................................................................................................100
7.1. Companion Diagnostics for Eligibility .................................................................100
7.2. Efficacy Assessments............................................................................................101
7.2.1. Primary Efficacy Endpoint: Radiographic Progression-Free Survival.....101
7.2.2. Assessment of Secondary Efficacy Endpoints .........................................102
7.2.3. Exploratory Efficacy Endpoint Assessments............................................103
7.3. Patient-Reported Outcomes Assessments .............................................................103
7.4. Pharmacokinetic Assessments...............................................................................104
7.5. Biomarkers ............................................................................................................104
7.5.1. China.........................................................................................................106
7.6. Banked Biospecimens ...........................................................................................106
7.6.1. Additional Research..................................................................................107
7.7. Imaging Assessments ............................................................................................107
7.8. Rater Qualifications...............................................................................................108
7.9. Safety Assessments ...............................................................................................108
7.9.1. Adverse Events.........................................................................................108
7.9.2. Physical Examinations..............................................................................108
7.9.3. Vital Signs ................................................................................................108
7.9.4. Clinical Laboratory Assessments .............................................................108
8. ADVERSE EVENT REPORTING....................................................................................110
8.1. Requirements.........................................................................................................110
8.1.1. Additional Details On Recording Adverse Events on the CRF................111
8.1.2. Eliciting Adverse Event Information........................................................111

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8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Patient Withdrawal section)...........................................................................111
8.1.4. Time Period for Collecting AE/SAE Information....................................111
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................112
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............112
8.1.5. Time Period for Collecting AEs and/or Research Related Injuries for 
Patients Who Sign the Molecular Prescreening Consent...............................112
8.1.5.1. Adverse Events........................................................................112
8.1.5.2. Research-Related Injuries........................................................113
8.1.6. Causality Assessment ...............................................................................113
8.1.7. Sponsor’s Reporting Requirements to Regulatory Authorities ................114
8.2. Definitions.............................................................................................................114
8.2.1. Adverse Events.........................................................................................114
8.2.2. Abnormal Test Findings ...........................................................................115
8.2.3. Serious Adverse Events ............................................................................115
8.2.4. Hospitalization..........................................................................................116
8.3. Severity Assessment..............................................................................................117
8.4. Special Situations ..................................................................................................118
8.4.1. Protocol-Specified Serious Adverse Events.............................................118
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................118
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................120
8.4.3.1. Exposure During Pregnancy....................................................120
8.4.3.2. Exposure During Breastfeeding ..............................................121
8.4.3.3. Occupational Exposure ...........................................................121
8.4.4. Medication Errors .....................................................................................121
8.4.4.1. Medication Errors....................................................................122
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................123
9.1. Sample Size Determination...................................................................................123
9.2. Analysis Sets .........................................................................................................127
9.2.1. Intent-to-Treat Population ........................................................................128
9.2.2. Safety Population......................................................................................129
9.2.3. Patient-Reported Outcome Population .....................................................129

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9.2.4. Pharmacokinetic Analysis Population ......................................................129
9.3. Efficacy Analysis ..................................................................................................129
9.3.1. Primary Endpoint: Radiographic PFS ......................................................129
9.3.2. Analysis of Secondary Efficacy Endpoints ..............................................130
9.3.3. Analysis of Exploratory Endpoints...........................................................131
9.4. Patient-Reported Outcome Analyses ....................................................................131
9.5. Pharmacokinetic Analyses ....................................................................................132
9.6. Biomarker Analyses ..............................................................................................133
9.7. Safety Analysis......................................................................................................134
9.7.1. Adverse Events.........................................................................................134
9.7.2. Analysis of Clinical Laboratory Results...................................................134
9.8. Interim Analysis ....................................................................................................135
9.8.1. Primary Endpoint......................................................................................135
9.9. Data Monitoring Committee .................................................................................136
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................136
11. DATA HANDLING AND RECORD KEEPING ...........................................................137
11.1. Case Report Forms/Electronic Data Record .......................................................137
11.2. Record Retention.................................................................................................137
12. ETHICS............................................................................................................................138
12.1. Institutional Review Board/Ethics Committee....................................................138
12.2. Ethical Conduct of the Study ..............................................................................138
12.3. Patient Information and Consent.........................................................................138
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................140
13. DEFINITION OF END OF STUDY...............................................................................140
13.1. End of Study in All Participating Countries........................................................140
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................140
15. PUBLICATION OF STUDY RESULTS........................................................................140
15.1. Communication of Results by Pfizer ..................................................................140
15.2. Publications by Investigators ..............................................................................141
16. REFERENCES ................................................................................................................143
17. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................149

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17.1. Appendix 1: Abbreviations .................................................................................149
17.2. Appendix 2: France Appendix ............................................................................154
17.3. Appendix 3: GCP Training .................................................................................154
17.4. Appendix 4: Investigational Product...................................................................154
17.5. Appendix 5: eGFR Calculation Prior to Randomization ....................................155
17.6. Appendix 6: China-Specific Requirements.........................................................156
17.7. Cohort Appendix 7: Country-Specific Requirements .........................................157

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LIST OF TABLES
Table 1.
Study Schedule of Activities: Prescreening (Optional) and Screening ................37
Table 2.
Study Schedule of Activities: Treatment Period ..................................................41
Table 3.
Study Schedule of Activities: Long-term Follow-up............................................45
Table 4.
Objectives and Endpoints for Study Part 1 (Open-Label Treatment)...................61
Table 5.
Objectives and Endpoints for Study Part 2 (Double-Blind Treatment)................62
Table 6.
Target Safety Events: Part 1 (Open-Label Treatment).........................................84
Table 7.
Talazoparib or Talazoparib/Placebo Dose Modification Levels for Adverse 
Reactions...............................................................................................................85
Table 8.
Dose Modification of Talazoparib or Talazoparib/Placebo Due to Adverse 
Events ...................................................................................................................85
Table 9.
Talazoparib or Talazoparib/Placebo Dose Escalation After 6 Weeks of 
Enzalutamide Discontinuation..............................................................................88
Table 10.
Criteria for Temporary Withholding of Study Treatment in Association 
With Liver Test Abnormalities.............................................................................88
Table 11.
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury....................90
Table 12.
Required Laboratory Tests (fasting is not mandatory).......................................109
LIST OF FIGURES
Figure 1.
Dual Cytotoxic Mechanisms of PARP Inhibitors.................................................47
Figure 2.
Study Schematic ...................................................................................................69
Figure 3.
China Cohort.......................................................................................................156
CCI

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PROTOCOL SUMMARY 
Overview
Talazoparib (also known as PF-06944076, MDV3800) in combination with enzalutamide is 
being investigated for the treatment of metastatic castration-resistant prostate cancer 
(mCRPC) unselected for deoxyribonucleic acid (DNA) damage repair (DDR) deficiencies 
(referred to as “all-comers population”).  Although patients will be unselected for DDR status 
in the all-comers population, DDR deficiency assessment prior to randomization is required 
for stratification.
Enrollment will begin in the all-comers population, Cohort 1.  Once enrollment is complete 
in Cohort 1, enrollment will continue but will be restricted to patients with DDR deficiencies 
(Cohort 2). 
Analysis on all-comers will include patients randomized into the DDR unselected cohort 
(Cohort 1).  Analysis on the DDR-deficient population will include DDR-deficient patients 
enrolled in Cohort 2 as well as any patients enrolled in Cohort 1 who are DDR-deficient. 
Exploratory subgroup analyses in patients with mCRPC not harboring DDR deficiencies will 
be conducted. 
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 mCRPC were docetaxel, cabazitaxel and sipuleucel-T.  The approval 
of NHT in mCRPC previously treated with docetaxel7,12 represented a therapeutic advance 
for these patients, followed shortly thereafter by their approvals for the larger population of 
men with chemotherapy-naïve mCRPC. 
Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) and PARP2 play 
important roles in DNA repair.25,26  Inhibition of PARP catalytic activity results in 
accumulation of single-strand DNA breaks, which in turn leads 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.1,33
Talazoparib is a potent, small molecule PARP inhibitor in development for the treatment of a 
variety of human cancers.  Talazoparib is a particularly potent PARP trapper, a property that 
is associated with cytotoxicity in preclinical models.1  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.

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Proof of concept of PARP inhibitor efficacy in prostate cancer with DDR deficiency was 
established in a Phase 2 study (TOPARP-A) with olaparib, which enrolled men heavily 
pre-treated with taxane-based chemotherapy and NHT.33  Furthermore, the potential for 
improved efficacy via combination of PARP inhibitors with NHT is being evaluated in 
ongoing Phase 1 and 2 studies.
Data presented at the 2018 American Society of Clinical Oncology (ASCO) Annual 
Meeting35 and published in Lancet Oncology, from a Phase 2 study of 142 men with mCRPC 
regardless of mutation status, revealed that the combination of PARP inhibitor olaparib with 
the antiandrogen agent abiraterone acetate reduced the risk of disease progression or death by 
35% compared with abiraterone alone in pretreated patients with mCRPC (hazard ration 
[HR]: 0.65; 95% confidence interval: 0.44-0.97; p-value 0.034).  Moreover homologous 
recombination repair (HRR) mutation status was available for only 56 (39%) of the 
142 patients.  Of these patients, 21 had HRR mutations and 35 did not.  In the cohort of 
21 HRRm patients, 11 received the combination and 10 were treated with abiraterone alone.  
The median progression free survival (PFS) was 17.8 months in the experimental arm 
compared with 6.5 months in the control arm (HR, 0.74; 95% CI, 0.26-2.12).  Among 
35 homologous recombination repair mutation status (HRRm) wild-type patients, the median 
PFS was 15.0 months for 15 patients receiving olaparib/abiraterone compared with 
9.7 months for 20 patients receiving abiraterone alone (HR, 0.52; 95% CI, 0.24-1.15).  
Therefore, this Phase II trial results suggested that targeting antiandrogen pathway with 
abiraterone in combination with PARP inhibitor olaparib significantly improved median PFS 
among patients with metastatic castration-resistant prostate cancer.48
The current study was designed given the results of TOPARP-A, the recently published 
results of olaparib in combination with abiraterone, and the role of NHTs such as 
enzalutamide in the treatment of mCRPC. 
Rationale for combining PARP inhibitors with androgen-receptor (AR) signaling inhibitors 
in castration-resistant prostate cancer (CRPC) regardless of DDR mutational status is based 
on research on nonclinical models and clinical samples.  AR signaling inhibition suppresses 
the expression of homologous recombination repair genes including breast cancer 
1 (BRCA1), resulting in “BRCAness” and sensitivity to PARPi.  PARP1 activity has been 
shown to be required for maximal AR function and thus inhibiting PARP is expected to 
reduce AR signaling and increase sensitivity to NHT.  Clinical resistance to AR blockade is 
sometimes associated with co-deletion of retinoblastoma RB and BRCA2, which is in turn 
associated with sensitivity to PARP inhibition.
Recently, several investigations are focusing on the identification of BRCAness phenotype 
changes in sporadic cancers that would lead to similar treatment tumor sensitivity.  The 
therapeutic aim of induction of BRCAness is to expand the use of PARP inhibitors to other 
tumor types whereas additional inhibition of other DNA repair pathways might lead to 
synthetic lethality in HR-deficient cells.  Multiple lines of evidence link androgen receptor 
(AR) signaling to the DNA damage response (DDR) in prostate cancer cells and preclinical 
studies suggested that BRCAness phenotype can be achieved with a therapeutic combination 
of antiandrogen (enzalutamide) and PARP inhibitor given the ability of enzalutamide to 

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down-regulate the expression of genes encoding components of cellular HR machinery.  
Hence, concomitant administration of these 2 classes of drugs can pharmacologically 
induce BRCAness and expand the clinical use of PARP inhibitors in the treatment of 
mCRPC.43
Objectives and Endpoints
Part 1 (Open-Label Treatment)
Primary Objective 
To determine the starting dose of talazoparib when given in combination with enzalutamide 
during Part 2 (double-blind treatment period).
Secondary Objectives
To characterize the steady state pharmacokinetics (PK) of talazoparib and enzalutamide and 
its N-desmethyl metabolite when given in combination. 
Exploratory Objectives

To explore correlation of changes in circulating tumor cells (CTCs) with efficacy 
outcome parameters.

To identify potential biomarkers associated with response and/or resistance to 
talazoparib in combination with enzalutamide.

To explore correlations between talazoparib/enzalutamide exposure and biomarker, 
efficacy and safety outcome parameters if data allow.

To collect banked biospecimens for exploratory research, unless prohibited by local 
regulations or ethics committee decision.
Part 2 (Double-Blind Treatment)
Primary Objectives

To demonstrate that talazoparib in combination with enzalutamide is superior to 
placebo in combination with enzalutamide in prolonging blinded independent central 
review (BICR) assessed rPFS in patients with mCRPC unselected for DDR status.

To demonstrate that talazoparib in combination with enzalutamide is superior to 
placebo in combination with enzalutamide in prolonging BICR assessed rPFS in 
patients with mCRPC harboring DDR deficiencies.

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Secondary Objectives
Key Secondary Objectives:

To demonstrate that talazoparib in combination with enzalutamide is superior to 
placebo in combination with enzalutamide in prolonging overall survival (OS) in
patients with mCRPC unselected for DDR status.

To demonstrate that talazoparib in combination with enzalutamide is superior to 
placebo in combination with enzalutamide in prolonging OS in patients with mCRPC 
harboring DDR deficiencies.
Other Secondary Objectives:

To evaluate anti-tumor activity in patients with mCRPC unselected for DDR status 
and in patients with mCRPC harboring DDR deficiencies with respect to the 
following:

BICR assessed objective response in measurable soft tissue disease;

BICR assessed duration of response in measurable soft tissue disease;

Prostate-Specific Antigen (PSA) Response;

Time to PSA progression;

Time to initiation of cytotoxic chemotherapy;

Time to initiation of antineoplastic therapy;

Time to first symptomatic skeletal event;

Progression free survival (PFS) on next line therapy (PFS2);

Opiate use for prostate cancer pain.

To evaluate the safety of talazoparib and enzalutamide administered in combination.

To evaluate the PK of talazoparib and enzalutamide (and its N-desmethyl metabolite) 
when dosed in combination.

To evaluate the following patient-reported outcomes in each treatment arm in patients 
with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR 
deficiencies:

Pain symptoms;

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
Cancer-specific global health status/Quality of life (QoL), functioning, and 
symptoms;

General health status. 
Exploratory Objectives

To explore BICR assessed rPFS in patients with mCRPC without DDR deficiencies.

To explore correlation of changes in circulating tumor cells (CTCs) with efficacy 
outcome parameters.

To identify potential biomarkers associated with response and/or resistance to 
talazoparib in combination with enzalutamide.

To explore correlations between talazoparib exposure and biomarker, efficacy and 
safety endpoints if data allow.

To collect banked biospecimens for exploratory research, unless prohibited by local 
regulations or ethics committee decision.

To explore concordance of DDR deficiency results between the blood and tumor 
tissue based tests.
Endpoints
Part 1
Primary Endpoint

Occurrence of target safety events.
Secondary Endpoint

Multiple-dose PK parameters of talazoparib and enzalutamide and its N-desmethyl 
metabolite: Multiple-dose maximum plasma concentration (Cmax), lowest plasma 
concentration of drug directly before next dose (Ctrough), time to reach peak 
concentration following drug administration (Tmax), area under the plasma 
concentration-time curve over the dosing interval (from time zero to 24 hours 
post-dose) (AUC), and apparent oral clearance (CL/F) as data permit. 

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Exploratory Endpoints

Proportion of patients with conversion from 5 or more CTCs per 7.5 mL at baseline 
to 4 or fewer CTCs per 7.5 mL post-baseline.

Proportion of patients with conversion from detectable CTCs per 7.5 mL at baseline 
to CTCs = 0 per 7.5 mL post-baseline.

Proportion of patients with baseline CTCs <5 who show increased CTCs 
post-baseline.

Molecular profiling of tumor tissue remaining after genomic testing for eligibility and 
of saliva and circulating tumor deoxyribonucleic acid (ctDNA); circulating protein 
biomarker profiles.

Potential results from exploratory analyses of banked biospecimens. 
Part 2 
Primary Endpoints

BICR assessed rPFS per Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 (soft tissue disease) and Prostate Cancer Working Group (PCWG3) (bone disease) 
in patients with mCRPC unselected for DDR status.

BICR assessed rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) 
in patients with mCRPC harboring DDR deficiencies.
Key Secondary Endpoints (alpha-protected)

OS inpatients with mCRPC unselected for DDR status (alpha-protected).

OS in patients with mCRPC harboring DDR deficiencies (alpha-protected).
Other Secondary Endpoints

Proportion of patients with measurable soft tissue disease at baseline with an 
objective response per RECIST 1.1 (assessed by the BICR) in patients with mCRPC 
unselected for DDR status and in patients with mCRPC harboring DDR deficiencies. 

Duration of soft tissue response per RECIST 1.1 (assessed by the BICR) in patients 
with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR 
deficiencies.

Proportion of patients with PSA response 50% in patients with mCRPC unselected 
for DDR status and in patients with mCRPC harboring DDR deficiencies. 

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
Time to PSA progression in patients with mCRPC unselected for DDR status and in 
patients with mCRPC harboring DDR deficiencies.

Time to initiation of cytotoxic chemotherapy in patients with mCRPC unselected for 
DDR status and in patients with mCRPC harboring DDR deficiencies.

Time to initiation of antineoplastic therapy in patients with mCRPC unselected for 
DDR status and in patients with mCRPC harboring DDR deficiencies.

Time to first symptomatic skeletal event in patients with mCRPC unselected for DDR 
status and in patients with mCRPC harboring DDR deficiencies.

PFS2 based on investigator assessment in patients with mCRPC unselected for DDR 
status and in patients with mCRPC harboring DDR deficiencies.

Time to opiate use for prostate cancer pain in patients with mCRPC unselected for 
DDR status and in patients with mCRPC harboring DDR deficiencies. 

Incidence of adverse events characterized by type, severity (graded by National 
Cancer Institute [NCI] Common Toxicity Criteria for Adverse Events [CTCAE] 
version 4.03), timing, seriousness and relationship to study treatment.

PK characterized by pre-dose trough and post-dose plasma concentrations of 
talazoparib and enzalutamide and its N-desmethyl metabolite.

Patient Reported Outcomes (PROs) in patients with mCRPC unselected for DDR 
status and in patients with mCRPC harboring DDR deficiencies:

Change from baseline in patient-reported pain symptoms per brief pain 
inventory-short form (BPI-SF);

Change from baseline in patient-reported general health status per European 
Quality of Life 5-dimension, 5-level scale (EQ-5D-5L);

Change from baseline in patient-reported cancer-specific global health 
status/QoL, functioning, and symptoms per European Organisation for Research 
and Treatment of Cancer (EORTC) QLQ-C30;

Time to deterioration in patient-reported pain symptoms per BPI-SF;

Time to definitive deterioration in patient-reported global health status/QoL per 
European Organisation for Research and Treatment of Cancer cancer-specific 
global health questionnaire (EORTC QLQ-C30); 

Time to definitive deterioration in patient-reported disease-specific urinary 
symptoms per European Organisation for Research and Treatment of Cancer 
disease specific urinary symptoms questionnaire (EORTC QLQ-PR25). 

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Exploratory Endpoints

BICR assessed rPFS per RECIST 1.1 (soft-tissue disease) and PCWG3 (bone disease) 
in patients with mCRPC without DDR deficiencies.

Proportion of patients with conversion from 5 or more CTCs per 7.5 mL at baseline 
to 4 or fewer CTCs per 7.5 mL post-baseline, in patients with mCRPC unselected for 
DDR status and in patients with mCRPC harboring DDR deficiencies.

Proportion of patients with conversion from detectable CTCs per 7.5 ml at baseline to 
CTCs = 0 per 7.5 ml post-baseline, in patients with mCRPC unselected for DDR 
status and in patients with mCRPC harboring DDR deficiencies.

Proportion of patients with baseline CTC counts <5 who show increased CTC counts 
post-baseline, in patients with mCRPC unselected for DDR status and in patients with 
mCRPC harboring DDR deficiencies.

Molecular profiling of tumor tissue remaining after genomic testing for eligibility 
during prescreening/screening, of saliva, and ctDNA; circulating protein biomarker 
profiles.

Concordance of DDR deficiency results between the blood and tumor tissue based 
tests.
Study Design
This is an international, Phase 3, two-part study enrolling patients with mCRPC where no 
systemic cancer treatments have been initiated after documentation of CRPC with the 
exception of androgen deprivation therapy and first generation anti-androgens. 
Part 1 was open-label and non-randomized and evaluated the safety, tolerability, and PK of 
talazoparib in combination with enzalutamide.  Part 2 is randomized, double-blind, and
placebo-controlled and will evaluate the safety and efficacy of talazoparib in combination 
with enzalutamide compared with placebo in combination with enzalutamide. Part 2 will 
enroll two patient cohorts.  The first cohort (Cohort 1) will enroll approximately 750 mCRPC 
patients unselected for DDR status (all-comers population).  Although patients will be 
unselected for DDR status, DDR deficiency assessment prior to randomization is required for 
stratification.
After enrollment in Cohort 1 is completed, enrollment will continue but will be restricted to 
patients with DDR deficiencies (Cohort 2).  Cohort 2 will enroll approximately 
268 additional patients harboring DDR gene mutations likely to sensitize to PARP inhibition 
(DDR-deficient).  Patients who are DDR-deficient from Cohorts 1 and 2 will be combined 
such that a total of approximately 380 DDR-deficient patients are enrolled to assess efficacy 
separately within this population.

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Approximately 1037 men (19 in Part 1 and approximately 1018 in Part 2) with mCRPC will 
be enrolled.  Genomic screening to identify alterations in DDR genes is optional for patients 
in Part 1, but is required for randomization in Part 2. Mutational status for patients 
randomized in Part 2 will be determined by testing for the presence of mutations in defined 
DDR genes likely to sensitize to PARP inhibition using next generation sequencing (NGS) 
based gene panel test.
A patient will participate in up to 5 periods: prescreening (optional), screening, open-label 
(Part 1) or double-blind (Part 2), safety follow-up, and long-term follow-up.  Testing for 
DDR gene mutational status will be performed at prescreening or screening.
The primary objective of Part 1 was to determine the starting dose of talazoparib in 
combination with enzalutamide to be used in Part 2.  The first patients enrolled into Part 1 
initially received a starting dose of talazoparib 1 mg once a day in combination with 
enzalutamide 160 mg once a day, since talazoparib has demonstrated efficacy as a single 
agent at a dose of 1 mg once a day in patients with germline BRCA mutation, human 
epidermal growth factor receptor 2 (HER2) negative and locally advanced and/or metastatic 
breast cancer. 
Evaluation of available preliminary safety data from patients enrolled with a starting dose of 
talazoparib of 1 mg once daily in combination with 160 mg once daily enzalutamide showed 
higher than expected dose reductions and interruptions mainly due to Grade 3 hematological 
toxicities.  Evaluation of available preliminary talazoparib PK data indicated that 
enzalutamide increased talazoparib Ctrough at Week 5 Visit by ~2-fold compared to 
talazoparib steady-state Ctrough in patients with advanced solid tumors and in patients with 
breast cancer receiving 1 mg once a day monotherapy.  Based on these preliminary safety 
and PK data, talazoparib dose was reduced from 1 mg once a day to 0.5 mg once a day for all 
patients continuing to receive talazoparib in combination with enzalutamide in Part 1.  
Additional patients were enrolled in Part 1 and received a talazoparib starting dose of 0.5 mg 
once a day in combination with 160 mg once a day enzalutamide.
Safety and PK data from patients who received talazoparib at the 0.5 mg once a day 
talazoparib dose level either as a starting dose or for patients who started on 1 mg once a day 
and later reduced to 0.5 mg showed an acceptable safety profile and comparable Ctrough to 
that achieved in patients with advanced solid tumors and in patients with breast cancer 
receiving 1 mg once a day.  This indicates that reducing the talazoparib dose to 0.5 mg once a 
day in combination with enzalutamide is expected to account for the observed drug-drug 
interaction (DDI) and maintain similar talazoparib exposure and safety profile to that 
achieved with 1 mg once a day monotherapy.  Therefore, a talazoparib dose of 0.5 mg once a 
day will be administered in combination with enzalutamide 160 mg once a day in Part 2 of 
this study.  The starting dose of talazoparib for patients with moderate renal impairment will 
be 0.35 mg once a day to account for the lower talazoparib clearance in this subpopulation.

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In Part 2, patients will be randomized to receive either talazoparib or placebo in combination 
with open-label enzalutamide.  For all patients, study treatment (including enzalutamide) 
should continue until radiographic progression is determined by blinded independent central 
review (BICR) (Part 2) or local review (Part 1), unless in the opinion of the investigator the 
patient is still deriving benefit at this time, or following radiographic progression the patient 
is then no longer clinically benefitting in the opinion of the investigator, or an adverse event 
leading to permanent discontinuation, or patient decision to discontinue treatment, or death.  
During Part 2, study treatment(s) should not be discontinued based solely on increases in 
PSA levels in the absence of documented radiographic disease progression.
Safety follow-up visit will occur approximately 28 days after the last dose of study treatment 
(either the combination or enzalutamide or talazoparib or talazoparib/placebo whichever is 
later) or before initiation of a new antineoplastic or investigational therapy, whichever occurs 
first. 
Long-term follow-up will begin after safety follow-up and will follow the radiographic 
imaging schedule (ie, every 8 weeks through Week 25 and then every 12 weeks thereafter 
until death, withdrawal of consent for follow-up, or study termination by the Sponsor).  In 
Part 2, patients for whom study treatment was permanently discontinued without 
radiographic progression will continue with per-protocol imaging in long-term follow-up 
until such radiographic progression is documented regardless of initiation of a new 
antineoplastic therapy.
Study Treatments
During Part 1, patients will receive talazoparib in combination with enzalutamide.  During 
Part 2, patients will be randomized to one of two treatment groups: talazoparib in 
combination with enzalutamide, or matching placebo in combination with enzalutamide.
 
 
 
 
 
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Enrollment will begin in the all-comers population, Cohort 1.  Once enrollment is complete 
in Cohort 1, enrollment will continue but will be restricted to patients with DDR deficiencies 
(Cohort 2). 
Analysis on all-comers population will include patients randomized into the DDR unselected 
cohort (Cohort 1).  Analysis of the DDR-deficient population data will include patients with 
DDR deficiencies from both Cohorts 1 and 2.
The intent-to-treat (ITT) population will be defined as all patients randomly assigned to 
double-blind study treatment.  All safety analyses will use the safety population, defined as 
all patients who receive at least one dose of study treatment.
The PRO population will be defined as a subset of ITT patients in Part 2 who have completed 
a baseline and at least one post-baseline quality-of-life assessment prior to the end of study.
The primary endpoint of rPFS in Part 2 (evaluated separately in the all-comers population 
and the DDR-deficient population which are subsets of the ITT population) is defined as the 
time from the date of randomization to first objective evidence of radiographic progression as 
assessed in soft tissue per RECIST 1.1 or in bone (upon subsequent confirmation) per 
PCWG359 guidelines by BICR, or death, whichever occurs first.  
 
 
 
 
 
 
 
 
 
 
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Objective response rate will be evaluated in the subset of patients with measurable soft tissue 
disease at baseline.  Confirmation of soft tissue response will be required. 
 
