A PHASE 3, OPEN-LABEL, RANDOMIZED PARALLEL,2-ARM,MULTI-CENTER STUDY OF TALAZOPARIB(BMN 673) VERSUS PHYSICIAN'S CHOICE IN GERMLINE BRCA MUTATION SUBJECTS WITH LOCALLY ADVANCED AND/OR METASTATIC BREAST CANCER, WHO HAVE RECEIVED PRIOR CHEMOTHERAPY REGIMENS FOR METASTATIC DISEASE
Phase: PHASE3
Conditions: Breast Neoplasms, BRCA 1 Gene Mutation, BRCA 2 Gene Mutation
Sponsor: Pfizer

FINAL 14Dec2015
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Open-Label, Randomized, Parallel, 2-Arm, Multi-Center
Study of Talazoparib (BMN 673) versus Physician’s Choice in 
Germline BRCA Mutation Subjects with Locally Advanced and/or 
Metastatic Breast Cancer, Who Have Received Prior Chemotherapy 
Regimens for Metastatic Disease
Protocol Number:
673-301
Active Investigational 
Product:
Talazoparib (also known as MDV3800, BMN 673)
IND and EudraCT 
Numbers:
108708 and 2013-002716-28
Indication:
Locally advanced and/or metastatic breast cancer with germline 
BRCA1 or BRCA2 mutations
Sponsor:
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
Development Phase:
Phase 3
Sponsor's Responsible 
Medical Monitor:
, MD
Telephone:
Email:
Study Design:
Open-Label, Randomized, Parallel, 2-Arm
Comparison:
Active comparator – physician’s choice
Duration of Subject 
Participation:
Until death
Dose:
1.0 mg/day
Study Population:
Locally advanced and/or metastatic breast cancer subjects with 
germline BRCA1 or BRCA2 mutations
Original Protocol:
v1.0 – 17 July 2013
Amendment 1
v2.0 – 14 December 2015
This study will be conducted according to the principles of Good Clinical Practice as described in 
International Conference on Harmonisation guidelines, including the archiving of essential documents.
PPD
PPD
PPD
PPD
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2
SYNOPSIS
NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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AUTHORITY USE 
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TITLE OF STUDY: 
A Phase 3, Open-Label, Randomized, Parallel, 2-Arm, Multi-Center Study of Talazoparib (BMN 673)
versus Physician’s Choice in Germline BRCA Mutation Subjects with Locally Advanced and/or 
Metastatic Breast Cancer, Who Have Received Prior Chemotherapy Regimens for Metastatic Disease
PROTOCOL NUMBER:
673-301
STUDY SITES:
This study will be conducted at approximately 230 sites internationally in 16 countries (United States, 
Brazil, Russia, Spain, United Kingdom, Israel, Australia, France, Germany, Italy, Belgium, Ireland, 
South Korea, Poland, Taiwan, Ukraine). Additional countries and sites may be added. 
PHASE OF DEVELOPMENT:
Phase 3
STUDY RATIONALE:
The mutation that predisposes breast cancer susceptibility gene (BRCA) mutation carriers to cancer 
formation selectively renders tumor cells susceptible to poly ADP ribose polymerase (PARP) 
inhibition while sparing normal cells that, possessing a normal BRCA allele, are relatively resistant to 
PARP inhibition.
The selection of appropriate therapy for metastatic breast cancer is complex because of the many 
treatment options and biologic heterogeneity of the disease, including several that have led to 
development of targeted therapeutics. Among others, the potential treatment options are influenced by 
estrogen and progesterone receptor and human epidermal growth factor receptor 2 (HER2) status of 
the tumor. Treatment options for subjects presenting with metastatic breast cancer may also be 
influenced by what adjuvant therapy was used, how soon after adjuvant therapy the subject relapses, 
and by sites of metastasis. 
No therapies have been approved to date that take advantage of the well-defined vulnerability of 
BRCA mutant tumors. It would be a significant advance to provide a therapy which exploits the 
vulnerability of BRCA-mutant bearing tumors while sparing normal cells carrying one healthy BRCA 
allele. 
However, the lack of prospective, controlled studies in BRCA1 and BRCA2-mutant disease, along 
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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with the mixed data from small retrospective studies, underscores the lack of information for making 
treatment decisions for these subjects. The potential role of BRCA1 in mediation of taxane 
cytotoxicity is consistent with the observation that the taxanes may be less effective in treatment of 
BRCA1-associated metastatic breast cancer than sporadic disease. 
This coupled with the potential to specifically target the underlying genetic abnormality of the disease 
highlights the unmet need as well as the need for prospective evaluation of a molecularly rational, 
targeted therapy in comparison to the standard drugs used. While several agents have been shown to 
prolong progression-free survival (PFS) and some have modestly improved survival in metastatic 
breast cancer, the disease is, nevertheless, nearly uniformly fatal. Moreover, standard, non-targeted 
therapies are associated with substantial toxicity, which limits the quality of life of subjects while they 
are undergoing treatment.
Two studies of the PARP inhibitor, olaparib, given as a single agent to breast cancer subjects have 
been published. In one study, subjects with germline BRCA mutations were treated with either 400 mg 
twice daily or 100 mg twice daily in a non-randomized fashion. Eleven of 27 subjects (41%) receiving 
the higher dose had objective responses while 6 of 27 (22%) of subjects receiving the lower dose 
responded. In a second trial, olaparib was evaluated in subjects with germline mutations as well as 
subjects with triple negative breast cancer in the absence of germline mutations. Ten subjects with 
germline mutations were enrolled, including 6 with measurable disease. While there were no objective 
responders, 5 subjects had stable disease. There were also no responders among 16 triple negative 
breast cancer subjects who either did not have germline BRCA mutations or had unknown BRCA 
status.
In the Phase 1 study of talazoparib (also known as MDV3800, BMN 673), PRP-001, 18 breast cancer 
subjects with germline BRCA mutations, who had previously been treated with more than one 
chemotherapy regimen (range: 1 to 13), were enrolled during dose escalation (n=6) and expansion 
(n=12) as of 31 Mar 2015. All 18 subjects were treated with talazoparib at dose levels of 900 to 1100 
μg/day including 12 in the expansion phase at 1000 μg/day (9 of the 12 subjects have been in the study 
for ≥ 3 cycles). Eight of 18 subjects have had objective responses, including one confirmed complete 
response (CR) in a subject with a BRCA2 deleterious mutation.
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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OBJECTIVES: 
The primary objective of the study is to compare PFS of subjects treated with talazoparib as a 
monotherapy relative to those treated with protocol-specific physician’s choice.
The secondary objectives of the study are to evaluate the following:
!
Objective response rate (ORR)
!
Overall survival (OS)
!
Safety
!
Pharmacokinetics of talazoparib
The exploratory objectives are to evaluate the following:
!
Duration of response (DOR) for objective responders 
!
Quality of life for all enrolled subjects (European Organization for Research and Treatment of 
Cancer [EORTC] Quality of Life Questionnaire [QLC-C30]/ EORTC Quality of Life 
Questionnaire – Breast Cancer Module [QLQ-BR23])
!
Research assessments related to blood and tumor sampling that includes characterization of 
tumor sensitivity and resistance to talazoparib
STUDY DESIGN AND PLAN: 
The study is an open-label, 2-arm, 2:1 randomized trial of talazoparib versus protocol-specific 
physician’s choice. Subjects with germline BRCA mutations who have received no more than 3 prior 
cytotoxic chemotherapy regimens for locally advanced and/or metastatic breast cancer will be 
enrolled. Options for protocol-specific physician’s choice include one of the following single-agent 
chemotherapies: 
!
Capecitabine, eribulin, gemcitabine, vinorelbine 
o
The protocol-specific physician’s choice must be determined prior to randomization 
for each individual subject. 
Subjects will be centrally randomized with stratification by the following:
!
Number of prior cytotoxic chemotherapy regimens for locally advanced and/or metastatic 
disease (0 vs. 1, 2, or 3)
!
Triple negative (estrogen-receptor negative, progesterone-receptor negative, HER2-negative) 
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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vs. non-triple negative status based on most recent biopsy
!
History of central nervous system (CNS) metastases vs. no CNS metastases
Subjects must start treatment ≤ 5 days from randomization; starting later will be considered a protocol 
deviation. Treatment with talazoparib or protocol-specific physician’s choice will continue until 
radiographic disease progression as determined by the central Independent Radiology Facility (IRF), 
unacceptable toxicity, consent withdrawal, physician’s decision to terminate treatment, or Sponsor’s 
decision to terminate the trial. Subjects who discontinue from study medication for any reason other 
than radiographic disease progression as determined by the IRF or initiation of a new antineoplastic 
therapy must be followed to radiographic progression by imaging assessments (eg, computed 
tomography [CT] scans). All subjects will be followed for anticancer treatment and survival status 
until death.
NUMBER OF SUBJECTS PLANNED:
Up to 429 subjects will be enrolled. Subjects randomized into the study will not be replaced. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION: 
Individuals eligible to participate in this study must meet all of the following criteria:
!
Histologically or cytologically confirmed carcinoma of the breast
!
Locally advanced breast cancer that is not amenable to curative radiation or surgical cure 
and/or metastatic disease appropriate for systemic single cytotoxic chemotherapy
!
Documentation of a deleterious, suspected deleterious, or pathogenic germline BRCA1 or 
BRCA2 mutation from Myriad Genetics or other laboratory approved by the Sponsor; for data 
obtained regarding a BRCA1/2 mutation from a non-Myriad laboratory, the pathology report 
must be submitted to and approved by the Sponsor and a blood sample sent to Myriad for 
analysis before randomization may occur
!
No more than 3 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic 
disease (no limit on prior hormonal therapies or targeted anticancer therapies such as 
mechanistic target of rapamycin [mTOR] or CDK4/6 inhibitors, immuno-oncology agents, 
tyrosine kinase inhibitors, or monoclonal antibodies against CTL4 or VEGF)
!
Prior treatment with a taxane and/or anthracycline in the neoadjuvant, adjuvant, locally 
advanced, or metastatic setting unless medically contraindicated
!
18 years of age or older
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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!
Have measurable or non-measurable, evaluable disease by the revised response evaluation 
criteria in solid tumors (RECIST) v.1.1
!
Eastern Cooperative Oncology Group (ECOG) performance status ≤2
!
Adequate organ function as defined below:
o
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × 
upper limit of normal (ULN); if liver function abnormalities are due to hepatic 
metastasis, then AST and ALT ≤5 × ULN
o
Total serum bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert’s syndrome)
o
Calculated creatinine clearance ≥ 30 mL/min by local laboratory or Cockcroft-Gault 
formula
o
Hemoglobin ≥9.0 g/dL with last transfusion at least 14 days before randomization
o
Absolute neutrophil count (ANC) ≥1500/mm3
o
Platelet count ≥100,000/mm3
!
Able to take oral medications
!
Willing and able to provide written, signed informed consent after the nature of the study has 
been explained, and prior to any research-related procedures
!
A female of childbearing potential (defined in Section 9.7.4.6) must not be pregnant and must 
agree to avoid pregnancy during the study by using a highly effective birth control method 
(defined in Section 9.7.4.6) from the time of the first dose of study drug through 45 days after 
the last dose of study drug
!
Male subjects must use a condom when having sex with a pregnant woman and when having 
sex with a woman of childbearing potential from the time of the first dose of study drug 
through 105 days after the last dose of study drug. Contraception should be considered for 
a nonpregnant female partner of childbearing potential
!
Male and female subjects must agree not to donate sperm or eggs, respectively, from the first 
dose of study drug through 105 days and 45 days after the last dose of study drug, respectively
!
Females of childbearing potential (defined in Section 9.7.4.6) must have a negative serum 
pregnancy test at Screening and be willing to have additional pregnancy tests during the study
!
Willing and able to comply with all study procedures
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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study:
!
First-line locally advanced and/or metastatic breast cancer with no prior adjuvant 
chemotherapy unless the Investigator determines that one of the 4 cytotoxic chemotherapy 
agents in the control arm would be otherwise offered to the subject
!
Prior treatment with a PARP inhibitor (not including iniparib)
!
Not a candidate for treatment with at least 1 of the treatments of protocol-specific physician’s 
choice (ie, capecitabine, eribulin, gemcitabine, vinorelbine)
!
Subjects who had objective disease progression while receiving platinum chemotherapy 
administered for locally advanced or metastatic disease; subjects who received low-dose 
platinum therapy administered in combination with radiation therapy are not excluded
!
Subjects who have received platinum in the adjuvant or neoadjuvant setting are eligible; 
however, subjects may not have relapsed within 6 months of the last dose of prior platinum 
therapy
!
Cytotoxic chemotherapy within 14 days before randomization
!
Radiation or anti-hormonal therapy or other targeted anticancer therapy within 14 days before 
randomization
!
Has not recovered from the acute toxicities of previous therapy, except treatment-related 
alopecia or laboratory abnormalities otherwise meeting the inclusion requirements stated in the 
inclusion criteria
!
HER2 positive breast cancer
!
Active inflammatory breast cancer
!
CNS metastases
o
Exception: Adequately treated brain metastases documented by baseline CT or MRI 
scan that has not progressed since previous scans and that does not require 
corticosteroids (except prednisone ≤5 mg/day or equivalent) for management of CNS 
symptoms. A repeated CT or MRI following the identification of CNS metastases 
(obtained at least 2 weeks after definitive therapy) must document adequately treated 
brain metastases
o
Subjects with leptomeningeal carcinomatosis are not permitted
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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!
Prior malignancy except for any of the following:
o
Prior BRCA-associated cancer as long as there is no current evidence of the prior 
cancer 
o
Carcinoma in situ or non-melanoma skin cancer
o
A cancer diagnosed and definitively treated ≥ 5 years before randomization with no 
subsequent evidence of recurrence
!
Known to be human immunodeficiency virus positive
!
Known active hepatitis C virus, or known active hepatitis B virus
!
Use of any investigational product (IP) or investigational medical device within 14 days before 
randomization
!
Major surgery within 14 days before randomization
!
Myocardial infarction within 6 months before randomization, symptomatic congestive heart 
failure (New York Heart Association [NYHA] > class II), unstable angina, or unstable cardiac 
arrhythmia requiring medication) 
!
Female subjects who are breastfeeding at Screening or planning to become pregnant at any 
time during study participation through 45 days after the last dose of study drug; male subjects 
who are planning to impregnate a partner at any time during study participation through 
105 days after the last dose of study drug
!
Concurrent disease or condition that would interfere with study participation or safety, such as 
any of the following:
o
Active, clinically significant infection either grade > 2 by National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 or 
requiring the use of parenteral anti-microbial agents within 14 days before 
randomization
o
Clinically significant bleeding diathesis or coagulopathy, including known platelet 
function disorders
!
Non-healing wound, ulcer, or bone fracture, not including a pathological bone fracture caused 
by a pre-existent pathological bone lesion
!
Known hypersensitivity to any of the components of talazoparib
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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Page: 
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INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
Talazoparib will be administered orally once daily (ie, continuous dosing). Talazoparib should be 
taken at approximately the same time each day, preferably in the morning. Talazoparib will be 
swallowed whole, and may be taken with or without food. On days of clinic visits when PK samples 
are to be drawn, talazoparib should be taken at the clinic after completion of the pre-dose sampling and 
assessments.
The IP is talazoparib tosylate, a white to off-white crystalline powder. The drug substance is a 
4-methylbenzenesulfonate (tosylate) salt of talazoparib free base, the active moiety. The drug product 
consists of the drug substance formulated with a pharmaceutically suitable excipient filled into 
hydroxymethylpropylcellulose capsules. Capsules will be provided to the sites in dose strengths of 
0.25 mg and 1.0 mg capsules. The dosage strengths are based on the active moiety (talazoparib free 
base). The capsules for each dose strength are provided in dose-specific colors to provide a visual 
method of distinguishing dose strengths. 
Talazoparib should be stored at room temperature (15 to 30°C; 59 to 86°F). The capsules are supplied 
in 30-count induction-sealed high-density polyethylene (HDPE) bottles. 
Daily dosing of talazoparib can be interrupted for recovery from toxicity for up to 28 days. For 
interruptions longer than 28 days, treatment at the same or a reduced dose can be considered based on 
a discussion between the Sponsor or designee and Investigator if evidence of response or clinical 
benefit to talazoparib is noted. Dose modifications must be made based on observed toxicity as 
described in Section 9.4.7.1. 
DURATION OF TREATMENT: 
Subjects are eligible to receive treatment until radiographic disease progression as determined by the 
IRF, occurrence of unacceptable toxicity, subject or physician decision to stop treatment, or until the 
study is terminated by the Sponsor. 
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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Page: 
Reference: 
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REFERENCE THERAPIES, DOSE, ROUTE AND REGIMEN: 
Treatment of protocol-specific physician’s choice is to include any one of the single-agent 
chemotherapies listed below. Suggested dosing schedules are noted, but if institution dose and regimen 
guidelines differ, the site may utilize institution guidelines: 
!
Capecitabine: 1250 mg/m2, oral, twice daily, from Day 1 through 14 of a 21-day cycle, 
30 minutes after meal.
!
Eribulin mesylate: 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2), infusion over 2-5 minutes, 
Days 1 and 8 of 21-day cycles
!
Gemcitabine: 1250 mg/m2, infusion over 30 minutes, Days 1 and 8 of 21-day cycles
!
Vinorelbine: 30 mg/m2, weekly infusion over 6 to 10 minutes, Days 1, 8 and 15 of 21-day 
cycles
Dose modifications and reductions are to occur per the package insert and institutional practice, and as 
described in Section 9.4.7.3.
CRITERIA FOR EVALUATION: 
Efficacy: 
The primary efficacy measure will be the ability of the treatment to delay progression of breast cancer, 
assessed using sequential imaging studies digitally submitted to and reviewed by the central IRF. 
Progression and response will be defined according to RECIST v.1.1 with modifications. Radiographic
disease assessment (CT and/or magnetic resonance imaging [MRI]) will be performed within 28 days 
prior to randomization. Subjects will undergo radiographic disease assessment every 6 weeks 
(± 7 days) from the date of randomization for 30 weeks. 
Thereafter, imaging assessments will be performed every 9 weeks (± 7 days) until progressive disease 
is radiographically documented as determined by the IRF or the time of initiation of a new 
antineoplastic therapy. Clinical disease progression should be verified by radiographic imaging as 
determined by the IRF before discontinuing study treatment (or the subject will not be considered to 
have a progressive disease event for the purposes of the analysis). Imaging assessments should
continue according to the schedule of assessments until radiographic progression is observed by the 
IRF, unless the subject withdraws consent or initiates a new antineoplastic therapy. 
The secondary efficacy measures include ORR (RECIST v.1.1 with modifications) as assessed by the 
IRF and OS. Confirmation of objective response (CR or partial response [PR]) is not required.
The exploratory efficacy measures are to evaluate DOR in responding subjects and quality of life 
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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(EORTC QLQ-C30/EORTC QLQ-BR23).
Safety:
The following safety outcome measurements will be assessed:
!
Incidence of adverse events (AEs), including serious AEs (SAEs) 
!
Change in clinical laboratory tests (serum chemistry and hematology)
!
Change in vital signs
!
Change in physical examination 
!
Concomitant medication use
Pharmacokinetics:
The following PK parameters will be determined from plasma talazoparib concentrations:
!
Trough concentrations of talazoparib
A population PK modeling approach will be used to estimate individual values of apparent clearance 
(CL/F) and central volume of distribution (Vc/F). Individual CL/F estimates will then be used to 
estimate individual area under the concentration time curve over a dosing interval (AUCτ).
STATISTICAL METHODS: 
Primary Efficacy Analysis:
The primary efficacy analysis is the comparison of PFS in subjects treated with talazoparib versus 
treatments of protocol-specific physician’s choice.
PFS is defined as time from randomization until the date of radiologic progressive disease (per 
RECIST v.1.1 with modifications as described in Section 24.3) as determined by the central IRF or 
death from any cause, whichever comes first. 
The primary analysis will be conducted when at least 288 PFS events have been observed, and will be 
performed using the intent-to-treat (ITT) population, defined as all randomized subjects. 
The primary analysis will include only radiographic progression events as determined by the central 
IRF per RECIST v.1.1 with modifications and deaths. Clinical deterioration or radiographic 
progression determined by Investigators will not be considered progression events for the primary 
analysis.