 
The time from the first objective evidence of a complete response (CR) or partial response 
(PR) to the first objective evidence of disease progression or death (whichever occurs first) 
will be analyzed in the subset of ITT patients entering with measurable soft tissue disease 
and a reported CR or PR on study.
The proportion of patients with a ≥50% decline from baseline in PSA that is confirmed by a 
second consecutive value at least 21 days later will be calculated for each treatment arm 
PFS2 is defined as time from randomization to investigatordocumented disease progression 
(PSA progression, progression on imaging, or clinical progression) on the first subsequent 
antineoplastic therapy for prostate cancer, or death from any cause, whichever occurs first. 
Time to deterioration of pain (≥2-point increase from baseline question 3 of the BPI-SF) will 
be measured.  Pain and analgesic assessments will be completed (via pain and analgesic logs, 
respectively) for 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.
Time to definitive deterioration of patient-reported global health status/QoL and time to 
deterioration of patient-reported urinary symptoms will be summarized 
 
  Definitive deterioration of 
patient-reported global health status/QoL is defined as ≥10-point decrease from baseline and 
no subsequent observations of a <10-point decrease from baseline.  Definitive deterioration 
of patient-reported urinary symptoms is defined as ≥10-point increase from baseline and not 
subsequent observations of a <10-point increase from baseline.
 
 
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Safety will be evaluated for the safety population using adverse event, laboratory and vital 
sign data.  All adverse events (AEs) will be coded to preferred term and system organ class 
using current Medical Dictionary for Regulatory Activities (MedDRA).  Treatment-emergent 
AEs will be presented with and without regard to causality based on the investigator’s 
judgment and by frequency of overall toxicity categorized by NCI CTCAE (version 4.03) 
grades.  Laboratory shift tables of baseline to maximum post-baseline results to each 
subsequent visit will be produced as appropriate.
For patients who participate in Part 1, the final PK data analyses will include calculation of 
steady state PK parameters (as specified in secondary endpoints for Part 1) of talazoparib, 
enzalutamide, and its N-desmethyl metabolite.  For all patients (Part 1 and Part 2), PK data 
analyses will include descriptive summary statistics of the pre-dose trough concentration 
(Cmin) and post-dose plasma concentrations of talazoparib, enzalutamide and its N-desmethyl 
metabolite by study visit and time point.  In addition, the PK data from this study may be 
used to develop a population PK model.  The correlation between exposure parameters and 
biomarker, efficacy and safety endpoints may be explored if data allows.  The results of these 
modeling analyses may be reported separately from the clinical study report. 

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SCHEDULE OF ACTIVITIES
The schedule of activities tables (Table 1, Table 2, and Table 3) provide an overview of the protocol visits (including prescreening 
[optional], screening, and long term follow-up) and procedures.  Refer to the STUDY PROCEDURES and ASSESSMENTS sections 
(Section 6 and Section 7 respectively) of the protocol for detailed information on each procedure and assessment required for 
compliance with the protocol. 
The investigator may schedule unplanned visits, assessments or tests to conduct evaluations or assessments required to protect the 
well-being of the patient.
Table 1.
Study Schedule of Activities: Prescreening (Optional) and Screening 
Prescreen Visit is optional.
The purpose of this visit is to allow for blood/plasma testing (circulating tumor DNA or ctDNA), tumor biopsy testing (de novo, archival) or obtaining 
Sponsor pre-approval for historical FoundationOnetest results for eligibility prior to other screening activities.
General Activities
Comments
Prescreening informed consent, SSID 
number
Prescreen
(optional) 
Prescreening activities may be performed after molecular prescreening consent is signed 
(before consent is signed for the screening period) for the sole purpose of submitting blood 
samples (liquid biopsy), and de novo or archival tumor tissue, or obtaining Sponsor 
pre-approval for use of prior FoundationOne® test result for eligibility. 
Blood, de novo or archival tumor 
tissue for genomic testing or 
historical FoundationOneresults 
with Sponsor pre-approval
X
Required for patients enrolling in Part 2 (optional for patients enrolling in Part 1):

Submit 20 mL of blood for DDR assessment.  Blood sample for prospective DDR 
assessment is not required in China.
AND

Tissue of tumor biopsy (de novo biopsy or archival tissue) for DDR assessment. 
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. 
OR

Historical FoundationOnetest results may be used for eligibility (after Sponsor 
pre-approval).

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Table 1.
Study Schedule of Activities: Prescreening (Optional) and Screening 
Prescreen Visit is optional.
The purpose of this visit is to allow for blood/plasma testing (circulating tumor DNA or ctDNA), tumor biopsy testing (de novo, archival) or obtaining 
Sponsor pre-approval for historical FoundationOnetest results for eligibility prior to other screening activities.
General Activities
Comments
Both blood and tumor tissue biopsy must be provided prior to randomization (it is not 
necessary to submit both at the prescreening visit).  Results from either blood or tissue biopsy 
(or historical result for tissue biopsy) will be needed for eligibility and randomization 
(stratification).  If results from liquid and tumor tissue sample are available prior to 
randomization and results are not concordant for the presence of the selected DDR 
mutation(s), positive DDR results will be used for eligibility and stratification regardless of 
the tissue used to generate the data.  If either the blood or tissue sample is not provided during 
prescreening, the missing sample will have to be submitted prior to randomization (at 
screening) for retrospective concordance studies.  In cases where historical FoundationOne
test results are approved by the Sponsor, tumor tissue is not required for the study, but may be 
requested by the Sponsor if available.  
Demography
X
Adverse Event review
X
For prescreening only: Record adverse events (AEs) and research-related injuries in the CRF 
from the time the blood sample was collected or de novo biopsy procedure was performed 
through and including 14 days.  See Section 8.1.5.
Screening Visit
General Activities
-28 to -1 
days
Comments
Screening activities may be repeated any time as clinically indicated.
Informed consent, 
SSID number, contact 
cards.
Screening
X
Obtain any time before any study-specific procedures.  Ensure consent is on the current version of the form 
approved by the ethics committee and Sponsor. Consent can be obtained up to 42 days prior to randomization. All 
other screening tests and assessments (excluding CT/MRI and bone scans) must be done within 28 days prior to 
randomization. For information about the contact card please see section 4.5.
Blood, de novo or 
archival tumor tissue 
for genomic testing or 
historical 
FoundationOne®
results with Sponsor 
pre-approval
X
ONLY IF NOT DONE DURING A PRE-SCREEN VISIT submit blood and tumor tissue samples.  
Blood sample for prospective DDR assessment is not required in China.
If either the blood or tumor tissue sample was not provided during prescreening, the missing sample will have to be 
submitted for retrospective concordance studies. In cases where historical FoundationOnetest results are approved 
by the Sponsor, tumor tissue is not required for the study, but may be requested by the Sponsor if available.

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Screening Visit
Demographics
X
Medical History
X
Includes histology, TNM classification and Gleason score assessment, and all other medical history. 
Prior treatment for 
prostate cancer
X
Eligibility criteria
X
Enrollment 
/Randomization 
authorization form 
X
Complete, sign, and fax or email the form with requested items to the sponsor or designee at least 2 business days 
before Day 1 for Part 1 or randomization for Part 2. 
12-Lead 
electrocardiogram
X
Local (Note, ECG monitoring during the study for signs or symptoms of ischemic heart disease is to be per general 
clinical practice and local guidelines).
Vital signs, weight, 
height
X
Measure blood pressure, heart rate, temperature, weight, and height.  
ECOG performance 
status
X
Complete physical 
examination
X
Assess systems (eg, general appearance, head, eyes, ears, nose, mouth, skin, heart, lung, lymph nodes, 
gastrointestinal, genitourinary, neurologic, and skeletal).  
Adverse events review
X
Report serious and non-serious adverse event information from time informed consent form is signed through screen 
failure or through a minimum of 28 days after the last dose of study treatment (talazoparib or talazoparib/placebo or 
enzalutamide, whichever is taken last).  See Section 8.1.4 for additional details.
Prior and concomitant 
medications and 
treatments
X
Contraception 
X
The investigator is to assess if the patient is capable of ejaculating.  If capable, instruct the patient to always use a 
condom to avoid partner/fetal exposure and instruct the patient not to donate sperm for 4 months after last dose of 
talazoparib.  For these patients the investigator is to confirm correct contraception use or note changes in 
contraception use in the patient medical record as per Table 2.  See Section 4.4.1. for contraception.
Brief Pain Inventory –
Short Form 
X
Administer question #3 of the questionnaire.  Score on question 3 must be <4 to qualify for entry.  (Referred to as 
“Modified Brief Pain Inventory – Full Form” in the CRF).
Laboratory 
Evaluations
Hematology, serum 
chemistry, reticulocyte 
count, erythropoietin, 
serum folate and B12
X
Local laboratory test results will be used. 
Testosterone, PSA
X
Local laboratory test results will be used.

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Screening Visit
Prostate specific antigen (PSA) progression defined by rising PSA of at least 2 consecutive rises in most recent PSA 
to be documented over a reference value (measure 1) taken at least 7 days apart within the last 12 months.  If the 
third PSA measure is not greater than the second measure, a fourth PSA measure is required to be taken and be 
greater than the second measure. The third (or the fourth) confirmatory PSA should be taken within 4 weeks prior 
to randomization.  The PSA value obtained before randomization (third or fourth measurement) must be ≥1 µg/L.  
HIV (ELISA) in South 
Africa only
X
Optional HIV testing using the ELISA test may be conducted for subjects of unknown HIV status per investigator 
discretion.  Subjects will be asked to sign an HIV consent form and be given pre and post test counseling at the site.  
Part 2 only: Blood 
sample for CTC 
analysis
X
Collect 1 tube of 10 mL of blood.  Please make sure no less than 10 ml are collected.  These samples are sent to the 
central laboratory immediately upon collection at room temperature; see Section 7.5 and Central Laboratory 
Manual.
Part 2 only: Blood 
sample for ctDNA
X
Collect 20 mL of blood optimized for plasma preparation at indicated visits.  These samples are sent to the central 
laboratory and results obtained will be used for exploratory analyses as defined in Section 7.5 and Central 
Laboratory Manual. 
Study Day
-42 to -1
Comments
Radiographic 
Assessments
May use scans obtained as part of standard of care before consent was signed and within 42 days before Day 1 
(randomization for Part 2) if scans were performed per the specific study requirements (per imaging manual).  
CT scan of chest; CT 
or MRI of abdomen 
and pelvis 
X
Computed tomography scan, magnetic resonance imaging.  
Whole-body bone scan 
X
CRF = case report form; CT = computed tomography; CTCs = circulating tumor cells; ctDNA = circulating tumor deoxyribonucleic acid; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; MRI = magnetic resonance imaging; PSA = prostate-specific antigen; 
SSID = single subject identification; TNM = Classification of Malignant Tumours.

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Table 2.
Study Schedule of Activities: Treatment Period
Study Period or Visit
Treatment
Unscha
Safety 
FUb
Study Week
1
3
5
7
9
11
13
15
17
21
25
29, 33, 37, 41, 
45, 49, 53c
37, 49, 61, 73,
85, 97, 109y +
Varies
Varies
Window (Days)d
na
3 (7 for scans)
na
3
Part 1 (Open-label treatment: 
Enrollment, number
Part 2 (Double-blind treatment): 
Randomization,e and randomization 
numbers
X
General Activities
Vital signs, height and weightf
X
X
X
X
X
X
X
X
X
X
Physical examinationg
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
BPI-SFh
X
X
X
X
X
X
X 
X
X
EORTC QLQ-C30h
X
X
X
X
X
X
X 
X
X
EORTC QLQ-PR25h
X
X
X
X
X
X
X 
X
X
EQ-5D-5Lh
X
X
X
X
X
X
X 
X
X
Pain Logi
X
X
X
X
X
X 
X
X
Analgesic Logj
X
X
X
X
X
X 
X
X
Symptomatic skeletal event 
evaluationz
X
X
X
X
X
X
X
X
X
X
Adverse events reviewk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
Contraception Usex
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study treatment dispensingl
Xm
X
X
X
X
X
X
X
X
Study treatment accountability
X
X
X
X
X
X
X
X
Lab Evaluations
Hematology, reticulocyte count, 
erythropoietin, serum folate, B12 
and serum chemistryn
X
X
X
X
X
X
X
X
X
X
X 
X
X
X
Prostate-specific antigeno
X
X
X
X 
X (q8weeks)
X
X
Blood sample for PKp
X (Part 1 
only)
X
X
X 
X
X
X
Blood samples for CTC analysisq
X
X
X
X
X
Blood samples for ctDNAr
X
X
X
X
X

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Table 2.
Study Schedule of Activities: Treatment Period
Study Period or Visit
Treatment
Unscha
Safety 
FUb
Study Week
1
3
5
7
9
11
13
15
17
21
25
29, 33, 37, 41, 
45, 49, 53c
37, 49, 61, 73,
85, 97, 109y +
Varies
Varies
Window (Days)d
na
3 (7 for scans)
na
3
Blood samples for protein 
biomarkerss
X
X
X
X
X
Blood sample for banked 
biospeciment
X
Blood sample to be stored for reflex 
testing for HBV and HCVu
X
Saliva sample for germline 
comparatorv
X
Radiographic Assessmentsw
CT scan of chest
X
X
X
X
Xa
CT or MRI of abdomen and pelvis
X
X
X
X
Xa
Bone scan 
X
X
X
X
Xa
Anti-HBc = hepatitis B core antibody; BICR = blinded independent central review; BPI-SF = Brief Pain Inventory Short Form; CRF = case report form; CT = computed 
tomography; CTCs = circulating tumor cell; ctDNA = circulating tumor DNA; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EORTC = European Organisation for Research and Treatment of Cancer; EQ-5D-5L = European Quality of Life 5-Domain 5-Level Scale; FFPE = formalin-fixed 
paraffin-embedded; FU = follow-up; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; lab = laboratory; MRI = magnetic resonance 
imaging; na = not applicable; PCWG = Prostate Cancer Working Group; PK = pharmacokinetics; PSA = prostate specific antigen; QLQ-C30 = Quality of Life Cancer 
Questionnaire; QLQ-PR25 = Quality of Life Questionnaire-Prostate 25; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; unsch = unscheduled.
a.
Unscheduled assessments/visits may be done anytime necessary to assess or follow up adverse events (eg, labs or ECG), at the patient’s request, or per investigator decision 
or due to missed assessments or sample not analyzed due to technical issues.  Perform imaging if disease progression is suspected.  
b.
28 days after permanent treatment discontinuation of all study treatments (talazoparib, talazoparib/placebo or enzalutamide) or before initiation of a new antineoplastic or 
investigational therapy, whichever occurs first.  Final CTC, ctDNA and protein biomarker samples are to be collected.  Phone patients for adverse event follow-up if they do 
not come to the clinic. 
c.
Visits are to be every 2 weeks through Week 17, every 4 weeks through Week 53 and following Week 53, visits repeat every 8 weeks while on study treatment – and are to 
continue every 8 weeks until study treatment is discontinued.  Radiographic imaging is every 8 weeks through Week 25 of the study, then every 12 weeks thereafter – and are 
to continue every 12 weeks until study treatment is discontinued for radiographic progression.  During this time visits must be within 60 days to allow for accurate drug 
dispensing (sites will dispense 2 bottles per visit).  
d.
Dispensing of study treatment should be taken into account when scheduling visits: visits up to Week 53 should occur within 30 days for drug dispensing (sites will dispense a 
30 day drug supply). 
e.
Patients should start treatment within 3 days after randomization.  Day 1 is the first day of dosing for Part 1 and the day of randomization for Part 2. 
f.
Measure blood pressure, heart rate, temperature, height and weight (Height is only applicable to patients in Part 2 and only required to be collected at Screening).

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Table 2.
Study Schedule of Activities: Treatment Period
Study Period or Visit
Treatment
Unscha
Safety 
FUb
Study Week
1
3
5
7
9
11
13
15
17
21
25
29, 33, 37, 41, 
45, 49, 53c
37, 49, 61, 73,
85, 97, 109y +
Varies
Varies
Window (Days)d
na
3 (7 for scans)
na
3
g.
Assess systems (eg, general appearance, head, eyes, ears, nose, mouth, throat, skin, heart, lung, lymph nodes, gastrointestinal, genitourinary, neurologic, and skeletal) per 
standard of care at the study site or as clinically indicated by symptoms. 
h.
Part 2: Patients are to complete questionnaires before the first dose of study treatment on Day 1.  At all subsequent visits, the patient is to complete the questionnaires before 
any other study activities.  Questionnaires should be completed while alone in the same order at each visit.  Perform post-baseline assessments every 4 weeks through 
Week 53, or radiographic progression, whichever is earlier; every 8 weeks after Week 53 until radiographic progression when no such progression had been previously 
documented; every 12 weeks after radiographic progression until end of study.  In Part 1 the BPI-SF is completed per paper version.
i.
Pain log is to be completed by patients in Part 2 for each of 7 consecutive days preceding scheduled site visits.
j.
Analgesic log is to be completed by patients in Part 2 for each of 7 consecutive days preceding scheduled site visits.
k.
Collect serious and non-serious adverse event information from the time of signed informed consent through a minimum of 28 days after the last dose of study treatment.  
Refer to Section 8.1.4 regarding the reporting timeframe for SAEs.  Any diagnosis of myelodysplastic syndrome or acute myeloid leukemia must be reported as an SAE. 
l.
Administer talazoparib in the clinic on study days with PK assessments. 
m.
Instruct patient to self-administer study treatments. 
n.
Hematology, reticulocyte count, erythropoietin, serum folate, B12 and serum chemistry are to be evaluated locally per the visit schedule (every 2 weeks through Week 17, 
then every 4 weeks trough Week 53, and then every 8 weeks thereafter).  Investigators may collect samples for laboratory assessment up to 3 days prior to a scheduled visit to 
guide decision making.  Samples for PK, CTC, ctDNA, protein biomarkers, and a sample for reflex HBV and HCV testing are to be evaluated via the central laboratory.  
Refer to the central laboratory instruction manual for sample processing. 
o.
Collect samples for analysis of PSA every 8 weeks until determination of radiographic progression (local for Part 1 or by BICR for Part 2).  An additional PSA is to be 
collected at Week 53 visit, then to continue every 8 weeks thereafter, thus aligning the PSA and site visits to be every 8 weeks.  
p.
Treatment Part 1: Collect blood samples for PK pre-dose, 1, 2, 4, 6 and 24 hours post-dose at Day 1 (Week 1) and Week 9.  Collect blood samples for PK pre-dose and 
2 hours post-dose at Week 5 and pre-dose at Week 13.
Treatment Part 2: Collect blood samples for PK pre-dose and 2 hours post-dose at Weeks 3, 5 and 9, and pre-dose at Weeks 13 and 17.  All patients: Additional PK should be 
taken based on discretion of investigators, eg, adverse events.  Record the dose amounts and time of dose administration on both the day of and the day before PK sampling.  
Record the date and time of each PK sample.  Scheduled PK samples for enzalutamide should be collected if talazoparib or talazoparib/placebo is discontinued.  Similarly, 
scheduled PK samples for talazoparib or talazoparib/placebo should be collected if enzalutamide is discontinued.
q.
For CTC analysis, collect 1 tube of 10 mL of blood at Day 1 prior to dosing and 1 tube of 10 mL at all other visits per schedule.  Please make sure no less than 10 ml are 
collected.  These samples are sent to the central laboratory immediately upon collection at room temperature.  Subjects who prove non-evaluable for CTC enumeration at 
baseline (both screening and Day 1 sample must be non-evaluable) may forego collection of additional CTC samples.  See Section 7.5 and Central Laboratory Manual.  For 
subjects enrolled in China: instructions for CTC samples are in Section 7.5.1.
r.
For ctDNA collect 20 mL of blood optimized for plasma preparation at indicated visits.  See Section 7.5 and Central Laboratory Manual.  For subjects enrolled in China: 
instructions for the ctDNA sample are in Section 7.5.1.

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Table 2.
Study Schedule of Activities: Treatment Period
Study Period or Visit
Treatment
Unscha
Safety 
FUb
Study Week
1
3
5
7
9
11
13
15
17
21
25
29, 33, 37, 41, 
45, 49, 53c
37, 49, 61, 73,
85, 97, 109y +
Varies
Varies
Window (Days)d
na
3 (7 for scans)
na
3
s.
For protein biomarkers collect 10 mL of whole blood for processing into serum at indicated visits.  See Section 7.5 and Central Laboratory Manual.  For subjects enrolled in 
China: instructions for the protein biomarker sample are in Section 7.5.1.  Protein biomarkers sample will not be collected and analyzed in China.
t.
Unless prohibited by local regulations or ethics committee decision, collect a blood sample (4 mL) optimized for DNA analysis before the first dose of study treatment.  
Retain for potential pharmacogenomic/biomarker analyses.  Refer to Section 7.6 and Central Laboratory Manual.  See Section 7.5 and Central Laboratory Manual.  If not 
collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a patient visit.  Blood sample for 
banked biospecimens will not be collected and analyzed in China.
u.
Collect sample to be stored centrally for reflex testing for HBV (HBsAg, anti-HBc) and HCV (HCV Ab, reflex testing for HCV RNA if positive).  Tests on this sample will 
be done if liver toxicities occur during treatment period.
v.
Optional for Part 1; collect only if tumor tissue provided for the same patient. 
Required for Part 2, unless prohibited by local regulations or ethics committee decision, collect a saliva sample optimized for DNA analysis before the first dose of study 
treatment.  Refer to Section 7.5 and Central Laboratory Manual.  For subjects enrolled in China: instructions for saliva sample are in Section 7.5.1.  Depending on assay 
availability, blood may be substituted for saliva in China.
w.
CT and MRI to be done for assessment of soft tissue disease only. Bone lesions will be evaluated only on bone scans. Radiographic imaging should be performed every 
8 weeks through Week 25 and then every 12 weeks until radiographic progression is determined by investigator (Part 1) or by investigator and BICR (Part 2) regardless of 
initiation of subsequent antineoplastic therapy.  RECIST 1.1 and PCWG3 assessments are to be completed when radiographic imaging tests are done and documented on the 
CRF.  If radiographic progression is documented per BICR and investigator for Part 2 and investigator for Part 1 and the patient continues on study treatment as the patient is 
clinically benefitting per investigator, all radiographic imaging is to be continued per standard of care at the institution.
x.
For patients capable of ejaculation, the investigator is to instruct the patient to always use a condom to avoid partner/fetal exposure and instruct the patient not to donate sperm 
for 4 months after last dose of talazoparib.  Refer also to Section 4.4.1 for contraception language.  Document in the patient medical records if the patient was informed on 
how to prevent partner/fetal exposure, not to donate sperm for 4 months after discontinuation of talazoparib, and if contraception instructions were provided.  
y.
For patients remaining on study treatment beyond radiographic progression per BICR and investigator for Part 2 and investigator for Part 1 (because in the opinion of the 
investigator the patient is still deriving benefit at this time), subsequent radiographic imaging should continue per standard of care at the institution.  
z.
Symptomatic skeletal event evaluation includes symptomatic fractures, surgery or radiotherapy to the bone and spinal cord compression.  Non-symptomatic fractures will be 
also recorded in the CRF.58

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Table 3.
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 and may be conducted by telephone unless 
imaging is required. 
Follow-up frequency is per the radiographic imaging schedule based on Day 1 and is every 
8 weeks through week 25 of the study, then every 12 weeks thereafter until the patient dies or 
withdraws consent for follow-up, or the study is terminated by the Sponsor.  
Window (Days)
7
General Activities
Radiographic imaging (Part 1 and 2) 
and PSA assessment (Part 2 only)
X
Continue radiographic imaging and PSA assessment (per imaging schedule) for patients who 
permanently discontinue study treatment for any reason other than radiographic progression 
determined by investigator for Part 1 or investigator and BICR for Part 2 regardless of the 
initiation of a new antineoplastic therapy, until radiographic progression is determined by 
investigator for Part 1 or investigator and BICR for Part 2, withdrawal of consent for 
follow-up, or death.  RECIST 1.1 and PCWG3 assessments are to be done when radiographic 
assessment required and documented in the CRF.  For patients on new anticancer therapy, 
scans should continue according to the schedule of assessments, or, if this is not possible, as 
per local SOC.
New antineoplastic therapy(ies)
X
Record all subsequent treatments  for patients starting a new antineoplastic or investigational 
therapy.  
Diagnosis of myelodysplastic syndrome 
or acute myeloid leukemia 
X
Record any diagnosis of myelodysplastic syndrome or acute myeloid leukemia and report as 
an SAE.  Provide tissue samples and other supporting data used to enable the diagnosis of 
myelodysplastic syndrome or acute myeloid leukemia for central review if requested and 
possible.  
Survival status
X
Obtain survival status by any means including telephone, clinic visit, chart review, or by 
communicating with an individual (eg, family, friend, or referring health care provider) who is 
knowledgeable of the patient’s survival status.  
Part 2: BPI-SF, EORTC QLQ-C30 and 
QLQ-PR25, EQ-5D-5L, Pain Log, and 
Analgesic Log via electronic patient 
reported outcome device 
X
Ask the patient to complete the questionnaires before any other study activities.  
Questionnaires should be completed independently and in the same order at each visit.  Pain
and analgesic assessments (via pain and analgesic logs, respectively) will be completed for 
7 consecutive days before a study visit until study results are determined.  During Long Term 
Follow up when the visits may be conducted by telephone (if imaging is not being performed 
due to radiographic progression being met) these assessments should also be completed 
remotely from home as per the long term visit schedule.  
Symptomatic skeletal event assessment
X
Every effort should be taken to follow patients who have not had a symptomatic skeletal event 
for the onset of such an event.

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Table 3.
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 and may be conducted by telephone unless 
imaging is required. 
Follow-up frequency is per the radiographic imaging schedule based on Day 1 and is every 
8 weeks through week 25 of the study, then every 12 weeks thereafter until the patient dies or 
withdraws consent for follow-up, or the study is terminated by the Sponsor.  
Window (Days)
7
BICR = blinded independent central review; BPI-SF = Brief Pain Inventory Short Form; CRF = case report form; EORTC = European Organisation for Research and 
Treatment of Cancer; EQ-5D-5L = European Quality of Life 5-Domain 5-Level Scale; Part 1 = open-label treatment; Part 2 = double-blind treatment; PCWG3 = Prostate 
Cancer Working Group; QLQ-C30 = Quality of Life Cancer Questionnaire; QLQ-PR25 = Quality of Life Questionnaire-Prostate 25; RECIST = Response Evaluation 
Criteria in Solid Tumors; SAE = serious adverse event. 

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1. INTRODUCTION
1.1. Overview and Mechanism of Action
1.1.1. Overview
Talazoparib (also known as PF-06944076, MDV3800) in combination with enzalutamide is 
being investigated for the treatment of metastatic castration-resistant prostate cancer 
(mCRPC) unselected for deoxyribonucleic acid (DNA) damage repair (DDR) deficiencies
(referred to as “all-comers population”).  Although patients will be unselected for DDR 
status, DDR deficiency assessment prior to randomization is required for stratification.
1.1.2. Mechanism of Action/Indication
Talazoparib is a potent, small molecule poly (adenosine diphosphate [ADP]-ribose) 
polymerase (PARP) inhibitor in development for the treatment of a variety of human cancers.  
Talazoparib exerts 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.1
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 161,360 men in the United States (US) were diagnosed with 
prostate cancer and approximately 26,730 will die of the disease in 2017.2  In Europe in 
2012, prostate cancer was the third most common cancer, with an estimated 416,700 new 
cases and 92,200 deaths.3  
The androgen receptor (AR) signaling axis, the principal driver of prostate cancer growth, 
has been targeted by castration and other systemic therapies.  However, a proportion of 
tumors progress despite castrate levels of testosterone, at which point the disease is 
considered castration-resistant.  Castration-resistant prostate cancer 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 AR remains functional in a majority of 
progressing tumors.4  Rationally designed therapies targeting the AR signaling pathway in 
the castrate setting include enzalutamide, a novel AR signaling inhibitor active in the 
presence of AR overexpression;5 and abiraterone acetate/prednisone,6,7 an inhibitor of 
17,20-lyase (an androgen biosynthetic enzyme overexpressed in CRPC).8,9  These therapies 
have conferred improved overall survival and radiographic progression-free survival (PFS) 
benefit compared with prednisone or placebo in patients with mCRPC, in both pre- and 
post-chemotherapy settings.7,10,11,12  Recently, addition of abiraterone plus prednisone (or 
prednisolone) to androgen deprivation therapy (ADT) was also shown to improve overall 
survival and radiographic PFS in men with high-risk metastatic hormone-naïve prostate 
cancer (metastatic [M1] HNPC)13,14 while enzalutamide has been shown superior to placebo 
in extending metastasis-free survival of patients with non-metastatic CRPC.15
The PROSPER study evaluated enzalutamide plus ADT versus ADT alone in 1,401 patients 
with non-metastatic CRPC.  The study met its primary endpoint, demonstrating that the use 
of enzalutamide plus ADT significantly reduced the risk of developing metastasis or death 
compared to ADT alone.  The median for the primary endpoint, metastasis-free survival 
(MFS), was 36.6 months for men who received XTANDI compared to 14.7 months with 
ADT alone (n=1401; HR=0.29 [95% CI: 0.24-0.35]; p<0.0001).  As such, the Food and Drug 
Administration (FDA) has approved enzalutamide also for the treatment of patients with 
nonmetastatic castration-resistant prostate cancer (CRPC) in July 2018 based on the results of 
the study.
In the same setting, in February 2018, FDA approved apalutamide, next-generation 
nonsteroidal antiandrogen, for patients with non-metastatic castration-resistant prostate 
cancer (NM-CRPC).  In SPARTAN study apalutamide significantly improved 
metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer.  
The estimated median MFS was 40.5 months for patients receiving apalutamide and 
16.2 months for those receiving placebo (hazard ratio 0.28; 95% CI: 0.23, 0.35; p<0.0001).