A stratified log-rank 2-sided test with a 0.05 level of significance will be used to compare treatment 
groups. The stratification factors will be the same as used to stratify the randomization schedule as 
documented in the interactive voice and Web response system (IXRS). 
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
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The median PFS and the associated 95% confidence interval (CI) for each treatment arm will be 
estimated using the Kaplan-Meier method. 
The hazard ratio (HR=λtalazoparib/ λcontrol) and the associated 95% CI will be estimated using a Cox 
regression model with treatment group as the only main effect and stratifying by the same stratification 
factors as were used for the log-rank test. An unstratified HR and the associated 95% CI will also be 
presented.
If the p-value for the stratified log-rank test is statistically significant (< 0.05, two-sided) and the 
observed HR (λtalazoparib/ λcontrol) is < 1, the null hypothesis of no difference in PFS will be rejected and 
it will be inferred that PFS is statistically prolonged in the group receiving talazoparib compared with 
the group receiving protocol-specific physician’s choice of therapy.
Secondary Efficacy Analysis: 
Secondary efficacy endpoints include ORR and OS. To maintain experiment-wise 2-sided type I error 
at 0.05, a detailed multiplicity adjusted inferential procedure for the primary and secondary efficacy 
analyses will be provided in the Statistical Analysis Plan. 
The ORR will be determined by the IRF and is defined as the proportion of subjects with a partial or 
complete response as defined by RECIST v.1.1 with modifications. 
The primary analysis of ORR will be performed among the subjects with baseline measurable disease
in the ITT population. In the analysis of ORR, subjects who do not have any post-baseline adequate 
tumor assessments will be counted as non-responders. Formal hypothesis testing of ORR will be 
performed using the stratified Cochran-Mantel-Haenszel test. The stratification factors will be the 
same used to stratify the randomization schedule as documented in the IXRS. The CR responders will 
be reported separately for the non-measurable disease subjects.
OS is defined as the time from randomization to death due to any cause.
There will be an interim and final analysis for OS. The interim analysis of OS will be conducted at the 
time of the primary analysis of PFS. At the interim analysis, OS data will be summarized to detect a 
statistical trend in OS (no formal hypothesis testing). The formal analysis of OS will be conducted 
when approximately 321 deaths have been observed, and will be performed using the ITT population. 
The testing of OS will be conducted using a stratified log-rank 2-sided test. The stratification factors 
will be the same used to stratify the randomization schedule as documented in the IXRS.
The median OS and the associated 95% CI for each treatment arm will be estimated using the 
Kaplan-Meier method. The HR and the associated 95% CI will be estimated using a Cox regression 
model with treatment group as the only main effect and stratifying by the same stratification factors as 
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
were used for the log-rank test. An unstratified HR and the associated 95% CI will also be presented.
Determination of Sample Size:
This study is designed to provide adequate power for PFS and OS.
For PFS, based on 2:1 randomization allocation ratio, a total of 288 events provide the study with 90% 
power for a 2-sided log-rank test with a 0.05 level of significance to detect a 50% increase in PFS 
(hazard ratio [HR]=0.67). 
Assuming an exponential distribution of PFS, this corresponds to an increase in median PFS from 
20 weeks to 30 weeks. In the current design, the minimum observed effect that would result in 
statistical significance for PFS is a 28% improvement (HR = 0.78) from 20 to 25.6 weeks. 
Up to 429 subjects will be randomized (2:1) and followed to observe the required number of events 
within the planned study duration (approximately 39 months accrual; approximately 41 months total to 
observe the required PFS events).
For OS, approximately 321 death events will provide the study with 80% power for a 2-sided log-rank 
test with an overall 0.05 level of significance to detect a 39% increase in OS (HR=0.72). Assuming an 
exponential distribution of OS, this corresponds with an increase in median OS from 20 months to 
27.8 months. 
Safety Analysis:
The analyses of safety will include all subjects who receive any study drug (talazoparib or active 
control) throughout the study duration.
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
Investigator will classify the severity of AEs using the CTCAE v 4.03. A treatment emergent adverse 
event (TEAE) is defined as any event with an onset date on or after date of first dose of study drug, or 
any event present before treatment that worsens after treatment. Only TEAEs with an onset date prior 
to date of last dose + 30 days or the date of initiation of a new antineoplastic therapy (whichever 
occurs first) will be tabulated in summary tables. 
The number and percentage of subjects who experience AEs will be summarized by system organ 
class, preferred term, relationship to study drug, and severity for each treatment group. A by–subject 
listing will be provided for those subjects who experience an SAE, including death, or experience an 
AE associated with discontinuation from study drug. 
Clinical laboratory data will be summarized by the type of laboratory test. The number and percentage 
of subjects who experience abnormal (ie, outside of reference ranges) and/or clinically significant 
abnormalities after study drug administration will be presented for each clinical laboratory 
measurement. For each clinical laboratory measurement, descriptive statistics will be provided for 
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NAME OF COMPANY
Medivation, Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105
NAME OF FINISHED PRODUCT:
Talazoparib
NAME OF ACTIVE INGREDIENT:
Talazoparib tosylate
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
baseline and all subsequent post-treatment scheduled visits. Changes from baseline to the 
post-treatment visits will also be provided. Descriptive statistics of vital signs will also be provided in 
a similar manner. In addition, shift from baseline in CTCAE grade (where applicable) and by high/low 
flags (where CTCAE grades are not defined) will be presented by treatment group.
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3
TABLE OF CONTENTS
1
TITLE PAGE....................................................................................................................1
2
SYNOPSIS..........................................................................................................................2
3
TABLE OF CONTENTS ................................................................................................15
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................20
5
ETHICS ............................................................................................................................23
5.1
Institutional Review Board or Independent Ethics Committee or Research 
Ethics Board..............................................................................................................23
5.2
Ethical Conduct of Study..........................................................................................23
5.3
Subject Information and Informed Consent..............................................................24
6
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...................25
7
INTRODUCTION............................................................................................................26
7.1
Study Background.....................................................................................................26
7.1.1
Talazoparib..................................................................................................26
7.1.2
Nonclinical Study Findings for Talazoparib ...............................................26
7.1.3
Preliminary Clinical Study Findings for Talazoparib .................................26
7.2
Study Rationale.........................................................................................................29
7.3
Summary of Overall Risks and Benefits...................................................................31
8
STUDY OBJECTIVES....................................................................................................33
9
INVESTIGATIONAL PLAN .........................................................................................34
9.1
Overall Study Design and Plan.................................................................................34
9.2
Discussion of Study Design, Including Choice of Control Group............................41
9.3
Selection of Study Population...................................................................................42
9.3.1
Inclusion Criteria.........................................................................................42
9.3.2
Exclusion Criteria........................................................................................43
9.3.3
Removal of Subjects from Study or from Study Treatment........................45
9.3.4
Subject Identification and Replacement of Subjects...................................46
9.3.5
Duration of Subject Participation................................................................47
9.3.6
Prohibited Medications................................................................................47
9.4
Treatments.................................................................................................................48
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9.4.1
Treatments Administered ............................................................................48
9.4.2
Identity of Investigational Product..............................................................48
9.4.2.1
Product Characteristics and Labeling ..........................................48
9.4.3
Physician’s-Choice Comparator..................................................................49
9.4.4
Storage.........................................................................................................49
9.4.5
Directions for Administration .....................................................................49
9.4.6
Method of Assigning Subjects to Treatment Groups..................................49
9.4.7
Selection of Doses Used in the Study .........................................................50
9.4.7.1
Talazoparib: Timing of Administration and Dose 
Reduction Guidelines...................................................................50
9.4.7.2
Protocol-Specific Physician’s-Choice Comparators: 
Timing of Administration and Dose Reduction Guidelines ........52
9.4.7.3
Liver Safety Test Monitoring and Assessments 
(Talazoparib or Protocol-Specific Physician’s Choice 
Comparators)................................................................................52
9.4.8
Blinding.......................................................................................................55
9.4.9
Prior and Concomitant Medications............................................................55
9.4.10 Treatment Compliance ................................................................................56
9.5
Investigational Product Accountability.....................................................................56
9.5.1
Return and Disposition of Clinical Supplies...............................................56
9.6
Dietary or Other Protocol Restrictions......................................................................57
9.7
Efficacy and Safety Variables...................................................................................57
9.7.1
Efficacy and Safety Measurements Assessed .............................................57
9.7.2
Primary Efficacy Variable...........................................................................57
9.7.3
Secondary Variables....................................................................................58
9.7.3.1
Pharmacokinetics.........................................................................58
9.7.3.2
Exploratory Efficacy Variables....................................................58
9.7.4
Safety Variables ..........................................................................................58
9.7.4.1
Adverse Events ............................................................................59
9.7.4.2
Clinical Laboratory Assessments.................................................59
9.7.4.3
Pharmacokinetic Assessments .....................................................61
9.7.4.4
Research Exploratory Assessments .............................................62
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9.7.4.5
Vital Signs, Physical Examinations and Other
Observations Related to Safety....................................................62
9.7.4.6
Reproductive Considerations.......................................................62
10 REPORTING ADVERSE EVENTS ..............................................................................64
10.1 Adverse Events .........................................................................................................64
10.2 Serious Adverse Events ............................................................................................67
10.3 Overdose ...................................................................................................................68
10.3.1 Talazoparib..................................................................................................68
10.3.2 Treatment of Physician’s choice .................................................................68
10.4 Pregnancy..................................................................................................................69
10.5 Reporting Liver Test Abnormalities .........................................................................69
10.6 Urgent Safety Measures............................................................................................70
10.7 Serious Adverse Event and Event of Special Interest Reporting..............................70
10.8 Clarification in Reporting of Deaths.........................................................................71
10.9 Clarification in Reporting of Disease Progression as an Adverse Event..................72
11 APPROPRIATENESS OF MEASUREMENTS...........................................................73
12 STUDY PROCEDURES .................................................................................................75
12.1 Pre-study ...................................................................................................................75
12.2 Screening/Baseline Visits .........................................................................................75
12.3 Treatment Visits........................................................................................................77
12.3.1 Cycles 1 and 2 .............................................................................................77
12.3.1.1
Cycles 1 and 2, Day 1 ..................................................................78
12.3.1.2
Cycles 1 and 2, Day 8 (± 3 days).................................................79
12.3.1.3
Cycles 1 and 2, Day 15 (± 3 days)...............................................79
12.3.2 Cycles ≥ 3....................................................................................................80
12.3.2.1
Cycle ≥ 3, Day 1 ..........................................................................81
12.3.2.2
Cycles ≥ 3, Day 8 (± 3 days)........................................................82
12.3.2.3
Cycles ≥ 3, Day 15 (± 3 days)......................................................82
12.3.3 Unscheduled Visits......................................................................................82
12.3.4 Timing of Tumor Assessments....................................................................83
12.3.5 Timing of Quality of Life Assessments ......................................................83
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12.4 End of Treatment and Follow-up Visits....................................................................84
13 DATA QUALITY ASSURANCE ...................................................................................86
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........87
14.1 Statistical and Analytical Plans.................................................................................87
14.1.1 Interim Analyses..........................................................................................87
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data..........87
14.2 Primary Efficacy Analysis ........................................................................................87
14.3 Secondary Efficacy Analysis ....................................................................................88
14.4 Exploratory Efficacy Analysis..................................................................................89
14.4.1 Pharmacokinetic Analyses ..........................................................................90
14.5 Safety Analysis .........................................................................................................90
14.6 Determination of Sample Size ..................................................................................91
14.7 Analysis Populations.................................................................................................91
14.8 Statistical Criteria for Termination of the Study.......................................................91
14.9 Changes in the Conduct of the Study or Planned Analyses......................................91
15 DATA MONITORING COMMITTEE.........................................................................93
16 BLINDED CENTRAL INDEPENDENT RADIOLOGY FACILITY........................94
16.1 Confirmation of Progression.....................................................................................94
17 COMPENSATION, INSURANCE AND INDEMNITY ..............................................95
18 CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................96
19 STUDY MONITORING AND AUDITING ..................................................................97
20 RETENTION OF RECORDS ........................................................................................98
21 USE OF INFORMATION AND PUBLICATION........................................................99
22 REFERENCES...............................................................................................................100
23 SIGNATURE PAGE......................................................................................................102
24 APPENDICES................................................................................................................103
24.1 ECOG Performance Status......................................................................................103
24.2 Common Terminology Criteria for Adverse Events...............................................103
24.3 Response Assessment using RECIST v.1.1 Criteria with Modifications ...............104
24.3.1 Image Included in the Assessment ............................................................104
24.3.2 Overview of Assessment Process..............................................................104
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24.3.3 Measurable and Non-Measurable Disease ................................................105
24.3.4 Baseline Lesion Selection and Documentation.........................................106
24.3.5 Assessment of Response ...........................................................................107
24.4 EORTC QLQ-C30/ EORTC QLQ-BR-23..............................................................112
List of Tables
Table 9-1:
Schedule of Events...........................................................................................36
Table 9-2:
Dose Modifications Based on Hematologic or Nonhematologic 
Toxicity............................................................................................................50
Table 9-3:
Dose Modifications for Toxicities ...................................................................52
Table 9-4:
Liver Test Abnormalities That May Require Dose Modifications..................53
Table 9-5:
Liver Monitoring After Events Meeting Hy’s Law Criteria or 
Suggesting Potentially Severe Drug-Induced Liver Injuries ...........................54
Table 9-6:
Clinical Laboratory Tests.................................................................................60
Table 10-1:
Causal Attribution Guidance............................................................................66
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations
ADL
activities of daily living
ADP
adenosine diphosphate
AE
adverse event
ALT
alanine aminotransferase 
ANC
absolute neutrophil count 
aPTT
activated partial thromboplastin time 
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase 
AUCτ
area under the concentration time curve over a dosing interval
AUC0-24
area under the concentration time curve from 0 to 24 hours 
BOR
best overall response
BRCA1
breast cancer susceptibility gene 1
BRCA2
breast cancer susceptibility gene 2
BUN
blood urea nitrogen 
CFR
Code of Federal Regulations
CI
confidence interval
CL/F
apparent clearance 
CMF
cyclophosphamide, methotrexate, and fluorouracil
Cmax
maximum plasma concentration
CNS
central nervous system
CR
complete response 
CRA
clinical research associate
CT
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram 
ECOG
Eastern Cooperative Oncology Group 
eCRF
electronic case report form
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EORTC 
European Organization for Research and Treatment of Cancer 
EU
European Union
EudraCT
EU Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
G-CSF
granulocyte-colony stimulating factor
GCP
Good Clinical Practice
HDPE
high density polyethylene
HER2
human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
IB
Investigator Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
ICH E6
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical 
Practice E6
IEC
independent ethics committee
IND
Investigational New Drug (application)
INR
international normalized ratio 
IP
investigational product
IRB
institutional review board
IRF
independent radiology facility
ITT
intent-to-treat
IXRS
interactive voice and Web response system
LDH
lactate dehydrogenase 
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging 
MTD
maximum tolerated dose 
NCI
National Cancer Institute 
NE
non evaluable
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
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PARP
poly(ADP-ribose) polymerase 
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic 
PR
partial response 
PT
prothrombin time 
QLQ-BR23
Breast Cancer-Specific Quality of Life Questionnaire 
QLQ-BR30
Quality of Life Questionnaire
RBC
red blood cell (count)
REB
research ethics board
RECIST v.1.1
revised response evaluation criteria in solid tumors 
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SPECT
single-photon emission computed tomography imaging
SWOG
South West Oncology Group
TEAE
treatment emergent adverse event
US
United States
ULN
upper limit of normal 
Vc/F
apparent central volume of distribution 
WBC
white blood cell (count)
Definition of Terms: 
Investigational Product (IP): “A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical trial, including a product with a marketing 
authorization when used or assembled (formulated or packaged) in a way different from the 
approved form, or when used for an unapproved indication, or when used to gain further 
information about an approved use” (from International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonised 
Tripartite Guideline: Guideline for Good Clinical Practice E6 [ICH E6]). The terms “IP” and 
“study drug” may be used interchangeably in the protocol.
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5
ETHICS
5.1
Institutional Review Board or Independent Ethics Committee or Research 
Ethics Board
Prior to initiating the study, the Investigator will obtain written confirmation that the 
institutional review board (IRB), independent ethics committee (IEC) or Research Ethics 
Board (REB) is properly constituted and compliant with International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and Good Clinical Practice (GCP) requirements, applicable laws and local 
regulations. A copy of the confirmation from the IRB/EC/REB will be provided to the 
Sponsor or designee. The Investigator or designee will provide the IRB/EC/REB with all 
appropriate material, including the protocol, Investigator Brochure (IB), the Informed 
Consent Forms (ICFs) including compensation procedures, and any other written information 
provided to the subjects, including all ICFs translated to a language other than the native 
language of the clinical site. The study will not be initiated and investigational product (IP) 
supplies will not be shipped to the site until appropriate documents from the IRB/EC/REB 
confirming unconditional approval of the protocol, the ICF and all subject recruitment 
materials (if any) are obtained in writing by the Investigator and copies are received by the 
Sponsor or designee. The approval document should refer to the study by protocol title and 
Sponsor protocol number (if possible), identify the documents reviewed, and include the date 
of the review and approval. The Sponsor will ensure that the appropriate reports on the 
progress of the study are made to the IRB/EC/REB and the Sponsor by the Investigator in 
accordance with applicable guidance documents and governmental regulations.
5.2
Ethical Conduct of Study
This study will be conducted in accordance with the following:
!
United States (US) Code of Federal Regulations (CFR) sections that address clinical 
research studies, and/or other national and local regulations, as applicable
!
ICH Harmonised Tripartite Guideline: Guideline for GCP E6 (ICH E6)
!
The ethical principles established by the Declaration of Helsinki
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB/EC/REB and will be conducted by scientifically and medically qualified persons. The 
benefits of the study are in proportion to the risks. The rights and welfare of the subjects will 
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be respected and subject participation continued as long as the Investigators conducting the 
study do not find the hazards to outweigh the potential benefits. 
Each subject, or his/her legally authorized representative will provide written, informed 
consent before any study-related tests or evaluations are performed.
5.3
Subject Information and Informed Consent
A properly written and executed ICF, in compliance with the Declaration of Helsinki, 
ICH E6 (Section 4.8), US CFR, 21 CFR §50 and other applicable local regulations, will be 
obtained for each subject prior to entering the subject into the study. The Investigator or 
designee will prepare the ICF and provide the documents to the Sponsor for approval prior to 
submission to the IRB/EC/REB approval. The Sponsor and the IRB/EC/REB must approve 
the documents before they are implemented. A copy of the approved ICF from each 
investigational site and, if applicable, a copy of the approved subject information sheet and 
all ICFs translated to a language other than the native language of the clinical site, must also 
be received by the Sponsor or designee prior to any study-specific procedures being 
performed.
A main and a BRCA test ICF will be included as part of this clinical trial:
!
The main ICF includes subject consent for all procedures that are part of this clinical 
trial (this informed consent must be completed by all subjects before any 
study-related procedures are performed, except BRCA1/2 mutation testing); the
28-day Screening Period starts when the subject signs the main informed consent
!
The BRCA test ICF provides subject consent for only the blood test for determination 
of germline BRCA1/2 mutation status; it does not provide consent for other 
study-related procedures (a separate BRCA test ICF is not required if the subject has 
already signed the main informed consent)
Separate additional ICFs may be included as part of the trial according to country 
requirements (eg, certain countries may require separate ICFs for genetic and/or tissue 
sampling).
The Investigator will provide copies of the signed ICF to each subject (or the legally 
authorized representative of the subject) and will maintain the original in the record file of 
the subject. The Investigator will also fully document the informed consent process in the 
subject’s source documents.
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INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Prior to beginning the study, the Investigator at each site must provide to the Sponsor or 
designee, a fully executed and signed US Food and Drug Administration (FDA) Form FDA 
1572, a current and signed Curriculum vitae and a Financial Disclosure Form. All 
sub-Investigators must be listed on Form FDA 1572. Financial Disclosure Forms must also 
be completed for all sub-Investigators listed on the Form FDA 1572 who will be directly 
involved in the treatment or evaluation of subjects in this study. Any change in the Principal 
Investigator at the site requires Sponsor approval.  