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Taxane-based chemotherapy (docetaxel, cabazitaxel) has been shown to improve 
progression-free survival (PFS) and overall survival in patients with mCRPC.16,17  At present, 
patients whose disease progresses on novel hormonal agents are recommended treatment 
with taxane-based chemotherapy, based on retrospective series supporting efficacy, although 
no randomized study data are available.18,19  Recently, docetaxel-based chemotherapy also 
has been shown to provide significant benefit on overall survival when given in combination 
with androgen deprivation therapy in high-volume, metastatic or locally advanced, 
hormone-naïve disease;20,21,22 such chemotherapeutic treatment earlier in the disease course 
may affect treatment decisions (such as re-treatment with docetaxel) once patients develop 
mCRPC.  Additionally, many patients with advanced prostate cancer may not be candidates 
for taxane-based chemotherapy due to their comorbidities or performance status or may 
prefer to delay treatment with such chemotherapy as a last resort.
Other agents approved for treatment of mCRPC have more specific indications, including 
radium-223 for symptomatic osseous disease without known visceral disease23 and 
sipuleucel-T for asymptomatic or minimally symptomatic mCRPC.24  Thus, a significant 
unmet medical need remains for new therapeutic options for men with mCRPC.
1.2.2. PARP Inhibition
PARP1 and PARP2 play important roles in DNA repair.25,26  Following DNA damage, 
PARP1 and PARP2 bind to single-stranded DNA breaks, cleave nicotinamide adenine 
dinucleotide, and attach multiple ADP-ribose units to the target protein, including itself.27-30  
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.  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 (ie, become trapped), thereby 
inhibiting DNA repair, replication, and transcription, which is cytotoxic to cancer cells.  
Although other PARP inhibitors possess both activities (ie, inhibition of PARP catalytic 
activity and PARP trapping), in vitro studies demonstrated that talazoparib is a more potent 
PARP trapper than other PARP inhibitors in clinical development, a property that has been 
associated with significant cytotoxicity in preclinical models.30,31,32
1.2.3. PARP Inhibitors as a Potential Targeted Therapy in mCRPC, Including in 
Androgen Pathway Manipulation
Proof of concept for the efficacy of PARP inhibition in prostate cancer with DDR deficiency 
was established in a Phase 2 study (TOPARP-A) with the PARP inhibitor olaparib.33  In the 
TOPARP-A study, 50 patients with mCRPC were treated with the monotherapy 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 

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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 
(CTCs) 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 
DDR.  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 DDR deficiencies and 5 of those 7 (71%) had a 
partial response (PR) per RECIST 1.1.  Patients with DDR deficiencies had longer median 
rPFS (9.8 vs 2.7 months) and median overall survival (13.8 vs 7.5 months) compared with 
patients without DDR deficiencies. 
In an integrated analysis of somatic and germline mutation status in tumor biopsies from 
150 patients with mCRPC, 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.4  Loss of BRCA2 was observed in 12.7% of 
cases (approximately 90% of these were biallelic loss), and 8% harbored a germline 
alteration.  Another clinical targeted sequencing analysis of prostate cancer identified similar 
frequencies of somatic and germline alterations in DDR genes BRCA2, BRCA1, and ATM.34
There is a three-fold rationale for combining PARP inhibitors with androgen-receptor (AR) 
signaling inhibitors in CRPC regardless of DDR mutational status, based on research on 
nonclinical models and clinical samples: First, AR signaling inhibition suppresses the 
expression of homologous recombination repair genes including BRCA1, resulting in 
“BRCAness” and sensitivity to PARPi.43,44  Second, PARP1 activity has been shown to be 
required for maximal AR function46 and thus inhibiting PARP is expected to reduce AR 
signaling and increase sensitivity to NHT.  Third, clinical resistance to AR blockade is 
sometimes associated with co-deletion of RB and BRCA2, which is in turn associated with 
sensitivity to PARP inhibition sensitivity.45
In a recent double-blind, randomized, placebo-controlled Phase 2 study, 142 patients with 
mCRPC who had previously received docetaxel were randomly assigned to receive olaparib 
plus abiraterone (n=71) or placebo and abiraterone (n=71).  The objective of the study was to 
assess efficacy of olaparib plus abiraterone in patients regardless of homologous 
recombination DDR mutations.  The primary endpoint was rPFS, with secondary endpoints 
of safety and tolerability, time to second progression, overall survival, time to first 

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subsequent anticancer therapy, time to second subsequent anticancer therapy, and change in 
circulating tumor cell count.  Olaparib plus abiraterone provided a significant rPFS benefit to 
mCRPC patients compared with abiraterone alone; median rPFS was 13.8 months (95% CI 
10.8–20.4) with olaparib and abiraterone and 8.2 months (5.5–9.7) with placebo and 
abiraterone (hazard ratio [HR] 0.65, 95% CI 0.44–0.97, p=0.034). 
A prespecified subgroup analyses of rPFS by DDR mutation status revealed that within the 
cohort of patients with DDR mutation rPFS was 17.8 months (95% CI 2.9–27.6) in the 
olaparib group compared with 6.5 months (2.7–not reached) in the placebo group (N=21 in 
patients with DDR mutation [HR 0.74; 95% CI 0.26, 2.12]).  Among the DDR wild-type 
subgroup the median rPFS of 15.0 months (95% CI 5.4–not reached) in the olaparib group 
versus 9.7 months (2.9–17.5) in the placebo group (N=35 in wild-type [HR 0.52; 95% CI 
0.24, 1.15]).  Finally median rPFS median rPFS was 13.1 months (95% CI 8.1–22.4) in the 
olaparib group versus 6.4 months in subgroup of patients whose DDR status was reported to 
be unknown.  (N=142 in ITT [HR 0.65; 95% CI 0.44, 0.97]).  Overall, the efficacy results of 
this study indicated that the pharmacological alteration of AR signaling in combination with 
the administration of PARP inhibitor prolonged clinical benefit in patients with mCRPC, 
regardless of DDR mutation status.  As expected more adverse events were reported with 
olaparib plus abiraterone than abiraterone alone with nausea (37% vs 18% respectively), 
anemia (21% vs none respectively), pneumonia (6% vs 4% respectively), and myocardial 
infraction (6% vs none respectively) being the most frequent.  More serious adverse events 
were reported with olaparib plus abiraterone (34%) than abiraterone alone (18%).  There was 
1 treatment-related death that occurred in the olaparib plus abiraterone group.35  The results 
of this study, coupled with the pre-clinical rationale detailed above, provides support for the 
inclusion of patients without DDR deficiencies or with unknown DDR mutational status in 
addition to those with DDR deficiencies to allow for evaluation of rPFS in mCRPC patient 
treated with talazoparib plus enzalutamide compared to placebo plus enzalutamide 
irrespective of DDR status as a primary objective. 
1.3. Summary of Relevant Clinical Experience with Talazoparib
The clinical data presented here are as of 31 Jan 2018, unless otherwise stated.  
Approximately 659 patients and 18 healthy volunteers have received talazoparib at doses up 
to 2 mg/day in company sponsored clinical studies in hematologic malignancies and solid 
tumors.  Aggregate safety data from 5 open label studies, including 1 randomized, company 
sponsored clinical study (PRP-001, 673 201, 673-301, MDV3800-13, and MDV3800 14; 
N=502 patients) evaluating talazoparib monotherapy at the proposed dose of 1 mg/day 
(Talazoparib 1 mg/day Population) provide the basis for the reported treatment emergent 
adverse events (TEAEs). 
Results from these company-sponsored studies are summarized in the following sections. 

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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 30 Nov 2015, objective responses (CR or PR) per RECIST 1.1 were 
observed in 8 of 18 patients (44%) with breast cancer and 12 of 25 patients (48%) with 
ovarian/primary peritoneal cancer with deleterious germline BRCA mutations; clinical 
benefit (CR, PR, or stable disease 24 weeks) was observed in 13 of 18 patients (72%) and 
19 of 25 patients (76%), respectively.  Seven of 12 patients with confirmed objective 
responses were treated with talazoparib at 0.1 to 0.9 mg/day, and 5 patients were treated at 
the recommended dose of 1 mg/day.
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 who are 
either platinum responders (Cohort 1) or had at least 3 prior chemotherapy regimens with no 
platinum for metastatic disease (Cohort 2).  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. 
In addition, talazoparib significantly extended progression-free survival in the Phase 3 Study 
673-301 (EMBRACA).  The EMBRACA study, which was a global, open-label, randomized, 
parallel, 2-arm study of talazoparib versus protocol-specific physician’s choice of standard 
single-agent chemotherapy (PCT [capecitabine, eribulin, gemcitabine or vinorelbine]) in 
gBRCA+ patients who may have received up to three prior cytotoxic chemotherapy regimens 
for locally advanced and/or metastatic breast cancer.  Patients enrolled had a diagnosis of 
triple-negative breast cancer (TNBC) or HR+/HER2-negative breast cancer.  The study 
randomized (2:1) 431 patients to receive talazoparib (1.0 mg) once daily or PCT.
The primary objective was progression-free survival, assessed by blinded independent central 
review, and secondary objectives were overall survival, overall response rate and clinical 
benefit rate at 24 weeks, and safety.  Patient-reported outcomes were also measured.
Median PFS was 8.6 months (95% CI: 7.2, 9.3) for patients treated with talazoparib and 
5.6 months (95% CI: 4.2, 6.7) for those treated with chemotherapy [HR: 0.54 (95% CI: 0.41, 
0.71), p<0.0001].  This represents a 46% reduction in the risk of disease progression.  In 
addition, the proportion of patients achieving a complete or partial response (objective 
response rate) in the talazoparib group was more than twice that of the control arm 
(62.6% for talazoparib vs. 27.2% for chemotherapy [OR: 4.99 (95% CI: 2.9-8.8), p<0.0001]).  
In addition PFS benefit consistent across metastatic BRCA-positive patients, including those 
with hormone receptor-positive and triple negative disease.49  Finally patients who received 
talazoparib reported better global health status across all functional domains, including global 

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health status (mean change from baseline 3.0 in the talazoparib group vs –5.4 in the standard 
chemotherapy group, p<0.001).  Talazoparib is approved in the U.S. for the treatment of 
adult patients with deleterious or suspected deleterious germline breast cancer susceptibility 
gene (gBRCA)-mutated human epidermal growth factor receptor 2-negative (HER2-), locally 
advanced or metastatic breast cancer.  Select patients for therapy based on an FDA-approved 
companion diagnostic for talazoparib.  In addition, on April 26, 2019 European Medicines 
Agency (EMA) also adopted a positive opinion recommending talazoparib for marketing 
authorization in the European Union (EU). 
1.3.2. Safety
This is the first study evaluating the efficacy and safety of talazoparib and enzalutamide 
when administered in combination.
TEAEs in 20% of the 502 patients in the talazoparib 1 mg/day population were related to 
myelosuppression (anemia, neutropenia), gastrointestinal (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 treatment 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 patients in the Talazoparib 1 mg/day population had a TEAE that led to 
death (8 associated with malignancies including 1 also associated with pneumonia; 
2 dyspnea; 2 general physical health deterioration; 3 disease progression; and 1 each lung 
infection, cerebral hemorrhage, cerebrovascular accident, fatigue (after the data cutoff date of 
31 January 2018, the adverse event of Grade 5 fatigue was changed to Grade 5 failure to 
thrive), liver disorder, neurological symptom, respiratory failure, and veno-occlusive liver 
disease).  Of these, only veno-occlusive liver disease (reported in 1 patient in the Phase 3 
Study 673-301) was assessed as related to study treatment 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 
and pleural effusion (2.2% each).  Forty-seven (47) patients had SAEs considered related to 
study treatment.  Study treatment-related SAEs occurring in 1% of patients 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 treatment due to a TEAE.  The events that led to study treatment 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).

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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 study the adverse events observed with talazoparib were consistent with 
findings from previous studies.  The most common 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 serious AEs was 31.8% in the talazoparib arm 
and 29.4% in the PCT arm.  Discontinuations due to AEs occurred in 7.7% of patients in the 
talazoparib arm and 9.5% of patients in the PCT arm.
Recent results from an international, Phase 2, open-label, response rate study of talazoparib in 
DDR-deficient mCRPC patients (TALAPRO-1) demonstrated that talazoparib 1 mg/day was 
generally tolerated and TEAEs were manageable through dosing interruption, dose reduction, 
and/or standard supportive care. The safety profile to date in the TALAPRO-1 study was 
consistent with the known safety profile of talazoparib. No new safety signals were 
identified.
Additional safety information from other talazoparib studies may be found in the current 
talazoparib Investigator’s Brochure. 
1.3.3. Pharmacokinetics and Metabolism
1.3.3.1. Talazoparib
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% based 
on excretion of unchanged talazoparib in urine.  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 talazoparib with food (a high-fat, high-calorie meal) had no impact on the 
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 generally driven by total exposure.  
Therefore, talazoparib can be taken with or without food.
Mean talazoparib binding to human plasma proteins is 74%.  Population PK analysis showed 
that talazoparib apparent steady-state volume of distribution (Vss/F) was 420 L, which is 
significantly greater than total body water (42 L), indicating that talazoparib extensively 
distributes to peripheral tissues.
Talazoparib undergoes minimal hepatic metabolism.  Based on population PK analysis, there 
was no effect of mild hepatic impairment (total bilirubin upper limit of normal [ULN] and 
AST > ULN, or total bilirubin >1.0 to 1.5 ULN and any AST) on talazoparib exposure.  No 
dose adjustment is necessary for patients with mild hepatic impairment.

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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 apparent oral clearance (CL/F) was 6.45 L/hr.  Excretion of unchanged 
talazoparib in urine was the major route of elimination accounting for 54.6% of the 
administered dose.  Population PK analysis showed that talazoparib CL/F was reduced by 
14.4% and 37.1% in patients with mild renal impairment (creatinine clearance [CrCl], 60 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 in combination with 
enzalutamide is 0.35 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 5.9.
1.3.3.2. Enzalutamide
The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl 
enzalutamide) were evaluated in patients with mCRPC and healthy male volunteers.  Peak 
enzalutamide concentrations were generally achieved 0.5 to 3 hours after oral administration.  
With daily administration, enzalutamide steady state is achieved by Day 28 consistent with a 
mean terminal half-life of 5.8 days.  The mean terminal half-life for N-desmethyl 
enzalutamide is approximately 7.8 to 8.6 days. 
Administration of enzalutamide with a high-fat meal in healthy volunteers did not alter the 
AUC for enzalutamide or N-desmethyl enzalutamide compared to administration in fasted 
condition.  Therefore, enzalutamide can be administered without regard to food.
No significant difference in enzalutamide clearance was observed in patients with mild to 
moderate renal impairment compared to patients with baseline normal renal function 
(creatinine clearance (CrCL) 90 mL/min).  Therefore, no dose adjustment is necessary for 
patients with mild to moderate renal impairment.  Exposure of enzalutamide and its 
N-desmethyl metabolite was similar in subjects with mild or moderate hepatic impairment as 
compared to subjects with normal hepatic function.  Therefore, no enzalutamide dose 
adjustment is necessary for patients with baseline mild or moderate hepatic impairment.
In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid 
metabolite are not substrates for human P-gp.  In vitro, enzalutamide and N-desmethyl 
enzalutamide exhibited both induction and inhibition properties of human P-gp [XTANDI
US Package Insert (USPI)].  Furthermore, in vitro studies showed that enzalutamide is an 
inhibitor of BCRP.  However, the in vivo effect of enzalutamide on exposure of P-gp and 

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BCRP substrates, such as talazoparib, has not been studied prior to the initiation of Part 1 of 
the current study. 
1.3.3.3. Drug Drug Interactions between Talazoparib and Enzalutamide 
Enzalutamide is primarily eliminated by hepatic metabolism mainly by cytochrome 
P450 (CYP450) enzymes CYP2C8 and CYP3A4.  At the therapeutic dose of 1 mg/day, 
talazoparib did not markedly induce or inhibit CYP450 enzymes or transporters and is 
therefore unlikely to demonstrate clinically significant drug drug interactions or drug 
transporter inhibition when co-administered with corresponding substrates.  Preliminary 
enzalutamide and N-desmethyl enzalutamide Ctrough values from Part 1 were generally 
consistent with published enzalutamide monotherapy Ctrough indicating no apparent effect 
of talazoparib on enzalutamide exposure.50
Talazoparib is a substrate of P-gp and BCRP, and plasma talazoparib concentrations may 
increase when co administered with P-gp or BCRP inhibitors (Section 1.3.3.1).  In vitro data
show that enzalutamide and its N-desmethyl metabolite are potential inhibitors and inducers, 
but not substrates, of the efflux transporter P-gp.  The in vivo effect of enzalutamide on 
exposure of P-gp substrates, such as talazoparib, has not been studied prior to the initiation of 
Part 1 of the current study (XtandiSummary of Product Characteristics).  Part 1 safety and 
PK data showed higher than expected frequency of Grade 3/4 hematological AEs and a 
~2-fold higher than expected talazoparib Ctrough at Week 5 when talazoparib 1 mg once daily 
was administered in combination with enzalutamide.  The increase in talazoparib exposure 
might be due to inhibition of P-gp and/or BCRP by enzalutamide and its N-desmethyl 
metabolite.  Reducing talazoparib dose to 0.5 mg once daily in combination with 
enzalutamide is expected to account for the observed interaction and maintain similar 
talazoparib exposure to that achieved with 1 mg once daily monotherapy with an acceptable 
safety profile (Section 1.6.1). 
Based on existing clinical experience with enzalutamide from AFFIRM, PREVAIL, and 
PROSPER study as well as clinical experience with talazoparib monotherapy data, fatigue 
and gastrointestinal signs symptoms and hematological AEs may be reasonably expected 
with combination therapy.  Additional information for talazoparib may be found in the 
Investigator’s Brochure, which is the single reference safety document (SRSD) for 
talazoparib.  The SRSD for enzalutamide is the Summary of Product Characteristics (SmPC), 
which is available in the European public assessment reports for Xtandi(enzalutamide). 
1.4. Talazoparib Benefits and Risks Assessment
The doses of talazoparib in this protocol are supported by nonclinical studies, 
Phase 1-3 studies in patients with advanced malignancies, and studies in patients with 
germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer.  The 
expected adverse events with talazoparib include myelosuppression, gastrointestinal toxicity, 
fatigue, and alopecia.  Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), 
hepatotoxicity, second primary non hematologic malignancies and pneumonitis are adverse 
events of special interest per the Investigator’s Brochure.  The activity of talazoparib as 
monotherapy and in combination with other agents is being evaluated in multiple indications.

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1.5. Enzalutamide Benefits and Risks Assessments
The tolerability, pharmacological property, and efficacy of enzalutamide were first 
investigated in a multicenter, open-label, dose-escalation Phase I/II study.  A total of 
140 men with CRPC were enrolled in the study, the majority with bone metastasis (78%) and 
half of whom had previously received chemotherapy (54%).  The oral daily doses of 
enzalutamide ranged from 30 to 600 mg depending on the dosing cohort until the occurrence 
of disease progression or intolerable adverse events.
Fatigue was the most common dose-limiting toxicity, occurring at a Grade 3 or greater 
(Grade 3/4) severity in 11% and the maximum tolerated dose for sustained treatment 
>28 days was established as 240 mg.  Subsequent studies in both the post- and 
pre-chemotherapy settings used 160 mg enzalutamide once daily as the recommended dose 
for further development of enzalutamide to be tested.
Enzalutamide received initial FDA approval on August 31, 2012, for the treatment of patients 
with mCRPC who have previously received docetaxel based on the results of the AFFIRM 
study, an international, Phase 3, randomized, double blind, placebo-controlled study of 
enzalutamide in CRPC patients previously treated with one or two chemotherapy regimens, 
at least one of which contained docetaxel.51  The AFFIRM study enrolled 1199 patients 
(800 in the enzalutamide arm and 399 in the placebo arm) with a primary end point of overall 
survival (OS).  Secondary end points included measures of response (PSA-level response, 
objective soft tissue response according to RECISTv1.1, and quality of life [QoL] score 
responses) and measures of progression (time to PSA progression [TTPP], radiographic 
progression-free survival [rPFS], and time to the first skeletal related event [SRE]).  At the 
time of the prespecified interim analysis, enzalutamide significantly prolonged OS compared 
to placebo (HR 0.63; 95% CI 0.53-0.75; P <0.001) which indicated a reduced risk of death of 
37% (median rPFS of 18.4 vs. 13.6 months). 
PREVAIL was a Phase III study comparing enzalutamide activity with placebo in 
asymptomatic or minimally symptomatic chemotherapy-naive mCRPC patient.  The 
co-primary end points of the study were rPFS and OS.11  The results revealed that 
enzalutamide treatment significantly improved OS compared to placebo (HR 0.71; 95% CI 
0.60–0.84; P <0.001) corresponding to a 29% decrease in the risk of death (median OS of 
32.4 months vs. 30.2 months).  The OS benefit of enzalutamide was consistent across all 
prespecified subgroups including elderly patients, visceral metastatic diseases, and anemic 
patients at baseline.
The FDA recently (July 2018) approved enzalutamide for the treatment of patients with 
nonmetastatic castration-resistant prostate cancer (CRPC).  The approval is based on the 
Phase III PROSPER study, in which the combination of enzalutamide and androgen 
deprivation therapy (ADT) reduced the risk of metastases or death by 71% compared with 
ADT alone for patients with non-metastatic CRPC (HR 0.29; 95% CI, 0.24-0.35; P ,0.001).  
In the double-blind study, the median metastasis-free survival (MFS) was 36.6 months with 
enzalutamide plus ADT versus 14.7 months with ADT alone.

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The Grade 3/4 adverse events (AEs) that occurred in the enzalutamide and placebo arms 
were 45.3 and 53.1%, respectively.  Specifically the more common AEs with enzalutamide 
(all Grades) were fatigue (34 vs. 29% in the placebo arm), diarrhea (21 vs. 18%), hot flush 
(20 vs. 10%), musculoskeletal pain (14 vs. 10%), and headache (12 vs. 6%).  Grade 3 or 
greater side effects of interest were fatigue (6.3% in the MDV3100 group versus 7.3% in the 
placebo group), cardiac disorders (0.9% versus 2.0%) including myocardial infarction 
(0.3% versus 0.5%), seizure (0.6% versus 0.0%) and liver function test abnormalities 
(0.4% versus 0.8%).  On the other hand the discontinuations due to AEs were reported in
8% of the patients in the enzalutamide arm and in 10% of the patients in the placebo arm.  
Some of the patients who manifested a seizure had potentially predisposing factors, including 
brain metastasis, lidocaine injection, and brain atrophy.
In the subsequent PREVAIL study, the safety profile was generally consistent with the 
previous AFFIRM results.  More Grade 3/4 AEs were reported in the enzalutamide arm than 
in the placebo arm (43 vs. 37%).  Seizure occurred in only 1 patient (0.1%) who had a history 
of seizure in the enzalutamide arm.  Hypertension was more commonly observed in the 
enzalutamide arm than in the placebo arm (13 vs. 4%) all Grades.  A similar proportion of 
patients in each arm discontinued the treatment due to AE (6%) and notably in contrast to the 
other antiandrogens, enzalutamide was not associated with hepatotoxicity.
Also in PROSPER study the adverse events were generally consistent with those reported in 
prior enzalutamide clinical studies in patients with mCRPC.52  Grade 3 or higher adverse 
events were reported in 31% of men treated with Enzalutamide plus ADT and in 23% of men 
treated with ADT alone. The most common (2%) Grade 3 or higher adverse events that 
were reported more often in enzalutamide plus ADT-treated patients included hypertension 
(5% vs. 2%) and fatigue (3% vs. 1%).1%). 5% of patients who received enzalutamide plus 
ADT and 3% with ADT alone had major adverse cardiovascular events.  Three seizures 
(<1%) were reported with enzalutamide plus ADT patients and none were reported for those 
who received ADT alone.  The percentage of patients in whom adverse events were the 
primary reason leading to treatment discontinuation was low in both study arms (9% with 
enzalutamide plus ADT versus 6% with ADT alone). 
In the combined Phase-3 studies, the incidence of ischemic heart disease events was higher in 
the enzalutamide group compared with the placebo group (2.6% vs 1.3%).  Grade 3 events 
of ischemic heart disease occurred in 1.5% of patients in the enzalutamide group compared 
with 0.7% in the placebo group.  Events of ischemic heart disease that led to death were 
reported in 0.4% of patients in the enzalutamide group compared with 0.1% in the placebo 
group. 
The incidence of TEAEs of any event of fracture in the combined Phase 3 studies was higher 
in the enzalutamide group compared with placebo (10.2% vs 4.4%).  When adjusted for 
differences in treatment duration, the event rates per 100 patient-years of treatment were 
8.1 vs 4.8.  The most common types of fracture reported among the enzalutamide group of 
the combined Phase 3 studies were rib fracture (2.4%) followed by spinal compression 
fracture (1.2%), femur fracture (0.4%) and upper limb fracture (0.3%).  However the 
incidence of SAEs of fractures was low in the enzalutamide group of the combined Phase 3 

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studies (2.9%) as were Grade 3 events of fracture (2.6%) and any event of fracture as the 
primary reason for discontinuation (0.1%).  Finally the incidence of fractures increased with 
the length of treatment duration.  The incidence of any event of fracture during the first 
30 days of treatment in the combined Phase 3 studies was 0.5% for both the enzalutamide 
and placebo groups.  During the first 180 days of treatment, the incidence of fractures was 
slightly higher in the enzalutamide group compared with the placebo group (3.1% vs 2.6%). 
For the others TEAEs of interest in the combined Phase 3 Studies please refer to the 
Enzalutamide SmPC.
1.6. Rationale for Combination Treatment 
Prior to the recent approval of novel hormonal therapies (NHTs) (enzalutamide, abiraterone 
acetate/prednisone), the only approved therapies for mCRPC were docetaxel, cabazitaxel, 
and (for asymptomatic or minimally symptomatic mCRPC), sipuleucel-T.24  The approval of 
NHTs in mCRPC patients previously treated with docetaxel7,12 represented a therapeutic 
advance for these patients, followed shortly thereafter by their approvals for the larger 
population of men with chemotherapy-naïve mCRPC.  Genomically unselective studies of 
enzalutamide and abiraterone acetate/prednisone in patients with mCRPC who have not 
received chemotherapy11,37,38,39 have demonstrated similar median radiographic PFS and 
overall survival of approximately 16 and 35 months, respectively.  Unfortunately, disease 
progression eventually occurs and leads to death absent other fatal comorbidities.  Thus, an 
unmet medical need remains to further improve the treatments available for these patients 
with mCRPC.  The development program of which the current study is a part was prompted 
based on the results of the TOPARP-A study33 and the established use of NHTs such as 
enzalutamide in mCRPC patients.  Furthermore preclinical data demonstrated potential 
biochemical basis for synergy between androgen receptor signaling and DNA repair 
mechanism pathway and the combined inhibition of both pathways selectively leads to 
synthetic lethality in prostate cancer.53
In a recent double-blind, randomized, placebo-controlled Phase 2 study, 142 patients with 
mCRPC who had previously received docetaxel were randomly assigned to receive olaparib 
plus abiraterone (n=71) or placebo and abiraterone (n=71).  The aim of the study was to 
assess efficacy of olaparib plus abiraterone in patients regardless of homologous 
recombination DDR mutations.  The primary endpoint was rPFS, with secondary endpoints 
of safety and tolerability, time to second progression, overall survival, time to first 
subsequent anticancer therapy, time to second subsequent anticancer therapy, and change in 
circulating tumor cell count.  Olaparib plus abiraterone provided a significant rPFS benefit to 
mCRPC for patients compared with abiraterone alone. More adverse events were reported 
with olaparib plus abiraterone than abiraterone alone with nausea (37% vs 18% respectively), 
anemia (21% vs none respectively), pneumonia (6% vs 4% respectively), and myocardial 
infraction (6% vs none respectively) being the most frequent.  More serious adverse events 
were reported with olaparib plus abiraterone (34%) than abiraterone alone (18%).  There was 
1 treatment-related death that occurred in the olaparib plus abiraterone group.35  In summary, 
in the light of preclinical and clinical data suggesting that blocking androgen receptor 
signaling could induce a BRCAness phenotype, making tumors more sensitive to PARP 
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with enzalutamide versus placebo in combination with enzalutamide in mCRPC regardless 
the present of DDR deficiencies.  Backbone treatment with enzalutamide is justified given 
that enzalutamide is currently approved and recommended treatment, irrespective of genomic 
status, per clinical practice guidelines.  In addition, PARP inhibitors have demonstrated 
substantial clinical efficacy in ovarian cancer and breast cancer with DDR deficiencies.  As 
such, it is expected that talazoparib, may significantly improve clinical outcomes in mCRPC 
when combined with enzalutamide in all-comers population.
1.6.1. Rationale for Study Treatment Dose
1.6.1.1. Talazoparib
Talazoparib has demonstrated efficacy as single agent at a dose of 1 mg once daily in patients 
with germline BRCA mutation and locally advanced and/or metastatic breast cancer.  
Therefore, the first patients enrolled into Part 1 initially received 1 mg once daily. 
As of 04 May 2018, evaluation of available preliminary safety data from 13 patients enrolled 
with a starting dose of talazoparib of 1 mg once daily in combination with 160 mg once daily 
enzalutamide showed higher than expected dose reductions and interruptions due to Grade 3 
hematological toxicities (anemia, thrombocytopenia and neutropenia) which were reported in 
7 patients.  Dose modifications (reductions and interruptions) were reported in 9 patients and 
treatment discontinuation in 1 patient.  Evaluation of available preliminary talazoparib PK 
data (Ctrough at Week 5, n=11 patients who received talazoparib 1 mg once daily) suggested
that enzalutamide increased talazoparib Ctrough at Week 5 Visit by ~2-fold compared to 
talazoparib steady-state Ctrough in patients with advanced solid tumors and in patients with 
breast cancer receiving 1 mg once daily monotherapy.  The increase in talazoparib exposure 
might be due to inhibition of P-glycoprotein by enzalutamide and its N-desmethyl metabolite 
in the intestine (increasing talazoparib bioavailability) or the renal tubules (reducing 
talazoparib elimination), or both.  Based on these preliminary safety and PK data, talazoparib 
dose was reduced from 1 mg once daily to 0.5 mg once daily for all patients continuing to 
receive talazoparib in combination with enzalutamide in Part 1.  Additional patients were 
enrolled in Part 1 and received a talazoparib starting dose of 0.5 mg once daily in 
combination with enzalutamide to evaluate safety and PK data at the reduced talazoparib 
dose. 
As of 18 October 2018, 13 patients received talazoparib with a starting dose of 1 mg/day in 
combination with 160 mg once daily enzalutamide for a median of 25.4 weeks 
(4.0 weeks - 39.6 weeks) and 6 patients received talazoparib with a starting dose of 
0.5 mg/day in combination with 160 mg once daily enzalutamide for a median of 11.0 weeks 
(8.1 weeks - 16.3 weeks).  Patients that started talazoparib dosing at 1 mg/day (n=13) had 
their dose reduced either due to AE (n=6) or per Sponsor communication (n=4) while 
3 patients discontinued treatment prior to dose reduction.  Adverse events reported in the 
4 patients whose dose was reduced per Sponsor communication and the 6 patients starting at 
0.5 mg/day showed acceptable safety profile for the 0.5 mg once daily talazoparib dose in 
combination with 160 mg once daily enzalutamide.  Evaluation of PK data from 6 patients 
who started on 0.5 mg once daily talazoparib and from patients who started on 1 mg once 
daily and later reduced to 0.5 mg once daily suggested that a starting dose of talazoparib 

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0.5 mg once daily in combination with enzalutamide is expected to maintain talazoparib 
AUCat levels similar to that obtained with talazoparib 1 mg once daily monotherapy.  This 
indicates that reducing the talazoparib dose to 0.5 mg once daily in combination with 
enzalutamide is expected to account for the observed interaction and maintain similar 
talazoparib exposure to that achieved with 1 mg once daily monotherapy with an acceptable 
safety profile. 
Therefore, a talazoparib dose of 0.5 mg once daily will be administered in combination with 
enzalutamide 160 mg once daily in Part 2 of this study.  The starting dose of talazoparib for 
patients with moderate renal impairment will be 0.35 mg once daily to account for the lower 
talazoparib clearance in this subpopulation (refer to Section 1.3.3.1). 
1.6.1.2. Enzalutamide
Enzalutamide is administered at the approved dose of 160 mg once daily via oral 
administration with or without food.  No enzalutamide dose adjustment is necessary for 
patients with mild to moderate renal impairment or patients with mild or moderate hepatic 
impairment given the similar enzalutamide exposure compared to patients with normal organ 
function.
2. STUDY OBJECTIVES AND ENDPOINTS
The study will include an open-label treatment period, hereafter referred to as Part 1, which 
will include a limited number of patients to confirm the starting dose of talazoparib for the 
double-blind period, hereafter referred to as Part 2. 
Study objectives and corresponding endpoints for Part 1 and Part 2 are provided in 
Table 4 and Table 5, respectively.
Table 4.
Objectives and Endpoints for Study Part 1 (Open-Label Treatment)
Primary Objective(s):
Primary Endpoint(s):

To determine the starting dose of talazoparib when 
given in combination with enzalutamide during Part 2 
(double-blind treatment period).

Occurrence of target safety events.
Secondary Objective(s):
Secondary Endpoint(s):

To characterize the steady state PK of talazoparib and 
enzalutamide and its N-desmethyl metabolite when 
given in combination.

Multiple-dose PK parameters of talazoparib and 
enzalutamide and its N-desmethyl metabolite 
(Multiple-dose Cmax, Ctrough, Tmax, AUCand CL/F 
as data permit).
Exploratory Objective(s):
Exploratory Endpoint(s):

To explore correlation of changes in CTCs with 
efficacy outcome parameters.

To identify potential biomarkers associated with 
response and/or resistance to talazoparib in 
combination with enzalutamide.

To explore correlations between 
talazoparib/enzalutamide exposure and biomarker, 
efficacy and safety outcome parameters if data allow.

Proportion of patients with conversion from 5 or 
more CTCs per 7.5 mL at baseline to 4 or fewer 
CTCs per 7.5 mL post-baseline.

Proportion of patients with conversion from 
detectable CTCs per 7.5 mL at baseline to 
CTCs = 0 per 7.5 mL post-baseline.

Proportion of patients with baseline CTCs <5 who 
show increased CTCs post-baseline.

Molecular profiling of tumor tissue remaining 
after genomic testing for eligibility and of saliva 

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Table 4.
Objectives and Endpoints for Study Part 1 (Open-Label Treatment)

To collect banked biospecimens for exploratory 
research, unless prohibited by local regulations or 
ethics committee decision.
and ctDNA; circulating protein biomarker 
profiles.

Potential results from exploratory analyses of 
banked biospecimens.
CTCs = circulating tumor cells; NHT = novel hormonal therapy; PK = pharmacokinetics.
Table 5.
Objectives and Endpoints for Study Part 2 (Double-Blind Treatment)
Primary Objective(s):
Primary Endpoint(s):

To demonstrate that talazoparib in combination with 
enzalutamide is superior to placebo in combination 
with enzalutamide in prolonging BICR assessed rPFS, 
in patients with mCRPC unselected for DDR status. 

To demonstrate that talazoparib in combination with 
enzalutamide is superior to placebo in combination 
with enzalutamide in prolonging BICR assessed rPFS, 
in patients with mCRPC harboring DDR deficiencies.  

BICR assessed rPFS per RECIST 1.1 (soft tissue 
disease) and PCWG3 (bone disease) in patients 
with mCRPC unselected for DDR status.

BICR assessed rPFS per RECIST 1.1 (soft tissue 
disease) and PCWG3 (bone disease) in patients 
with mCRPC harboring DDR deficiencies.
Secondary Objective(s):
Secondary Endpoint(s): 
Key Secondary Objectives:

To demonstrate that talazoparib in combination with 
enzalutamide is superior to placebo in combination 
with enzalutamide in prolonging OS in patients with 
mCRPC unselected for DDR status. 

To demonstrate that talazoparib in combination with 
enzalutamide is superior to placebo in combination 
with enzalutamide in prolonging OS in patients with 
mCRPC harboring DDR deficiencies.
Other Secondary Objectives:

To evaluate anti-tumor activity in patients with 
mCRPC unselected for DDR status and in patients 
with mCRPC harboring DDR deficiencies with respect 
to the following:

BICR assessed objective response in measurable 
soft tissue disease;

BICR assessed duration of response in 
measurable soft tissue disease;

PSA response;

Time to PSA progression;

Time to initiation of cytotoxic chemotherapy;

Time to initiation of antineoplastic therapy;

Time to first symptomatic skeletal event;

PFS on next line therapy (PFS2);
Key Secondary Endpoints:

OS in patients with mCRPC unselected for DDR 
status (alpha-protected).

OS patients with mCRPC harboring DDR 
deficiencies (alpha-protected).
Other Secondary Endpoints:

Proportion of patients with measurable soft tissue 
disease at baseline with an objective response per 
RECIST 1.1 (assessed by BICR) in patients with 
mCRPC unselected for DDR status and in patients 
with mCRPC harboring DDR deficiencies. 

Duration of soft tissue response per RECIST 1.1 
(assessed by BICR) in patients with mCRPC 
unselected for DDR status and in patients with 
mCRPC harboring DDR deficiencies.

Proportion of patients with PSA response 50% 
in patients with mCRPC unselected for DDR 
status and in patients with mCRPC harboring 
DDR deficiencies.

Time to PSA progression in patients with mCRPC 
unselected for DDR status and in patients with 
mCRPC harboring DDR deficiencies. 

Time to initiation of cytotoxic chemotherapy in 
patients with mCRPC unselected for DDR status 

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Table 5.
Objectives and Endpoints for Study Part 2 (Double-Blind Treatment)

Opiate use for prostate cancer pain.

To evaluate safety of talazoparib and enzalutamide 
administered in combination. 

To evaluate the PK of talazoparib and enzalutamide 
(and its N-desmethyl metabolite) when dosed in 
combination.

To evaluate the following patient-reported outcomes in 
each treatment arm in patients with mCRPC unselected 
for DDR status and in patients with mCRPC harboring 
DDR deficiencies:

Pain symptoms;

Cancer-specific global health status/QoL, 
functioning, and symptoms outcomes; 

General health status. 
and in patients with mCRPC harboring DDR 
deficiencies. 

Time to initiation of antineoplastic therapy in 
patients with mCRPC unselected for DDR status 
and in patients with mCRPC harboring DDR 
deficiencies.

Time to first symptomatic skeletal event in 
patients with mCRPC unselected for DDR status 
and in patients with mCRPC harboring DDR 
deficiencies.

PFS2 based on investigator assessment separately 
in patients with mCRPC unselected for DDR 
status and in patients with mCRPC harboring 
DDR deficiencies. 

Time to opiate use for prostate cancer pain in 
patients with mCRPC unselected for DDR status 
and in patients with mCRPC harboring DDR 
deficiencies. 

Incidence of adverse events characterized by type, 
severity (graded by NCI CTCAE version 4.03), 
timing, seriousness and relationship to study 
treatment.

PK characterized by pre-dose trough and 
post-dose plasma concentrations of talazoparib, 
enzalutamide and its N-desmethyl metabolite.

PROs in patients with mCRPC unselected for 
DDR status and in patients with mCRPC 
harboring DDR deficiencies:

Change from baseline in patient-reported 
pain symptoms per BPI-SF;

Change from baseline in patient-reported 
general health status per EQ-5D-5L;

Change from baseline in patient-reported 
cancer-specific global health status/QoL, 
functioning, and symptoms per EORTC 
QLQ-C30;

Time to deterioration in patient-reported pain 
symptoms per BPI-SF;

Time to definitive deterioration in 
patient-reported global health status/QoL per 
EORTC QLQ-C30;

Time to definitive deterioration in 
patient-reported disease-specific urinary 
symptoms per EORTC QLQ-PR25.

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Table 5.
Objectives and Endpoints for Study Part 2 (Double-Blind Treatment)
Exploratory Objective(s):
Exploratory Endpoint(s):

To explore BICR assessed rPFS in patients with 
mCRPC without DDR deficiencies.

To explore correlation of changes in CTCs with 
efficacy outcome parameters.

To identify potential biomarkers associated with 
response and/or resistance to talazoparib in 
combination with enzalutamide.

To explore correlations between talazoparib exposure 
and biomarker, efficacy and safety endpoints if data 
allow. 

To collect banked biospecimens for exploratory 
research, unless prohibited by local regulations or 
ethics committee decision.

To explore the concordance of DDR deficiency results 
between blood and tumor tissue based tests.

BICR assessed rPFS per RECIST 1.1 (soft tissue 
disease) and PCWG3 (bone disease) in patients 
with mCRPC without DDR deficiencies.

Proportion of patients with conversion from 5 or 
more CTCs per 7.5 mL at baseline to 4 or fewer 
CTCs per 7.5 mL post-baseline, in patients with 
mCRPC unselected for DDR status and in patients 
with mCRPC harboring DDR deficiencies.

Proportion of patients with conversion from 
detectable CTCs at baseline to CTCs = 0 per 
7.5 mL post-baseline, in patients with mCRPC 
unselected for DDR status and in patients with 
mCRPC harboring DDR deficiencies.

Proportion of patients with baseline CTCs <5 who 
show increased CTCs post-baseline, in patients 
with mCRPC unselected for DDR status and in 
patients with mCRPC harboring DDR 
deficiencies.

Molecular profiles of tumor tissue remaining after 
genomic testing for eligibility during 
prescreening/screening, and of saliva and, of 
ctDNA; circulating protein biomarker profile.

Potential results from exploratory analysis of 
banked biospecimens.

Concordance of DDR deficiency results between 
blood and tumor tissue based tests.
ctDNA = circulating tumor DNA; CTCAE = Common Toxicity Criteria for Adverse Events; CTCs = circulating 
tumor cells; DDR = DNA damage repair; EORTC = European Organisation for Research and Treatment of Cancer; 
QLQ-PR25; EORTC Quality-of-Life Cancer Questionnaire Prostate Cancer Module; EQ-5D-5L = European 
Quality-of-Life 5-Domain 5-Level Scale; NCI = National Cancer Institute; PFS = progression-free survival;
PK = pharmacokinetics; PSA = prostate-specific antigen; QLQ-C30 = Quality-of-Life Cancer Questionnaire. 
Efficacy assessments are described in Section 7.2.  Response in soft tissue disease will be 
evaluated only on CT or MRI per Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1), and bone disease progression will be evaluated only on bone scan per Prostate 
Cancer Working Group 3 (PCWG3) 59 by the investigator for Part 1 and BICR for Part 2.  
Safety assessments are described in Section 7.9.  An external data monitoring committee 
(E-DMC) will conduct unblinded safety reviews throughout Part 2 of the study and will also 
conduct unblinded efficacy reviews at the pre-planned interim analyses (Section 9.8).  
Frequency of the E-DMC review meetings will be defined in the E-DMC charter.

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3. STUDY DESIGN
This is an international, Phase 3, two-part study enrolling patients with mCRPC where no 
systemic cancer treatments have been initiated after documentation of CRPC with the 
exception of ADT and first generation anti-androgen agents. 
Part 1 was open-label and non-randomized, and evaluated the safety, tolerability and PK of 
talazoparib in combination with enzalutamide.  Part 2 is randomized, double-blind, and 
placebo-controlled, and will evaluate the safety and efficacy of talazoparib in combination 
with enzalutamide versus placebo in combination with enzalutamide.
Two cohorts will be enrolled in Part 2.  Cohort 1 will enroll approximately 750 mCRPC 
patients unselected for DDR status (all-comers population).  Although patients will be 
unselected for DDR status, DDR efficiency assessment  prior to randomization is required for 
stratification.
Once enrollment in Cohort 1 is complete, enrollment will continue but will be restricted to 
patients harboring DDR gene mutations likely to sensitize to PARP inhibition (Cohort 2).  
Approximately 268 additional patients harboring DDR gene mutations likely to sensitize to 
PARP inhibition (DDR-deficient) will be enrolled into Cohort 2.  Patients who are 
DDR-deficient from Cohorts 1 and 2 will be combined such that a total of approximately 
380 DDR-deficient patients are enrolled to assess efficacy separately within this population.
Approximately 1037 men (19 enrolled in Part 1 and approximately 1018 in Part 2) with 
mCRPC will be enrolled.  Genomic screening to identify alterations in DDR genes is 
optional for patients in Part 1, but is required for enrollment in Part 2. 
Mutational status for patients randomized in Part 2 will be determined by testing for the 
presence of mutations in defined DDR genes likely to sensitize to PARP inhibition using the 
FoundationOne® or the FoundationOneLiquid® next generation sequencing (NGS) gene 
panel, consisting of over 300 genes.  For enrolled subjects, results for these defined DDR 
genes and other genes included in the FoundationOne® panels used in these tests will also be 
used to support the exploratory correlative analyses detailed in Section 7.5.
This study will be conducted at approximately 270 sites worldwide.
Eligible patients may have received taxane-based chemotherapy or NHT (second generation 
anti-androgens are excluded) in the castration-sensitive prostate cancer (CSPC) setting. 
Genomic screening of circulating tumor DNA (blood/plasma) or tumor tissue (de novo 
biopsy or archival, previously collected tissue) to identify alterations in DDR genes will be 
done by testing for the presence of mutations likely to sensitize to PARP inhibition using 
NGS-based gene panel tests.  (Refer to the Laboratory manual for specific information on the 
genes included in the NGS panel; assessment described in Section 7.1).  This testing will be 
performed during an optional prescreening visit or during the screening period. For patients 
enrolling in Part 1, submission and testing of tumor tissue is optional and patients do not 
need to have a genomic deficiency in DDR genes to enroll.  However, patients enrolling in 
Part 2 are required to give consent during an optional prescreening period or at screening to 
submit both a peripheral blood sample (liquid biopsy) and sufficient tumor tissue (de novo or 

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archived tissue) for genomic assessment; the result from the central laboratory is required 
prior to patient randomization in to Part 2 of the study for stratification.  Prior (ie, historical) 
testing results of tumor tissue performed using the FoundationOnetest may be considered 
upon Sponsor pre-approval.  
Preferably both liquid and tumor tissue (or request for approval to use historical data) will be 
submitted at prescreening.  In cases where historical FoundationOnetest results are 
approved by the Sponsor, tumor tissue is not required for the study, but may be requested by 
the Sponsor if available.  
If blood and tumor tissue are not submitted at the same time, patients will be stratified 
according to the results obtained from the analysis of either the liquid or the tumor tissue, 
depending on which test result is available.  If the test results are inconclusive or no result 
could be obtained due, for example, to technical reasons the investigator may submit the 
alternative sample (tumor tissue or blood) for testing as well.  If the blood and tumor tissue 
are not submitted at the same time and results required for eligibility and stratification are 
already available, the sample (tumor tissue or liquid biopsy) submitted at a later point (but 
prior to randomization) will be analyzed for exploratory concordance analyses and to help 
support development of potential diagnostic tests for talazoparib for use in this and future 
clinical trials.  If results from liquid and tumor tissue sample are available prior to 
randomization and results are not concordant for the presence of the selected DDR 
mutation(s), positive DDR results will be used for eligibility and stratification regardless of 
the tissue used to generate the data.  
A patient will participate in up to 5 periods: prescreening (optional), screening, open-label 
(Part 1) or double-blind treatment (Part 2), safety follow-up, and long-term follow-up.  The 
study schematic is provided in Figure 2.  Testing for tumor DDR gene mutational status will 
be performed at prescreening or screening.  Details regarding conduct of Part 1 and Part 2 are 
provided in Section 3.1 and Section 3.2, respectively.
For all patients, study treatment (including enzalutamide) should continue until-radiographic 
progression is determined by BICR (Part 2) or investigator (Part 1) unless in the opinion of 
the investigator the patient is still deriving benefit at this time, or following radiographic 
progression the patient is then no longer clinically benefitting in the opinion of the 
investigator, or an adverse event leading to permanent study treatment discontinuation, or 
patient decision to discontinue treatment, or death. 
For patients remaining on study treatment beyond radiographic progression, additional 
therapy (ie, radiotherapy or surgery) will be allowed, following consultation with the 
Sponsor.  Specifically, palliative radiotherapy may be used for the treatment of pain at the 
site of bone metastases that were present at baseline.  Patients should continue to be 
monitored as per usual schedule (see Table 2).  
If talazoparib or talazoparib/placebo is permanently discontinued due to an AE, dosing with 
enzalutamide may continue.  If enzalutamide is permanently discontinued due to an AE, the 
talazoparib or talazoparib/placebo dose at the time of enzalutamide discontinuation may be 
doubled after 6 weeks of enzalutamide discontinuation, based on patient’s safety and 
tolerability and only after investigator discussion with the sponsor.  

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France only: During Part 2, the discontinuation of study treatment(s) based on increases in 
PSA levels is not required if the patient entered the study base on eligibility criteria of 
progressive disease per soft tissue progression or bone disease progression.  If the patient 
entered the study based on eligibility criteria of progressive disease solely per PSA 
progression (see Section 4.1), study treatment(s) must be discontinued if PSA continues to 
rise above maximum eligibility level without an initial confirmed biological response 
(PSA response) without any clinical or radiological progression.  These patients are to 
continue to be followed for radiographic progression and survival status.
Safety follow-up visit will occur 28 days after permanent treatment discontinuation of all 
study treatments (either the combination or enzalutamide or talazoparib or 
talazoparib/placebo whichever is later) or before initiation of a new antineoplastic or 
investigational therapy, whichever occurs first. 
Long-term follow-up will begin after safety follow-up and will follow the radiographic 
imaging schedule (ie, every 8 weeks through Week 25 and then every 12 weeks thereafter 
until death, withdrawal of consent for follow-up, or study termination by the Sponsor).  
Radiographic imaging (for Part 1 and 2) and PSA assessment (for Part 2 only) should 
continue during long-term follow-up for patients who permanently discontinue study 
treatment(s) for any reason other than radiographic progression until radiographic 
progression as determined by the investigator (patients in Part 1) or by the investigator and 
BICR (patients enrolled in Part 2) regardless of the initiation of a new antineoplastic therapy.  
Survival status, diagnosis of myelodysplastic syndrome or acute myeloid leukemia, onset of 
symptomatic skeletal events,58 and initiation of a new antineoplastic therapy (or therapies) 
will be monitored until the patient dies or withdraws consent for follow-up, or the study is 
terminated by the Sponsor. 
An independent E-DMC will be established to review interim analysis of radiographic 
PFS during Part 2 (see details in Section 9.8) and analyses of aggregate safety data.  The 
roles and responsibilities of the E-DMC will be described in a separate charter. 
For all patients, disease status will be assessed at screening and at regular intervals (as well 
as when investigator assessment of signs and symptoms is warranted) during the study by 
computed tomography (CT) scans (chest, abdomen, pelvis) or magnetic resonance imaging 
(MRI) (abdomen, pelvis) for assessment only of soft tissue disease, whole-body bone scan, 
PSA measurements, and patient-reported outcome measures.  To determine the primary 
endpoint of radiographic progression, radiographic assessments will be performed at 
screening, every 8 weeks from Week 9 through Week 25, and every 12 weeks thereafter until 
radiographic progression is determined by investigator (Part 1) or investigator and BICR 
(Part 2) regardless of the initiation of a new antineoplastic therapy.  Response and 
progression for soft tissue disease will be evaluated per Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1) and bone disease progression will be evaluated only per 
Prostate Cancer Working Group 3 (PCWG3). 
Time to cytotoxic chemotherapy and time to opiate use for prostate cancer pain will be 
evaluated with concomitant and follow-up medication assessments. 

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In Part 2, patient-reported outcomes will be assessed to determine time to deterioration in 
pain using the Brief Pain Inventory Short Form (BPI-SF); to evaluate global health 
status/quality of life (QoL), functions, and symptoms using the EORTC QLQ-C30 and 
QLQ-PR25 questionnaires; and general health status using the EQ-5D-5L health 
questionnaire.  These assessments will be performed at: 

Baseline (Day 1); 

Every 4 weeks through Week 53, or centrally determined radiographic progression, 
whichever is earlier; 

Every 8 weeks after Week 53 until centrally determined radiographic progression 
when no such progression had been previously documented; 

Every 12 weeks after centrally determined radiographic progression until end of 
study.
Procedures to account for any missing data for patient-reported outcome assessments will be 
described in the statistical analysis plan. 
Unless prohibited by local regulation or ethics committee decision, a blood sample optimized 
for DNA analysis will be collected on Day 1 prior to the first dose of talazoparib or matching 
placebo and retained as a banked biospecimen for potential 
pharmacogenomics/genomic/biomarker analyses related to drug response and prostate
cancer.  For enrolled subjects, exploratory targeted and/or whole exome/genome sequencing 
and/or transcriptome and/or epigenetic analyses will be performed using the de novo or 
archival tumor tissue samples submitted at prescreening or screening remaining after 
eligibility assessment (optional for patients in Part 1).  Additional patient samples including 
saliva and blood will be obtained for exploratory biomarker assessments as described in the 
Schedule of Activities and Section 7.5. 
Hematology, reticulocyte count, erythropoietin, serum folate, B12 and serum chemistry 
samples will be collected every 2 weeks through Week 17, every 4 weeks through Week 53, 
and every 8 weeks thereafter until the end of treatment; a final sample will be collected 
approximately 28 days after the last dose of study treatment or prior to initiation of new 
antineoplastic therapy, whichever occurs first.  Investigators may collect samples for 
laboratory assessment up to 3 days prior to a scheduled visit to guide decision making.  
Samples for analysis of PSA will be collected every 8 weeks until confirmation of 
radiographic progression, and other general and laboratory assessments will be performed at 
regular intervals throughout the study according to the schedules of activities (Table 1, 
Table 2, and Table 3). 
Safety will be assessed by adverse events, physical examinations, vital signs, and clinical 
laboratory tests.  Assessment of abnormal liver tests is described in Section 5.6.3. 