The study will be administered by and monitored by employees or representatives of the 
Sponsor. Clinical Research Associates (CRAs) or trained designees will monitor each site on 
a periodic basis and perform verification of source documentation for each subject as well as 
other required review processes. The Sponsor Regulatory Affairs Department, in conjunction 
with the Drug Safety & Pharmacovigilance Department (or their respective designees) will 
be responsible for the timely reporting of serious adverse events (SAEs) to appropriate 
regulatory authorities as required.
Clinical laboratory evaluations will be performed at the local laboratories associated with the 
study sites, with the exception of the hematologic evaluations noted in Section 12.3.2. For 
subjects with acceptable retrospective BRCA testing, confirmation of BRCA carrier status 
will be done at a specific central laboratory. For all other subjects, prospective BRCA testing 
performed at a regional central laboratory is required before randomization. The specific 
laboratories and instructions for sample collection, processing and shipment are provided in 
the laboratory manual.
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INTRODUCTION
A comprehensive review of talazoparib (also known as MDV3800, BMN 673) is contained 
in the Investigator Brochure (IB) supplied by the Sponsor. Investigators are to review this 
document prior to initiating this study.
7.1
Study Background
7.1.1
Talazoparib
Poly ADP-ribose polymerase (PARP) represents a family of enzymes, of which at least two 
(PARP1 and PARP2) play important roles in deoxyribonucleic acid (DNA) repair. The study 
drug, talazoparib, is a potent and specific inhibitor of PARP 1 and 2 with activity in tumor 
cell lines bearing DNA repair deficiencies. PARP inhibition induces synthetic lethality in 
tumor cells bearing mutations in the genes encoding breast cancer susceptibility gene 1 
(BRCA1) and breast cancer susceptibility gene 2 (BRCA2), both of which are key 
components in the pathway of repair for DNA double-strand breaks. Treatment with a PARP 
inhibitor results in cell cycle arrest and apoptosis.
7.1.2
Nonclinical Study Findings for Talazoparib
The nonclinical study findings in the rat and the dog for talazoparib are described in full in 
the IB. The main nonclinical findings were early hematological changes and subsequent bone 
marrow and lymphoid organ depletion, as well as focal necrosis, after repeat administration 
of talazoparib tosylate, the drug substance containing talazoparib. These findings were in
accordance with the mechanism of action and the exposure/ distribution pattern of the study 
drug and were reversible. The hematological changes, which consisted of decreases in the 
reticulocyte, platelet, red blood cell (RBC) and white blood cell (WBC) counts, were a 
sensitive and early marker of target organ toxicity and were used to clinically monitor safety. 
7.1.3
Preliminary Clinical Study Findings for Talazoparib
Two Phase 1 studies (PRP-001 and PRP-002) of talazoparib were conducted; one Phase 2 
study (673-201) has been initiated. 
The first-in-human study of talazoparib (PRP-001) was initiated in the first quarter of 2011. 
This is a Phase 1, single-arm, open-label, dose-escalation study of once daily, orally 
administered talazoparib for advanced or recurrent solid tumors (those that have defects in 
DNA repair). PRP-002, a Phase 1, 2-arm, open-label, dose-escalation study for talazoparib
for the treatment of subjects with advanced hematological malignancies was initiated in July 
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2011. This study enrolled subjects with acute myeloid leukemia, myelodysplastic syndrome, 
chronic lymphocytic leukemia or mantle cell lymphoma. 
The primary objective of the Phase 1 studies is to establish the maximum tolerated dose 
(MTD) of once daily, orally administered talazoparib, and to assess the safety, 
pharmacokinetics, pharmacodynamics and preliminary efficacy in an expanded cohort of 
subjects with genetically defined tumors.
In June 2013, preliminary data from PRP-001 were presented at the American Society of 
Clinical Oncology (ASCO) 2013 (de Bono, 2013, J.Clin Oncol.) and are described below. 
As of June 2013, 70 subjects (60 women/10 men) enrolled into the study; 39 subjects 
(33 women/6 men) with solid tumors were enrolled in the dose escalation phase of the study 
in 9 cohorts ranging from 25 to 1100 μg/day that defined a MTD of 1000 μg/day. On 
defining the MTD, 31 subjects with breast, ovarian, and pancreas cancer with deleterious 
germline mutations; small cell lung cancer; and Ewing’s sarcoma, were enrolled in the 
expansion phase of the study to further characterize safety and efficacy. The median (range) 
age for all 70 subjects was 51.5 years (18 to 81), performance status (PS) was 0 (0 to 1) and 
number of prior therapies was 4 (1 to 13), with 48 subjects having deleterious BRCA 
mutations. Tumors (number with deleterious BRCA 1/2 mutations) included 
34 ovarian/ primary peritoneal (28); 20 breast (18); 8 Ewing’s; 4 pancreas; 2 colon; 
1 prostate (1), and 1 mullerian carcinosarcoma. A total of 27 and 21 subjects had 
BRCA 1 and 2 mutations, respectively. 
Dose-limiting thrombocytopenia occurred in 1 of 6 subjects at 900 μg/day and 2 of 5 subjects 
at 1100 μg/day, respectively. 
!
Subject 
 (0.9 mg/day): Grade 3 thrombocytopenia reported on Days 29-42
resolved after discontinuation of study drug; no hemorrhage was noted. Grade 3 
anemia observed during this time also resolved
!
Subject 
 (1.1 mg/day): Grade 3 thrombocytopenia reported on Days 22-26, 
became Grade 4 thrombocytopenia on Days 26-32. It resolved after discontinuation of 
study drug; the subject received a platelet transfusion. No hemorrhage was noted. The 
subject died on Day 52 due to invasive breast cancer
!
Subject 
 (1.1 mg/day): Grade 3 thrombocytopenia reported on Days 28-32 
resolved after discontinuation of study drug; no hemorrhage was noted
None of the 6 subjects who received a dose of 1 mg/day during the dose-escalation phase of 
this study had a dose-limiting toxicity, although Grade 3 anemia and neutropenia were 
observed in later treatment cycles. Based on these results, the MTD was defined at a dose of 
1000 μg/day. Related adverse events (AEs) occurring in >10% of all 70 subjects included 
PPD
PPD
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fatigue (30%), nausea (29%), alopecia (21%), anemia (20%), thrombocytopenia (19%) and 
neutropenia (11%). One subject had drug-related grade 4 thrombocytopenia without 
hemorrhage. Grade 3 related AEs included fatigue in 1 subject (1%), anemia and 
thrombocytopenia each in 9 subjects (13%) and neutropenia in 4 subjects (6%). Dose 
reductions occurred in 11 subjects due to myelosuppression. No subjects discontinued due 
to AEs. 
After closure of enrollment to this study, 110 subjects had received at least one dose of 
talazoparib of which 77 subjects received the recommended dose of 1 mg/day. Dose 
reductions were reported for 26 (34%) of the 77 subjects treated at the recommended dose. 
The dose was reduced once (to 0.75 mg/day) for 14 subjects, twice (to 0.75 mg/day, then 
0.5 mg/day) for 11 subjects, and three times (to 0.75 mg/day, 0.5 mg/day, then 0.25 mg/day)
for one subject. In 20 (77%) of the 26 subjects with dose reductions, the dose reductions were 
due to an AE. The most frequently reported AEs leading to dose modification were 
thrombocytopenia and anemia, each reported for 20 subjects, followed by neutropenia 
reported for 12 subjects.
Inhibition of PARP activity in peripheral blood mononuclear cell was observed at doses 
≥100 μg/day. Talazoparib plasma concentrations peaked 1 to 2 hours post-dose; in general, 
exposure increased dose proportionally. Steady state plasma concentrations were reached by 
the end of the second week of daily dosing. At the recommended dose of 1 mg/day, the mean 
maximum plasma concentration (Cmax) was 10.6 (± 4.2) ng/mL on Day 1, and 
21.0 (± 8.0) ng/mL on Day 35. The mean area under the concentration time curve from 0 to 
24 hours (AUC0-24) at the recommended dose of 1 mg/day was 85.1 (± 29.1) and 202.0 
(± 54.0) ng-hr/mL on Day 1 and Day 35, respectively. 
Objective (RECIST v.1.1) and/or CA-125 responses occurred at doses ≥ 100 μg/day in 11 of 
25 subjects (44%) and 19 of 27 subjects (70%) with BRCA-carrier ovarian and peritoneal 
cancer, respectively. Clinical benefit (complete response [CR]/partial response [PR]/stable 
disease [SD] > 24 weeks) occurred in 23 of 28 subjects (82%) with BRCA-carrier ovarian 
and peritoneal cancer. 
Objective responses occurred in 8 of 18 (44%) BRCA-carrier breast cancer subjects. Clinical 
benefit (CR/PR/SD >12 weeks) occurred in 12 of 18 (67%) of BRCA-carriers. 
Overall, talazoparib was well tolerated with impressive anti-tumor activity in subjects with 
BRCA mutations with a single agent recommended dose of 1000 μg/day due to dose-limiting 
thrombocytopenia.
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7.2
Study Rationale
The mutation that predisposes BRCA mutation carriers to cancer formation selectively 
renders tumor cells susceptible to PARP inhibition while sparing normal cells that, 
possessing a normal BRCA allele, are relatively resistant to PARP inhibition.
The selection of appropriate therapy for metastatic breast cancer is complex because of the 
many treatment options and biologic heterogeneity of the disease, including several that have 
led to development of targeted therapeutics. Among others, the potential treatment options 
are influenced by estrogen and progesterone receptor and human epidermal growth factor 
receptor 2 (HER2) status of the tumor. Treatment options for subjects presenting with 
metastatic breast cancer may also be influenced by what adjuvant therapy was used, how 
soon after adjuvant therapy the subject relapses, and by sites of metastasis. 
No therapies have been approved that take advantage of the well-defined vulnerability of 
BRCA mutant tumors. It would be a significant advance to provide a therapy which exploits 
the vulnerability of BRCA-mutant bearing tumors while sparing normal cells carrying one 
healthy BRCA allele.
Prognosis and best treatment practices in breast cancer subjects with germline BRCA1 or 
BRCA2 mutations have, for the most part, been characterized in retrospective studies from 
single institutions. When compared to sporadic primary breast cancer, BRCA1 disease is 
more likely to be hormone receptor negative and BRCA2 disease is more likely to be 
hormone receptor positive (Atchley, 2008, J.Clin.Oncol.), (Verhoog, 1999, J.Clin.Oncol.). 
BRCA1 and BRCA2 breast cancers have been reported to be higher grade and higher stage 
and to have more extensive and extracapsular lymph node involvement compared to 
non-BRCA cancers (Atchley, 2008, J.Clin.Oncol.), (Rennert, 2007, N.Engl.J.Med.). 
However, a review of 20 studies regarding disease outcomes in primary BRCA-associated 
breast cancer concluded that while these subjects have an increased risk of contralateral 
breast cancer, the presence of the mutation provided no other prognostic information 
(Liebens, 2007, Eur.J.Cancer).
First-line therapy of metastatic breast cancer often includes an anthracycline and/or taxane. 
The combination of doxorubicin and paclitaxel in newly metastatic breast cancer was shown 
to improve response rates and time to treatment failure relative to either doxorubicin or 
paclitaxel given as single agents but had no significant impact on overall survival (OS) 
(Sledge, 2003, J.Clin.Oncol.). This supports the use of single-agent chemotherapy where 
survival is not adversely impacted while limiting the toxicity of therapy. 
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The utility of anthracyclines is also limited by cardiotoxicity concerns, particularly if the 
subject was exposed to anthracyclines in the adjuvant setting. In addition, growing evidence 
from nonclinical studies suggests that sensitivity to taxanes may require functional BRCA1 
protein (Lafarge, 2001, Oncogene), (Quinn, 2003, Cancer Res.), (Tassone, 2003, 
Br.J.Cancer). In response to abnormal mitosis induced by taxanes, BRCA1 protein activates 
the mitotic spindle checkpoint and promotes apoptosis by the c-Jun-N-terminal kinase/stress-
activated protein kinase pathway, leading to cell death (Harkin, 1999, Cell), (Quinn, 2009, 
Gynecol.Oncol.).
Responsiveness of BRCA-associated breast cancer to chemotherapy is poorly understood, 
and the data are conflicting. Retrospective neoadjuvant subject series have suggested that 
primary breast cancer in BRCA1 carriers is platinum-sensitive and relatively unresponsive to 
anthracyclines and/or taxanes (Byrski, 2010, J.Clin.Oncol.) while other studies have found 
that BRCA1 is relatively responsive to anthracyclines and/or taxanes while BRCA2 disease 
is less responsive than sporadic primary breast cancer to these drug classes (Arun, 2011, 
J.Clin.Oncol.). More recent data (Tutt, 2014, SABCS) demonstrated a prolonged median PFS 
in TNBC patients with a known deleterious BRCA1/2 mutation when carboplatin was 
administered compared with docetaxel.  
The efficacy of standard chemotherapeutics in BRCA mutation carriers with metastatic 
breast cancer is unclear. In one retrospective review of first-line treatment of metastatic 
disease, BRCA1 subjects had a similar response rate and survival to those with sporadic 
disease treated with standard regimens (anthracycline-based, taxane-based or the 
combination regimen of cyclophosphamide, methotrexate, and fluorouracil [CMF]), while 
BRCA2 subjects appeared to have higher response rates with better survival than sporadic 
subjects (Kriege, 2009, J.Clin.Oncol.). In another series from the same institution evaluating 
taxane sensitivity in first- to third-line metastatic breast cancer, BRCA1 subjects appeared to 
be less responsive to docetaxel or paclitaxel than subjects with sporadic breast cancer, while 
BRCA2 subjects appeared to be more sensitive (Kriege, 2012, Cancer). 
Sensitivity of BRCA1- and BRCA2-associated breast cancer to other standard 
chemotherapeutic agents has not been reported but is not generally perceived to be different 
from sporadic breast cancer. However, the lack of prospective, controlled studies in BRCA1 
and BRCA2-mutant disease along with the mixed data from small retrospective studies 
underscores the lack of information for making treatment decisions for these subjects. The 
potential role of BRCA1 in mediation of taxane cytotoxicity is consistent with the 
observation that the taxanes may be less effective in treatment of BRCA1-associated 
metastatic breast cancer than sporadic disease. This, coupled with the potential to specifically 
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target the underlying genetic abnormality of the disease, highlights the unmet need as well as 
the need for prospective evaluation of a molecularly rational, targeted therapy in comparison 
to the standard drugs used. 
While several agents have been shown to prolong progression-free survival (PFS) and some 
have modestly improved survival in metastatic breast cancer, the disease is, nevertheless, 
nearly uniformly fatal. Moreover, standard, non-targeted therapies are associated with 
substantial toxicity, which limits the quality of life of subjects while they are undergoing 
treatment.
Two studies of the PARP inhibitor, olaparib, given as a single agent to breast cancer subjects 
have been published. In one study, subjects with germline BRCA mutations were treated 
with either 400 mg twice daily or 100 mg twice daily in a non-randomized fashion. Eleven of 
27 subjects (41%) receiving the higher dose had objective responses while 6 of 27 (22%) of 
subjects receiving the lower dose responded (Tutt, 2010, Lancet). In a second trial, olaparib 
was evaluated in subjects with germline mutations as well as subjects with triple negative 
breast cancer in the absence of germline mutations. 
Ten subjects with germline mutations were enrolled, including 6 with measurable disease. 
While there were no objective responders, 5 subjects had stable disease. There were also no 
responders among 16 triple negative breast cancer subjects who either did not have germline 
BRCA mutations or had unknown BRCA status (Gelmon, 2011, Lancet Oncol.).
In talazoparib Phase 1 PRP-001, 18 breast cancer subjects with germline BRCA mutations, 
who have previously been treated with more than one chemotherapy regimen (range: 
1 to 13), have been enrolled during dose escalation (n=6) and expansion (n=12) as of 
31 Mar 2015. All 18 subjects were treated with talazoparib at dose levels of 900 to 
1100 μg/day including 12 in the expansion phase at 1000 μg/day (9 of the 12 subjects have 
been in the study for ≥ 3 cycles). Eight of 18 subjects have had objective responses, including 
one confirmed CR in a subject with a BRCA2 deleterious mutation. Two of 2 BRCA breast 
responders had responded to prior platinum while 0 of 4 non-responders to prior platinum 
responded to talazoparib. Six of 12 BRCA breast subjects with no prior platinum have 
responded.
7.3
Summary of Overall Risks and Benefits
Talazoparib was selected for clinical evaluation in tumors with demonstrated or potential 
defects in DNA repair pathways, such as BRCA mutations based on its mechanism of action, 
preclinical activity and PK and toxicity profiles. Talazoparib has been shown to be a highly 
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selective and potent cytotoxic agent in human cancer cell lines and in animal models of 
tumors harboring mutations that compromise DNA repair pathways.
Preliminary data from PRP-001 show inhibition of PARP activity in peripheral blood 
mononuclear cell at doses ≥100 μg/day. Objective (RECIST v.1.1) and/or CA-125 responses 
occurred at doses ≥ 100 μg/day in 11 of 25 subjects (44%) and 19 of 27 subjects (70%) with 
BRCA-carrier ovarian and peritoneal cancer, respectively. Clinical benefit (CR/PR/SD
>24 weeks) occurred in 23 of 28 (82%) BRCA-carrier ovarian and peritoneal cancer subjects. 
Objective responses occurred in 8 of 18 (44%) BRCA-carrier breast cancer subjects. Clinical 
benefit (CR/PR/SD >12 weeks) occurred in 12 of 18 (67%) of BRCA-carriers.
Pharmacokinetic parameters demonstrated a high bioavailability with a distribution profile 
indicating extensive tissue distribution, and a duration of exposure sufficient to support once 
daily dosing. Changes in hematology parameters were early markers of toxicology findings. 
Anemia, thrombocytopenia, and neutropenia have all been observed in the Phase 1 trials, 
including grade 3 to 4 events; however, these subjects did not require discontinuation of 
study drug or withdrawal from the study. All subjects are being monitored for 
myelosuppression in the ongoing studies. In PRP-001, 8 of 18 breast cancer subjects with 
germline BRCA mutations have had objective responses, including one confirmed CR. 
These data, together with those reported from recent literature in the rationale section above, 
support the clinical investigation of talazoparib in a Phase 3 study in locally advanced or 
metastatic breast cancer subjects with germline BRCA1 or BRCA2 mutations. 
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8
STUDY OBJECTIVES
The primary objective of the study is to compare PFS of subjects treated with talazoparib as 
a monotherapy relative to those treated with protocol-specific physician’s choice.
The secondary objectives of the study are to evaluate the following:
!
Objective response rate (ORR)
!
Overall survival (OS)
!
Safety
!
Pharmacokinetics of talazoparib
The exploratory objectives are to evaluate the following:
!
Duration of response (DOR) for objective responders 
!
Quality of life for all enrolled subjects (European Organization for Research and 
Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLC-C30]/ EORTC 
Quality of Life Questionnaire – Breast Cancer Module [QLQ-BR23])
!
Research assessments related to blood and tumor sampling that includes 
characterization of tumor sensitivity and resistance to talazoparib
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
The study is an open-label, 2-arm, 2:1 randomized trial of talazoparib versus 
protocol-specific physician’s choice. Subjects with germline BRCA mutations who have 
received no more than 3 prior cytotoxic chemotherapy regimens for locally advanced and/or
metastatic breast cancer will be enrolled. 
Options for protocol-specific physician’s choice include one of the following single-agent 
chemotherapies: 
!
Capecitabine, eribulin, gemcitabine, vinorelbine
o
The protocol-specific physician’s choice must be determined prior to 
randomization for each individual subject. 
Subjects will be centrally randomized with stratification by the following:
!
Number of prior cytotoxic chemotherapy regimens for locally advanced and/or
metastatic disease (0 vs. 1, 2, or 3)
!
Triple negative (estrogen-receptor negative, progesterone-receptor negative, 
HER2-negative) vs. non-triple negative breast cancer based on most recent biopsy
!
History of central nervous system (CNS) metastases vs. no CNS metastases
A Screening visit will occur within 28 days before randomization and a baseline visit within 
7 days before randomization.