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Figure 2.
Study Schematic
Informed Consent
Prescreening (optional): collection of blood sample and tumor tissue for genomic assessment of DDR status (or
historical results by Foundation Medicine with Sponsor pre-approval)
Screening 
Blood sample and
Tissue collection (de novo or archival)
for genomic assessment of DDR status, or
historical results by Foundation
Medicine with Sponsor pre-approval
(if not completed at prescreening)
        Optional for Part 1
        Required for Part 2 
Men with mCRPC
Patients who received any prior systemic cancer treatment 
initiated in the mCRPC or nmCRPC disease state are not eligible 
(N=1037)
Talazoparib
(Starting dose 1 mg/day)
+
Enzalutamide
160 mg/day
(N = 19)
Open – label Treatment
Minimum N = 12
(19 enrolled)
Remain on Open-label Treatment
Part 1: Open-Label Treatment 
for Safety, Tolerability and PK
Determine starting dose of talazoparib 
Part 1 comprehensive safety review 
after treatment through Week 5 
MUST OCCUR PRIOR TO PART 2
N = 1018
1:1 Randomization;
Blinded Treatment
Study Treatment
Discontinuation criteria met
Safety Follow-Up
Through 28 days after last dose 
of study treatment
Talazoparib
0.5 mg once daily
0.35 mg once daily if moderate 
renal impairment
Placebo
Long-Term Follow-Up
Follows imaging schedule 
Imaging and PSA measurement must 
continue for patients until 
radiographic progression is 
determined by blinded independent 
central and local review (Part 2); 
investigator (Part 1 only)
Part 2: Double-Blind Treatment 
Follow-Up
Survival status, 
diagnosis of MDS/AML,PROs, SREs, and 
initiation of new antineoplastic 
therapy(ies)
Remain on Blinded Treatment
750 unselected for DDR status (cohort 1),
Once enrollment in cohort 1 is complete 
approximately 268 additional patients harboring 
DDR deficiencies will be enrolled (cohort 2)
In combination with open-label 
enzalutamide 160 mg/day

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3.1. Part 1: Open-Label Treatment 
Patients enrolled in Part 1 were not required to test for DDR deficiency but were permitted to 
submit tissue for genomic testing.  Patients with moderate renal impairment (estimated 
glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m2 by the Modification of Diet in Renal 
Disease [MDRD] equation) at screening were not eligible for Part 1. 
The preliminary results summarizing the safety profile and PK data of talazoparib in 
combination with enzalutamide in Part 1 are discussed in Section 1.6.1.  Briefly, 
enzalutamide increased talazoparib Ctrough at Week 5 Visit by ~2-fold compared to 
talazoparib steady-state Ctrough in patients with advanced solid tumors and in patients with 
breast cancer receiving 1 mg once daily monotherapy.  The increase in talazoparib exposure 
was associated with higher than expected incidence of Grade 3/4 hematological AEs.  The 
results of Part 1 suggested that reducing the talazoparib dose to 0.5 mg once daily in 
combination with enzalutamide is expected to account for the observed interaction and 
maintain similar talazoparib exposure to that achieved with 1 mg once daily monotherapy 
with an acceptable safety profile.  Therefore, a talazoparib dose of 0.5 mg once daily will be 
administered in combination with enzalutamide 160 mg once daily in Part 2 of this study 
(refer to Section 1.6.1).  The starting dose of talazoparib for patients with moderate renal 
impairment will be 0.35 mg once daily to account for the lower talazoparib clearance in this 
subpopulation (refer to Section 1.3.3.1).
Patients receiving treatment in Part 1 will undergo study assessments (Table 2 and Table 3) 
and may continue treatment despite radiographic progression as long as in the opinion of the 
investigator the patient is still deriving benefit, and do not meet other discontinuation criteria. 
3.2. Part 2: Double-Blind Treatment
Approximately 1018 patients are planned to be enrolled in Part 2.  Initially, approximately 
750 patients unselected for DDR deficiencies (referred to as “all-comers population”) will be 
enrolled.  Although patients will be unselected for DDR status, DDR deficiency assessment 
from a blood sample or the most recent tumor tissue sample completed prior to 
randomization is required for stratification.  Once enrollment is complete in the all-comers 
population, enrollment will continue in a separate cohort of patients harboring DDR 
deficiencies. Additional all-comers patients will be randomized in China while 
randomization into Cohort 2 continues as described in Appendix 6. 
Patients will be randomly assigned to either of 2 treatment groups as follows:

Talazoparib in combination with enzalutamide.

Placebo capsules identical in appearance to talazoparib capsules in combination with 
enzalutamide.
Talazoparib or identical placebo treatment will be blinded.  Enzalutamide will be open-label. 

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In addition to analyses in the all-comers population (Cohort 1), analyses will be performed 
on the DDR-deficient population which will include patients who are identified as 
DDR-deficient from the all-comers population combined with patients from the 
DDR-deficient Cohort 2.  Based on review of safety and PK data from Part 1 of this study 
(see Section 1.6.1) the dose of talazoparib to be given in combination with enzalutamide is 
0.5 mg once daily.  During Part 2, patients with moderate renal impairment (eGFR 
30-59 mL/min/1.73 m2 by the MDRD equation) at screening may be enrolled and the 
talazoparib dose will be 0.35 mg once daily. 
Patients will take all study treatments daily (at approximately the same time) and undergo the 
assessments shown in Table 2 and Table 3 until permanent discontinuation criteria are met. 
Dose modifications are permitted and are described in Section 5.6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

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Analyses on the all-comers population will include patients randomized into the first cohort 
of patients unselected for DDR status.  Analysis on the DDR-deficient population will 
include DDR-deficient patients enrolled into Cohort 2 as well as any patients enrolled into 
Cohort 1 who are DDR-deficient. 
4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol. 
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team 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. At least 18 years of age.  For Japan, at least 20 years of age.
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without 
small cell or signet cell features.  If the patient does not have a prior histological 
diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis and to 
support biomarker analysis. 
3. Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer 
(mCRPC) (score on BPI-SF Question #3 must be <4). 
CCI

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4. For enrollment into Part 2 only (optional in Part 1): assessment of DDR mutation 
status by prospective analysis of blood (liquid biopsy), or tissue (de novo or archival 
tissue), or historical analysis (with Sponsor pre-approval), of most recent tumor tissue 
per FoundationOnetesting.  (Note: for patients enrolling in Part 1, DDR deficiency 
testing is optional).

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. 
5. For enrollment into Part 2 only (optional for Part 1): Unless prohibited by local 
regulations or ethics committee decision, consent to a saliva sample collection for 
retrospective sequencing of the same DDR genes tested on tumor tissue and blood  
(liquid biopsy), or a subset thereof, and to serve as a germline control in identifying 
tumor mutations. 
6. Surgically or medically castrated, with serum testosterone 50 ng/dL (1.73 nmol/L) 
at screening.  Ongoing androgen deprivation therapy with a gonadotropin releasing 
hormone (GnRH) agonist or antagonist for patients who have not undergone bilateral 
orchiectomy must be initiated at least 4 weeks before Day 1 (Part 1) or randomization 
(Part 2) and must continue throughout the study.
7. Metastatic disease in bone documented on bone scan or in soft tissue documented on 
CT/MRI scan.  Scans obtained as part of standard of care in the 6 weeks (42 days) 
prior to Day 1 (Part 1) or randomization (Part 2) can be used if they meet study 
requirements.  Measurable soft tissue disease is not required.  (Adenopathy below the 
aortic bifurcation alone does not qualify).
8. Progressive disease at study entry in the setting of medical or surgical castration as 
defined by 1 or more of the following 3 criteria:

Prostate specific antigen (PSA) progression defined by rising PSA of at least 
2 consecutive rises in most recent PSA to be documented over a reference value 
(measure 1) taken at least 7 days apart within the last 12 months.  If the third PSA
measure is not greater than the second measure, a fourth PSA measure is required 
to be taken and be greater than the second measure.  The third (or the fourth) 
confirmatory PSA should be taken within 4 weeks prior to randomization.  The 
third (or the fourth) PSA value, obtained before randomization must be ≥1 µg/L if 
qualifying only by PSA progression.  

Soft tissue disease progression as defined by RECIST 1.1. 

Bone disease progression defined by Prostate Cancer Working Group (PCWG3) 
with 2 or more new metastatic bone lesions on a whole body radionuclide bone 
scan. 

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9. Ongoing bisphosphonate or denosumab use prior to Day 1 (Part 1) or randomization 
(Part 2) is allowed but not mandatory. 
10. Eastern Cooperative Oncology Group (ECOG) performance status 1. 
11. Life expectancy 12 months as assessed by the investigator. 
12. Able to swallow the study treatment and have no known intolerance to study 
treatments or excipients. 
13. Sexually active participants that in the opinion of the investigator are capable of 
ejaculating, must agree to use a condom when having sex with a partner (female or 
male) from the time of the first dose of study treatment through 4 months after last 
dose of study treatment.  Must also agree for female partner of childbearing potential 
to use an additional highly effective form of contraception (Section 4.4.1) from the 
time of the first dose of study treatment through 4 months after last dose of study 
treatment when having sex with a non-pregnant female partner of childbearing 
potential. 
14. Must agree not to donate sperm from the first dose of study treatment to 4 months 
after the last dose of study treatment.
15. Evidence of a personally signed and dated informed consent document (and 
molecular prescreening consent if appropriate) indicating that the patient [or a legally 
acceptable representative] has been informed of all pertinent aspects of the study. 
16. 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 be excluded:
1. Any prior systemic cancer treatment initiated in the non-metastatic CRPC or mCRPC 
disease state. (ADT and first generation anti-androgens received in the CRPC disease 
state are NOT exclusionary). 
2. Patients whose only evidence of metastasis is adenopathy below the aortic 
bifurcation.
3. Prior treatment with second-generation androgen receptor inhibitors (enzalutamide, 
apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or 
mitoxantrone for prostate cancer.
4. Prior treatment with platinum-based chemotherapy within 6 months (from the last 
dose) prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease 
progression on platinum-based therapy within 6 months (from the last dose). 

Prior docetaxel for mCSPC is allowed if more than 4 weeks have elapsed from the 
last dose of docetaxel.  

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5. Treatment with cytotoxic chemotherapy which includes but is not limited to 
docetaxel, biologic therapy including sipuleucel-T, or radionuclide therapy received 
in the castration-sensitive prostate cancer is NOT exclusionary if discontinued in the 
28 days prior to Day 1 (Part 1) or randomization (Part 2).  Prior treatment with 
abiraterone in the castration-sensitive settings is not exclusionary if discontinued prior 
to randomization. Hormonal therapy (eg, bicalutamide, nilutamide, flutamide, 
estrogens) are not exclusionary if discontinued prior to randomization.  Prednisone  
>10 mg/day (or equivalents) is exclusionary.  
6. Treatment with any investigational agent within 4 weeks before Day 1 (Part 1) or 
randomization (Part 2).
7. Prior treatment with opioids for pain related to either primary prostate cancer or 
metastasis within 28 days prior to Day 1 (Part 1) or randomization (Part 2). 
8. Current use of potent P-gp inhibitors within 7 days prior to Day 1 (Part 1) or 
randomization (Part 2).  For a list of potent P-gp inhibitors, and other medications 
which are exclusionary because of interaction with either talazoparib or enzalutamide, 
refer to Section 5.9.
9. Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) 
or randomization (Part 2), or palliative localized radiation therapy within 3 weeks 
before randomization (Part 2). 
10. Clinically significant cardiovascular disease, including any of the following: 

Myocardial infarction or symptomatic cardiac ischemia within 6 months before 
Day 1 (Part 1) or randomization (Part 2).

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.  However, patients can be 
rescreened after adequate control of blood pressure is achieved.

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11. Significant renal dysfunction as defined by any of the following laboratory 
abnormalities: 

eGFR <30 mL/min/1.73 m2 by the MDRD equation (available via 
www.mdrd.com, see Appendix 5). 

Patients enrolled in Part 1 only: Moderate renal impairment 
(eGFR 30-59 mL/min/1.73 m2) at screening.
12. Significant hepatic dysfunction as defined by any of the following laboratory 
abnormalities on screening labs: 

Total serum bilirubin >1.5 times the upper limit of normal (ULN) (>3 × ULN for 
patients with documented 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 (>5 × ULN if liver function abnormalities are due to hepatic metastasis).

Albumin <2.8 g/dL.
13. Absolute neutrophil count (ANC) <1500/L, platelets <100,000/L, or hemoglobin 
<9 g/dL (may not have received growth factors or blood transfusions within 14 days 
before obtaining the hematology laboratory tests at screening). 
14. Known or suspected brain metastasis or active leptomeningeal disease.
15. Symptomatic or impending spinal cord compression or cauda equina syndrome.
16. Any history of myelodysplastic syndrome, acute myeloid leukemia, or prior 
malignancy except for any of the following: 

Carcinoma in situ or non melanoma skin cancer.

Any prior malignancies ≥3 years before randomization with no subsequent 
evidence of recurrence or progression regardless of the stage.

Stage 0 or Stage 1 cancer <3 years before randomization that has a remote 
probability of recurrence or progression in the opinion of the investigator.
17. In the opinion of the investigator, any clinically significant gastrointestinal disorder 
affecting absorption. 
18. Fertile male subjects who are unwilling or unable to use a condom and highly 
effective methods of contraception as appropriate as outlined in this protocol for the 
duration of the study and for 4 months after the last dose of investigational product.

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19. 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.
20. Other acute or chronic medical (concurrent disease, infection, or comorbidity) or 
psychiatric condition including recent (within the past year) or active suicidal ideation 
or behavior or laboratory abnormality that interferes with ability to participate in the 
study, 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.
21. History of seizure or any condition that may predispose to seizure (eg, prior cortical 
stroke, significant brain trauma).  Also, history of loss of consciousness or transient 
ischemic attack within 12 months of randomization (Part 2).
4.3. Randomization Criteria
In Part 2, central randomization (1:1) will be used to assign eligible patients to one of the 
treatment groups.  Randomization will be stratified by the following factors: 

Previous treatment with NHT or taxane-based chemotherapy for CSPC (yes/no).

Prior treatment with NHT refers only to prior treatment with abiraterone or 
orteronel in the castration sensitive setting since starting with amendment 4 prior 
treatment with enzalutamide, darolutamide or apalutamide is prohibited.

DDR mutation status (deficient vs. non deficient/unknown):

In the case of a test failure due to not meeting specified quality control metrics, or 
insufficient or inadequate blood or tumor tissue sample, the patient DDR 
mutational status will be considered unknown. 

If results from liquid and tumor tissue sample are available prior to randomization 
and results are not concordant for the presence of the selected DDR mutation(s), 
positive DDR results will be used for stratification regardless of the tissue used to 
generate the data.
The stratification factors will be specified by the investigator and recorded in the Interactive 
Web Response System (IWRS) before randomization.  Refer to Section 5.1 for additional 
information.
Initially 750 patients will be enrolled regardless of DDR mutation status (Cohort 1).  These 
patients will be stratified by DDR mutation status but will be considered an all-comers
population as there will be not restrictions on the number of patients with or without DDR 
deficiencies or with unknown mutation status.

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Once enrollment is complete in the all-comers population, additional patients harboring DDR 
deficiencies will be enrolled (Cohort 2) until there are approximately 380 patients with 
mCRPC harboring DDR deficiencies including patients with DDR deficiencies from 
Cohorts 1 and 2.  Analysis on the DDR-deficient population will include DDR-deficient 
patients enrolled into Cohort 2 as well as any patients within the first cohort who are 
DDR-deficient. 
4.4. Lifestyle Requirements
4.4.1. Contraception 
All sexually active male patients that in the opinion of the investigator are capable of 
ejaculating must agree to prevent potential transfer to and exposure of partner (female or 
male) of drug through ejaculate (even after vasectomy) by using a condom consistently and 
correctly, beginning with the first dose of study treatment and continuing for at least 
4 months after the last dose of study treatment.
In addition, participants with female partners of child bearing potential will be advised to use 
an additional highly effective method of contraception.  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.
The investigator is to assess if the patient is biologically capable of fathering a child or 
exposing a fetus via ejaculate.  If capable, at screening instruct the patient to use a condom to 
avoid pregnancy and/or fetal exposure and verify at every visit that the patient is following 
instructions provided.  The investigator or designee will instruct the subject to call 
immediately if the selected contraception method is discontinued.  Investigators should 
document this/these conversations with the patient in the medical records. 
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 subject or 
male subject’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 sterilization with absence of sperm in the post-vasectomy ejaculate. 
4. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).

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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 fertile male must agree not to donate sperm from the first dose of study treatment to 
4 months after the last dose of study treatment.
4.5. 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 or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (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 study, 
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, talazoparib or placebo is being investigated in combination with enzalutamide.
5.1. Allocation to Treatment
For Part 1, talazoparib and enzalutamide were open-label.  Every patient signing either the 
prescreening or screening informed consent document (ICD) will be assigned a single 
subject/patient identification (SSID) number. 

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For Part 2, allocation of patients to talazoparib or identical placebo will be blinded, while 
enzalutamide will be open-label.  Randomization to talazoparib or placebo will proceed 
through the use of the IWRS based on the following stratification factors: 

Previous treatment with NHT or taxane-based chemotherapy for CSPC (yes/no).

Prior treatment with NHT refers only to prior treatment with abiraterone or 
orteronel in the castration sensitive setting since starting with amendment 4 prior 
treatment with enzalutamide, darolutamide or apalutamide is prohibited.

DDR mutation status (deficient vs. non deficient/unknown):

In the case of a test failure due to not meeting specified quality control metrics, or 
insufficient or inadequate blood or tumor tissue sample, the patient DDR 
mutational status will be considered unknown.

If results from liquid and tumor tissue sample are available prior to randomization 
and results are not concordant for the presence of the selected DDR mutation(s), 
positive DDR results will be used for stratification regardless of the tissue used to 
generate the data.
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 and the 
protocol number.  The site personnel will then be provided with an SSID number.  After 
confirming eligibility and obtaining approval from Pfizer personnel or designee, site 
personnel will randomize the patient via IWRS.  The patient’s randomization number and a 
dispensable unit (DU) or container number will be provided.  The IWRS will provide a 
confirmation report containing the SSID number, randomization number, and DU or 
container number assigned.  The confirmation report must be stored in the site’s files.
The study-specific IWRS reference manual will provide the contact information and further 
details on the use of the IWRS system. 
5.2. Breaking the Blind
Part 2 of the study will be patient and investigator blinded to talazoparib or matching 
placebo; enzalutamide will be open-label.
At the initiation of Part 2, the investigator site will be instructed on the method for breaking 
the blind.  The method will be an electronic process.  Blinding codes should be broken only 
in exceptional circumstances when knowledge of the actual treatment code is absolutely 
essential for further management of the subject.  Investigators are encouraged to discuss with 
a member of the study team if they believe that unblinding is necessary.  When the blinding 
code is broken, the reason must be fully documented and entered on the case report form 
(CRF).

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5.3. Patient Compliance
In Part 1, for self-administration of talazoparib and enzalutamide at home, compliance will 
be captured by the sites’ drug accountability data.  In Part 2, patients will record the daily 
self-administration of all study treatments (talazoparib/placebo and enzalutamide) using an 
electronic diary.  Data entered in the diary will be compared with drug accountability done at 
the site prior to dispensing additional study treatment.  In the event of unexplained 
discrepancies, drug accountability data will prevail in determining patients’ degree of 
compliance, which will be recorded in the CRF.  Patients will be considered out of 
compliance if 20% of monthly doses of each treatment are missed. 
5.4. Investigational Product Supplies
5.4.1. Dosage Forms and Packaging
5.4.1.1. Talazoparib and Identical Placebo
Talazoparib will be provided as capsules for oral administration containing talazoparib 
tosylate formulated with silicified microcrystalline cellulose filled into hydroxypropyl 
methylcellulose as immediate-release capsules.  The 0.25 mg and 0.1 mg capsules will be 
supplied in separate bottles and labeled according to local regulatory requirements.  
Talazoparib is packaged in induction sealed, high density polyethylene bottles with child 
resistant caps of a single strength per bottle. 
Placebo capsules, which do not contain talazoparib, will be identical in appearance to each 
dosage strength of talazoparib capsules and will be provided by the sponsor.
5.4.1.2. Enzalutamide
Enzalutamide will be provided as soft gelatin capsules of 40 mg for oral administration. 
For patients in Part 1, enzalutamide capsules were sourced by the site to the patient. 
In Part 2, enzalutamide will be provided to the sites by the Sponsor, and dispensed from the 
sites to the patients.  All supplies of these drugs will be used in accordance with local 
regulations. 
5.4.2. Preparation and Dispensing
For Part 1, open-label talazoparib and enzalutamide will be dispensed manually (without the 
use of an IWRS system) every 4 weeks through Week 25 and every 12 weeks thereafter.  A 
qualified staff member will dispense the investigational product in bottles provided, in 
quantities appropriate for the study visit schedule.  The patient/caregiver should be instructed 
to maintain the product in the bottle provided throughout the course of dosing and return the 
bottle to the site at the next study visit. 

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For Part 2, talazoparib or matching placebo and enzalutamide will be dispensed using an 
IWRS drug management system every 4 weeks through Week 53 and every 8-weeks 
thereafter.  A qualified staff member will dispense the investigational product via unique 
container numbers in bottles provided, in quantities appropriate for the study visit schedule.  
The patient/caregiver should be instructed to maintain the product in the bottle provided 
throughout the course of dosing and return the bottle to the site at the next study visit. 
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.  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 study treatment.
5.5. Administration
5.5.1. Talazoparib or Blinded Therapy
Talazoparib (or blinded therapy) will be self-administered by mouth outside the clinic, except 
on days when PK is assessed; patients will withhold their dose until after the pre-dose PK 
blood sample is drawn.  For Part 1, patients initially received a starting dose of 1 mg once 
daily prior to reducing the dose to 0.5 mg/day based on results from a review of available 
safety and PK data (Section 1.6.1).
Talazoparib (or blinded therapy) should be administered with enzalutamide at approximately 
same time (morning of each day to ensure that PK collection is compliant per protocol).  
Switching to evening dosing, if necessary, is permitted after Week 13 and Week 17 visit, 
which is the last scheduled PK sample collection in Part 1 and Part 2 respectively.
The starting dose of blinded therapy for Part 2 will be 0.5 mg once daily, and will be 
administered as two 0.25 mg capsules.  The starting dose for patients with moderate renal 
impairment (30 to 59 ml/min/1.73 m2 by the MDRD equation per www.mdrd.com) 
(permitted to enroll only in Part 2) will be 0.35 mg once daily, and will be administered as 
one 0.25 mg capsule and one 0.1 mg capsule. 
Talazoparib or talazoparib/placebo can be administered with or without food.  Patients will 
swallow the investigational product whole with a large glass of water (~250 ml), and will not 
manipulate or chew, dissolve, or open the capsules prior to swallowing. 
If a patient forgets his daily dose of talazoparib or talazoparib/placebo at the time he typically 
takes it, but remembers this on the same day, within 12 hours of the usual dose time, the dose 
may be taken at that time.  Any dose that is missed (not taken within 12 hours of the intended 
time) should be skipped and should not be replaced or made up on the following day.  
Patients should not make up vomited doses; dosing should resume on the next calendar day 
unless otherwise instructed.

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5.5.1.1. Talazoparib Overdose
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 or 
talazoparib/placebo should be stopped, and physicians should consider gastric 
decontamination, follow general supportive measures and treat symptomatically. 
5.5.2. Enzalutamide
Enzalutamide will be administered by mouth as four 40-mg soft gelatin capsules once daily
(160 mg per day).  If a patient forgets his daily dose of enzalutamide at the time he typically 
takes it, but remembers this on the same day, within 12 hours of the usual dose time, the dose 
may be taken at that time.  Any dose that is missed (not taken within 12 hours of the intended 
time) should be skipped and should not be replaced or made up on a subsequent day.  
Patients should not make up vomited doses; dosing should resume on the next calendar day 
unless otherwise instructed.
Enzalutamide can be administered with or without food.  Enzalutamide should be 
administered with talazoparib or talazoparib/placebo at the same time each day (ie, morning 
of each day with switching to evening doses permitted after Week 13 (Part 1) and Week 17 
visit (Part 2). 
Patients will swallow the investigational product whole, and will not manipulate or chew, 
dissolve, or open the capsules prior to swallowing. 
Reduction of the enzalutamide dose to 120 mg (3 capsules) or 80 mg (2 capsules) daily is 
permitted per the enzalutamide label. 
Patients should be instructed to take study treatments with a large glass of water (~250 ml) at 
the same time each day. 
5.6. Dose Modifications
5.6.1. Part 1: Talazoparib Dose Determination 
The preliminary results summarizing the safety profile and PK data of talazoparib in 
combination with enzalutamide in Part 1 are discussed in Section 1.6.1.  Briefly, 
enzalutamide increased talazoparib Ctrough at Week 5 Visit by ~2-fold compared to 
talazoparib steady-state Ctrough in patients with advanced solid tumors and in patients with 
breast cancer receiving 1 mg/day monotherapy.  The increase in talazoparib exposure was 
associated with higher than expected incidence of Grade 3/4 hematological AEs.  The results 
of Part 1 suggested that reducing the talazoparib dose to 0.5 mg QD in combination with 
enzalutamide is expected to account for the observed interaction and maintain similar 
talazoparib exposure to that achieved with 1 mg QD monotherapy with an acceptable safety 
profile.  Therefore, a talazoparib dose of 0.5 mg QD will be administered in combination 
with enzalutamide 160 mg QD in Part 2 of this study.
See Section 1.6.1.1 for the summary of Part 1 safety and PK data.

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The Sponsor evaluated the emerging safety data including the occurrence of the listed target 
safety events defined in Table 6. 
Table 6.
Target Safety Events: Part 1 (Open-Label Treatment)
Hematologic Toxicity
Any of the following considered possibly or probably related to talazoparib:

Grade 4 anemia;

Grade 4 thrombocytopenia;

Grade 4 neutropenia (ANC <500/µL or <0.5 × 109/L);

Grade 3 thrombocytopenia associated with clinically significant bleeding;

Grade 3 neutropenia or Grade 3 thrombocytopenia if daily dosing is interrupted for 7 days;

Febrile neutropenia, defined as ANC <1000/µL with a single temperature of >38.3C (>101F) or a 
temperature of >38C (100.4F) sustained over a 1-hour period;

Neutropenic infection (ANC <1000/µL or <1.0 × 109/L).
Nonhematologic Toxicity
Any Grade 3 adverse event considered possibly or probably related to talazoparib excluding the following:

Grade 3 laboratory abnormalities not considered clinically significant; 

Grade 3 adverse event not considered clinically significant;

Grade 3 nausea or vomiting that responds to medical intervention within 72 hours;

Grade 3 diarrhea that can be medically managed to Grade 2 within 72 hours;

Grade 3 fatigue that improves to Grade 2 within 7 days.
Liver Toxicity
Any of the following considered possibly or probably related to talazoparib:

ALT or AST >3 × ULN if baseline ALT or AST 3 × ULN;

ALT or AST >5 × ULN (a lower threshold should be considered if the ALT or AST abnormalities are 
accompanied by symptoms and signs of hepatitis) AND 2-fold increases above baseline;

ALT or AST 3 × ULN and total bilirubin >2 × ULN;

Total bilirubin >5 × ULN.
ANC = absolute neutrophil count, ALT = alanine aminotransferase, AST = aspartate aminotransferase, 
ULN = upper limit of normal.
Toxicities will be classified by severity according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 4.03.
5.6.2. Study Treatment Dose Modification
5.6.2.1. Dose Modifications for Talazoparib or Talazoparib/Placebo Due to Adverse 
Events
In Part 2, a 0.5 mg once daily dose of talazoparib (or placebo) will be administered in 
combination with enzalutamide.  The daily dose of talazoparib/placebo may be reduced 
sequentially to 0.35 mg once daily, 0.25 mg once daily and 0.1 mg once daily to manage 
adverse events as described in Table 7.  The starting dose of talazoparib/placebo for patients 
with moderate renal impairment per www.mdrd.com will be 0.35 mg once daily with 
potential for sequential dose reductions to 0.25 mg once daily and 0.1 mg once daily to 
manage toxicity (Table 7).