Subjects must start treatment ≤ 5 days from randomization; starting later will be considered a 
protocol deviation. Subjects will present for weekly treatment visits for the first 2 cycles of 
talazoparib or protocol-specific physician’s choice. Treatment with talazoparib or 
protocol-specific physician’s choice will continue until radiographic disease progression as 
determined by the central Independent Radiology Facility (IRF), unacceptable toxicity, 
consent withdrawal, physician’s decision to terminate treatment, or Sponsor’s decision to 
terminate the trial. 
Talazoparib will be administered orally daily for 21 days in repeated 21-day cycles at 
1.0 mg/day with provision for dose modifications as described in Section 9.4.7.1. 
Protocol-specific physician’s choice will also be administered in 21-day cycles in accordance 
with the dose and regimens suggested below unless institution dose and regimen guidelines 
differ in which case the site may utilize institution guidelines: 
!
Capecitabine: 1250 mg/m2, oral, twice daily from Day 1 through 14 of 21-day cycles, 
30 minutes after meal.
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!
Eribulin mesylate: 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2), infusion over 
2-5 minutes, Days 1 and 8 of 21-day cycles
!
Gemcitabine: 1250 mg/m2, infusion over 30 minutes, Day 1 and 8 of 21-day cycles
!
Vinorelbine: 30 mg/m2, weekly infusion over 6-10 minutes, Day 1, 8, and 15 of 
21-day cycles
Dose modifications and reductions for protocol-specific physician’s choice are to occur per 
the package insert and institutional practice.
Tumor assessments will be performed for subjects by computed tomography (CT [preferred 
method]), magnetic resonance imaging (MRI), and x-ray. All subjects will also have nuclear 
medicine whole body bone scans within 12 weeks before randomization. 
Tumor assessments are to be performed every 6 weeks (± 7 days) from the date of 
randomization for the initial 30 weeks, and every 9 weeks thereafter (± 7 days), regardless of
any dose interruptions or dose delays until radiographic disease progression as determined by 
the IRF or initiation of a new antineoplastic therapy. Tumor assessments can occur as 
clinically indicated anytime during the study, and at the time of clinical suspicion of disease 
progression. Optional tumor marker assessments (eg, CA15-3 or CA27-29) are to be 
performed every 6 weeks (± 7 days) from the date of randomization for the initial 30 weeks, 
every 9 weeks thereafter (± 7 days), and at the End of Treatment but should not be repeated if 
normal at baseline. If bone metastasis is seen at Baseline, bone scans will be repeated every 
12 weeks (± 7 days) until radiographic disease progression as determined by the IRF or 
initiation of a new antineoplastic therapy and as clinically indicated. In subjects without 
baseline bone lesions, bone scans should be repeated only as clinically indicated.
An End of Treatment visit will be performed for subjects 30 days (-3 or +10 days postdose) 
after the last dose of study drug. 
Subjects who discontinue from study drug for reasons other than radiographic disease 
progression as determined by the IRF or initiation of a new antineoplastic therapy should be 
followed to radiographic progression by imaging assessments (eg, CT scans) unless the 
subject withdraws consent. Clinical disease progression should be verified by radiographic 
imaging as determined by the IRF; study treatment should continue until radiographic 
progression has occurred. All subjects will be followed for anticancer treatment and survival
status. Survival follow-up will continue until death. Follow-up for anticancer therapy and 
survival status will occur every 60 days (± 7 days) after the last dose of study drug for 1 year 
and every 90 days (± 14 days) thereafter, or when requested by the Sponsor. 
A summary of events and assessments are provided by visit in Table 9-1. 
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Table 9-1:
Schedule of Events
Screening/
Baseline a
Cycles 1 - 2 c
Cycles ∀3c
Every 
6 Weeks 
(for 1st 
30 weeks)
Every 9 Weeks 
(starting 
39 weeks after 
randomization)
Unschj
End of 
Treat
ment
Visit e
Long-Term 
Follow-Up f
Procedure/Assessment b
(Day
-28 to -1)
(Day
-7 to -1)
Day
1
Day
8 c
(± 3)
Day
15 
(± 3)
Day
1
Day 8 d
(± 3)
Day 15 d
(± 3)
Weeks 6, 
12, 18, 24, 
30
(± 7)
Weeks 39+
(± 7)
na
30 days 
postdose(
-3 to 
+10)
See footnote f
for schedule
Informed consent g
X
Medical history h
X
Vital signs i
X
X
X
X
X
X
[X]
X
Physical examination k
X
X
X
X
[X]
X
ECOG assessment l
X
X
X
X
Tumor assessment m
X
X
X
[X]
X 
Optional tumor marker 
assessment (eg, CA15-3, 
CA27-29) m
[X]
[X]m
[X]m
[X]
Brain CT or MRIm
X
[X]
[X]
[X]
Bone scanm
X
Every 12w
Every 12w
[X]
PK blood sampling n
X 
X 
[X]
Clinical laboratory tests o
  Hematology o
X
X
X
X
X
X
[Xo]
[Xo]
[X]
X
  Serum chemistry o
X
X
X
X
[X]
X
  Coagulation/urinalysis o
X
Calculated creatinine  
clearance o
X
Serum pregnancy test p
X
[X]
[X]
[X]
[X]
Urine pregnancy testp
X
X
[X]
X
Quality of life questionnaireq
X
X
X
X
AEs and SAEs r
X
X
X
X
X
X
[X]
[X]
X
X
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Screening/
Baseline a
Cycles 1 - 2 c
Cycles ∀3c
Every 
6 Weeks 
(for 1st 
30 weeks)
Every 9 Weeks 
(starting 
39 weeks after 
randomization)
Unschj
End of 
Treat
ment
Visit e
Long-Term 
Follow-Up f
Procedure/Assessment b
(Day
-28 to -1)
(Day
-7 to -1)
Day
1
Day
8 c
(± 3)
Day
15 
(± 3)
Day
1
Day 8 d
(± 3)
Day 15 d
(± 3)
Weeks 6, 
12, 18, 24, 
30
(± 7)
Weeks 39+
(± 7)
na
30 days 
postdose(
-3 to 
+10)
See footnote f
for schedule
ECG s
X 
[X]
X
Concomitant medications t
X
X
X
X
X
X
[X]
[X]
X
X
Subject contact: OS, obtain 
cancer treatment 
X 
Talazoparib treatment u
Once-daily dosing 
Chemotherapy treatment v
X
[X]
[X]
X
[X]
[X]
Documentation of BRCA1, 
BRCA2 mutation w
X
Blood sample (germline 
BRCA assay) x  
X
Blood sample (Genomic) y
X
[X]
Tumor tissue collection z
X
Optional tumor biopsy aa
[X]
[X]
[X] denotes an optional test. 
Abbreviations: AE, adverse event; CT, computed tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; MRI, magnetic 
resonance imaging; na, not applicable; OS, overall survival; PK, pharmacokinetics; SAE, serious adverse event; unsch, unscheduled; w, week
a
The Screening visit must occur within 28 days before randomization, and the baseline visit must occur within 7 days before randomization. If Screening is 
performed within 7 days before randomization, physical examination, vital signs, and clinical laboratory assessments do not need to be repeated at baseline. 
Screening and baseline procedures may be performed on the same day as long as it is within 7 days before randomization. Subjects must receive their first 
treatment with talazoparib or protocol-specific physician’s choice within 5 days of being randomized.
b
All assessments will be performed before dosing except as indicated.
c
Each cycle will be 21 days long, with daily dosing with talazoparib on Days 1 to 21. The first day of treatment in Cycle 1 is defined as Day 1; a # 3 day 
window (relative to Day 1) is allowed for any Day 8 or Day 15 clinic visit. 
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d
The Day 8 or Day 15 visit may be omitted in Cycles ≥3 for subjects not experiencing significant toxicities. Subjects assigned to talazoparib or capecitabine 
are not required to ingest the Day 8 or Day 15 dose at the clinic on a day the visit is optional. A Day 8 or Day 15 visit may not be required for a hematology 
assessment as the hematology assessment can be performed at a local laboratory outside of the investigational site laboratory as long as laboratory reports are 
provided to the Investigator for evaluation 24 hours prior to dosing.
e
This visit may occur 27 to 40 days after the last dose of study drug. Tumor assessments are only required if not performed in the previous 28 days. 
f
Long-term Follow-up: Subject contact for: survival, cause of death, and additional cancer treatment every 60 days (± 7 days) after last dose for 1 year, every 
90 days (± 14 days) thereafter, or when requested by the Sponsor.
g
Written informed consent using the main informed consent form is required before any protocol-specified procedures or assessments are performed.
Written informed consent for only the BRCA1/2 mutation testing blood test may be obtained at any time (including prior to the screening period).
h
Includes full oncologic history, prior treatments, and demographics.
i
Systolic and diastolic blood pressure, heart rate, respiration rate, and temperature at scheduled time points; weight only at Screening, baseline, Cycle 1 Day 1 
pre-dose, Day 1 of each Cycle pre-dose, End of Treatment; height at Screening only.
j
Anytime necessary to assess or follow up AEs, to perform scans, at the subject request, or at the Investigator request. Record the date and reason for the 
unscheduled visit in the source documentation. Perform study procedures as clinically appropriate. Imaging may be performed, as appropriate, for subjects 
who are symptomatic and/or for whom radiographic disease progression or response is being determined.
For subjects assigned to talazoparib only, obtain PK samples as appropriate. 
k
Screening/baseline physical examination to be a complete exam; subsequent examinations to be focused on physical examinations at the discretion of the 
Investigator based on the subject’s clinical condition.
l
ECOG performance status.
m
CT (preferred), MRI, or X-ray. 
     A brain MRI or CT is to be performed at Screening/baseline to evaluate subjects for presence/absence of brain metastases. Newly diagnosed CNS metastases 
at Baseline/Screening makes a patient ineligible until such time as it can be adequately treated, at which point the patient may be re-screened. If adequately 
treated metastatic disease to the brain is present at Screening/Baseline, an MRI or CT will be performed during the study as clinically indicated. Post-baseline 
assessments should be performed using the same technique used at Screening/Baseline. CT/MRI scans performed as standard of care before the main ICF was 
signed and within the 28-day screening period may be used as the Screening tumor assessments if the scans were completed per the specific study 
requirements (as specified in the Imaging Manual).
Tumor assessment to be performed every 6 weeks (± 7 days) from the date of randomization for initial 30 weeks, and every 9 weeks thereafter (# 7 days), 
regardless of any dose interruptions or dose delays. Tumor assessments can occur as clinically indicated anytime during the study, and at the time of clinical 
suspicion of disease progression. Clinical disease progression should be verified by radiographic imaging as determined by the IRF; study treatment should 
continue until radiographic progression has occurred. Tumor assessments will also continue to be performed for subjects who discontinue from study drug for 
reasons other than radiographic disease progression as determined by the IRF or initiation of a new antineoplastic therapy. Post-baseline tumor assessments 
should be performed using the same technique used at Screening/baseline. 
Optional tumor marker assessments (eg, CA15-3, CA27-29) are to be performed every 6 weeks (± 7 days) for the initial 30 weeks, every 9 weeks (± 7 days) 
thereafter, and at the End of Treatment, but should not be repeated if normal at baseline. 
Bone scan will be performed at Screening/baseline (a bone scan obtained up to 12 weeks before randomization may be substituted). If metastatic disease to 
the bone is present at Screening/Baseline, a bone scan will be performed every 12 weeks (± 7 days) and as clinically indicated. Post-baseline assessments 
should be performed using the same technique used at Screening/Baseline.
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n
Sparse PK samples will be collected on Day 1 of Cycles 1 through 4 from subjects randomized to receive talazoparib. Sparse PK sampling will consist of a 
pre-dose sample collected ≤ 60 minutes prior to dosing, and 2 post-dose samples collected ≥ 30 minutes after dosing. For the pre-dose sample, collection of 
whether the subject has or has not eaten within 2 hours before dosing should also be performed. The collection times of the 2 post-dose samples will be 
separated by ≥ 2 hours. Within individual subjects, efforts should be made to collect PK samples at different times relative to dosing across the study days 
with PK assessments. Samples may be collected at unscheduled visits. In the event of a dose delay on Day 1 of Cycles 1-4, the pre and post-dose PK sample 
should be drawn on the day the subject resumes their next dose of talazoparib. 
o
Hematology: hemoglobin, hematocrit, platelet count, red blood cell (RBC), white blood cell (WBC) count, absolute neutrophil count (ANC), and WBC 
differential (absolute and/or percent) (refer to Table 9-6). Weekly blood counts are to be obtained during the first 2 cycles. Starting with Cycle 3, hematology 
counts will be obtained in each cycle on Day 1 and on either Day 8 (± 3 days) or Day 15 (± 3 days). Hematology assessments done at visits other than Day 1 
of each cycle may be performed at a local laboratory outside of the investigational site laboratory as long as laboratory reports are provided to the Investigator 
for evaluation 24 hours prior to dosing. Hematology assessments scheduled for the day of the dosing must be available and assessed for abnormalities before 
dosing. The sampling for the hematology assessment can be drawn within 72 hours prior to dosing.
Serum chemistry: total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), 
total protein, albumin, sodium, potassium, chloride, carbon dioxide (or bicarbonate), calcium, phosphorus, magnesium, blood urea nitrogen (BUN; also called 
urea), creatinine, uric acid, glucose. Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time (PT)/international normalized ratio 
(INR); will be assessed only at baseline.
Urinalysis (dipstick): pH, specific gravity, protein, glucose, ketones, bilirubin, blood, leukocyte esterase. Microscopy is required if dipstick results for blood 
and leukocyte esterase are positive; will be assessed only at baseline.
Calculated creatinine clearance: to be performed at Screening. Use local laboratory results or calculate by Cockcroft-Gault formula.
Serum chemistry can be drawn within 72 hours prior to dosing.
p
For women of child-bearing potential only. The protocol definition of “women not of childbearing potential” is provided in Section 9.7.4.6. Local urine or
serum (as per local regulations/practice) pregnancy test should be performed at Day 1 of each cycle, prior to administration of study medication; if a urine 
pregnancy test is positive, study drug must be interrupted and a serum pregnancy test performed. Additional pregnancy testing may be performed throughout 
the study as clinically indicated.
q
EORTC QLQ-C30/EORTC QLQ-BR23 quality of life questionnaire 
r
After written informed consent but before study drug initiation, only SAEs associated with protocol-imposed interventions will be recorded. For Cycles ≥3
Day 8 or Day 15, if the subject is not seen in clinic, the subject should be contacted by phone and assessed for AEs or SAEs. After the first dose of study drug, 
all SAEs and AEs will be recorded until 30 days after the last dose of study drug (permanent discontinuation) or before initiation of a new antineoplastic 
therapy, whichever occurs first. For events outside of this reporting period, only SAEs assessed as related to study drug will be reportable. SAEs, AEs and 
pregnancies ongoing at the End of Treatment visit will be followed until resolution or until the condition is considered stable by the Investigator.
s
Baseline 12–lead ECG; End of Treatment, if clinically indicated.
t
All concomitant medications or therapies, including herbal supplements, taken from 28 days before randomization to 30 days after the last dose will be 
recorded. For Cycles ≥3 Day 8 or Day 15, if the subject is not seen in clinic, the subject should be contacted by phone and assessed for concomitant 
medications.  
u
Talazoparib will be administered orally daily for 21 days in repeated 21-day cycles. On selected days of clinic visits, the drug will be taken at the clinic to 
allow pre-dose collection of safety data.
v
Chemotherapy treatment: See Study Reference Manual 
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Documentation of a deleterious, suspected deleterious, or pathogenic germline BRCA1 or BRCA2 mutation may be provided for enrollment based on a prior 
analysis. The pathology laboratory must be pre-approved by the Sponsor.  
x
For subjects who have prior documentation of BRCA carrier status, blood sample for BRCA germline testing will be collected at any time during the 
Screening/baseline period (Day -28 to Day -1). For subjects who must undergo prospective BRCA germline testing, blood sample testing must be collected as 
early as possible during the screening period. 
y
Blood sample for disease-related research, including but not limited to genomic analysis. Genomic blood sample will be collected at any time during the 
Screening/baseline period (Day -28 to Day -1) and at radiographic disease progression (+ 35 days).
z
Archival formalin-fixed paraffin-embedded (FFPE) tumor tissue slides. Tumor blocks may be submitted with Sponsor approval. A subject may be 
randomized without availability of tumor tissue slides or blocks. See the Laboratory Manual for preparation of slides or tumor blocks.  
aa Optional tumor biopsy to be performed only if subject consent is provided. Biopsy will be collected at any time during the Screening/baseline period (Day -28 
to Day -1) and at radiographic disease progression (+ 35 days) or at the time of discontinuation of study treatment.
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9.2
Discussion of Study Design, Including Choice of Control Group
This is a Phase 3, open-label, randomized, parallel, 2-arm, multi-center study of talazoparib
vs. protocol-specific physician’s choice in germline BRCA mutation subjects with locally 
advanced and/or metastatic breast cancer, who have received no more than 3 prior cytotoxic 
chemotherapy regimens for locally advanced and/or metastatic disease. 
The rationale for this study is outlined below and described in detail in Section 7.2. 
The subject population of germline BRCA mutation subjects with locally advanced and/or
metastatic breast cancer was chosen for this study as there is a current unmet need to treat 
this population and interim results from the Phase 1 study (PRP-001) indicated objective 
responses to talazoparib in 8 of 18 subjects, including one confirmed CR. 
An open-label design was selected as a double-blind design was not possible given the 
different chemotherapy cycle regimens for talazoparib vs. the control group regimens. 
A 2-arm, randomized, parallel-group design was chosen as this was considered most suitable 
for assessing the safety and efficacy endpoints in the talazoparib group compared with the 
control group. 
Talazoparib will be administered as a single agent in this study at a dose of 1.0 mg/day with 
provision for dose reductions to 0.75 mg/day and 0.5 mg/day (or lower) in case of toxicity. 
This dose regimen was chosen based on preliminary results from the Phase 1 clinical trial 
(PRP-001) involving breast cancer subjects, which reported good tolerability of talazoparib
up to 1000 μg/day but dose-limiting thrombocytopenia at higher doses (1100 μg/day). 
The control group in this study is treatment by protocol-specific physician’s choice of any 
one of the single-agent chemotherapies: capecitabine, eribulin, gemcitabine or vinorelbine. 
These reference chemotherapies were chosen as they are considered to be standard 
single-agent therapies for subjects with locally advanced and/or metastatic breast cancer. 
Dose modifications and reductions are permitted per the package inserts and institutional 
practice. 
The study drug will be administered until radiographic disease progression as determined by 
the IRF, occurrence of unacceptable toxicity, subject or physician decision to stop treatment 
or until the study is terminated by the Sponsor. 
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9.3
Selection of Study Population
9.3.1
Inclusion Criteria
Individuals eligible to participate in this study must meet all of the following criteria:
!
Histologically or cytologically confirmed carcinoma of the breast
!
Locally advanced breast cancer that is not amenable to curative radiation or surgical 
cure and/or metastatic disease appropriate for systemic single cytotoxic chemotherapy
!
Documentation of a deleterious, suspected deleterious, or pathogenic germline 
BRCA1 or BRCA2 mutation from Myriad Genetics or other laboratory approved by 
the Sponsor; for data obtained regarding a BRCA1/2 mutation from a non-Myriad 
laboratory, the pathology report must be submitted to and approved by the Sponsor 
and a blood sample sent to Myriad for analysis before randomization may occur
!
No more than 3 prior chemotherapy-inclusive regimens for locally advanced and/or 
metastatic disease (no limit on prior hormonal therapies or targeted anticancer 
therapies such as mechanistic target of rapamycin [mTOR] or CDK4/6 inhibitors, 
immuno-oncology agents, tyrosine kinase inhibitors, or monoclonal antibodies 
against CTL4 or VEGF)
!
Prior treatment with a taxane and/or anthracycline in the neoadjuvant, adjuvant, 
locally advanced, or metastatic setting unless medically contraindicated
!
18 years of age or older
!
Have measurable or non-measurable, evaluable disease by the revised response 
evaluation criteria in solid tumors (RECIST) v.1.1
!
Eastern Cooperative Oncology Group (ECOG) performance status ≤2
!
Adequate organ function as defined below:
o
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 × upper limit of normal (ULN); if liver function abnormalities are due to 
hepatic metastasis, then AST and ALT ≤5 × ULN
o
Total serum bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert’s syndrome)
o
Calculated creatinine clearance ≥ 30 mL/min by local laboratory or 
Cockcroft-Gault formula
o
Hemoglobin ≥9.0 g/dL with last transfusion at least 14 days before 
randomization
o
Absolute neutrophil count (ANC) ≥1500/mm3
o
Platelet count ≥100,000/mm3
!
Able to take oral medications
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Willing and able to provide written, signed informed consent after the nature of the 
study has been explained, and prior to any research-related procedures
!
A female of childbearing potential (defined in Section 9.7.4.6) must not be pregnant 
and must agree to avoid pregnancy during the study by using a highly effective birth 
control method (defined in Section 9.7.4.6) from the time of the first dose of study 
drug through 45 days after the last dose of study drug
!
Male subjects must use a condom when having sex with a pregnant woman and when 
having sex with a woman of childbearing potential from the time of the first dose of 
study drug through 105 days after the last dose of study drug. Contraception should 
be considered for a non-pregnant female partner of childbearing potential
!
Male and female subjects must agree not to donate sperm or eggs, respectively, from 
the first dose of study drug through 105 days and 45 days after the last dose of study 
drug, respectively
!
Females of childbearing potential (defined in Section 9.7.4.6) must have a negative 
serum pregnancy test at Screening and be willing to have additional pregnancy tests 
during the study. 
!
Willing and able to comply with all study procedures
9.3.2
Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study:
!
First-line locally advanced and/or metastatic breast cancer with no prior adjuvant 
chemotherapy unless the Investigator determines that one of the 4 cytotoxic 
chemotherapy agents in the control arm would be otherwise offered to the subject
!
Prior treatment with a PARP inhibitor (not including iniparib)
!
Not a candidate for treatment with at least 1 of the treatments of protocol-specific 
physician’s choice (ie, capecitabine, eribulin, gemcitabine, vinorelbine)
!
Subjects who had objective disease progression while receiving platinum
chemotherapy administered for locally advanced or metastatic disease; subjects who 
received low-dose platinum therapy administered in combination with radiation 
therapy are not excluded
!
Subjects who have received platinum in the adjuvant or neoadjuvant setting are 
eligible; however, subjects may not have relapsed within 6 months of the last dose of 
prior platinum therapy
!
Cytotoxic chemotherapy within 14 days before randomization 
!
Radiation or anti-hormonal therapy or other targeted anticancer therapy within 
14 days before randomization
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!
Has not recovered from the acute toxicities of previous therapy, except treatment-
related alopecia or laboratory abnormalities otherwise meeting the inclusion 
requirements stated in the inclusion criteria
!
HER2 positive breast cancer
!
Active inflammatory breast cancer
!
CNS metastases
o
Exception: Adequately treated brain metastases documented by baseline CT 
or MRI scan that has not progressed since previous scans and that does not 
require corticosteroids (except prednisone ≤5 mg/day or equivalent) for 
management of CNS symptoms. A repeat CT or MRI following the
identification of CNS metastases (obtained at least 2 weeks after definitive 
therapy) must document adequately treated brain metastases
o
Subjects with leptomeningeal carcinomatosis are not permitted
!
Prior malignancy except for any of the following:
o
Prior BRCA-associated cancer as long as there is no current evidence of the 
prior cancer 
o
Carcinoma in situ or non-melanoma skin cancer
o
A cancer diagnosed and definitively treated ≥5 years before randomization
with no subsequent evidence of recurrence
!
Known to be human immunodeficiency virus positive
!
Known active hepatitis C virus, or known active hepatitis B virus
!
Use of any IP or investigational medical device within 14 days before randomization
!
Major surgery within 14 days before randomization
!
Myocardial infarction within 6 months before randomization, symptomatic 
congestive heart failure (New York Heart Association [NYHA] > class II), unstable 
angina, or unstable cardiac arrhythmia requiring medication 
!
Female subjects who are breastfeeding at Screening or planning to become pregnant 
at any time during study participation through 45 days after the last dose of study 
drug; male subjects planning to impregnate a partner at any time during study 
participation through 105 days after the last dose of study drug
!
Concurrent disease or condition that would interfere with study participation or 
safety, such as any of the following:
o
Active, clinically significant infection either grade > 2 by National Cancer 
Institute (NCI) Common Terminology Criteria for AEs (CTCAE) v4.03 or 
requiring the use of parenteral anti-microbial agents within 14 days before 
randomization
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o
Clinically significant bleeding diathesis or coagulopathy, including known 
platelet function disorders
!
Non-healing wound, ulcer, or bone fracture, not including a pathological bone 
fracture caused by a pre-existent pathological bone lesion
!
Known hypersensitivity to any of the components of talazoparib
9.3.3
Removal of Subjects from Study or from Study Treatment
Subjects should be encouraged to continue to provide study data until the primary outcome of 
radiographic disease progression as determined by the IRF or death has occurred. This is to 
avoid any potential for bias or mis-estimation of treatment effect as a result of missing and 
therefore censored data. This encouragement should continue even in the event of 
discontinuation of study drug administration. Notwithstanding the above, subjects may 
withdraw their consent to participate in the study and Investigators may withdraw subjects at 
any time without prejudice. Subjects may withdraw consent for study drug treatment (only), 
for any follow-up radiographic imaging, or for long-term follow-up for survival status and 
anticancer therapy. The specific type of withdrawal of consent should be documented in the 
medical chart. When possible, the tests and evaluations listed for the End of Treatment visit 
should be carried out.
The Sponsor must be notified of all subject withdrawals as soon as possible. The Sponsor 
also reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance.
Reasons for which the Investigator or Sponsor may discontinue administration of study drug 
include, but are not limited to, the following:
!
Subject experiences a serious or intolerable AE or clinically significant laboratory 
abnormality (see Section 9.4.7)
!
Subject requires medication or medical procedure prohibited by the protocol 
(Section 9.3.6)
!
Subject does not adhere to study requirements specified in the protocol
!
Subject was erroneously admitted into the study or does not meet entry criteria
!
Subject is lost to follow-up
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!
Subject becomes pregnant (refer to Section 10.4 for details on the reporting 
procedures to follow in the event of pregnancy)
!
Subjects may be removed from study if considered by the Investigator or Sponsor to 
be in the best interest of the subject 
If a subject discontinues from treatment but remains on study, every effort should be made to 
continue the subject’s assessments according to the schedule of assessments (Table 9-1) 
through the end of the study. For subjects who withdraw from the study, procedures and 
assessments for the End of Treatment visit (Section 12.4) should be performed (unless the 
subject withdraws consent to do so).
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone, study site personnel may 
contact the subject’s family member or legally authorized representative, if appropriate. A
certified letter should be sent to the subject (or the subject’s legally authorized representative, 
if appropriate) requesting contact with the Investigator. As permitted by local law, study site 
personnel may use public databases, perform an internet search, or review obituaries to 
determine date of death. This information should be recorded in the study records. 
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC/REB. It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject, or if appropriate, the subject’s 
legally authorized representative. If permission to use protected health information is 
withdrawn, it is the Investigator’s responsibility to obtain a written request, to ensure that no 
further data will be collected from the subject and the subject will be removed from the 
study.
9.3.4
Subject Identification and Replacement of Subjects
All reports and subject samples will be identified only by a subject identification number and 
actual initials (if permitted) or mock initials and date of birth (month/year only if no date is 
permitted) to maintain subject confidentiality. This unique identifier will be on all electronic 
case report form (eCRF) pages. A new subject identification number will be assigned to any 
subjects who are re-screened after a screen failure. Subjects who discontinue the study will 
not be replaced.
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9.3.5
Duration of Subject Participation
Subjects will attend a Screening visit within 28 days before randomization and a baseline 
visit within 7 days before randomization.
Subjects must start treatment ≤ 5 days from randomization; starting later will be considered a 
protocol deviation. Talazoparib or protocol-specific physician’s choice will be administered 
in repeated 21-day cycles. Subjects will present for weekly treatment visits for the first 
2 cycles of talazoparib or protocol-specific physician’s choice. Treatment with talazoparib or 
protocol-specific physician’s choice will continue until radiographic disease progression as 
determined by the central IRF, unacceptable toxicity, consent withdrawal, physician’s 
decision to terminate treatment, or Sponsor’s decision to terminate the trial. Tumor 
assessments are to be performed every 6 weeks (± 7 days) from the date of randomization for 
the initial 30 weeks, and every 9 weeks thereafter (± 7 days), regardless of any dose 
interruptions or dose delays until radiographic disease progression as determined by the IRF 
or initiation of a new antineoplastic therapy.
An End of Treatment visit will be performed for subjects 30 days (-3 days or +10 days) after 
the last dose of study drug. 
Subjects who discontinue from the study drug for any reason other than radiographic disease 
progression as determined by the IRF or initiation of a new antineoplastic therapy will also 
be followed to radiographic progression by imaging assessments (eg, CT scans) unless the 
subject withdraws consent. All subjects will be followed for anticancer treatment and 
survival status. Survival follow-up will continue until death. Follow-up for anticancer 
therapy and survival status will occur every 60 days (± 7 days) after the last dose of study 
drug for 1 year and every 90 days (± 14 days) thereafter, or when requested by the Sponsor. 
9.3.6
Prohibited Medications
The following medications and procedures are prohibited through study drug discontinuation:
!
Any investigational agent other than talazoparib
!
Any anticancer treatment other than talazoparib, the protocol-specified comparator 
agents, bisphosphonates and denosumab
Bisphosphonates and the monoclonal antibody denosumab are permitted for treatment, or
prophylaxis, of bone metastases as per local standards of care. Examples of other permitted 
medications are outlined in Section 9.4.9. 
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9.4
Treatments
9.4.1
Treatments Administered
The Sponsor and/or its designee will provide the study site with a supply of talazoparib
sufficient for the completion of the study. 
All physician’s choice drugs are commercially available in all planned study countries, 
except for eribulin, which is not available in some of the planned study countries. All 
physician’s choice comparator drugs should be supplied by the local pharmacy (if possible 
per local regulations). The physician’s choice drugs are to be labeled, packaged, and stored 
according to local regulations and manufacturer’s instructions. Physician’s choice drug costs 
will be reimbursed by the Sponsor where necessary.  
9.4.2
Identity of Investigational Product
9.4.2.1
Product Characteristics and Labeling
The IP is talazoparib tosylate, a white to off-white crystalline powder. The drug substance is 
a 4-methylbenzenesulfonate (tosylate) salt of talazoparib free base, the active moiety.
The drug product consists of the drug substance formulated with a pharmaceutically-suitable 
excipient filled into hydroxymethylpropylcellulose capsules. 
Capsules will be provided to the sites in dose strengths of 0.25 mg and 1.0 mg capsules. The 
dosage strengths are based on the active moiety (talazoparib free base). The capsules for each 
dose strength are provided in dose-specific colors to provide a visual method of 
distinguishing dose strengths. The capsules will be supplied in 30-count induction-sealed 
high density polyethylene (HDPE) bottles. 
Talazoparib is considered a cytotoxic agent; precautions regarding appropriate secure storage 
and handling must be used by healthcare professionals, including personal protective 
clothing, disposable gloves, and equipment (Goodin, 2011, J.Oncol.Pract.). Subjects should 
be advised that oral anticancer agents are toxic substances and that (other than the subject) 
caregivers should always use gloves when handling the capsules.
The label will vary in content and/or language, depending upon requirements of individual 
countries and the design of the clinical trial. At a minimum, each bottle label will provide the 
following information: study Sponsor identification, dosage form, route of administration, 
quantity and potency, batch number, directions for use, required storage conditions, caution 
statements (including “for clinical trial use only” language), study identification, and product 
retest or expiration date.
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9.4.3
Physician’s-Choice Comparator
Treatment of protocol-specific physician’s choice is to include any one of the following 
single-agent chemotherapies: capecitabine, eribulin, gemcitabine or vinorelbine. All 
physician’s choice comparator drugs should be supplied by the local pharmacy (except where 
not allowed by local law). Some subjects will receive protocol-specific physician’s choice 
study drug by mail-order pharmacy. They are to be labeled, packaged, and stored according 
to local regulations and manufacturer’s instructions. Comparator drug costs will be 
reimbursed by the Sponsor where necessary.   
9.4.4
Storage
At the study site, all talazoparib must be stored under the conditions specified in the IB in a 
secure area accessible only to the designated pharmacists and clinical site personnel. 
Talazoparib must be stored at room temperature (15 to 30°C; 59 to 86°F), inventoried and the 
inventories must be carefully and accurately documented according to applicable state, 
federal and local regulations, ICH GCP, and study procedures.
The protocol-specific physician’s choice comparators should be stored per the package insert 
and institutional practice. 
9.4.5
Directions for Administration
Talazoparib will be taken orally once daily (i.e., continuous dosing). Talazoparib should be 
taken at approximately the same time each day, preferably in the morning. Talazoparib will 
be swallowed whole and may be taken with or without food. If a subject vomits a dose, the 
subject should not take a second dose that calendar day. The subject should resume daily 
dosing the next day. On days of clinic visits when PK samples are to be drawn, talazoparib
should be taken at the clinic after completion of the pre-dose sampling and assessments.
The protocol-specific physician’s choice comparators should be administered per the package 
insert or institutional practice. Suggested dosing schedules are provided in Section 9.1. 
9.4.6
Method of Assigning Subjects to Treatment Groups
Subjects will be randomized (2:1) centrally based on the following stratifications:
!
Number of prior cytotoxic chemotherapy regimens for locally advanced and/or
metastatic disease (0, vs 1, 2, or 3)
!
Triple negative (estrogen-receptor negative, progesterone-receptor negative, 
HER2-negative) vs. non-triple negative status based on the most recent biopsy
!
History of CNS metastases vs. no CNS metastases
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Assignment to study drug arms will be based on a computer-generated schedule before the 
start of the study. The schedule will be developed according to the Randomization Plan. The 
approved randomization schedule will be implemented in an interactive voice and Web 
response system (IXRS). The IXRS will assign a subject to talazoparib or protocol-specific 
physician’s choice based on the subject’s strata and allocate a randomization number. For 
subjects assigned to the physician’s choice arm, the protocol-specific physician’s choice 
should be determined prior to randomization. A subject may only receive one randomization 
number; each randomization number may only be assigned to one subject. 
A subject will be considered randomized into the study when a randomization number is 
assigned. At the end of the trial the completed randomization schedule will be transferred to 
the Sponsor. 
9.4.7
Selection of Doses Used in the Study
The selection of doses used in this study is described in Section 7.2 and Section 9.2. 
9.4.7.1
Talazoparib: Timing of Administration and Dose Reduction Guidelines 
Talazoparib should be taken orally once daily (ie, continuous daily dosing) at approximately 
the same time each day (preferably in the morning). On days of clinic visits when PK 
samples are to be drawn, talazoparib should be taken at the clinic after completion of 
pre-dose sampling and assessments; on these PK sample dates, the clinic visit should be 
scheduled for approximately the same time of day that the dose is typically taken.
Daily dosing of talazoparib can be interrupted for recovery from toxicity for up to 28 days. 
For interruptions longer than 28 days, treatment at the same or a reduced dose can be 
considered based on a discussion between the Sponsor or designee and Investigator if 
evidence of response or clinical benefit to talazoparib is noted. 
Dose modifications should be made based on the observed toxicity, as summarized in 
Table 9-2.
Table 9-2:
Dose Modifications Based on Hematologic or Nonhematologic Toxicity
Toxicity 
Recommended Dose Modification
Liver test abnormalities
Refer to the liver safety test monitoring and assessment
rules in Section 9.4.7.3. 
Dose interruption and/or dose reduction may be required 
for Grade 2 AST or ALT values, depending on the liver 
test values at Screening.
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Toxicity 
Recommended Dose Modification
Grade 1 or 2 toxicity (other than 
liver test abnormalities)
No requirement for dose interruption or dose reduction. 
If the toxicity persists at Grade 2 (for ≥7 days), a dose 
reduction to the next lower dose level (eg, from 1.0 mg/day 
to 0.75 mg/day) may be implemented at the discretion of 
the Investigator.
Grade 3 nonhematologic toxicity 
(other than liver test
abnormalities)
Daily dosing must be held for Grade 3 AEs considered 
related to talazoparib. 
Supportive care should be implemented as appropriate 
(eg, anti-emetics, anti-diarrheal agents). Talazoparib dosing 
may resume at the next lower dose level (eg, from 
1.0 mg/day to 0.75 mg/day, 0.75 mg/day to 0.5 mg/day to 
0.25 mg/day) when toxicity resolves to Grade 1 or returns 
to baseline.
Grade 3 hematologic toxicity
Daily dosing must be held for Grade 3 laboratory 
abnormalities known to be associated with talazoparib per 
the current IB. 
Supportive care should be implemented as appropriate 
(eg, growth factor support, blood products). Talazoparib
dosing may resume at the next lower dose level when 
toxicity resolves to Grade 1 or would meet the eligibility 
criteria (Section 9.3).
Grade 4 nonhematologic toxicity 
(other than liver test
abnormalities)
Daily dosing must be held for Grade 4 AEs (regardless of 
relationship to talazoparib). 
Supportive care should be implemented as appropriate 
(eg, anti-emetics, anti-diarrheal agents). Talazoparib may 
resume at a lower dose level (1-2 dose level decrease) 
when toxicity resolves to Grade 1 or returns to baseline.
Grade 4 hematologic toxicity
Daily dosing must be held for Grade 4 laboratory 
abnormalities (regardless of relationship to talazoparib). 
Supportive care should be implemented as appropriate 
(eg, growth factor support, blood products). Talazoparib 
may resume but must be at a lower dose level when 
toxicity resolves to Grade 1 or would meet the eligibility 
criteria (Section 9.3); this should be a 1-2 dose level 
decrease per Investigator discretion.
Refer to Table 9-3 for additional information.
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Table 9-3:
Dose Modifications for Toxicities
Dose Level
Initial dose level
1.0 mg/day
First dose level reduction
0.75 mg/day
Second dose level reduction
0.5 mg/day
Third dose level reduction
0.25 mg/day
Talazoparib will be permanently discontinued for individual subjects as a result of any 
unresolved Grade 3 or Grade 4 toxicity or based on a decision by the subject or Investigator 
that continued talazoparib treatment is not in the subject’s best interest.
9.4.7.2
Protocol-Specific Physician’s-Choice Comparators: Timing of 
Administration and Dose Reduction Guidelines 
Treatment of protocol-specific physician’s choice is to include any one of the single-agent 
chemotherapies listed below. Suggested dosing schedules are noted, but if institution dose 
and regimen guidelines differ, the site may utilize institution guidelines: 
!
Capecitabine: 1250 mg/m2, oral, twice daily from Days 1 through 14 of a 21-day 
cycle, 30 minutes after meal
!
Eribulin mesylate: 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2), infusion over 
2-5 minutes, Days 1 and 8 of 21-day cycles
!
Gemcitabine: 1250 mg/m2, infusion over 30 minutes, Days 1 and 8 of 21-day cycles
!
Vinorelbine: 30 mg/m2, weekly infusion over 6-10 minutes, Days 1, 8 and 15 of 
21-day cycles
Dose modifications and reductions are to occur per the package insert and institutional 
practice. Dose adjustments based on abnormal liver test results should follow the instructions 
in Section 9.4.7.3. Dose adjustments based on renal insufficiency should follow the Summary 
of Product Characteristics or manufacturer’s prescribing information. 
Toxicities will be managed as defined in the Summary of Product Characteristics or 
manufacturer’s prescribing information and institutional practice.
9.4.7.3
Liver Safety Test Monitoring and Assessments (Talazoparib or 
Protocol-Specific Physician’s Choice Comparators)
Subjects who develop abnormal liver tests (ie, AST, ALT, total bilirubin) and/or international 
normalized ratio [INR] values, and/or signs/symptoms of hepatitis during the study treatment 
period, may meet the criteria for withholding or permanent discontinuation of study drug 
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(talazoparib or treatment of physician’s choice) as specified in US FDA Guidance for 
Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation (2009).
Subjects who meet permanent discontinuation criteria or temporary withholding criteria, or 
who do not meet permanent discontinuation criteria or temporary withholding criteria but 
who have abnormal liver tests are to be followed according to the recommendations in this 
section.