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Dose modifications for talazoparib (Part 1) and talazoparib/placebo (Part 2) due to adverse 
events are described in Table 7 and Table 8 below.
Table 7.
Talazoparib or Talazoparib/Placebo Dose Modification Levels for 
Adverse Reactions
Dose Level
Dose
Administration of Dose
Starting dose
0.5 mg once 
daily 
two 0.25 mg capsules once daily 
First dose reductiona
0.35 mg once 
daily 
one 0.25 mg capsule and one 0.1 mg capsule once 
daily 
Second dose reduction
0.25 mg once 
daily 
one 0.25 mg capsule once daily
Third dose reduction
0.1 mg once 
daily 
one 0.1 mg capsule once daily 
a.
Starting dose for patients with moderate renal impairment (eGFR 30-59 mL/min/1.73 m2 based on 
MDRD equation) at Screening.  See Appendix 5.
Table 8.
Dose Modification of Talazoparib or Talazoparib/Placebo Due to Adverse 
Events
Toxicity
Management of Adverse Events
Grade 1 or 2
No requirement for dose interruption or dose reduction.  
Grade 1 or 2 anemia
If Grade 1 or 2 anemia is clinically symptomatic (eg fatigue), management 
per investigator may be warranted.  Dose interruption is allowed for 
talazoparib/placebo for 4-8 weeks.  However, patients should resume 
talazoparib/placebo as soon as symptoms that resulted in dose interruption 
have ceded to minimize treatment interruptions.  If the talazoparib or 
talazoparib/placebo dose was reduced because of Grade 1 or 2 anemia, 
re-escalation by 1 dose level is allowed if symptoms improve.
Grade 3 or 4 Anemia 
(hemoglobin <8.0 g/dL)
Hold talazoparib or talazoparib/placebo and implement supportive care per 
local guidelines. 
Monitor weekly until hemoglobin returns to ≥9 g/dL or better, then resume 
talazoparib or talazoparib/placebo at a reduced dose level. Dose 
re-escalation is NOT allowed once dose of talazoparib or 
talazoparib/placebo was reduced due to Grade 3 or 4 anemia.  
If anemia persists for >8 weeks without recovery to at least 9.0 g/dL despite 
supportive care measures, discontinue talazoparib or talazoparib/placebo and 
refer to a hematologist for evaluation.

Transfusions and erythropoiesis-stimulating agents are permitted to 
support management of hematological toxicities.  (see Section 5.9).
Grade 3 or 4 Neutropenia 
(ANC <1000/µL)
Hold talazoparib or talazoparib/placebo and implement supportive care per 
local guidelines. 
Monitor weekly until ANC 1500/L, then resume talazoparib or 
talazoparib/placebo at a reduced dose level.
If neutropenia recurs after the dose reduction, hold talazoparib or 
talazoparib/placebo and implement supportive care per local guidelines.  

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Table 8.
Dose Modification of Talazoparib or Talazoparib/Placebo Due to Adverse 
Events
Toxicity
Management of Adverse Events
Monitor weekly until ANC 1500/L, then resume talazoparib or 
talazoparib/placebo at a further reduced dose.
If neutropenia persists for >4 weeks without recovery to 1500/L at any 
dose level despite supportive care measures, discontinue talazoparib or 
talazoparib/placebo and refer to a hematologist for evaluation.

G-CSF and GM-CSF may be used at investigators discretion for the 
supportive treatment of neutropenia (see Section 5.9).
Grade 3 or 4 
Thrombocytopenia (platelets 
<50,000/µL)
Hold talazoparib or talazoparib/placebo and implement supportive care per 
local guidelines. 
Monitor weekly until platelets 50,000/L, and then resume talazoparib or
talazoparib/placebo treatment at a reduced dose.
If thrombocytopenia (<50,000/L) recurs after one dose reduction, hold 
talazoparib or talazoparib/placebo and implement supportive care per local 
guidelines.  Monitor weekly until platelets 75,000/L, then resume 
talazoparib or talazoparib/placebo at a further reduced dose.
If thrombocytopenia persists for >4 weeks without recovery to 75,000/L 
despite supportive care measures, discontinue talazoparib or 
talazoparib/placebo and refer to a hematologist for evaluation.

Thrombopoietin analogues and/or platelet transfusions may be used at 
investigators discretion for the supportive treatment of 
thrombocytopenia. (see Section 5.9).
Nonhematologic laboratory 
Grade 3 events, considered 
related to talazoparib or 
talazoparib/placebo, except 
abnormal liver tests
Hold talazoparib or talazoparib/placebo as follows:
For Grade 3 laboratory abnormalities, hold talazoparib or 
talazoparib/placebo until the laboratory abnormality resolves to Grade 2 (to 
baseline grade for creatinine increases).  Resume talazoparib or 
talazoparib/placebo at the same dose or reduce by 1 dose level.
For Grade 4 laboratory abnormalities, hold talazoparib or 
talazoparib/placebo until the laboratory abnormality resolves to Grade 2 (to 
baseline grade for creatinine increases).  Resume talazoparib or 
talazoparib/placebo at a 1 dose level reduction.
Implement supportive care per local guidelines. 
Contact the sponsor to discuss potential dose modification. 
Talazoparib or talazoparib/placebo 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
Hold talazoparib or talazoparib/placebo for liver test abnormalities as 
specified in Section 5.6.3.  Guidelines for follow-up for possible 
drug-induced liver injury and for resuming talazoparib or 
talazoparib/placebo after the liver test abnormalities resolve to baseline 
grade are provided in Section 5.6.3. 

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Table 8.
Dose Modification of Talazoparib or Talazoparib/Placebo Due to Adverse 
Events
Toxicity
Management of Adverse Events
The criteria for permanent discontinuation talazoparib or talazoparib/placebo 
are provided in Section 5.6.3.  
Nonlaboratory Grade 3 
events, considered related to 
talazoparib or 
talazoparib/placebo
Hold talazoparib or talazoparib/placebo as follows:
For Grade 3 adverse events, hold talazoparib or talazoparib/placebo until the 
adverse event resolves to Grade 1 or baseline.  Resume talazoparib or 
talazoparib/placebo at the same dose or reduce by 1 dose level.
For Grade 4 adverse events, permanently discontinue talazoparib or 
talazoparib/placebo except for the following:

Vomiting that responds to medical intervention within 3 days;

Diarrhea that is medically managed to Grade 2 within 3 days;

Constipation that is medically managed to Grade 2 within 7 days.
Resume talazoparib or talazoparib/placebo at a 1 dose level reduction.
Implement supportive care per local guidelines.  
For non-hematologic events, not related to study treatment, talazoparib or talazoparib/placebo dose 
re-escalation may be allowed after the reduced dose is tolerated without recurrence of toxicities, and only 
after investigator discussion with the sponsor.  
5.6.2.2. Dose Modifications for Enzalutamide Due to Adverse Events
Dose modifications of enzalutamide are to occur according to the local label.  If talazoparib 
or talazoparib/placebo is permanently discontinued, enzalutamide may continue.  Scheduled 
PK samples for enzalutamide should be collected if talazoparib or talazoparib/placebo is 
discontinued as shown in Table 2.
5.6.2.3. Talazoparib or Talazoparib/Placebo Dose Escalation Only if Enzalutamide 
Permanently Discontinued
If enzalutamide treatment is permanently discontinued while continuing talazoparib or 
talazoparib/placebo treatment, the talazoparib or talazoparib/placebo dose at the time of 
enzalutamide discontinuation may be escalated after 6 weeks of enzalutamide discontinuation 
as illustrated in Table 9 based on patient’s safety and tolerability and only after investigator 
discussion with the sponsor.  Should this decision be made, the escalated talazoparib or 
talazoparib/placebo dose will be dispensed at an unplanned study visit.  Scheduled PK 
samples for talazoparib or talazoparib/placebo should be collected if enzalutamide is 
discontinued as shown in Table 2.

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Table 9.
Talazoparib or Talazoparib/Placebo Dose Escalation After 6 Weeks of 
Enzalutamide Discontinuationa
Talazoparib or Talazoparib/Placebo Dose At 
the time of Enzalutamide Discontinuation 
(mg once daily)
Talazoparib or Talazoparib/Placebo Dose Levels 
After 6 Weeks From Enzalutamide Discontinuation 
(mg once daily)
0.5
1
0.35
0.75
0.25
0.5
0.1
0.2
a.
After escalation, talazoparib or talazoparib/placebo dose can be reduced in 0.25 mg decrements to 
manage AEs (refer to Table 7 and Table 8).  Patients on 0.2 mg can dose reduce to 0.1 mg.
5.6.3. Modifications Due to Abnormal Liver Tests (All Treatments)
Both talazoparib or talazoparib/placebo and enzalutamide should be withheld if liver 
enzymes abnormalities are reported.  Patients who develop abnormal liver tests (AST, ALT, 
total bilirubin [TBili]), abnormal international normalized ratio (INR) values, or signs or 
symptoms consistent with hepatitis during study treatment may meet the criteria for 
temporarily withholding or permanently discontinuing study treatment talazoparib (or 
placebo) and enzalutamide.  Patients who have abnormal liver tests or meet the criteria for 
permanent discontinuation or temporary withholding of study treatment will be followed up 
according to the recommendations in this section. 
Both study treatments should be withheld for any liver test abnormality listed in Table 10.  
When withholding study treatments, follow-up should continue for possible drug-induced 
liver injury (Section 8.4.2) until the liver test abnormalities resolve to baseline grade. 
Table 10.
Criteria for Temporary Withholding of Study Treatment in Association 
With Liver Test Abnormalities
Baselinea AST or ALT Value
Elevationb
3 × ULN

>5 × ULN 

ALT or AST 3 × ULN with the presence of signs and symptoms 
consistent with acute hepatitis and/or eosinophilia 
(500 eosinophils/L)
>3 × ULN and 5 × ULN
>8 × ULN
Baselinea Total Bilirubin Value
1.5 × ULN
>3 × ULN 
>1.5 × ULN and 3 × ULN
(Patients with Gilbert syndrome or 
for whom indirect bilirubin 
concentrations suggest an 
extrahepatic source of elevation) 
>5 × ULN
For rechallenge, dose modification may be required per Table 7.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.
a.
Baseline value is the laboratory value obtained at Day 1 prior to dosing. 
b.
Talazoparib or talazoparib/placebo should be permanently discontinued if any elevation related to study 
treatments persists for more than 7 days or AST/ALT >20 × ULN persists for longer than 3 days.

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Rechallenge with enzalutamide may only be considered according to local label.  
Rechallenge with talazoparib or talazoparib/placebo following liver test abnormalities is not 
permitted if these abnormalities are accompanied with signs or symptoms consistent with 
drug-induced liver toxicity or meet permanent discontinuation criteria.  Rechallenge with 
talazoparib (or identical placebo) may be considered at 1 reduced dose level (see Table 7) if 
an alternative cause for the abnormal liver tests (ALT, AST, Tbili) is discovered and the 
laboratory abnormalities resolve to normal or baseline values.  The investigator and sponsor 
should discuss and agree with any decision to rechallenge any of the assigned study 
treatments.  Following rechallenge, patients should be closely monitored for signs and 
symptoms of hepatitis and/or abnormal liver test results. 
Study treatment should be permanently discontinued permanently if any of the following 
criteria are met and no alternative cause explains the laboratory abnormalities: 

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 (Note: in the presence of elevated alkaline phosphatase 
associated with bone metastases, gamma glutamyl transferase [GGT] should be tested 
and the results should be within the reference range);

For subjects with baseline AST OR ALT OR Tbili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of Tbili above the normal range: Tbili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).

Patients with AST/ALT >5 × ULN that persists for more than 7 days 
(AST/ALT >8 × ULN for patients with hepatic involvement).

Patients with AST/ALT >20 × ULN that persists for longer than 3 days. 

Patients with Tbili >3 × ULN that persists for longer than 7 days (>5 × ULN for 
patients with Gilbert’s disease).
When study treatment is temporarily withheld or permanently discontinued due to a potential 
drug induced liver injury, a period of close observation is to commence until the liver test 
abnormalities return to baseline or normal values.  The evaluations listed in Table 11 should 
be performed. 

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Table 11.
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury
Results
Frequency for Repeating Liver (AST, ALT, Bilirubin 
[Total and Direct]) and INR Tests 
After the initial liver test abnormality 
Preferably within 48 hours (See Section 8.4.2). 
If AST or ALT 3 × ULN (>5 × ULN if 
baseline ALT/AST is >3 × ULN), and total 
bilirubin >2 × ULN or INR >1.5
Every 24 hours until laboratory abnormalities 
improve.
If ALT or AST 3 × ULN (>5 × ULN if 
baseline ALT/AST is >3 × ULN) and total 
bilirubin or INR are normal 
Every 48 to 72 hours until laboratory abnormalities 
improve.
If the liver test abnormalities improve AND the 
patient is asymptomatic
Frequency may decrease.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized 
ratio; ULN = upper limit of normal.  
As drug induced liver injury is a diagnosis of exclusion, it is important to initiate 
investigation of alternative causes for abnormal liver tests, which may include consultation 
with a hepatologist.  Contact the sponsor with questions regarding sufficient follow-up tests. 
5.6.4. End of Treatment
Patients are to continue study treatment until radiographic progression is determined (by 
local review in Part 1; by BICR in Part 2) unless in the opinion of the investigator the patient 
is still deriving benefit at this time, or following radiographic progression the patient is no 
longer clinically benefitting in the opinion of the investigator (see Section 3), or an adverse 
event leading to permanent discontinuation, or patient decision to discontinue study 
treatment, or death. 
5.7. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that talazoparib 
(or placebo) and enzalutamide are stored in a secured area with controlled access under 
required storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the talazoparib Investigator’s Brochure and the Summary of 
Product Characteristics for enzalutamide will be superseded by the storage conditions stated 
on the product label.

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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.
5.8. 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.
All bottles of study treatment must be returned to the investigator by the patient at every visit 
and at the end-of-treatment.  Patients who do not return bottles at the end-of-treatment will be 
reminded to bring them at their next visit.

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5.8.1. 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.
5.9. Concomitant Treatment(s)
Use of the following treatments is prohibited during the study:

Prednisone >10 mg (or equivalent) once daily (Note: short term use [<= 4 weeks] of 
higher doses of steroids although discouraged is permitted if no alternative therapy is 
available).

Cytotoxic chemotherapy (eg, platinum based chemotherapy, cyclophosphamide, 
taxanes, or mitoxantrone chemotherapy) for metastatic prostate cancer.

Hormonal therapy (eg, bicalutamide, nilutamide, flutamide, estrogens, 5-alpha 
reductase inhibitors), NHT with the exception of enzalutamide (eg, abiraterone, 
apalutamide, darolutamide), biologic therapy, or radionuclide therapy for prostate 
cancer or any other investigational agent.

Another PARP inhibitor.
Use of the following treatments is permitted during the study as below:

Treatment with bisphosphonates or denosumab during the study are permitted. 

If patient met eligibility requirements of medical castration, ongoing androgen 
deprivation therapy with a GnRH agonist or antagonist is required to continue 
throughout the study.

Hematopoietic growth factors (eg, granulocyte colony stimulating factor [G CSF], 
granulocyte macrophage colony stimulating factor [GM CSF]): Primary prophylactic 
use of granulocyte colony stimulating factors is not permitted but they may be used to 
treat treatment emergent neutropenia as indicated by the current American Society of 
Clinical Oncology (ASCO) guideline.  If neutropenic complications are observed in a 
cycle in which primary prophylaxis with colony stimulating factors (CSFs) was not 
received, secondary prophylaxis may be given at the discretion of the investigator, but 
only if dose reduction or delay are not considered a reasonable alternative.

Red blood cell (RBC) transfusions, erythropoietin and erythropoiesis-stimulating 
agents may be used at the investigator’s discretion for the supportive treatment of 
anemia.

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
Thrombopoietin analogues and/or platelet transfusions may be used at investigator’s 
discretion for the supportive treatment of thrombocytopenia.

COVID-19 vaccines are allowed. The timing of the vaccination relative to the 
administration of study treatments is at the discretion of the investigator.
The start date, stop date, and indication for concomitant treatments and/or therapies and 
medications received from screening until safety follow visit will be recorded on the CRF. 
In Part 2, patients will use an analgesic log to document their use of analgesics for prostate 
cancer pain during each of the 7 consecutive days before a scheduled visit (or scheduled 
contact during the post-treatment follow-up periods).
Analgesics (including opioids) will be collected on the concomitant medication CRF page 
where start and stop date, indication, dose and route is recorded from screening until end of 
treatment. 
Patients must also not take any of the following concomitant medications during the study: 

Prohibited medication due to potential DDI with enzalutamide (also to be considered 
as an exclusion criteria for enrollment if used within 7 days prior to Day 1 in Part 1 or 
randomization in Part 2): strong cytochrome P450 2C8 (CYP2C8) inhibitors 
(eg, clopidogrel, gemfibrozil) and inducers (eg, rifampin), strong CYP3A4 inducers 
(eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine and 
St. John’s Wort), moderate CYP3A4 inducers (eg, bosentan, efavirenz, etravirine, 
modafinil and nafcillin), or substrates of CYP3A4 (eg, alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and 
tacrolimus), CYP2C9 (eg, phenytoin, warfarin), or CYP2C19 (eg, S-mephenytoin) 
with a narrow therapeutic index unless considered medically necessary to treat a 
life-threatening condition.  If the use of warfarin cannot be avoided and is clinically 
necessary, caution and additional international normalized ratio (INR) monitoring is 
recommended. Patients treated with strong cytochrome P450 2C8 (CYP2C8) 
inhibitors (eg, clopidogrel, gemfibrozil) within 7 days from randomization are not 
eligible; if administration cannot be avoided during treatment, the dose of 
enzalutamide must be reduced to 80 mg once daily. 

Rivaroxaban and apixaban (both are direct oral anticoagulants and are substrates of 
CYP3A4 and P-gp) should be avoided as enzalutamide might result in reduced 
plasma exposure which may lead to loss of efficacy or bleeding complications.  
Switch to anticoagulants allowed per local enzalutamide prescribing information (if 
warfarin is used apply additional monitoring as stated above).  Dabigatran and 
edoxaban (direct oral anticoagulants that are substrates for P-gp but not for CYP3A4) 
should be used with caution given the unknown clinical effect of enzalutamide on 
P-gp inhibition; additional monitoring should be conducted as warranted. 

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
Prohibited medications due to potential DDI with talazoparib (also to be considered 
as an exclusion criteria for enrollment if used within 7 days prior to Day 1 in Part 1 or 
randomization in Part 2): Potent P-gp inhibitors that result in ≥2-fold increase in the 
exposure of an in vivo probe P-gp substrate according to the FDA website55 and 
University of Washington Drug-Drug Interaction database56 are not recommended: 
amiodarone, carvedilol, clarithromycin, cobicistat, dronedarone, erythromycin, 
glecaprevir/pibrentasvir, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, 
propafenone, quinidine, ranolazine, ritonavir, saquinavir, 
sofosbuvir/velpatasvir/voxilaprevir, telaprevir, tipranavir, valspodar and verapamil.  
Alternative therapies should be considered whenever possible.  If usage of any of the 
above treatment is deemed medically necessary, consultation and agreement with the 
Sponsor is required prior to treatment initiation as appropriate dose modification of 
talazoparib may be needed.  

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, elacridar 
[GF120918], eliglustat, eltrombopag, felodipine, flibanserin, fluvoxamine, piperine, 
quercetin, and schisandra chinensis extract.
Concomitant anticancer therapy is prohibited during the study.  Recording of prior and 
post-study cancer therapies including start and stop dates, and response to treatment, will be 
recorded in the CRF.
5.10. Rescue/Salvage Medication
New treatments for prostate cancer prior to the determination of radiographic progression are 
strongly discouraged.
6. STUDY PROCEDURES 
6.1. Prescreening (optional)
For prescreening procedures, see Table 1.
Prescreening is optional and may be performed at any time before the primary consent form 
is signed.  Patients who undergo prescreening will sign and date a prescreening consent form 
different from the main consent form signed at the screening visit.  Preferably a blood sample 
and tumor tissue (or historical results) will all be submitted at this time.  During this period, 
the blood sample will be analyzed at Foundation Medicine (FoundationOneLiquid test) to 
determine whether patients meet eligibility criteria (historical liquid biopsy results are not 
acceptable) and concordance assessment.  De novo or archival tumor tissue (preferably of 
metastatic disease, keeping in mind bone biopsies have high percentage of technical failure 
while lymph nodes have higher probability of success) will be also submitted for 
eligibility/stratification and concordance assessment with liquid biopsy results.  Patients who 
have prior FoundationOnetest results, based on tumor tissue, can submit their report 
indicating DDR gene status for evaluation by sponsor for eligibility consideration with 
Sponsor pre-approval.  If historical testing results will be used for eligibility and any tumor 

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tissue/DNA is still available at Foundation Medicine, the remaining tumor tissue/DNA may 
be used to confirm historical results.  Although results from either the liquid or tumor tissue 
are required for eligibility and stratification in IWRS, both blood and tumor tissue sample 
must be submitted prior to randomization.  Disease progression (eg, preliminary PSA 
increase) should be observed prior to submitting blood or tumor tissue samples for analysis to 
Foundation Medicine.  Demography, AE and research related injuries (see Section 8.1.5) will 
also be collected at this visit.
6.2. Screening
For screening procedures in Part 1 and Part 2, see Table 1.  All patients will sign and date an 
informed consent form prior to undergoing any study-specific procedures.  Screening 
activities may be repeated any time as clinically indicated.  Genomic testing will not be 
repeated if the patient was found genomically eligible by the central tissue lab during 
prescreening.  
If the patient did not participate in a prescreening visit, the blood sample and de novo or 
archival tumor tissue (preferably of metastatic disease) will be analyzed at Foundation 
Medicine (FoundationOne® Liquid test or FoundationOne® test) to determine whether 
patients meet eligibility criteria.  Patients who have prior FoundationOne® test results can 
submit their report indicating DDR gene status for evaluation by sponsor for eligibility 
consideration with Sponsor pre approval.  If historical testing results will be used for 
eligibility and any tumor tissue/DNA is still available at Foundation Medicine, the remaining
material may be used to confirm historical results.  Results from any one of these tests will be 
needed for eligibility and stratification.  If results from liquid and tumor tissue sample are 
available prior to randomization and results are not concordant for the presence of the 
selected DDR mutation(s), positive DDR results will be used for eligibility and stratification 
regardless of the tissue used to generate the data.
If not submitted during prescreening, a de novo or archival tumor tissue (preferably of 
metastatic disease) or a liquid biopsy will be also submitted for retrospective testing and 
exploratory concordance studies.  Tumor tissue may not be needed for patients with historical 
FoundationOne® results approved by the Sponsor.
Screening procedures are to be performed in the 28 days before enrollment (Part 1) or 
randomization (Part 2).  However, radiographic scans obtained in the 42 days preceding 
enrollment (Part 1) or randomization (Part 2) are acceptable.  Assessments obtained before 
the patient signs the informed consent form can be used to determine eligibility if obtained as 
part of standard of care and were performed per the specific study requirements. 
Laboratory evaluations to be done at Screening include hematology and serum chemistry, 
testosterone, PSA, and in Part 2 include CTCs, and ctDNA.  In South Africa only: Optional 
HIV testing using the ELISA test may be conducted for subjects of unknown HIV status per 
investigator discretion.  Subjects will be asked to sign an HIV consent form and be given pre 
and post test counseling at the site.

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Data collected will be recorded in CRF.
Histological characterization of prostate cancer will not be performed at Foundation 
Medicine, but must be provided by the site.  At the time of screening, the patient must 
provide the answer to question #3 of the BPI-SF to assess eligibility, and total testosterone 
must be measured to confirm that the patient is surgically or medically castrated.  The patient 
must have M1CRPC.  M1 disease means the cancer has to spread to the bone, distant lymph 
nodes (eg, aortic, common iliac, inguinal, supraclavicular, scalene, cervical lymph nodes) or 
distant organs.  Patients with evidence of disease spread to only regional lymph nodes (eg, 
pelvic, internal iliac [hypogastric], obturator, sacral) are not eligible.  Metastatic soft tissue 
disease must be seen on either CT scan (preferred) or MRI while bone lesions must be seen 
on bone scan (no other imaging modalities are allowed to assess bone lesions).  The last PSA 
value collected at screening prior to randomization must be at least 1 ng/ml.  Patients may 
have received abiraterone and taxane in the castration sensitive settings.  Abiraterone must be 
discontinued prior to randomization while docetaxel must be discontinued 28 days prior to 
randomization.  Abiraterone or taxanes or any other prostate cancer therapy (including 
sipuleucel-T) received in the CRPC settings (metastatic or non-metastatic) will be considered 
exclusionary.  Only prior treatment with first generation antiandrogens (eg, bicalutamide, 
nilutamide, flutamide) in conjunction with ADT or old hormonal therapies (eg, estrogen, 
cyproterone acetate) are allowed in the metastatic or non-metastatic CRPC setting if 
discontinued prior to randomization.  Prior treatment with enzalutamide, darolutamide, 
apalutamide is not allowed.
Investigator is to assess if the patient is biologically capable of fathering a child or exposing a 
fetus via ejaculate.  If applicable, 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.
6.3. Treatment Period (Part 1 and Part 2)
For procedures/assessments, see Table 2. 
Study visits during the treatment period will occur every 2 weeks through Week 17, every 
4 weeks through Week 53, and every 8 weeks after Week 53.  In Part 2 patients will 
document their prostate cancer pain symptoms and their use of analgesics for prostate cancer 
pain by completing both an electronic pain log and an electronic analgesic log during each of 
the 7 consecutive days preceding a scheduled visit as indicated on Schedule of Activities.
Patient-reported outcomes assessments will be conducted in Part 2 at baseline (Day 1) and 
are then to occur at scheduled study visits as follows: every 4 weeks through Week 53 or 
until determination of radiographic progression whichever is earlier; every 8 weeks after 
Week 53 until determination of radiographic progression when no such progression has been 

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previously documented; every 12 weeks after radiographic progression until the end of the 
study.
Blood samples will be collected for various assessments on Day 1, and at the following time 
points thereafter per the Schedule of Activities (SOA):

Hematology, serum chemistry, reticulocyte count, erythropoietin, serum folate and 
B12: every 2 weeks through Week 17, then every 4 weeks through Week 53, and then 
every 8 weeks thereafter.  Investigators may collect samples for laboratory 
assessment up to 3 days prior to a scheduled visit to guide decision making. Day 1 
only: sample to be stored for reflex testing for hepatitis B virus (HBV) (hepatitis B 
surface antigen [HbsAg], and anti-HBc), hepatitis C virus (HCV), hepatitis C 
antibody (HCV Ab), and reflex testing for HCV RNA if positive.  Tests on this 
sample will be done if liver toxicities occur during treatment period.

PSA assessments: every 8 weeks until determination of radiographic progression.  
Upon PSA progression or response, confirmation by a second consecutive value at 
least 21 days later is required.  (An additional PSA is to be collected at the Week 53 
visit, then to continue every 8 weeks thereafter thus aligning the PSA and site visits to 
be every 8 weeks). 

PK assessments: 

Part 1: Collect blood samples for PK pre-dose, 1, 2, 4, 6 and 24 hours post-dose at 
Day 1 (Week 1) and Week 9.  Collect blood samples for PK pre-dose and 2 hours 
post-dose at Week 5 and pre-dose at Week 13. 

Part 2: Collect blood samples for PK pre-dose and 2 hours post-dose at Weeks 3, 
5, and 9, and pre-dose at Weeks 13 and 17. 

All patients: Additional PK should be taken based on discretion of investigators, 
eg, adverse events. 

Record the dose amounts and time of dose administration on both the day of and 
the day before PK sampling.  Record the date and time of each PK sample.

Saliva sample for DNA sequencing (optional for Part 1) will be collected on Day 1.