It is recommended that study drug (talazoparib or treatment of physician’s choice) be 
withheld for any one of the liver test abnormalities listed in Table 9-4.
Table 9-4:
Liver Test Abnormalities That May Require Dose Modifications
Baseline AST or ALT Value
Elevation
≤ 3 × ULN
> 5 × ULN to ≤ 8 × ULN 
> 3 to ≤5 × ULN
> 8 × ULN 
Baseline Total Bilirubin Value
Elevation
≤ 1.5 × ULN
> 3 × ULN
Study drug (talazoparib or treatment of physician’s choice) should be withheld pending 
investigation into alternative causes of drug-induced liver injury (DILI). If study drug is 
withheld, the subject should be followed for possible DILI. Rechallenge may be considered 
if an alternative cause for the impaired liver tests (ie, ALT, AST, total bilirubin) is discovered 
and the laboratory abnormalities resolve to normal or baseline values.
The decision to rechallenge the subject should be discussed and agreed on unanimously by 
the subject, Investigator, and Sponsor. Following rechallenge, subjects should be closely 
monitored for signs and symptoms of hepatitis, and/or abnormal liver test results. If signs or 
symptoms recur with rechallenge, study drug (talazoparib or treatment of physician’s choice) 
should be permanently discontinued. Subjects who clearly meet the criteria for permanent 
discontinuation should never be rechallenged.
Study drug should be discontinued permanently if ALL of the following 4 criteria are met 
(ie, potential severe DILI/Hy’s Law case): 
1. AST or ALT increases to ≥ 3 × ULN (> 5 × ULN if baseline ALT/AST is > 3 and 
≤5 × ULN)
2. Total bilirubin increases to > 2 × ULN and/or INR > 1.5
3. Alkaline phosphatase (ALP) value does not reach 2 × ULN
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4. No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes include, but are not limited to:
o
Hepatobiliary tract disease
o
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, parvovirus)
o
Congestive heart failure, hypotension, or any cause of hypoxia to the liver 
causing ischemia
o
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms  
o
Alcoholic hepatitis
o
Non-alcoholic steatohepatitis (NASH) 
o
Autoimmune hepatitis 
o
Wilson’s disease and hemochromatosis
o
Alpha-one antitrypsin deficiency 
If an alternative cause for hepatotoxicity is identified or if the liver test abnormalities do not 
reach the specified severity, study drug should be withheld or permanently discontinued, as 
appropriate for the safety of the subject based on the patient population and/or severity of the 
hepatotoxicity or event.  
All subjects in whom study drug is withheld (either conditionally or permanently) due to a 
potential DILI are to undergo a period of “close observation” until the liver test abnormalities 
return to baseline or normal values.  The evaluations listed in Table 9-5 should be performed.
Table 9-5:
Liver Monitoring After Events Meeting Hy’s Law Criteria or Suggesting 
Potentially Severe Drug-Induced Liver Injuries
Results
Frequency for Repeating Liver (AST, ALT, 
Bilirubin [Total and Direct]) and INR Tests 
After the initial liver test abnormality
Within 24 hours
If AST or ALT ≥ 3 × ULN (> 5 × ULN if 
baseline ALT/AST is > 3 and ≤5 × 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 and ≤5 × ULN) and 
total bilirubin and/or INR are normal 
Every 48 to 72 hours until laboratory abnormalities 
improve
If the liver test abnormalities improve AND the 
subject is asymptomatic
Frequency may decrease
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As DILI is a diagnosis of exclusion, it is important to initiate investigation of alternative 
causes for abnormal liver tests; this may include consultation with a hepatologist.  The 
medical monitor should be contacted for questions regarding adequate follow-up tests.
9.4.8
Blinding
This is an open-label study. No blinding will be performed. Steps will be taken to ensure 
designated Sponsor staff responsible for study conduct and IRF members are appropriately 
blinded to subject treatment identity throughout the study.
9.4.9
Prior and Concomitant Medications
All prescription and over-the-counter medications taken by a subject for 28 days before 
randomization will be recorded on the designated eCRF. The Investigator may prescribe 
additional medications during the study, as long as the prescribed medication is not 
prohibited by the protocol (Section 9.3.6). In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor or designee 
must be notified of the use of any contraindicated medications immediately thereafter. Any 
concomitant medications added or discontinued during the study will be recorded on the 
eCRF, including the start and end dates of treatment, as applicable.
Supportive medications may be provided prophylactically or therapeutically at the 
Investigator’s discretion, with the exception that granulocyte-colony stimulating factor 
(G-CSF) is only allowed in the rescue setting. Allowed medications include (but are not 
limited to) anti-emetics, such as dexamethasone, metoclopramide, ondansetron, or aprepitant;
anti-diarrheals, such as loperamide hydrochloride; and appetite stimulants such as megestrol 
acetate. Bisphosphonates and the monoclonal antibody denosumab are also permitted for 
treatment, or prophylaxis, of bone metastases as per local standards of care. 
Guidelines for concomitant use of talazoparib with inhibitors or inducers of P-glycoprotein 
(P-gp) or inhibitors of breast cancer resistance protein (BCRP) are as follows 
!
Use of strong P-gp inhibitors (eg, dronedarone, itraconazole, quinidine, ranolazine, 
verapamil), P-gp inducers (eg, rifampin, tipranavir/ritonavir), or BCRP inhibitors 
(eg, elacridar [GF120918]) should be avoided
!
Caution should be used for coadministration of other P-gp inhibitors (eg, amiodarone, 
azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, 
diltiazem, erythromycin, felodipine, ketoconazole, lopinavir, ritonavir, quercetin), 
P-gp inducers (eg, avasimibe, carbamazepine, phenytoin, St John’s wort), or BCRP
inhibitors (eg, cyclosporine, eltrombopag, gefitinib)
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!
Refer to the following website for a complete list:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm093664.htm#inhibitors
External beam radiotherapy will be allowed, following consultation with the medical 
monitor. 
Subjects may not receive any other systemic anticancer therapies while on study prior to 
radiographic disease progression as determined by the IRF.
A subject may be referred for surgery of metastatic lesion(s), when it is in the best interest of 
the subject. The subject may continue on study if the subject is receiving clinical benefit from 
the study drug per Investigator discretion. If the target lesions are removed, the subject will 
be excluded from the measurable disease population. Resection of a subject’s target lesion(s)
should be discussed with the Medical Monitor prior to surgery. 
9.4.10 Treatment Compliance
Subjects will be instructed to bring all used and unused study drug containers to each study 
visit. Subject compliance with the dosing regimen of oral therapy (talazoparib and 
capecitabine) will be assessed by reconciliation of the used and unused study drug at least 
once per cycle. The quantity dispensed, returned, used, lost, etc. must be recorded by the 
Investigator or designee on the dispensing log provided for the study at least once per cycle.
9.5
Investigational Product Accountability
The Investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received, subjects (or their primary caregiver) to whom IP is 
dispensed (subject-by-subject dose specific accounting), and IP lost or accidentally or 
deliberately destroyed. The Investigator or designee must retain all unused or expired study 
supplies until the study monitor (on-site CRA) has confirmed the accountability data and the 
Sponsor has approved return or destruction.
9.5.1
Return and Disposition of Clinical Supplies
Unused study drug (including talazoparib and any other Investigational Medicinal Products 
provided by the Sponsor) must be kept in a secure location for accountability and 
reconciliation by the study monitor. The Investigator or designee must provide 
documentation for any destroyed or missing study drug or study materials.
Unused study drug may be destroyed on site, per the site’s standard operating procedures, but 
only after the Sponsor or designee has granted approval for drug destruction. The monitor 
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must account for all study drug in a formal reconciliation process, prior to study drug 
destruction (if possible). All study drug destroyed on site must be documented. 
Documentation must be retained in the Investigator study files. If a site is unable to destroy 
study drug, the site can return unused study drug to a central location for drug destruction. 
The return of study drug or study drug materials must be documented on the study drug 
return form.
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures.
9.6
Dietary or Other Protocol Restrictions
Not applicable.
9.7
Efficacy and Safety Variables
9.7.1
Efficacy and Safety Measurements Assessed
The Schedule of Events in Section 9.1 describes the timing of required evaluations.
9.7.2
Primary Efficacy Variable
The primary efficacy measure will be the ability of the treatment to delay radiographic 
progression of breast cancer, assessed using sequential imaging studies digitally submitted to 
and reviewed by the central IRF (refer to Section 16). 
Progression and response will be determined by the IRF and defined according to RECIST 
v.1.1 (Eisenhauer, Eur. J. Cancer. 2009) with modifications. Radiographic disease 
assessment (CT and/or MRI) will be performed within 28 days before randomization. 
Subjects will undergo radiographic disease assessment every 6 weeks (± 7 days) from the 
date of randomization for 30 weeks. 
Thereafter, imaging assessment will be performed every 9 weeks (± 7 days) until 
radiographic disease progression as determined by the IRF or the time of initiation of a new 
antineoplastic therapy. Clinical disease progression should be confirmed by radiographic 
imaging as determined by the IRF before discontinuing study treatment (or the subject will 
not be considered to have a progressive disease event for the purposes of the analysis). If a 
subject is suspected to have disease progression based on clinical signs or symptoms, the site 
should complete and submit the appropriate forms and scans for IRF determination. Imaging 
assessments should continue according to the schedule of assessments (Table 9-1) until 
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radiographic progression is observed by the IRF, unless the subject withdraws consent or 
initiates a new antineoplastic therapy.
The assessment of tumor response via RECIST v.1.1 with modifications is described in full 
in Section 24.3.
9.7.3
Secondary Variables
The secondary efficacy measures include ORR (RECIST v.1.1 with modifications) as 
assessed by the IRF and OS. Confirmation of objective response (CR or PR) is not required. 
The assessment of tumor response via RECIST v.1.1 with modifications is described in full 
in Section 24.3.
9.7.3.1
Pharmacokinetics 
The following PK parameters will be determined from plasma talazoparib concentrations:
!
Trough concentrations of talazoparib
A population PK modeling approach will be used to estimate individual values of apparent 
clearance (CL/F) and central volume of distribution (Vc/F). 
Individual CL/F estimates will then be used to estimate individual exposure parameters 
(eg, area under the concentration time curve over a dosing interval [AUCτ]). The association 
between talazoparib exposure parameters and efficacy and safety outcomes may be explored. 
9.7.3.2
Exploratory Efficacy Variables
The exploratory efficacy variables are DOR in responding subjects via RECIST v.1.1 with 
modifications (Section 24.3) and EORTC QLQ-C30/EORTC QLQ-BR23 (Section 24.4). 
9.7.4
Safety Variables
The following safety variables will be assessed:
!
The incidence of AEs, including SAEs 
!
Change in clinical laboratory tests (serum chemistry and hematology)
!
Change in vital signs
!
Change in physical examination 
!
Concomitant medication use
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9.7.4.1
Adverse Events
The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in Table 9-1. 
9.7.4.2
Clinical Laboratory Assessments
Specific visits for obtaining clinical laboratory assessment samples are provided in Table 9-1. 
The scheduled clinical laboratory tests are listed in Table 9-6. 
Refer to the Study Laboratory Manual for instructions on obtaining and shipping blood and 
tissue samples. 
Any abnormal test results determined to be clinically significant by the Investigator should 
be repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, 
the value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant.
All abnormal clinical laboratory result pages should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. An 
abnormal laboratory result should be recorded as an AE if it meets the criteria listed in 
Section 10.1.
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE eCRF.
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Table 9-6:
Clinical Laboratory Tests
Blood Chemistry
Hematology
Urinalysis (dipstick)a
Other
Albumin 
Hemoglobin 
pH
Serum or urine 
pregnancy test, if 
applicable
Alkaline phosphatase 
Hematocrit 
Specific gravity
ALT 
WBC count
Ketones
PK
AST 
RBC count
Protein 
Total bilirubin
Platelet count
Glucose 
BUN (or urea)
ANC b
Bilirubin
Calcium
WBC differential 
(absolute / percent)
Leukocyte esterase
Chloride
Blood
CO2 (or bicarbonate)
Creatinine
Coagulation
Glucose
aPTT (or TCA)
LDH
PT
Magnesium
INR
Phosphorus
Potassium
Total protein 
Sodium 
Uric acid 
Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; aPTT, activated partial 
thromboplastin time; PK, pharmacokinetic; PT, prothrombin time; INR, international normalized ratio; AST, 
aspartate aminotransferase; BUN, blood urea nitrogen; CO2, carbon dioxide; LDH, lactate dehydrogenase; 
RBC, red blood cell; TCA, temps de céphaline active; WBC, white blood cell.
a Microscopy is required if dipstick results for blood or leukocyte esterase are positive.
b For sites that do not provide an ANC, this should be calculated as WBC multiplied by percentage of 
neutrophils (or percentage of segmented neutrophils plus bands).
Blood samples for hematology assessments are to be obtained on a weekly basis (ie, Day 1, 
Day 8 and Day 15) during the first 2 cycles of treatment, as well as at Screening/baseline and 
End of Treatment. Starting with Cycle 3, hematology counts should be obtained in each cycle 
on Day 1 and on either Day 8 (± 3 days) or Day 15 (± 3 days). Hematology assessments 
obtained on days other than Day 1 of a Cycle may be performed at a local laboratory outside 
of the investigational site laboratory as long as laboratory reports are provided to the 
Investigator for evaluation 24 hours prior to dosing. Hematology assessments scheduled for 
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the day of dosing must be available and assessed for toxicity prior to dosing. Blood samples 
for hematology assessments can be drawn within 72 hours prior to dosing.
Blood samples for serum chemistry assessments are to be obtained on Day 1 of each 
treatment cycle, as well as at Screening/baseline and End of Treatment. Blood samples for 
serum chemistry assessments can be drawn within 72 hours prior to dosing.
For hematology and serum chemistry assessments, at least 1 blood sample must be collected 
before randomization (Screening/Baseline) and 1 blood sample must be collected after 
randomization and before dosing on Cycle 1 Day 1.
Calculated creatinine clearance will be assessed at Screening using the value provided by the 
local laboratory or using the Cockcroft-Gault formula.
Coagulation parameters will be assessed only at baseline.
Urinalysis (dipstick) parameters will be assessed only at baseline; microscopy is required if 
dipstick results for blood and leukocyte esterase are positive.
9.7.4.3
Pharmacokinetic Assessments
For the evaluation of plasma concentrations of talazoparib, sparse blood samples for PK 
analysis will be collected on Day 1 of treatment cycles 1 through 4 for subjects randomized 
to receive talazoparib. Sparse PK sampling will consist of a pre-dose sample collected 
≤60 minutes prior to dosing, and 2 post-dose samples collected ≥ 30 minutes after dosing. 
The collection times of the 2 post-dose samples will be separated by ≥2 hours. Within 
individual subjects, efforts should be made to collect PK samples at different times relative to 
dosing across the study days with PK assessments. In the event of a dose delay on Day 1 of 
Cycles 1 to 4, the pre- and postdose PK blood sample should also be delayed until the subject 
resumes their next dose of talazoparib. 
On study days with PK assessments, the dose of talazoparib will be administered in the 
clinic, and the dose amount, food status (within 2 hours before taking the talazoparib dose), 
and dosing date and time will be recorded in the eCRF. The dose amount and dosing date and 
time for the dose taken on the day before the study days with PK assessments will also be 
recorded in the eCRF.
PK samples will be collected at all study sites except those that are unable to perform 
PK studies with the agreement of the Sponsor.
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9.7.4.4
Research Exploratory Assessments
Blood and tumor samples will be collected for exploratory research to characterize tumor 
sensitivity and resistance to talazoparib, and for other disease-related research. Analyses will 
include but not be limited to genomic/genetic, cellular, molecular, histochemical, and 
biochemical assays. 
9.7.4.5
Vital Signs, Physical Examinations and Other Observations Related to Safety
Vital signs including systolic blood pressure, diastolic blood pressure, heart rate, respiration 
rate and temperature will be assessed at Screening, baseline, on relevant treatment days 
(Table 9-1) and at the End of Treatment. Any change in vital signs will be recorded as an AE
if it meets the criteria listed in Section 10.1.
Weight will be assessed at Screening, baseline, prior to dosing on Day 1 of each treatment 
cycle, and at the End of Treatment. Height will be assessed at Screening only. 
Standard 12-lead electrocardiograms (ECGs) will be performed at baseline and if clinically 
indicated, at End of Treatment. Any change in the 12-lead ECGs will be recorded as an AE
if it meets the criteria listed in Section 10.1.
9.7.4.6
Reproductive Considerations
Female Subjects
Female subjects of childbearing potential must use a highly effective form of contraception.  
from the time of the first dose of study drug through 45 days after the last dose of study drug, 
defined as:
!
Established use of an oral, intravaginal, or transdermal combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation
!
Established use of an oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation
!
Placement of an intrauterine device or intrauterine hormone-releasing system
!
Bilateral tubal ligation for ≥6 months before randomization
!
Partner vasectomized for ≥6 months before randomization
!
Sexual abstinence when in relation to the preferred and usual lifestyle of the subject
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Female subjects of childbearing potential will have a serum pregnancy test performed at 
Screening. Female subjects with a positive pregnancy test at Screening do not meet eligibility 
criteria for enrollment. 
A local serum or urine pregnancy test (per local regulations/practice) will be performed for 
female subjects of childbearing potential at Day 1 of each cycle and the End of Treatment. If 
a urine pregnancy test is positive or there is a clinical question regarding possible pregnancy, 
dosing will be interrupted. Any positive urine pregnancy test result will be confirmed by a 
serum pregnancy test. Urine pregnancy tests must have a limit of detection of 25 IU/L (or 
equivalent units) for human chorionic gonadotropin. 
Additional pregnancy tests will be performed if clinically indicated at any visit in which 
pregnancy status is in question. 
Females considered not of childbearing potential include those who are surgically sterile 
(bilateral salpingectomy, bilateral oophorectomy, or hysterectomy) or who are 
post-menopausal, defined as:
!
≥55 years of age with no spontaneous menses for ≥12 months before randomization
!
< 55 years of age with no spontaneous menses for ≥12 months before randomization 
and with a postmenopausal follicle-stimulating hormone (FSH) concentration 
> 30 IU/L (or meeting criteria for post-menopausal status by the local laboratory)
Male Subjects
Male subjects with partners of childbearing potential must use a condom and contraception 
should be considered for the female partner from the time of the first dose of study drug 
through 105 days after the last dose of study drug. Male subjects whose partners are pregnant 
should use condoms for the duration of the pregnancy.
Refer to Section 10.4 for details on the reporting procedures to follow in the event of 
pregnancy.
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10
REPORTING ADVERSE EVENTS
10.1
Adverse Events
!
For this protocol, a reportable AE is any untoward medical occurrence (eg, sign, 
symptom, illness, disease or injury) in a subject administered study drug or other 
protocol-imposed intervention, regardless of attribution. Examples of AEs include the 
following: 
!
A worsening, excluding minor fluctuations, in the nature, severity, frequency, or 
duration of a pre-existing condition
!
Development of an intercurrent illness during the study
!
Development of symptoms that may or may not be related to the use of a concomitant 
medication or investigational product
!
Injury or accidents: If a medical condition is known to have caused the injury or
accident, the medical condition and the accident should be reported as 2 separate
medical events (eg, for a fall secondary to dizziness, both “dizziness” and “fall”
should be recorded separately)
!
Investigational abnormalities (eg, laboratory parameters, vital signs, ECG data)
should be defined as AEs only if the abnormality meets one of the following criteria:
o
Induces clinical signs or symptoms
o
Needs active intervention
o
Needs interruption or discontinuation of study medication
o
Abnormality or investigational value is clinically significant in the opinion of
the Investigator
An AE does not include the following:
!
Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction,
transfusion); the condition that leads to the procedure is an AE
!
Pre-existing diseases or conditions present or detected before the start of study drug
administration that do not worsen
!
Situations where an untoward medical event has not occurred (eg, planned
hospitalization for an elective procedure as known at the time of informed consent)
Events of special interest: Adverse events of special interest are any events identified for
intensive monitoring during the study. For 673-301, events of special interest include
overdose (Section 10.3), pregnancy in the subject or partner (Section 10.4), and specified
liver test abnormalities (Section 10.5).
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An adverse drug reaction is any AE for which there is a reasonable possibility that study drug 
caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between study drug and the AE.
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series 
of terms relating to a diagnosis or a surgical procedure.
The reporting period for non-serious AEs is the period from the time of initial dose of study 
drug through 30 days after the last dose of study drug (permanent discontinuation of 
talazoparib or physician’s choice), or before initiation of a new antineoplastic therapy, 
whichever occurs first. If a non-serious AE remains unresolved at the conclusion of the 
study, the Investigator will assess whether continued follow-up of the AE is warranted, and 
the results of this assessment must be documented. Resolution is defined as the return to 
baseline status or stabilization of the condition with the expectation that it will remain 
chronic. The Investigator should follow all unresolved AEs until the events are resolved or 
stabilized, the subject is lost to follow-up, or it has been determined that the study drug or 
participation is not the cause of the AE. Resolution of AEs (with dates) should be 
documented on the appropriate eCRF page(s) and in the subject’s medical record.
The criteria for determining, and the reporting of, SAEs is provided in Section 10.2.
The Investigator responsible for the care of the subject or qualified designee will assess AEs 
for severity, for relationship to study drug, and seriousness (refer to Section 10.2 for SAE 
definition). 
Severity (as in mild, moderate or severe myocardial infarction) is not equivalent to 
seriousness, which is based on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject’s life or functioning. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations.
The Investigator will determine the severity of each event by using NCI CTCAE v4.03. 
Adverse events that do not have a corresponding CTCAE term will be assessed according to 
the general guidelines for grading used in the CTCAE v4.03 as stated below.
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Grade
Description
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
2
Moderate: minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)a
3
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADLb
4
Life threatening or debilitating: consequences; urgent intervention 
indicated
5
Death related to AE
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using 
the telephone, managing money.
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the 
toilet, taking medications, not bedridden.
The study Investigator responsible for the subjects care (or qualified designee) will assess 
causality of reportable AEs/SAEs. The causal attribution guidance in Table 10-1 will be 
applied.
Table 10-1:
Causal Attribution Guidance
Is there a reasonable possibility that the AE/SAE was caused by the study drug based on facts 
(evidence) or arguments to suggest a causal relationship?
YES (Possible, 
probable or 
definite)
If there is a plausible temporal relationship between the onset of the 
AE/SAE and study drug administration and the AE/SAE cannot be readily 
explained by the subject’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE/SAE follows a known pattern of response to study 
drug; and/or the AE/SAE abates or resolves upon discontinuation of study 
drug or dose reduction and, if applicable, reappears upon re-challenge.
NO 
(Not related or 
remote)
If data are available to identify a clear alternative cause for the AE/SAE 
other than study drug; such as the subject’s clinical state, concomitant 
therapy, and/or other interventions.
OR
The AE/SAE has no plausible temporal relationship to administration of 
study drug (eg, cancer diagnosed 2 days after first dose of study drug).
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The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process. Regardless of the “Yes” or “No” causality assessment for individual 
AE/SAE reports, the Sponsor will promptly evaluate all reported safety information against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to Investigators and applicable regulatory authorities. 
10.2
Serious Adverse Events
An SAE is any untoward medical occurrence that meets 1 or more of the following criteria:
!
Is fatal
!
Is life threatening 
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death.
!
Requires or prolongs in-patient hospitalization 
!
Results in persistent or significant disability or incapacity
!
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy
!
Is an important medical event or reaction, including events requiring medical 
intervention to prevent worsening to any of the previously noted seriousness criteria
Grade 4 laboratory abnormalities are not by definition serious, unless the subject 
was at immediate risk of death, prolonged hospitalization or was considered an 
important medical event.
The safety reporting period for SAEs begins from the time of signing of the main ICF 
through 30 days after the last dose of study drug (permanent discontinuation of talazoparib or 
physician’s choice), or before initiation of a new antineoplastic therapy, whichever occurs 
first. 
Any SAE, whether or not considered related to study drug, must be reported immediately 
(within 24 hours of knowledge of the event) to the Sponsor Pharmacovigilance by fax or 
email using the study-specific SAE Report Form. Each SAE must also be reported on the 
appropriate eCRF page(s). Investigators should not wait to collect information that fully 
documents the event before notifying the Sponsor Pharmacovigilance of an SAE. The 
Sponsor may be required to report certain SAEs to regulatory authorities within 7 calendar 
days of being notified about the event; therefore, it is important that Investigators submit any 
information requested by the Sponsor as soon as it becomes available. As additional 
information becomes available, including but not limited to the outcome of the SAE and any 
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medication or other therapeutic measures used to treat the event, it must be reported within 
24 hours by fax or email (using the study-specific SAE Report Form).
If an SAE remains unresolved at the conclusion of the study, follow-up will be done until the 
event is assessed by the Investigator as having resolved or improved to a stable, chronic 
condition, or the subject becomes lost to follow-up. Resolution of an SAE is defined as the 
return to baseline status or stabilization of the condition with the expectation that it will 
remain chronic. Serious adverse events reported to the Investigator after the safety reporting 
period should be reported to the Sponsor if the Investigator assesses the event as related to 
the study drug.
Reporting of SAEs to the IRB/IEC/REB will be done in compliance with the standard 
operating procedures and policies of the IRB/IEC/REB and with applicable regulatory 
requirements. Adequate documentation must be obtained by the Sponsor showing that the 
IRB/IEC/REB was properly and promptly notified as required.
10.3
Overdose
10.3.1 Talazoparib
The medical monitor must be contacted in the event of a study drug overdose. An overdose is 
defined as any dose greater than the protocol-specified dose of talazoparib 1.0 mg once daily. 
In the event of an overdose, treatment with study drug should be stopped and general 
supportive measures initiated, taking into consideration the half-life is 53.5 and 40 hours 
(comparing Day 1 and Day 35 of talazoparib). There is no known antidote to overdose.
All overdose events are to be reported as events of special interest within 24 hours of
awareness by the study site according to Section 10.7, whether or not the event meets
AE criteria.
10.3.2 Treatment of Physician’s choice
The medical monitor must be contacted in the event of a study drug overdose. Overdose for a 
protocol-specified treatment of physician’s choice is any dose greater than the 
protocol-specified dose as follows:
!
Capecitabine: 1250 mg/m2, oral, twice daily, from Day 1 through 14 of a 21-day 
cycle, 30 minutes after meal.
!
Eribulin mesylate: 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2), infusion over 
2-5 minutes, Days 1 and 8 of 21-day cycles 
!
Gemcitabine: 1250 mg/m2, infusion over 30 minutes, Days 1 and 8 of 21-day cycles
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!
Vinorelbine: 30 mg/m2, weekly infusion over 6 to 10 minutes, Days 1, 8 and 15 of 
21-day cycles
In the event of an overdose, treatment with study drug should be stopped and general 
supportive measures initiated, taking into consideration the half-life of the respective drug. 
The Package Insert or Summary of Product Characteristics for the treatment of physician’s 
choice should be followed regarding patient management in a setting of an overdose.  
All overdose events are to be reported as events of special interest within 24 hours of 
awareness by the study site according to Section 10.7, whether or not the event meets AE
criteria.
10.4
Pregnancy
Pregnancy in a subject or subject’s partner should be reported within 24 hours of the site 
becoming aware of the pregnancy by faxing or emailing the Pregnancy Form in the study 
reference materials to the Sponsor Drug Safety & Pharmacovigilance Department. In 
addition, pregnancy in a subject is also reported on the end of study eCRF. The Investigator 
must make every effort to follow the subject through resolution of the pregnancy (delivery or 
termination) and to report the resolution on the pregnancy follow-up form in the study 
reference materials. In the event of pregnancy in the partner of a study subject, the 
Investigator should make every reasonable attempt to obtain the woman’s consent for release 
of protected health information. This consent for release of protected medical information 
will be documented on the pregnancy and pregnancy follow-up report forms and will be 
maintained in the subject’s research record. Should the pregnancy result in an abortion of any 
kind, stillbirth, or if the infant is born with a congenital anomaly, these events should be 
reported as an SAE rather than as a pregnancy report. 
10.5
Reporting Liver Test Abnormalities
The following liver test abnormalities must be reported to the Sponsor as SAEs within 
24 hours of discovery or notification of the event (ie, before additional etiologic 
investigations are concluded): 
!
AST or ALT ≥ 3 × ULN (> 5 × ULN if baseline ALT/AST is > 3 and ≤5 × ULN), 
and total bilirubin > 2 × ULN or INR > 1.5
!
AST or ALT ≥ 3 × ULN with signs and symptoms consistent with hepatitis 
!
Other events of hepatotoxicity and potential drug-induced liver injury that meet the 
criteria for an SAE
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10.6
Urgent Safety Measures
The regulations governing clinical trials state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
IRB/EC/REB is notified at the same time.” The reporting period for these events which may 
require the implementation of urgent safety measures is the period from the time of signing 
of the main ICF through permanent discontinuation of talazoparib or physician’s choice, or 
before initiation of a new antineoplastic therapy, whichever occurs first. Investigators are 
required to report any events that may require the implementation of urgent safety measures 
to the Sponsor Drug Safety & Pharmacovigilance Department within 24 hours.
Examples of situations that may require urgent safety measures include discovery of the 
following:
!
An immediate need to revise the IP administration (ie, modified dose amount or 
frequency not defined in protocol)
!
Lack of study scientific value, or detrimental study conduct or management
!
Discovery that the quality or safety of the IP does not meet established safety 
requirements
10.7
Serious Adverse Event and Event of Special Interest Reporting
Study site personnel will collect SAE information from the time the subject signs the 
informed consent form through screen failure, 30 days after the last dose of study drug 
(permanent discontinuation), or before initiation of a new antineoplastic therapy, whichever 
occurs first. Serious adverse events reported to the Investigator after the safety reporting 
period should be reported to the Sponsor if the Investigator assesses the event as related to 
the study drug.
Using an SAE report form, all SAEs, events of overdose, and specified liver test 
abnormalities (Section 10.1) must be reported within 24 hours of the study site personnel’s 
knowledge of the event, regardless of the Investigator assessment of the relationship of the 
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event to study drug. The contact information for submission of SAEs and 24-hour reports for
events of overdose and specified liver test abnormalities is as follows:
Name:
Fax:
 (United States) 
   or designated regional toll-free number
Backup Fax:
 (United Kingdom)
Email:
Phone:
The initial report should include, at minimum, the following:
!
Study number (673-301)
!
Site name and number
!
Investigator name
!
Subject number, sex, and age
!
Details of study drug administration
!
The date of the report
!
A description of the SAE (event term, seriousness of the event)
!
Causal relationship to the study drug
If the subject died, the report should include the cause of death as the event term (with fatal
outcome) and whether or not the event leading to death was related to study drug, as well as
the autopsy findings if available.
10.8
Clarification in Reporting of Deaths
As overall survival is one of the study endpoints, all subjects must be followed for survival 
status until death, and information relating to the death (eg, date and primary cause) should 
be obtained and recorded. Fatal events (regardless of relationship to study drug) should be 
reported as SAEs during the safety reporting period (through 30 days after permanent 
treatment discontinuation). 
Death is not an AE but is an outcome of an AE. For this protocol, reports of death without an 
AE will be managed as expedited reports (SUSARs) until the Sponsor receives additional 
information.
PPD
PPD
PPD
PPD
PPD
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10.9
Clarification in Reporting of Disease Progression as an Adverse Event
Disease progression is not unexpected in this study population and the term “disease 
progression” should not be reported as an AE unless a more specific clinical term is not 
defined or available. When clinical disease progression is identified, the clinical event that 
identifies the disease progression, if known, should be reported as the AE.
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11
APPROPRIATENESS OF MEASUREMENTS
Efficacy endpoints will be assessed in this study using RECIST v.1.1, an internationally 
standardized and widely accepted standard for measuring response to treatment in cancer 
(Eisenhauer, Eur. J. Cancer. 2009). Modifications to the criteria, regarding progression by 
bone metastasis and a requirement for progression by imaging (omitting progression by 
digital photography or physical examination for superficial lesions), will be employed 
(detailed in Section 24.3). Efficacy endpoints based on tumor assessments have been 
increasingly used in drug development, and both PFS and time to tumor progression (TTP) 
have been accepted as markers of clinical benefit for drug approval. PFS is available earlier 
than OS, is less likely than OS to be influenced by competing causes of death, and is not 
influenced by treatments administered after progression in a given trial (Everardo D. Saad., 
2011). PFS is subject to measurement error and bias. Measurement error may result from 
inconsistent use of definitions and standards among Investigators and bias may result from 
unblinded ascertainment of progression and from the fact that the date at which progression 
is verified radiographically is a proxy for the true progression date, which lies somewhere 
within two successive assessments (Everardo D. Saad., 2011).
Overall survival has historically been considered the most important endpoint in medical 
oncology due to its objective measurement and the unquestionable benefit derived by 
patients. The US FDA considers OS a direct measure of treatment benefit; according to that 
agency, OS is usually the preferred endpoint when studies can be conducted to adequately 
assess survival (US Department of Health and Human Services, May 2007). However, OS is 
increasingly an elusive endpoint, mostly because it may be confounded by the use of 
treatments administered to patients after participation in a trial (Everardo D. Saad., 2011). 
The European Medicine’s Agency (EMA), Committee for Medicinal Products for Human 
Use (CHMP) Guideline on the Evaluation of Anticancer Medicinal Products in Man 
(EMA/CPMP/205/95/Rev.4, 2012) states that OS and PFS are acceptable endpoints and 
recommends that if PFS is selected as the primary endpoint, OS should be selected as a 
secondary endpoint. 
In this study, PFS (defined as time from randomization until the date of radiologic
progressive disease [per RECIST v.1.1 with modifications] as determined by the central IRF, 
or death from any cause, whichever comes first) has been selected as the primary endpoint. 
The potential for measurement error and bias, outlined above, has been reduced in this study 
by the use of a blinded central IRF and the use of a randomized study design in which a 
similar evaluation schedule is used for all treatment arms. Overall survival has been selected 
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as a secondary endpoint in this study in accordance with the regulatory guidance described 
above.
The secondary efficacy measure of ORR and exploratory efficacy measure of DOR are well 
accepted efficacy endpoints in clinical development for oncology studies and in line with 
recommendations in the EMA CHMP Guideline on the Evaluation of Anticancer Medicinal 
Products in Man (EMA/CPMP/205/95/Rev.4, 2012); and the US FDA Guidance for Industry 
on Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (US Department 
of Health and Human Services, May 2007). 
Quality of life will be assessed as an exploratory endpoint in this study using the EORTC 
QLQ-C30/ EORTC QLQ-BR23, which is a validated instrument for assessing quality of life 
in breast-cancer subjects. 
The safety and PK endpoints in this study are standard and well-understood endpoints in 
clinical oncology. 
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12
STUDY PROCEDURES
12.1
Pre-study
A subject may sign the BRCA test ICF that permits BRCA1/2 testing at any time. A subject 
may enter the 28-day screening period and be randomized after the main ICF is signed and 
dated by the subject, the Investigator or designee, and witness (if required) before any other 
study-related procedures are performed.  
12.2
Screening/Baseline Visits
There will be a Screening visit within 28 days before randomization and a baseline visit 
within 7 days before randomization. If the Screening visit occurs within 7 days before
randomization, physical examination, vital signs, and clinical laboratory assessments do not 
need to be repeated at baseline. All Screening and baseline procedures may be performed on 
the same day as long as it is within 7 days before randomization.
At the Screening visit (within 28 days before randomization), the following procedures and 
assessments will be performed:
!
Record full medical history, including oncologic history, prior treatments, and 
demographics
!
Collect vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, 
and temperature), record height and weight
!
Perform a full physical examination
!
ECOG assessment
!
Perform baseline tumor assessments. Tumor measurements will be based on 
computed tomography (CT; preferred), magnetic resonance imaging (MRI), or X-ray. 
CT/MRI scans performed as standard of care before the main ICF was signed and 
within the 28-day screening period may be used as the Screening tumor assessments 
if the scans were completed per the specific study requirement (as specified in the 
Imaging Manual) 
!
Perform optional tumor marker (eg, CA15-3, CA27-29) assessments
!
MRI or CT to be performed to evaluate subjects for presence/absence of brain 
metastases
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o
If newly diagnosed CNS metastases are discovered at Screening, the subject is 
not eligible for enrollment until the CNS disease has been adequately treated 
with radiotherapy and/or surgery. Following treatment, if the CNS metastases 
are adequately controlled and do not require corticosteroids (except 
prednisone ≤ 5 mg/day or equivalent) for management of CNS symptoms, the 
subject may be re-screened for eligibility. A repeat CT/MRI following the 
identification of brain metastases (obtained at least 2 weeks after definitive 
therapy) must document adequately treated brain metastases
!
Acquire whole body nuclear medicine bone scan within 12 weeks before
randomization
!
Collect samples for clinical laboratory tests (hematology and serum chemistry and a 
serum pregnancy test for women of childbearing potential)  
!
Calculate creatinine clearance (see Section 9.7.4.2)
!
Record any SAEs occurring after signing of the informed consent and related to study 
procedures or study conduct as outlined in Section 10.2
!
Record all concomitant medications or treatments (including herbal therapies) that the 
subject has received within 28 days before randomization
!
Documentation of deleterious, suspected deleterious, or pathogenic germline BRCA1 
or BRCA2 mutation must be provided for enrollment from prior analysis by Myriad 
Genetics or laboratory approved by the Sponsor
!
Obtain blood sample for germline BRCA assay. For subjects who have prior 
documentation of BRCA carrier status, a blood sample for retrospective BRCA 
germline testing will be collected during the Screening/baseline period (Day -28 to 
Day -1). Retrospective testing will be performed at the central laboratory. For 
subjects who must undergo prospective BRCA germline testing, blood sample must 
be collected as early as possible during the Screening period. Prospective BRCA 
testing will be performed at the central laboratory. Specific laboratories and 
instructions on collection, processing, and shipment are provided in the laboratory 
manual
!
Obtain blood sample for disease-related research, including but not limited to 
genomic analysis
!
Confirm availability of archived tumor tissue slides (formalin-fixed 
paraffin-embedded [FFPE]) and ship as instructed in laboratory manual; tumor blocks 
may be substituted if approved by the Sponsor. A subject may be randomized without 
availability of tumor tissue slides or blocks. See the Laboratory Manual for 
preparation of slides or tumor blocks
!
Collect a fresh tumor biopsy sample (this procedure is optional and should only be
performed if the subject has consented. The biopsy will be collected at any time 
during the Screening/baseline period (Day -28 to Day -1))
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At the Baseline visit (within 7 days before randomization), the following procedures and 
assessments will be performed:
!
Collect vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, 
and temperature), record weight
!
Perform a full physical examination
!
Collect samples for clinical laboratory tests (hematology, serum chemistry, 
coagulation, and dipstick urinalysis). The laboratory tests may be omitted if the 
Screening samples were obtained within 7 days before randomization. (At least 1 set 
of laboratory tests must be collected before randomization.)
!
EORTC QLQ-C30/EORTC QLQ-BR23 (see Section 24.4)
!
Record any SAEs occurring after signing of the informed consent and related to study 
procedures or study conduct as outlined in Section 10.2
!
Record any changes to the subject’s concomitant medications or treatments (including 
herbal therapies) since the previous visit
!
Obtain a 12-lead ECG
12.3
Treatment Visits
Throughout the study, hematology assessments scheduled for the day of the dosing must be 
available and assessed for abnormalities requiring dose adjustment before dosing. The 
sampling for the hematology assessment can be drawn within 72 hours prior to dosing. In 
addition, serum chemistry, coagulation and urinalysis can be drawn within 72 hours prior to 
dosing.  
The first day of treatment is defined as Day 1; a ± 3-day window is allowed for Day 8 and 15 
visits for all Cycles. If initiation of a new cycle is delayed, the Day 1 procedures for that 
cycle will be performed on the day that dosing is resumed.  
12.3.1 Cycles 1 and 2
Weekly blood counts are to be obtained during the first 2 cycles. Hematology assessments 
obtained on days other than Day 1 of a Cycle may be performed at a local laboratory outside 
of the investigational site laboratory, as long as laboratory reports are provided to the 
Investigator for evaluation 24 hours before dosing. 