Samples for CTC analysis, circulating tumor DNA (ctDNA), and protein biomarkers: 
at Day 1, Weeks 9, 17, 25, and then at safety follow-up visit.  Samples will be sent to 
a central laboratory  as detailed in the Central Laboratory Manual.
See Table 2 Schedule of Activities for details.
Radiographic scans (CT of chest, CT/MRI of abdomen and pelvis, and whole body bone 
scan) will be conducted every 8 weeks through Week 25, then every 12 weeks thereafter until 
progression is confirmed by the investigator (Part 1) or an independent blinded reviewer and 

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investigator (Part 2).  For Part 2 scans will be submitted electronically for BICR review and 
results will be communicated back to the site only if the request for progressive disease 
verification will be submitted to the vendor (see the imaging manual).  If radiographic 
progression is documented (by the BICR and investigator for Part 2 and investigator for 
Part 1) and the patient continues on study treatment as the patient is clinically benefitting per 
investigator, all radiographic imaging is to be continued per standard of care at the 
institution.
Any diagnosis of myelodysplastic syndrome (MDS) or AML for any patient 
enrolled/randomized will be reported as an SAE (Section 8.2.3). 
If disease progression is suspected, additional radiographic scans may be performed, and 
additional PSA may be collected.  These may be performed at an unscheduled visit as 
appropriate. 
6.4. Safety Follow-up
For safety follow-up procedures after Part 1 and Part 2, see Table 2.  Safety follow-up will 
occur approximately 28 calendar days after the last dose of study treatment (talazoparib, or 
talazoparib/placebo, or enzalutamide) or before initiation of a new antineoplastic therapy or 
investigational therapy (whichever occurs first).  Contact with the patient for AE follow-up 
may be done via phone call if the patient does not come to the site.
6.5. Long-Term Follow-up
For long-term follow-up procedures after Part 1 and Part 2, see Table 3.  This period begins 
after safety follow-up and can be conducted by telephone unless imaging is required. 
Survival status can be obtained by any means including telephone, during a visit, chart 
review, or contact with someone who is knowledgeable of the patient’s survival status 
(eg, relative, friend, referring healthcare provider).  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.
Patients who have not had a symptomatic skeletal event will continue to be assessed for the 
onset of such an event.
Patients will continue to complete the BPI-SF, EORTC QLQ-C30 and QLQ PR25, 
EQ 5D 5L, Pain Log, and Analgesic Log prior or during any scheduled visit as per Table 3.  
During Long Term Follow up when the visits may be conducted by telephone (if imaging is 
not being performed due to radiographic progression being met) these assessments should 
also be completed remotely from home as per the long term visit schedule.  
Patients will be followed for subsequent antineoplastic or investigational therapy treatments 
and for diagnosis of myelodysplastic syndrome or acute myeloid leukemia.

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Patients will be followed for radiographic progression (Part 1 and 2) and PSA assessments 
(Part 2 only) per the radiographic imaging schedule if radiographic progression was not 
determined prior to discontinuation of study treatments. 
6.6. Patient Withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) 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. 
There will be 3 forms of voluntary withdrawal from the study: withdrawal from further 
receipt of investigational product, withdrawal from further study procedures, and withdrawal 
from any post-treatment follow-up.  Consent withdrawal should only be obtained if 
withdrawing from any follow-up including overall survival.  These will be entered on the 
appropriate CRF page.  Patients who request to discontinue all study treatment will be asked 
to remain in the study and continue to be followed for protocol specified follow-up 
procedures.  Patients should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible.  The withdrawal of consent should be 
explained in detail in the medical records by the investigator.  In the event that vital status 
(whether the patient is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  This includes follow-up with persons authorized by the patient.  “Lost to follow-up” 
is defined by the inability to reach the patient after a minimum of 2 documented phone calls, 
faxes, or e-mails as well as lack of response by the patient to 1 registered mail letter.  All 
attempts to contact the patient and information received during contact attempts must be 
documented in the patient’s medical record and CRF.  If it is determined that the patient has 
died, the site will use locally permissible methods to obtain the date and cause of death.  If 
the investigator’s use of a third-party representative to assist in the follow-up portion of the 
study has been included in the patient’s informed consent, then the investigator may use a 
sponsor-retained third-party representative to assist site staff with obtaining the patient’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study.  The site staff and representative will consult publicly available sources, 
such as public health registries and databases, in order to obtain updated contact information.  
If, after all attempts, the patient remains lost to follow-up, then the last contact date should be 
reported and documented in the patient’s medical records and CRF. 
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 AEs.  If applicable, 
patients who return for a final visit will undergo safety follow-up procedures as shown in 
Table 2 and Table 3.

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If the patient withdraws from the study and also withdraws consent for the 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.
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.
7.1. Companion Diagnostics for Eligibility
Patients enrolling in Part 2 are required to have their disease assessed for a genomic mutation 
in one or more pre-defined DDR genes based on testing a blood sample or de novo or 
archival tumor tissue using the FoundationOnetests.  Testing may be performed at 
prescreening (optional) or screening.  Results from testing of tumor tissue with the 
FoundationOnetest may be obtained from results of previously performed FoundationOne
testing, with Sponsor pre-approval.  In cases where historical FoundationOnetest results are 
approved by the Sponsor, tumor tissue is not required for the study, but may be requested by 
the Sponsor if available.  Assessment of genomic deficiency in DNA damage repair genes is 
optional for patients enrolling in Part 1.
DDR gene deficiencies will be identified via an NGS gene panel using blood, or de novo or 
archival tumor tissue collected at prescreening (optional) or screening.  The panel evaluates 
genomic defects in genes involved in DDR associated with hereditary cancer syndromes and 
somatic genomic alterations (mutations, insertions/deletions, and copy number variants) in 
tumor DNA likely to respond to talazoparib (refer to the Laboratory Manual for specific 
information on the genes included in the biomarker panel).  The FoundationOneNGS gene 
panel test used to determine DDR gene status in tumor tissue samples will be performed by a 
single Certified Authorization Professional/Clinical Laboratory Improvement Act 
(CAP/CLIA)-certified central clinical laboratory site (Foundation Medicine), although results 
may be obtained from either study-sponsored prospective testing or from prior (ie, historic), 
non-study sponsored testing previously performed by Foundation Medicine. 

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Blood and tumor tissue samples will be sent to Foundation Medicine for analysis with results 
returned within 2 weeks (longer time is required in case of technical issues).  If blood and 
tumor tissue are not submitted at the same time, patients will be stratified according to the 
results obtained from the analysis of either the liquid or tumor tissue biopsy, depending on 
which test result is available.  All patients will have to submit a blood sample for ctDNA 
analysis.  All patients will have to submit a tumor tissue sample unless randomized using 
historical results approved by the Sponsor.  If the test results are inconclusive or no result 
could be obtained due for example to technical reasons, the investigator may submit the 
alternative sample (tumor tissue or blood) for testing as well.  In the case of both tests fail 
due to not meeting specified quality control metrics, or insufficient or inadequate tissue 
sample, the patient DDR mutational status will be considered unknown.  If results from 
liquid and tumor tissue sample are available prior to randomization and results are not 
concordant for the presence of the selected DDR mutation(s), positive DDR results will be 
used for eligibility and stratification regardless of the tissue used to generate the data.  See 
Section 7.5.1 for collection of these samples in China.
If the blood and tumor tissue are not submitted at the same time and results required for 
eligibility and stratification are already available, the sample (tumor tissue or liquid biopsy) 
submitted at a later point (but prior to randomization) will be analyzed for exploratory 
concordance analyses and to help support development of potential diagnostic tests for 
talazoparib for use in this and future clinical trials.
Patient mutational status will be considered positive if homozygous deletions, putative 
deleterious genomic alterations, or both are detected in genes in the panel.  Neither 
single-copy somatic deletions without mutations detected in the second allele nor 
mono-allelic loss will be considered positive. 
Alternately the patient mutational status will be considered negative if homozygous 
deletions, putative deleterious genomic alterations, or both are not detected in genes in the 
panel. 
7.2. Efficacy Assessments
7.2.1. Primary Efficacy Endpoint: Radiographic Progression-Free Survival
For Part 2, the primary efficacy endpoints are:

BICR assessed rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) 
in patients with mCRPC unselected for DDR status.

BICR assessed rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) 
in patients with mCRPC harboring DDR deficiencies.
Soft tissue disease status will be assessed at regular intervals during the course of the study 
by CT of chest and CT or MRI of abdomen and pelvis.  Bone disease status will be assessed 
by whole body radionuclide bone scan. 

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When medically acceptable, contrast-enhanced CT scan is the preferred method for 
assessment of soft tissue disease and will be performed on the chest, abdomen, and pelvis.  
Patients who are intolerant to CT contrast agents should undergo CT scans without contrast 
enhancement of the chest and contrast-enhanced MRI scans of the abdomen and pelvis for 
assessment of soft tissue disease.  As a final alternative, CT scans without contrast 
enhancement of the chest, abdomen and pelvis are also acceptable.  Soft tissue response and 
progression will be evaluated per RECIST 1.1.  Whole-body bone scans will be performed to 
assess the presence of bone disease.  Bone disease is not to be assessed by CT or MRI.  
Progression of bone disease will be evaluated per PCWG3 59.
For any given patient, the imaging modality(s) used for soft tissue assessment of a given 
lesion at screening should be the same used throughout the study, unless doing so would 
compromise patient safety.  The investigator is asked to inform the sponsor prior to a change 
in soft tissue imaging modality and the reason for doing do, prior to the radiographic 
assessment, whenever possible.
For patients enrolled in Part 1, all scans performed at screening and during the study will be 
read locally by radiologists and nuclear medicine bone scan readers at the study site and 
results entered in the CRF.
For patients enrolled in Part 2, all scans performed at screening and during the study will be 
submitted electronically or by mail to the blinded independent central reviewers, and results 
communicated back to the site as described in the imaging manual; please see Section 7.7.  
All images will also be read by radiologists at the study site and locally determined 
assessments will be entered in the appropriate CRF. 
7.2.2. Assessment of Secondary Efficacy Endpoints
The secondary efficacy endpoints include overall survival, proportion of patients with 
measurable soft tissue disease at baseline with a confirmed objective response, time to 
confirmed PSA progression, time to initiation of cytotoxic chemotherapy, proportion of 
patients with confirmed PSA response 50%, duration of soft tissue response, time to pain 
progression, time to first symptomatic skeletal event, time to initiation of antineoplastic 
therapy, and time to opiate use for prostate cancer pain.
The study assessments of efficacy for these endpoints will include standard radiographic and 
imaging methods to evaluate disease progression and response (Section 7.2.1), PSA, survival 
status monitoring (Section 6.5), evaluation of concomitant treatment (Section 5.9), and pain 
evaluation using the BPI-SF questionnaire. 
Blood samples will be drawn for analysis of PSA levels to determine biochemical response 
and progression.  PSA will be assessed locally throughout the study until radiographic 
progression according to the Schedules of Activities (Table 1, Table 2, and Table 3).  
Investigators are strongly discouraged from discontinuing study treatments or initiating new 
systemic therapy due to a rising PSA for patients in Part 2, where study treatment 
administration should continue until study discontinuation criteria (BICR determined 
radiographic progression, or the patient is no longer clinically benefitting in the opinion of 
the investigator, or unacceptable toxicity, or withdrawal of consent, or death) are met. 

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Time to first symptomatic skeletal event will be defined as time to spinal cord compression, 
symptomatic bone fracture, or radiotherapy or surgery to bone, whichever occurs first, as 
determined from assessment of adverse event data.
7.2.3. Exploratory Efficacy Endpoint Assessments
Proportion of patients with conversion from 5 or more CTCs per 7.5 ml at baseline to 4 or 
fewer CTCs per 7.5 ml post-baseline; proportion of patients with conversion from detectable 
CTCs at baseline to CTCs=0 post-baseline; proportion of patients with baseline CTCs 
<5 showing increased CTCs post baseline;54 molecular profiles of tumor tissue remaining 
after genomic testing for eligibility, of saliva, and of ctDNA; circulating protein biomarker 
profiles.  These results will be analyzed for patients with mCRPC unselected for DDR status 
and patients with mCRPC harboring DDR mutations.
7.3. Patient-Reported Outcomes Assessments
Patient-reported outcome assessments will be completed by patients in Part 2 as follows.  On 
Day 1, patients will complete PRO questionnaires before the first dose of study treatment.  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. 
Prostate cancer related pain will be assessed electronically using the BPI-SF questionnaire, a 
validated 9-item instrument that uses a self-reported scale assessing level of pain, its effect 
on activities of daily living, and analgesic medication use.  Pain severity at its worst will be 
assessed electronically using BPI-SF question 3.  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.  Pain (assessed 
using BPI-SF question 3) and analgesic use (assessed using an analgesic log) will be 
collected electronically for each of the 7 consecutive days prior to study visits; the timing of 
collection is shown in Table 2 and described in Section 6.2. 
Cancer-specific global health status/quality of life, functioning, and symptoms data will be 
collected electronically using the EORTC QLQ-C30 and QLQ-PR25 questionnaires and 
general health status will be assessed using the EQ-5D-5L health questionnaire.
The EORTC QLQ-C30 is a well-known standard instrument used in oncology trials. It 
consists of a 30-item questionnaire which are grouped into five multi-item functional 
subscales (physical, role, emotional, cognitive , and social functioning), three multi-item 
symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, 
and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer).  The 
questionnaire uses 4-point Likert scales with responses from “not at all” to “very much” to 
assess all functioning and symptoms items and two 7-point Likert scales for overall health 
and overall QOL.  Responses to all items are then converted to a 0 to 100 scale using a 
standard scoring algorithm.  For functional and global QOL scales, higher scores represent a 

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better level of functioning/QOL.  For symptom-oriented scales, a higher score represents 
more extreme symptoms. 
The EORTC QLQ-PR25 is a prostate cancer-specific module of the EORTC questionnaire 
that assesses the functioning and symptoms of prostate cancer patients.  Patients will self-rate 
their current state of pain as it relates to urination, ease and frequency of urination, and bowel 
and other symptoms and signs during the past week.  Patients will also answer 5 questions 
about weight loss/gain and sexual interest and 4 questions about sexual activity during the 
past 4 weeks.  Patients will choose 1 of 4 possible responses that record level of intensity 
(not at all, a little, quite a bit, very much) within each dimension.  
The EQ-5D-5L is a validated and standardized instrument that measures the general health 
status of patients.  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.”  
7.4. Pharmacokinetic Assessments
For patients participating in Part 1, blood samples for PK analysis of talazoparib, 
enzalutamide and its N-desmethyl metabolite will be collected as shown in Table 2. 
All patients participating in Part 2 will have blood samples collected for PK assessments as 
shown in Table 2.  For patients who receive talazoparib and enzalutamide, PK samples will 
be analyzed for talazoparib and enzalutamide (and its N-desmethyl metabolite) 
concentrations.  For patients who receive placebo and enzalutamide, PK samples will be 
analyzed for enzalutamide (and its N-desmethyl metabolite) concentration.  Additional PK 
blood samples may be collected from patients experiencing unexpected or serious adverse 
events, or adverse events that lead to discontinuation.
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  Samples obtained within 10% of the nominal time will be considered protocol 
compliant.  For pre-dose PK samples, collection should occur prior to administration of the 
investigational product on that day.  Patients must be instructed to withhold their daily dose 
of study treatment 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/reduced dose 
should also be recorded in the CRF.
Refer to the lab manual for detailed collection, processing and shipping procedures.
7.5. Biomarkers 
For enrolled subjects, exploratory targeted and/or whole exome/genome sequencing and/or 
transcriptome and/or epigenetic analyses will be performed using the remainder of the de 
novo or archival tumor tissue samples submitted at prescreening or screening for eligibility 

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assessment (optional for patients enrolled in Part 1) to gain insight into the mechanisms that 
confer sensitivity to study treatment.  The results of these analyses may be combined with the 
results from targeted gene sequencing performed for enrollment eligibility assessment 
(defined DDR genes and other genes included in the FoundationOne® gene panel used in this 
test, and potential additional genomic computational assessments determined using these 
FoundationOne® data such as genomic loss of heterozygosity, tumor mutational burden, and 
somatic-germline-zygosity analysis) to further explore correlations of molecular profile with 
response to study treatment.
For enrolled subjects, blood samples for circulating tumor DNA (ctDNA) analyses will be 
collected for central lab analysis using a targeted sequencing panel including DDR genes.  In 
addition, exploratory whole exome/genome sequencing and/or epigenetic analyses may be 
performed.  The goal of these analyses is to explore potential correlations of tumor molecular 
profile and, potentially, ctDNA burden (as assessed by variant allele frequency and/or other 
validated method) with response to study treatment and to understand potential mechanisms 
of acquired resistance to study treatment.  The results of these ctDNA analyses may be 
combined with the results from targeted gene sequencing performed for enrollment eligibility 
assessment (defined DDR genes and other genes included in the FoundationOne Liquid NGS 
gene panel used in this test, and any potential associated genomic computational 
assessments).  In addition, these samples may be used to help support development of a 
potential ctDNA-based diagnostic test for talazoparib.
Unless prohibited by local regulations or ethics committee decision, saliva samples will be 
collected on Day 1 before the first dose of study treatment for exploratory targeted and/or 
whole exome/genome sequencing.  These samples will be used to characterize the germline 
status of the DDR genes used to assess patient eligibility or a subset thereof (see STUDY 
DESIGN) in order to explore the potential contribution of germline DDR status to efficacy 
and safety/tolerability with study treatment.  They will not otherwise be used to generate 
free-standing germline sequencing results, but rather only as controls to assist in identifying 
and profiling somatic tumor DNA mutations.  Collection of these samples is optional for 
patients enrolled in Part 1 but they should be collected if tumor tissue for genomic screening 
is collected from the same patient; collection of these samples is required for patients 
enrolled in Part 2. 
CTC enumeration will be performed at a central lab using blood samples collected during the 
study.  CTC counts will be assessed as a candidate pharmacodynamic biomarker and/or 
predictive biomarker of response and/or resistance.  The proportion of patients with 
conversion from 5 or more CTCs per 7.5 ml blood at baseline to 4 or fewer CTCs per 7.5 ml 
blood post-baseline will be determined, as will the proportion of patients with conversion 
from detectable CTCs at baseline to CTCs=0 per 7.5 ml blood post-baseline.  In addition, the 
proportion of patients with baseline CTC counts <5 showing increased CTC counts 
post-baseline will be assessed.  Results will be analyzed for patients with mCRPC unselected 
for DDR status and for patients with mCRPC harboring DDR mutations.  Subjects who prove 
non-evaluable for CTC enumeration at baseline (both screening and Day 1 sample must be 
non-evaluable) may forego collection of additional CTC samples.

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Blood samples for protein biomarker analyses will be collected during the study for analyses 
to help understand the pharmacodynamic effects of study treatment and to explore candidate 
predictive molecular signatures associated with response and resistance.
Please refer to footnotes in Table 2, Schedule of Activities, for details.
7.5.1. China
Whole exome/genome sequencing and/or transcriptome and/or epigenetic analyses will not 
be required for subjects enrolled in China. Biospecimens for banking and protein biomarkers 
test will not be collected and analyzed in China.
Exploratory biomarker samples will not be required for subjects enrolled in China until the 
Human Genetics Resources Administration of China (HGRAC) approves the exploratory 
research.
Exploratory biomarkers are depicted under the Biomarker Assessment Category in the 
Schedule of Activities (Table 2).  Exploratory Biomarker Assessments in China include 
blood samples for CTC analysis, ctDNA, and saliva.  These samples should not be collected 
until the HGRAC approves the exploratory research.  Depending on assay availability, blood 
may be substituted for saliva in China for retrospective exploratory characterization of the 
germline status of the DDR genes used to assess patient eligibility or a subset thereof.  
Furthermore, depending on the assay availability, ctDNA might be tested by China local 
CRO using different NGS panel from FoundationOneLiquid®.  
7.6. Banked Biospecimens
Banked biospecimens will be collected from patients for exploratory research relating to the 
drug response and prostate cancer.  These collections are not typically associated with a 
planned assessment described in the protocol.  They will be handled in a manner that protects 
each patient’s privacy and confidentiality.  Banked biospecimens will be assigned the 
patient’s study identification code (ID) at the site.  The data generated from these banked 
biospecimens will also be indexed by this ID.  Biospecimens will be kept until destruction in 
facilities with access limited to authorized personnel, and biospecimen-derived data will be 
stored on password protected computer systems.  The key between the patient’s ID and the 
patient’s direct personally identifying information (eg, name, address) will be held at the 
study site.  Biospecimens will be used only for the purposes described in the protocol and 
informed consent document; any other uses require additional ethical approval.  Unless a 
time limitation is required by local regulations or ethical requirements, biospecimens will be 
stored for many years (no time limit) to allow for research in the future, including research 
conducted during the lengthy drug-development process and also post marketing research.  
Patients may withdraw their consent for the use of their banked biospecimens at any time by 
making a request to the investigator; in this case, any remaining biospecimens will be 
destroyed, but data already generated from the biospecimens will continue to be available to 
protect the integrity of existing analyses. 

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Unless prohibited by local regulations or ethics committee decision, a 4-mL blood genomic 
banked bio-specimen Prep D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] 
[K2EDTA] whole-blood collection optimized for DNA analysis) will be collected on Day 1 
as specified in Table 2 and will be retained for potential 
pharmacogenomic/genomic/biomarker analyses related to drug response and prostate cancer.  
For example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport 
protein genes, or genes thought to be related to the mechanism of drug action may be 
examined.  The primary purpose is to examine DNA; however, the biospecimen may also be 
used to study other molecules (eg, RNA, proteins, and metabolites).
The banked biospecimens will be collected from all patients unless prohibited by local 
regulations or IRB/EC decision.
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document that they will not be compensated 
in this event.
7.6.1. Additional Research
Unless prohibited by local regulations or IRB/EC decision, subjects will be asked to indicate 
on the consent form whether they will allow banked biospecimens to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Subjects may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
7.7. Imaging Assessments 
It is important to the integrity of the study that all imaging studies for patients in Part 2 are 
forwarded to the independent core imaging laboratory as soon as requested by the Sponsor. 
Further information on materials to be forwarded for independent review, correct procedures 
for the coding/blinding of the patient’s name/identity and the return of the source 
data/documents to the site is provided in the imaging manual.
Management of incidental findings 
An incidental finding is one unknown to the subject that has potential health or reproductive 
importance, which is discovered unexpectedly in the course of a research study, but is 
unrelated to the purpose and beyond the aims of the study.  If, during the independent review 
process, an unexpected observation is identified, this finding may be shared with the study 
sponsor for disclosure to the principal investigator.  The principal investigator will be 
responsible for reporting any AEs identified from incidental findings as described in the 
ADVERSE EVENT REPORTING section.  Identification of such incidental findings during 
the independent review process should not be expected, and the site maintains responsibility 
for performing local reads of all images obtained in the study. 

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7.8. Rater Qualifications
Radiologists will be board-certified in their discipline or carry similar credentials as outlined 
in the Independent Radiographic Review Charter.
7.9. Safety Assessments
Safety endpoints include adverse events (graded according to the NCI CTCAE, 
version 4.03), physical examination (including blood pressure and pulse), and laboratory tests 
(hematology and chemistry).  In South Africa only: Optional HIV testing using the ELISA 
test may be conducted for subjects of unknown HIV status per investigator discretion.  
Subjects will be asked to sign an HIV consent form and be given pre and post test counseling 
at the site.
7.9.1. Adverse Events
The procedures for the investigator assessment of adverse events are presented in Section 8.
7.9.2. Physical Examinations
Physical examinations will be conducted according to the schedule of activities in Table 1
and Table 2.  At screening, this will constitute an assessment of systems (eg, general 
appearance, head, eyes, ears, nose, mouth, throat, skin, heart, lung, lymph nodes, 
gastrointestinal, genitourinary, neurologic, and skeletal).  During treatment, systems will be 
assessed per standard of care at the study site or as clinically indicated by symptoms.
7.9.3. Vital Signs
Vital sign measurements (blood pressure, heart rate, and temperature) height and weight will 
be assessed as shown in Table 1 and Table 2.  Height is only applicable to patients in Part 2 
and only required to be collected at Screening.
7.9.4. Clinical Laboratory Assessments
Blood samples for hematology, serum chemistry assessments, PSA, testosterone, reticulocyte 
count, erythropoietin, serum folate and B12  will be collected as shown in Table 1 and 
Table 2.  The required laboratory tests are listed in Table 12.

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Table 12.
Required Laboratory Tests (fasting is not mandatory)
Hematology
Serum Chemistry
Additional
Hematocrit 
Albumin
PSA
Hemoglobin
Total protein
Testosterone (screening only)
Mean corpuscular volume
Alkaline phosphatase
Serum folateb
RBC
ALT
B12b
Platelets
AST
Reticulocyte countb
Total bilirubina
In South Africa only: Optional 
HIV testing using the ELISA test 
may be conducted for subjects of 
unknown HIV status per 
investigator discretion.  
Erythropoietinb
WBC with differentiald
BUN or urea

ANC
Creatinine

Lymphocytes
Glucose 

Monocytes
Bicarbonate or CO2c

Eosinophils
Calcium

Basophils
Chloride
Magnesium
Phosphate
Potassium
Sodium
LDH
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BUN 
= blood urea nitrogen; CRF = case report form; INR = international normalized ratio; LDH = lactate 
dehydrogenase; PT = prothrombin time; RBC = red blood cell; WBC = white blood cell.
a.
For potential Hy’s Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, 
PT/INR, and alkaline phosphatase.
b.
Not required if the test is not available at the site laboratory. 
c.
Not required if not included in the chemistry panel at the site laboratory.  Investigators will follow up per 
standard of care of the institution (eg, blood gas analysis) if warranted by required laboratory test results.
d.
Absolute values to be entered in the CRF.  If only percentages are provided by the local laboratory, 
percentages can be entered.  If % neutrophils are not provided, but % segmented neutrophils and % 
neutrophil bands are provided these should be entered in the CRF.  In the event that % segmented 
neutrophils and % bands are provided OR only % neutrophils are provided without ANC, the site must 
manually calculate ANC by using the formula at https://www.mdcalc.com/absolute-neutrophil-count-
anc).

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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 

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the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient/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 Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
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 
(talazoparib, talazoparib/placebo, enzalutamide, whichever is taken last). 

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A separate time period for actively eliciting and collecting AEs and “Research Related 
Injury” applies only to patients who sign the molecular prescreening consent as described in 
Section 8.1.5.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.  All SAEs of myelodysplastic syndrome (MDS) or 
acute myeloid leukemia (AML) are to be reported to Pfizer Safety irrespective of study 
treatment, 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. Time Period for Collecting AEs and/or Research Related Injuries for Patients 
Who Sign the Molecular Prescreening Consent
8.1.5.1. Adverse Events 
An AE is defined as any untoward medical occurrence and can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease, 
whether or not related to the subject’s participation in the study.

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During prescreening, any AE that occurs from the time the patient undergoes a procedure to 
obtain de novo tissue or blood through and including 14 days from completion of said 
procedure, must be recorded on the CRF.  The investigator is required to assess whether the 
AE may be related to the patient’s participation in the study.
The investigator must pursue and 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.
8.1.5.2. Research-Related Injuries
Should a subject, in the investigator’s opinion, suffer a medically important research-related 
injury following blood sample collection or de novo tumor biopsy at a prescreening visit 
caused by their participation in the study, the designated Pfizer clinician or sponsor must be 
notified immediately.  Any research related injury that occurs from the time the patient 
undergoes a procedure to obtain blood or de novo tissue through and including 14 days upon 
completion of said procedure, must be recorded on the CRF.
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 subject 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 
research related injury.
An investigator may be requested by the designated Pfizer clinician or sponsor 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 subject death, a summary of available autopsy findings 
must be submitted as soon as possible to Pfizer or its designated representative.
8.1.6. 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 

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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 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.7. 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;

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

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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 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms 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).

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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);

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
0 
No change from normal or reference range (This grade is not included in 
the Version 4.03 CTCAE document but may be used in certain 
circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated

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GRADE
Clinical Description of Severity
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
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;

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
For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
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 liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.

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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 treatment 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.
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).

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If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
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 study 
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 (talazoparib, talazoparib/placebo, enzalutamide) 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:

Lack of dose reduction as specified by the protocol;

Continuation of treatment although patient met discontinuation or drug 
withholding criteria;

Incorrect study treatment dose taken by patient (any overdose or underdose);

Patient did not take study medication for 6 or more days (approximately <80%) 
within 4 weeks, unless dose withheld due to an AE;

Patient did not receive treatment as assigned by IWRS (Part 2 only).

Potential medication errors or uses outside of what is foreseen in the protocol (or in 
the case of enzalutamide inconsistent with the Summary of Product Characteristics) 
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 should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
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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. Sample Size Determination
The primary objective of Part 1 was to determine the starting dose of talazoparib when given 
in combination with enzalutamide during Part 2 (double-blind treatment period).
In Part 2 enrollment will begin in the all-comers population, Cohort 1.  Once enrollment is 
complete in Cohort 1, enrollment will continue but will be restricted to patients with DDR 
deficiencies (Cohort 2). 
The primary objectives of Part 2 are: 
•
To demonstrate that talazoparib in combination with enzalutamide is superior to 
placebo in combination with enzalutamide in prolonging BICR assessed rPFS in 
patients with mCRPC unselected for DDR status.
•
To demonstrate that talazoparib in combination with enzalutamide is superior to 
placebo in combination with enzalutamide in prolonging BICR assessed rPFS in 
patients with mCRPC harboring DDR deficiencies.
The key secondary objectives of this study are:
•
To demonstrate that talazoparib in combination with enzalutamide is superior to 
placebo in combination with enzalutamide in prolonging overall survival in patients 
with mCRPC unselected for DDR status.
•
To demonstrate that talazoparib in combination with enzalutamide is superior to 
placebo in combination with enzalutamide in prolonging overall survival in patients 
with mCRPC harboring DDR deficiencies.
 
 
 
 
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9.2. Analysis Sets
Analyses on the all-comers population will include patients randomized into the first cohort 
of patients unselected for DDR status.  Analysis on the DDR-deficient population will 
include patients with DDR-deficient disease enrolled into Cohort 2 as well as any patients 
within the first cohort with DDR-deficient disease.  These populations will be subsets of the 
populations defined below.
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Exploratory analyses of patients with mCRPC without DDR deficiencies will also be 
provided.  These will be a subgroup of patients from the all comer population.
9.2.1. Intent-to-Treat Population
The intent-to-treat (ITT) population will be defined as all patients randomly assigned to 
double-blind study treatment in Part 2.  All efficacy analyses will be conducted using the ITT 
population or a subset of the ITT population as appropriate.  An example of the latter would 
be those in the ITT population who have measurable soft tissue disease at screening in the 
assessment of proportion of patients with soft tissue response.
Additional subsets will be described in the final SAP as appropriate.

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9.2.2. Safety Population
The safety population is defined as all patients who receive at least one dose of study 
treatment (open-label or double-blind).  Study treatments include talazoparib, placebo, and 
enzalutamide administered as part of this study.  Unless otherwise specified, all safety 
analyses will use the safety population according to the actual treatment received, not the 
treatment assigned.  All safety data analyses will be conducted on the safety population.
9.2.3. Patient-Reported Outcome Population
The PRO population will be defined as a subset of ITT population who have completed a 
baseline and at least one post-baseline quality-of-life assessment prior to the end of study.
9.2.4. Pharmacokinetic Analysis Population
The PK analysis set (PAS) consists of all patients who received at least one dose of 
talazoparib or enzalutamide and provided an evaluable PK sample.
9.3. Efficacy Analysis
9.3.1. Primary Endpoint: Radiographic PFS
Radiographic PFS is defined as the time from the date of randomization to first objective 
evidence of radiographic progression as assessed in soft tissue per RECIST 1.1 or in bone 
(upon subsequent confirmation) per PCWG3 guidelines by BICR, or death, whichever occurs 
first, and will be summarized in months using the following calculation: 
rPFS (months) = [date of first objective evidence of radiographic progression 
(unconfirmed RECIST 1.1 or confirmed PCWG3), death, or censoring –
randomization date +1]/30.4375 where date of bone disease progression is censored if 
not subsequently confirmed per PCWG3.
 
 
 
 
 
 
 
 
 
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9.3.2. Analysis of Secondary Efficacy Endpoints
OS is defined as the time from randomization to the date of death due to any cause.  Patients 
last known to be alive will be censored at the date of last contact.  
 
 
 
 
  
 
Additional secondary efficacy endpoints will be evaluated separately in the all-comers 
population and in the DDR-deficient population.  
 
 
Proportion of patients with measurable soft tissue disease at baseline who have a confirmed 
objective response per RECIST 1.1 will be summarized in the all-comers population and in 
the DDR-deficient population.  Soft tissue responses must be confirmed by a follow-up 
radiographic assessment at least 4 weeks later with no evidence of confirmed bone disease 
progression on repeated bone scans at least 6 weeks apart per PCWG3 criteria.  Patients 
without documented CR or PR will be considered non-responders.  The primary evaluation 
of objective response rate (ORR) will be based on BICR overall tumor assessment.  An 
evaluation of ORR based on derived investigator assessment using RECIST 1.1 will also be 
performed.
 
Time from the date of randomization to the date of the first PSA progression will also be 
analyzed.
 
 
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The time from the first objective evidence of a CR or PR to the first objective evidence of 
disease progression (assessed in soft tissue per RECIST 1.1 or in bone upon subsequent 
confirmation per PCWG3 guidelines) or death, whichever occurs first, will be analyzed in the 
subset of patients entering with measurable soft tissue disease.
The time from randomization to first objective evidence of spinal cord compression, 
symptomatic pathologic bone fracture, or radiation or surgery to bone; time from 
randomization to the initiation of antineoplastic therapy; and time to opiate use for prostate 
cancer pain will be analyzed using statistical methods defined in the SAP. 
PFS2 is defined as time from randomization to investigator documented disease progression 
(PSA progression, progression on imaging, or clinical progression) on the first subsequent 
antineoplastic therapy for prostate cancer, or death from any cause, whichever occurs first.
9.3.3. Analysis of Exploratory Endpoints
Biomarkers will be assessed separately for blood, CTCs, tumor tissue, and saliva collected 
during Part 1 and Part 2.  In each case, summaries of baseline levels, changes from baseline 
(where appropriate), expression, and mutation will be reported as applicable. 
 
  
9.4. Patient-Reported Outcome Analyses
The PRO population will be defined as the subset of ITT patients in Part 2 who have 
completed a baseline and at least one post-baseline quality-of-life assessment prior to the end 
of study.  Missing items will be handled per the scoring manuals of each questionnaire 
administered. 
Pain is measured using the BPI-SF Question #3.  Pain and analgesic assessments will be 
completed (via pain and analgesic logs) for 7 consecutive days before each study visit. 
Analgesic data will be mapped to the WHO analgesic usage score so that an analgesic score 
may be calculated for each of the 7 days. The pain score and the analgesic usage score for 
each visit is the mean score based on the corresponding scores on the day of the visit and the 
7 days prior to the visit, assuming at least 4 of these entries are non-missing. They are 
considered missing otherwise.  Deterioration in pain is defined as ı2-point increase from the 
baseline pain score.  
Definitive deterioration in patient-reported global health status/QoL is defined as a ≥10-point 
decrease from baseline and no subsequent observations with a <10-point decrease from 
baseline assessed by the EORTC QLQ-C30.42
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Definitive deterioration in patient-reported urinary symptoms is defined as a ≥10-point 
increase from baseline and no subsequent observations with a <10-point increase from 
baseline assessed by the EORTC QLQ-PR25.41
 
 
 
 
.
9.5. Pharmacokinetic Analyses
For patients who participate in Part 1, the final PK data analyses will include calculation of 
multiple dose PK parameters (as specified in secondary endpoints for Part 1) of talazoparib, 
enzalutamide, and its N-desmethyl metabolite.  These data will be summarized using 
descriptive statistics and compared with historic data of talazoparib and enzalutamide when 
given alone to characterize PK and evaluate the DDI effect.  Non-Compartmental Analysis 
(NCA) will be used for Part 1.  Population pharmacokinetic (PopPK) analysis may be used 
for both Part 1 and Part 2 if the data allows.
For all patients (Part 1 and Part 2), PK data analyses will include descriptive summary 
statistics of the pre-dose and post-dose plasma concentrations of talazoparib, enzalutamide 
and its N-desmethyl metabolite by study visit and treatment arm. 
In addition, the PK data from this study may be used to develop a population PK model.  The 
correlations between talazoparib exposure parameters in combination with enzalutamide and 
biomarker, efficacy and safety endpoints will be explored if data allows.  The results of these 
modeling analyses will be reported separately from the clinical study report.
The analytical laboratory, and Pfizer clinical assay group (CAG) personnel will be unblinded
to study treatment assignment; therefore, only talazoparib PK samples collected from patients 
randomized to the talazoparib + enzalutamide arm will be analyzed. All collected 
enzalutamide PK samples will be analyzed. If the need arises for early analysis of the PK 
data (before database lock and release of the randomization codes for the study), an early PK 
unblinding plan will be developed. PK analyst(s) and supporting colleagues who are not 
associated with the study team, will conduct the analysis to avoid unblinding of the study 
team.
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9.6. Biomarker Analyses
Data from biomarker assays will be summarized and analyzed using appropriate methods 
such as the Wilcoxon signed rank test.  
 
 
  Graphic displays will be presented.  Biomarker results from Part 1 and Part 2 
may also be combined for similar statistical analyses as warranted.
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9.7. Safety Analysis
Safety will be evaluated for the safety population using adverse event, laboratory and vital 
signs data.  Treatment-emergent safety data will be defined as events from the first dose of 
study treatment through 28 days after permanent discontinuation of all study-treatments 
(talazoparib, talazoparib/placebo, or enzalutamide), or before initiation of a new 
antineoplastic or any investigational therapy, whichever occurs first. 
9.7.1. Adverse Events
All analyses will be based on treatment-emergent events unless otherwise specified; events 
not considered treatment-emergent will be flagged in data listings.
All adverse events will be coded to preferred term and system organ class using current 
Medical Dictionary for Regulatory Activities (MedDRA).  AEs will be presented with and 
without regard to causality based on the investigator’s judgment and by frequency of overall 
toxicity categorized by NCI CTCAE (version 4.03) grades.  Summary tables will include 
system organ class and/or preferred term; these will be described in the full SAP.
In case a patient has events with missing and non-missing toxicity grades, the maximum of 
the non-missing grade will be displayed.  Missing grade will only be displayed in the event 
that only one event has been reported for a patient and the grade is missing.
9.7.2. Analysis of Clinical Laboratory Results
If necessary, laboratory results will be converted to International System of Units (Système 
International d’unités, SI) units which will be used for applying toxicity grades and for all 
summaries.
Baseline will be defined as the latest assessment performed prior to the first dose of study 
treatment (or latest assessment prior to randomization for patients randomized but not dosed).  
If there are multiple assessments that meet the baseline definition on the same day without 
the ability to determine which was truly last, then the worst grade will be assigned as the 
baseline grade. 
Laboratory results will be programmatically classified according to NCI CTCAE 
version 4.03.  Abnormalities will be described using the worst grade by scheduled time point 
and overall. 
Additional laboratory results that are not part of NCI CTCAE version 4.03 will be presented 
according to the following categories by scheduled time point as well as overall: below 
normal limit, within normal limits, and above normal limits.
Laboratory shift tables of baseline to maximum post-baseline results to each subsequent visit 
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9.8. Interim Analysis
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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Interim analysis results for the rPFS endpoints in all-comers and DDR-deficient populations 
will be assessed by the E-DMC.  
 
 
 
 
 
9.9. Data Monitoring Committee 
Part 2 of this study will use an independent external data monitoring committee (E-DMC) 
independent of the sponsor.  The E-DMC will be responsible for ongoing monitoring of the 
efficacy and safety of patients in the study according to the charter.  The recommendations 
made by the E-DMC to alter the conduct of the study will be forwarded to Pfizer for final 
decision.  Pfizer will forward such decisions, which may include summaries of aggregate 
analyses of endpoint events and of safety data that are not endpoints, to regulatory 
authorities, as appropriate.
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 
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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.  The investigator shall ensure that the 
CRFs/DCTs are securely stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to prevent access by 
unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician patient chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
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be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
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 comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The 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 
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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, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent documents and any subject 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 subject 
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 subject, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study, the sharing of 
data relating to the study and possible risks associated with participation, including the risks 
associated with the processing of the subject’s personal data.  The investigator further must 
ensure that each study subject, or his or her legally acceptable representative, is fully 
informed about his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data.
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 
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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 STUDY
13.1. End of Study in All Participating Countries 
End of study in all 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 study 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 study US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
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Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (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 

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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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de Bono JS, Smith MR, Saad F, et al.  Subsequent Chemotherapy and Treatment 
Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant 
Prostate Cancer: Post Hoc Analysis of COU-AA-302.  Eur Urol 2017;71(4):656-64.

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James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. 
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy 
in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, 
multistage, platform randomised controlled trial.  Addition of docetaxel, zoledronic 
acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): 
survival results from an adaptive, multiarm, multistage, platform randomised controlled 
trial.  Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone 
therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, 
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Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J 
Med. 2015 Aug 20;373(8):737-46.
22.
Vale C, Burdett S, Rydzewska LHM, et al.  Addition of docetaxel or bisphosphonates to 
standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: 
a systematic review and meta-analyses of aggregate data.  Lancet Oncol 
2016;17(2):243-256.
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Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha 
emitter radium 223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 
18;369(3):213 23.
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Sipuleucel – T [package insert].  Seattle, WA: Dendreon Corporation; 2014.  Available 
at http://www.valeant.com/Portals/25/Pdf/PI/Provenge-PI.pdf.  26 June 2017.
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Schreiber V, Dantzer F, Amé JC, de Murcia G. Poly(ADP ribose): novel functions for 
an old molecule. Nat Rev Mol Cell Biol. 2006 Jul;7(7):517 28.
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Curtin NJ. PARP inhibitors for cancer therapy. Expert Rev Mol Med. 2005 Mar 
15;7(4):1 20.
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Gibson BA, Kraus WL. New insights into the molecular and cellular functions of 
poly(ADP ribose) and PARPs. Nat Rev Mol Cell Biol. 2012 Jun 20;13(7):411-24.
28.
Schreiber V, Amé JC, Dollé P, Schultz I, Rinaldi B, Fraulob V, et al. Poly(ADP ribose) 
polymerase 2 (PARP 2) is required for efficient base excision DNA repair in association 
with PARP 1 and XRCC1. J Biol Chem. 2002 Jun 21;277(25):23028 36.
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Amé JC, Rolli V, Schreiber V, Niedergang C, Apiou F, Decker P, et al. PARP 2, a 
novel mammalian DNA damage dependent poly(ADP ribose) polymerase. J Biol Chem. 
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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 
1;57(3):442 5.

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31.
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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Lord et al. (2017) Science; 355 (6330): 1152-1158.
33.
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 
29;373(18):1697 708.
34.
Abida W, Curtis KR, Taylor BS, Arcila ME, Brennan R, Danila DC, et al. Genomic 
characterization of primary and metastatic prostate cancer (PC) using a targeted next 
generation sequencing assay [abstract]. J Clin Oncol. 2015 May 18;33(15 Suppl):5062.
35.
Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients 
with metastatic castration-resistant prostate cancer: a randomised, double-blind, 
placebo-controlled, phase 2 trial. Lancet Oncol 2018; 19:975-86.
36.
Development Safety Update Report, Talazoparib (PF-06944076), 20 Jan 2017.
37.
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. 
Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J 
Med. 2013 Jan 10;368(2):138-48.
38.
European public assessment report (EPAR) for Xtandi (enzalutamide). Accessed at 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/0026
39/human_med_001663.jsp&mid=WC0b01ac058001d124.  12 May 2017.
39.
European public assessment report (EPARs) for Zytiga (abiraterone). Accessed at 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/0023
21/human_med_001499.jsp&mid=WC0b01ac058001d124. 12 May 2017.
40.
Amit O, Mannino F, Stone AM, et al.  Blinded Independent Central Review of 
Progression in Cancer Clinical Trials: Results from a Meta-analysis.  European Journal 
of Cancer 2011; 47: 1772-8.
41.
Mathias SD, Crosby RD, Qian Y, et al. Estimating minimally important differences for 
the worst pain rating of the Brief Pain Inventory-Short Form. J Support Oncol 
2011;9(2):72-8.
42.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health 
related quality-of-life scores. J Clin Oncol 1998;16(1):139-44.
43.
Li L, Karanika S, Yang G, et al. Androgen receptor inhibitor-induced "BRCAness" and 
PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci 
Signal 2017; 10:eaam7479.

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44.
Polkinghorn WR, Parker JS, Lee MX, et al. Androgen receptor signaling regulates DNA 
repair in prostate cancers. Cancer Discov 2013; 3(11):1245-53.
45.
Chakraborty G, Armenia J, Mazzu YZ, et al. Concurrent deletion of BRCA2 and RB1 
and aggressive prostate cancer. J Clin Oncol 2018; 36(6):241.
46.
Kounatidou E, Nakjang S, McCracken SRC, Dehm SM, Robson CN, Jones D, 
Gaughan L.  A novel CRISPR-engineered prostate cancer cell line defines the AR-V 
transcriptome and identifies PARP inhibitor sensitivities.  Nucleic Acids Res. 2019 Apr 
22. pii: gkz286. doi: 10.1093/nar/gkz286. [Epub ahead of print].
47.
Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth 
and progression. Cancer Discov 2012; 2(12):1134-49.
48.
Cancer Discov. 2018 Aug;8(8):OF4. doi: 10.1158/2159-8290.CD-NB2018-084. Epub 
2018 Jun 28.
49.
N England Journal of Medicine 2018; published online Aug 15.  
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50.
Gibbons JA, Ouatas T, et al.  Clinical pharmacokinetic studies of enzalutamide.  Clin 
Pharmacokinet. 2015; 54: 1043-1055.
51.
Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate 
cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–1197.  Pivotal trial that 
demonstrate a survival advantage with enzalutamide in chemotherapy-pretreated 
patients, leading to drug approval.
52.
N Engl J Med 2018; 378:2465-2474.
53.
Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor 
signalling and the PARP pathway in prostate cancer. Nat Commun 2017; 8.
54.
Lorente D1,2, Olmos D3, Mateo J2, Dolling D2, Bianchini D2, Seed G2, Flohr P2, 
Crespo M2, Figueiredo I2, Miranda S2, Scher HI4, Terstappen LWMM5, de Bono JS2.  
Circulating Tumor Cell Increase as a Biomarker of Disease Progression in Metastatic 
Castration-Resistant Prostate Cancer Patients with Low Baseline CTC Counts.  Ann 
Oncol. 2018 May 7. doi: 10.1093/annonc/mdy172. 
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https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dru
gInteractionsLabeling/ucm093664.htm#table5-2.
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https://www.druginteractioninfo.org/.

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57.
Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, et 
al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant 
Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017 
Feb;71(2):151-154.
58.
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and
objectives for castration-resistant prostate cancer: updated recommendations from the 
Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016 Apr 
20;34(12):1402-18.
59.
The Prostate Cancer Working Group 3 (PCWG3) consensus for trials in 
castration-resistant prostate cancer (CRPC). Howard I. Scher, Michael J. Morris, 
Walter Michael Stadler, Celestia S. Higano, Susan Halabi, Matthew Raymond Smith, 
Ethan M. Basch, Karim Fizazi, Charles J. Ryan, Emmanuel S. Antonarakis, Paul Gettys 
Corn, Glenn Liu, Johann Sebastian De Bono, Lawrence H. Schwartz, Tomasz M. Beer, 
William Kevin Kelly, Maha Hussain, A. Oliver Sartor, Philip W. Kantoff, and Andrew 
J. Armstrong Journal of Clinical Oncology 2015 33:15_suppl, 5000-5000

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17. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
17.1. Appendix 1: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
ADP
adenosine disphosphate
ADT
androgen deprivation therapy
AE
adverse event
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
Anti-HBc
hepatitis B core antibody
AR
androgen receptor
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC
area under the plasma concentration-time curve over the dosing 
interval (from time zero to 24 hours post-dose)
BBS
Biospecimen Banking System
BCRP
breast cancer resistant protein
BICR
blinded independent central review
BPI-SF
Brief Pain Inventory-Short Form
BRCA
breast cancer
BUN
blood urea nitrogen
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
Ctrough
lowest plasma concentration before scheduled dose
CAP/CLIA
Certified Authorization Professional/Clinical Laboratory 
Improvement Act 
CI
confidence interval
CK
creatine kinase
CL/F
apparent oral clearance
CLss/F
apparent oral clearance, calculated when drug is at steady state
COVID-19
coronavirus disease 2019
CR
complete response
CrCL
creatinine clearance
CRF
case report form

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Abbreviation
Term
CRPC
castration-resistant prostate cancer
CSA
clinical study agreement
CSF
colony stimulating factors
CSPC
castration-sensitive prostate cancer
CSR
clinical study report
CT
computed tomography/clinical trial
CTA
clinical trial application
CTCs
circulating tumor cells
ctDNA
circulating tumor deoxyribonucleic acid
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
lowest plasma concentration of drug directly before next dose
CV
coefficient variation
CYP
cytochrome 450
DDI
drug-drug interaction
DDR
deoxyribonucleic acid damage repair
DILI
drug-induced liver injury
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
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer 
cancer-specific global health questionnaire
EORTC QLQ-PR25
European Organisation for Research and Treatment of Cancer 
disease specific urinary symptoms questionnaire
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
FFPE
formalin fixed paraffin embedded

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Abbreviation
Term
FSH
follicle-stimulating hormone
FU
follow-up
gBRCA
germline breast cancer susceptibility gene
G-CSF
Granulocyte colony-stimulating factor
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal 
GM-CSF
Granulocytemacrophage colony stimulating factor
GnRH
gonadotropin-releasing hormone
HBV
hepatitis B virus
HbsAG
hepatitis B surface antigen
HCP
health care professional
HCV
hepatitis C virus
HCV Ab
hepatitis C virus antibody
HER2
human epidermal growth factor receptor 2 
HGRAC
Human Genetics Resources Administration of China
HIV
human immunodeficiency virus
HNPC
hormone-naïve prostate cancer
HR
hazard ratio
HRR
homologous recombination repair
HRRm
homologous recombination repair mutational status
HRD
homologous recombination deficiency
HRQL
health-related quality of life
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
ID
identification
IDMS
isotope dilution mass spectrometry
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

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Abbreviation
Term
IUD
intrauterine device
IWRS
Interactive Web Response System
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LDH
lactate dehydrogenase
LFT
liver function test
LPLV
last patient last visit 
M0
non-metastatic
M1
metastatic
mCRPC
metastatic castration-resistant prostate cancer
MDRD
Modification of Diet in Renal Disease
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MFS
metastasis-free survival 
MnB
meningococcal serogroup B
MRI
magnetic resonance imaging
N/A
not applicable
NCA
non-compartmental analysis
NCI
National Cancer Institute
NGS
next generation sequencing
NHT
novel hormonal therapy
NLCB
no longer clinically benefitting
NM-CRPC
non-metastatic castration-resistant prostate cancer
ORR
Objective response rate
OS
overall survival
P-gp
P-glycoprotein
PARP
poly(adenosine diphosphate-ribose) polymerase
PAS
PK analysis set
PCD
primary completion date
PCT
physician’s choice of treatment 
PCWG
Prostate Cancer Working Group
PD
pharmacodynamics(s)
PFS
progression-free survival
PGx
pharmacogenomics(s)
PI
principal investigator
PID
patient identification

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Abbreviation
Term
PK
pharmacokinetic
PopPK
population pharmacokinetic
PR
partial response
PR-25
Quality of Life Questionnaire Prostate Cancer Module
PSA
prostate-specific antigen
PRO
patient reported outcomes
PT
prothrombin time
QD
one a day
QoL
quality of life
QLQ-PR25
Quality of Life Questionnaire (prostate cancer module)
QLQ-C30
Quality of Life Questionnaire (cancer module)
RB
retinoblastoma
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
rPFS
radiographic progression free survival
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCLC
Small cell lung cancer
SmPC
summary of product characteristics
SMQ
standardized MeDRA queries 
SOA
schedule of activities
SOP
standard operating procedure
SRE
skeletal related event
SRSD
single reference safety document
SSID
single subject identification
SUSAR
suspected unexpected serious adverse reaction
t½ 
half-life
TBili
total bilirubin
TEAE
treatment-emergent adverse event
Tmax
time to reach peak concentration following drug administration
TNBC
triple-negative breast cancer
TNM
classification of Malignant Tumours
TTPP
time to PSA progression

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Abbreviation
Term
ULN
upper limit of normal
US
United States
USPI
United States package insert
Vss/F
steady-state volume of distribution
WBC
white blood cell
WHO
World Health Organization
17.2. Appendix 2: France Appendix
This appendix applies to study sites located in France.
17.3. Appendix 3: 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.
17.4. Appendix 4: Investigational Product
No subjects or third-party payers will be charged for investigational product.

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17.5. Appendix 5: eGFR Calculation Prior to Randomization
It is important to correctly calculate the eGFR value at screening to assign the starting dose 
of the blinded therapy (talazoparib/placebo) in IWRS and avoid overdosing or underdosing 
errors (which should be reported as protocol deviations and medication errors).
In the protocol, a link to the four-variable MDRD equation is provided (www.mdrd.com). 
The four variables are the serum creatinine level, age, race, and gender.  Only this equation 
must be used by all sites.  Before starting to enter the 4 variables into the MDRD equation it 
is important to contact the local laboratory and clarify which method is used to measure 
serum creatinine.  Two methods for calculating the four-variable MDRD equation are 
available: a) older method and b) the isotope dilution mass spectrometry (IDMS) method.  
Most labs are using the IDMS method given that it is more accurate and less subject to bias 
compared to the older method.
Therefore:
1. Contact the laboratory to confirm which creatinine reference method is used. 
2. Go to www.mdrd.com and enter:
a.
The serum creatinine value (remember to select the correct unit);
b. The age of the patient at randomization; 
c.
The race;
d. Double check the gender is set on male;
e.
If the laboratory confirmed the IDMS method is used, YES is already pre-checked 
(since the IDMS method should be the most commonly used).
The eGFR value to be used to select the talazoparib starting dose in IWRS is provided under 
the line: MDRD study equation. 

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17.6. Appendix 6: China-Specific Requirements 
This appendix is relevant only to study sites located in China.
At least 113 mCRPC patients from China should be enrolled into the study per China’s
registration requirement.
Therefore, considering global enrollment in Cohort 1 of TALAPRO-2 will be completed 
prior to randomization of 113 patients from China, additional patients will continue to be 
randomized in an extension China cohort after completion of enrollment into Cohort 1.  
Patients enrolled in China in Cohort 1 and in the China extension cohort will be pooled 
together to form the China cohort (see Figure 3).
Figure 3.
China Cohort
Additional sites will be opened in China.  Refer to the body of the protocol for study 
endpoints, eligibility, and assessments required. No changes from prior requirements will be 
instituted with this Amendment 7. 
Data analysis of primary and secondary study endpoints will not include patients enrolled in 
this China extension cohort. Data from the China cohort will be analyzed separately per 
local regulatory requirement. The details of the analysis will be provided in a supplemental 
SAP.
Global Cohort 1 (n=~750 randomized globally)
China Cohort  
China 
Enrollment 
Start
Global Cohort 1 
Enrollment Completion
China Cohort 
Enrollment 
Completion
China Extension  Cohort

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17.7. Cohort Appendix 7: Country-Specific Requirements
Three country amendments were finalized for this protocol:
Amendment 3: country amendment for France.
Amendment 5: country amendment for South Africa.
Amendment 7: country amendment for China.
Language required by France and South Africa is included in the body of the protocol while 
language introducing the extension cohort in China is included only in Appendix 6.