For subjects assigned to talazoparib, daily dosing will begin on Day 1 and continue up to 
Day 21 for each cycle as described in Section 9.4.5. 
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For subjects assigned to protocol-specific physician’s choice, the following dosing schedules 
will apply for each cycle (unless institution dosing guidelines differ) as described in 
Section 9.4.5:
!
Capecitabine will be administered twice daily on Day 1 through Day 14
!
Eribulin will be administered on Day 1 and 8 
!
Gemcitabine will be administered on Day 1 and 8 
!
Vinorelbine will be administered on Day 1, 8, and 15 
12.3.1.1
Cycles 1 and 2, Day 1
On Day 1, the following procedures and assessments will be performed before dosing with 
talazoparib or protocol-specific physician’s choice:
!
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, 
and temperature) and weight
!
Focused physical examination at the discretion of the Investigator based on the 
subject’s clinical condition
!
ECOG assessment 
!
For women of childbearing potential only:  serum or urine pregnancy test
o
If urine pregnancy test is positive, interrupt study drug treatment and confirm 
with a serum pregnancy test
!
For subjects assigned to talazoparib only: Collect pre-dose PK blood sample (within 
60 minutes prior to dosing)
o
Also collect whether subject had or had not eaten within 2 hours before
collection of PK sample
!
Collect samples for clinical laboratory tests (hematology and serum chemistry) 
!
EORTC QLQ-C30/EORTC QLQ-BR23 (see Section 24.4)
!
Record any AEs observed or reported since the previous visit (Cycle 2, Day 1 only)
!
Record any SAEs occurring after signing of the informed consent and related to study 
procedures or study conduct (Cycle 1, Day 1), and any SAEs observed or reported 
since the previous visit (Cycle 2, Day 1) as outlined in Section 10.2
!
Record any changes to the subject’s concomitant medications or treatments (including 
herbal therapies) since the previous visit
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After completion of the pre-dose assessments, the following will occur:
!
Subjects assigned to talazoparib only will swallow the Day 1 dose of talazoparib at 
the clinic. The site will dispense sufficient talazoparib to last for one cycle. The 
subject will be instructed to take the assigned dose of talazoparib at approximately the 
same time each day, preferably in the morning
!
Subjects assigned to protocol-specific physician’s choice will receive the Day 1 dose 
of capecitabine, eribulin, gemcitabine, or vinorelbine. For subjects assigned to 
capecitabine, the site will dispense sufficient capecitabine to last for one cycle 
For subjects assigned to talazoparib only: After talazoparib dosing, the following procedures 
and assessments will be performed:
!
Collect sparse PK blood samples ≥ 30 minutes after dosing. Two post-dose samples 
will be collected, separated by ≥ 2 hours
12.3.1.2
Cycles 1 and 2, Day 8 (± 3 days)
On Day 8, the following procedures and assessments will be performed before dosing with 
talazoparib or protocol-specific physician’s choice:
!
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, 
and temperature)
!
Collect samples for clinical laboratory tests (hematology only); review the laboratory 
results for abnormalities before dosing
!
Record any AEs, including SAEs, observed or reported since the previous visit
!
Record any changes to the subject’s concomitant medications or treatments (including 
herbal therapies) since the previous visit
After completion of the pre-dose assessments the following will occur:
!
Subjects assigned to talazoparib only will swallow the Day 8 dose of talazoparib at 
the clinic
!
Subjects assigned to protocol-specific physician’s choice will receive the Day 8 dose 
of capecitabine, eribulin, gemcitabine, or vinorelbine
12.3.1.3
Cycles 1 and 2, Day 15 (± 3 days)
On Day 15, the following procedures and assessments will be performed before dosing with 
talazoparib or protocol-specific physician’s choice:
!
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, 
and temperature)
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!
Collect samples for clinical laboratory tests (hematology only); review the laboratory 
results for abnormalities before dosing
!
Record any AEs, including SAEs, observed or reported since the previous visit
!
Record any changes to the subject’s concomitant medications or treatments (including 
herbal therapies) since the previous visit
After completion of the pre-dose assessments the following will occur:
!
Subjects assigned to talazoparib only will swallow the Day 15 dose of talazoparib at 
the clinic
!
Subjects assigned to protocol-specific physician’s choice of vinorelbine will be 
administered the Day 15 dose of vinorelbine. Subjects assigned to protocol-specific 
physician’s choice of eribulin, gemcitabine and capecitabine will resume treatment at 
the next scheduled visit
12.3.2 Cycles ≥ 3
Subjects who do not experience radiographic disease progression as determined by the IRF, 
unacceptable toxicity, or other discontinuation criteria at the end of Cycle 2 may continue to 
receive treatment in additional 21-day cycles. 
For subjects assigned to talazoparib, daily dosing will begin on Day 1 and continue up to 
Day 21 for each cycle as described in Section 9.4.5. 
For subjects assigned to protocol-specific physician’s choice, the following proposed dosing 
schedules will apply (unless institution dosing guidelines differ) as described in 
Section 9.4.5:
!
Capecitabine will be administered twice daily on Day 1 through Day 14 of each cycle
!
Eribulin will be administered on Day 1 and 8
!
Gemcitabine will be administered on Day 1 and 8 
!
Vinorelbine will be administered on Days 1, 8, and 15 
In Cycles ≥3, the Day 8 and Day 15 clinic visits may be omitted for subjects assigned to 
talazoparib or capecitabine not experiencing significant toxicities. Similarly, the Day 15 
clinic visit may be omitted for subjects assigned to eribulin, gemcitabine or vinorelbine 
(depending on schedule of administration or toxicity). A hematology assessment must be 
performed on either Day 8 or Day 15; this may occur at a local laboratory outside of the 
investigational site laboratory as long as laboratory reports are provided to the Investigator 
for evaluation 24 hours before dosing. Subjects who do not come to the clinic for Day 8 or 
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Day 15 visits should be contacted by phone to review AEs and concomitant medications. The 
phone review should be documented in the subject’s source documents.
12.3.2.1
Cycle ≥ 3, Day 1
On Day 1, the following procedures and assessments will be performed before dosing with 
talazoparib or protocol-specific physician’s choice:
!
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, 
and temperature) and weight
!
Focused physical examination at the discretion of the Investigator based on the 
subject’s clinical condition
!
ECOG assessment 
!
For women of childbearing potential only:  serum or urine pregnancy test
o
If urine pregnancy test is positive, interrupt study drug treatment and confirm 
with a serum pregnancy test
!
For subjects assigned to talazoparib only in Cycles 3 and 4 only: Collect pre-dose PK 
blood sample (within 60 minutes prior to dosing)
o
Also collect whether subject had or had not eaten within 2 hours before
collection of PK sample
!
Collect samples for clinical laboratory tests (hematology and serum chemistry); 
review the laboratory results for abnormalities before dosing
!
EORTC QLQ-C30/EORTC QLQ-BR23 (see Section 24.4) 
!
Record any AEs, including SAEs, observed or reported since the previous visit
!
Record any changes to the subject’s concomitant medications or treatments (including 
herbal therapies) since the previous visit
After completion of the pre-dose assessments, the following will occur:
!
Subjects assigned to talazoparib will swallow the Day 1 dose of talazoparib at the 
clinic. The site will dispense sufficient talazoparib to last for one cycle
!
Subjects assigned to protocol-specific physician’s choice will receive the Day 1 dose 
of capecitabine, eribulin, gemcitabine, or vinorelbine. For subjects assigned to oral 
capecitabine, the site will dispense sufficient capecitabine to last for one cycle
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For subjects assigned to talazoparib only, in Cycles 3 and 4 only: After talazoparib dosing, 
the following procedures and assessments will be performed:
!
Collect sparse PK blood samples ≥ 30 minutes after dosing. Two post-dose samples 
will be collected, separated by ≥ 2 hours (for Cycle 3 and 4 only)
12.3.2.2
Cycles ≥ 3, Day 8 (± 3 days)
On Day 8, the following procedures and assessments will be performed before dosing with 
talazoparib or protocol-specific physician’s choice:
!
Collect samples for clinical laboratory tests (hematology only); review the laboratory 
results for abnormalities before dosing
o
Note: Starting with Cycle 3, hematology counts should be obtained in each 
cycle on either Day 8 (± 3 days) or Day 15 (± 3 days) 
!
Record any AEs, including SAEs, observed or reported since the previous visit; this 
information may be obtained via telephone for subjects who do not come to the clinic
!
Record any changes to the subject’s concomitant medications or treatments (including 
herbal therapies) since the previous visit; this information may be obtained via 
telephone for subjects who do not come to the clinic
12.3.2.3
Cycles ≥ 3, Day 15 (± 3 days)
On Day 15, the following procedures and assessments will be performed before dosing with 
talazoparib or protocol-specific physician’s choice:
!
Collect samples for clinical laboratory tests (hematology only); review the laboratory 
results for abnormalities before dosing
o
Note: Starting with Cycle 3, hematology counts should be obtained in each 
cycle on either Day 8 (± 3 days) or Day 15 (± 3 days)
!
Record any AEs, including SAEs, observed or reported since the previous visit; this 
information may be obtained via telephone for subjects who do not come to the clinic
!
Record any changes to the subject’s concomitant medications or treatments (including 
herbal therapies) since the previous visit; this information may be obtained via 
telephone for subjects who do not come to the clinic
12.3.3 Unscheduled Visits
Unscheduled visits may be performed if a subject comes in for a visit and the dose is delayed 
due to an AE. Unscheduled visits may also be performed anytime to assess or follow up AEs, 
to perform scans, at the subject request, or at the Investigator request. The date and reason for 
the unscheduled visit must be recorded in the source documentation.  
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A review of AEs and changes to the subject’s concomitant medications or treatments 
(including herbal therapies) occurring since the previous visit should be performed at 
unscheduled visits. Other study procedures may be performed as clinically appropriate.
Imaging may be performed, as appropriate, for subjects who are symptomatic and/or for 
whom radiographic disease progression or response is being determined. 
12.3.4
Timing of Tumor Assessments
Tumor assessments will be performed by CT (preferred), MRI or X-ray. A brain MRI or CT 
is required at Screening/Baseline. Newly diagnosed CNS metastases at Baseline/Screening 
makes a patient ineligible for enrollment until such time as the CNS disease has been 
adequately treated by radiotherapy and/or surgery and the CNS disease is adequately 
controlled as described in Section 12.2. At that point, the patient is eligible for re-screening. 
If adequately controlled metastatic disease in the brain is present at Screening/Baseline, the 
brain MRI or CT will be repeated as clinically indicated. Post-baseline tumor assessments 
should be performed using the same technique used at Screening/Baseline.
Tumor assessments are to be performed at Screening, every 6 weeks (± 7 days) for the initial 
30 weeks from the date of randomization, and every 9 weeks thereafter (± 7 days), regardless 
of any dose interruptions or dose delays until radiographic disease progression as determined 
by the IRF or initiation of a new antineoplastic therapy. Tumor assessments can occur as 
clinically indicated, and at the time of clinical suspicion of disease progression. Post-baseline 
tumor assessments should be performed using the same technique used at Screening/baseline.
Optional tumor marker assessments (eg, CA15-3, CA27-29) may be performed at baseline, 
every 2 cycles (± 7 days) and at the End of Treatment. Tumor marker assessments will not be 
repeated if normal at baseline.
A bone scan is required at Screening/Baseline (or within 12 weeks before randomization). 
If bone metastasis is present at Screening/Baseline, a bone scan will be repeated every 
12 weeks (± 7 days) and as clinically indicated. Post-baseline assessments should be 
performed using the same technique used at Screening/Baseline.
12.3.5
Timing of Quality of Life Assessments
EORTC QLQ-C30/EORTC QLQ-BR23 assessments will be performed at baseline, Day 1 of 
each treatment cycle, and at the End of Treatment. The EORTC QLQ-C30/EORTC QLQ-
BR23 is included in Section 24.4.  
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12.4
End of Treatment and Follow-up Visits
Following permanent treatment discontinuation, for any reason, the subject will return to the 
site 30 days (-3 days or +10 days [27-40 days postdose]) after the last dose of study drug for 
an End of Treatment visit. At the End of Treatment visit, the following procedures and
assessments will be performed (tumor assessments may be skipped if performed in the 
previous 28 days):
!
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, 
and temperature) and weight
!
Perform focused physical examination 
!
ECOG assessment
!
For women of childbearing potential only: Urine or serum pregnancy test (per local 
regulations):
o
If urine pregnancy test is positive, confirm with a serum pregnancy test
!
Perform tumor assessments by using the same techniques used at baseline (if not 
performed within the previous 28 days)
!
Optional tumor marker assessment (only for subjects with abnormal results at 
baseline)
!
Genomic blood sample at radiographic disease progression (+ 35 days)
!
Collect samples for clinical laboratory tests (hematology and serum chemistry only)
!
EORTC QLQ-C30/EORTC QLQ-BR23 (see Section 24.4)
!
Perform 12-lead ECG (if clinically indicated)
!
Record any changes to the subject’s concomitant medications or treatments (including 
herbal therapies) since the previous visit; note whether anticancer treatment has been 
provided since the last dose of study drug
!
Collect a fresh tumor biopsy sample (this procedure is optional and should only be 
performed if the subject has consented. The biopsy will be collected at radiographic 
disease progression [+ 35 days] or at the time of discontinuation of study treatment)
AEs will continue to be recorded until 30 days after the last dose of study drug (permanent 
discontinuation) or before initiation of a new antineoplastic therapy, whichever occurs first.
For events occurring outside of this reporting period, only SAEs occurring greater than 
30 days after last dose of study medication and assessed as related to study drug will be 
reportable.
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Long-term follow-up:  Subjects will be contacted after the End of Treatment visit to 
determine survival status, cause of death (if applicable) and subsequent anti-cancer treatment 
every 60 days (± 7 days) after last dose for the first year, every 90 days (± 14 days) 
thereafter, and when requested by the Sponsor.
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13
DATA QUALITY ASSURANCE
Sponsor personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory 
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on eCRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records. 
Data quality control and analysis will be performed by the Sponsor or a designee, based on a 
predefined analysis plan.
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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis. 
14.1.1 Interim Analyses
There will be an interim and the final analysis for OS. An interim analysis of OS will be 
conducted at the time of the primary analysis of PFS. As the OS data are not expected to be 
mature at the time of interim analysis, OS data will be summarized to detect a statistical 
trend. The formal analysis of OS will be conducted when approximately 321 death events 
have been observed. 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
All available data will be used. No efficacy or PK data will be imputed; missing values will 
be treated as missing.
14.2
Primary Efficacy Analysis
The primary efficacy analysis is the comparison of PFS in subjects treated with talazoparib
versus treatments of protocol-specific physician’s choice.
The primary endpoint is PFS, which is defined as time from randomization until the date of
radiologic progressive disease per RECIST v.1.1 with modifications as determined by the 
central IRF or death from any cause, whichever comes first. The primary analysis of PFS will 
be conducted when at least 288 PFS events have been observed. 
The primary analysis of PFS will be performed using the intent-to-treat (ITT) population, 
defined as all randomized subjects, and will include only radiographic progression events as 
determined by the central IRF per RECIST v.1.1 with modifications and deaths. Clinical 
deterioration or radiographic progression determined by Investigators will not be considered 
progression events for the primary analysis.
A stratified log-rank 2-sided test with a 0.05 level of significance will be used to compare 
treatment groups. The stratification factors will be the same used to stratify the 
randomization schedule as documented in the interactive voice and Web response system 
(IXRS). 
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The median PFS and the associated 95% confidence interval (CI) for each treatment arm will 
be estimated using the Kaplan-Meier method. The hazard ratio (HR; λtalazoparib/ λcontrol) and the 
associated 95% CI will be estimated using a Cox regression model with treatment group as 
the only main effect and stratifying by the same stratification factors as were used for the 
log-rank test. An unstratified HR and the associated 95% CI will also be presented.
If the p-value for the stratified log-rank test is statistically significant (< 0.05, two-sided) and 
the observed HR (λtalazoparib/ λcontrol) is < 1, the null hypothesis of no difference in PFS will be 
rejected and it will be inferred that PFS is statistically prolonged in the group receiving 
talazoparib compared with the group receiving protocol-specific physician’s choice of 
therapy.
14.3
Secondary Efficacy Analysis
Secondary efficacy endpoints include ORR and OS. To maintain experiment-wise 2-sided 
type I error at 0.05, a detailed multiplicity adjusted inferential procedure for the primary and 
secondary efficacy analyses will be provided in the Statistical Analysis Plan. 
Objective Response Rate
The ORR will be determined by the IRF and is defined as the proportion of subjects with 
a partial or complete response as defined by RECIST v.1.1 with modifications. 
The primary analysis of ORR will be performed among the subjects with baseline 
measurable disease in the ITT population. In the analysis of ORR, subjects who do not have 
any post-baseline adequate tumor assessments will be counted as non-responders. Formal 
hypothesis testing of ORR will be performed using the stratified Cochran-Mantel-Haenszel 
test. The stratification factors will be the same used to stratify the randomization schedule as 
documented in the IXRS. The CR responders will be reported separately for the 
non-measurable disease subjects.
Overall Survival
OS is defined as the time from randomization to death due to any cause.
There will be an interim and final analysis for OS. The interim analysis of OS will be 
conducted at the time of the primary analysis of PFS. At the interim analysis, OS data will be 
summarized to detect a statistical trend in OS (no formal hypothesis testing). The formal
analysis of OS will be conducted when approximately 321 deaths have been observed, and
will be performed using the ITT population. 
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The testing of OS will be conducted using a stratified log-rank 2-sided test. The stratification 
factors will be the same used to stratify the randomization schedule as documented in the 
IXRS.
The median of OS and the associated 95% CI for each treatment arm will be estimated using 
the Kaplan-Meier method. The HR and the associated 95% CI will be estimated using a Cox 
regression model with treatment group as the only main effect and stratifying by the same 
stratification factors as were used for the log-rank test. An unstratified HR and the associated 
95% CI will also be presented.
14.4
Exploratory Efficacy Analysis
The exploratory efficacy endpoints are duration of response in responding subjects and 
quality of life for all enrolled subjects, assessed using the EORTC QLQ-C30 / EORTC 
QLQ-BR23.  
Duration of response is defined, for subjects with an objective response, as the time from first 
radiographic documentation of CR or PR to disease progression by RECIST v.1.1 with 
modifications as determined by the IRF or death due to any cause, whichever occurs first. 
Median duration of response and its associated 95% CI will be estimated, by treatment group, 
using Kaplan-Meier methods. The difference between treatment groups will be analyzed 
using a stratified log-rank test, using the same stratification that was used for randomization. 
The EORTC QLQ-C30 / EORTC QLQ-BR23 is composed of a global health status scale, 
5 functional scales (physical, role, emotional, cognitive, and social), 3 symptom scales 
(fatigue, nausea & vomiting, and pain), and several single items, as well as a module 
designed specifically for breast cancer.
Summary statistics will be presented, by treatment group, at Baseline, at Day 1 of each cycle 
and at End of Treatment for the global health status scale, the functional and symptom scales, 
and the breast cancer module. Summary statistics for change from baseline will be presented 
at Day 1 of each cycle and at the End of Treatment. Differences between treatment groups 
will be analyzed using repeated measures analysis methods if applicable.
Blood and tumor samples will be collected for future exploratory research to identify 
additional marker profiles that indicate potential sensitivity to PARP inhibition, to 
characterize tumor sensitivity and resistance to talazoparib, and for other disease-related 
research. Analyses will include but not be limited to genomic/genetic, cellular, molecular, 
histochemical and biochemical assays. 
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14.4.1 Pharmacokinetic Analyses 
The PK analysis will include all subjects who receive at least 1 dose of talazoparib and 
provide at least 1 evaluable PK assessment. The pharmacokinetics of talazoparib will be 
evaluated by summary statistics of trough plasma concentrations collected on Day 1 of 
Cycles 2, 3, and 4.
A population PK modeling approach will be used to estimate individual values of apparent 
clearance (CL/F) and central volume of distribution (Vc/F) from the sparse post-dose PK 
samples. Individual CL/F estimates will then be used to estimate individual exposure 
parameters (eg, area under the concentration time curve over a dosing interval [AUCτ]). The 
association between talazoparib exposure parameters and efficacy and safety outcomes may
be explored.
14.5
Safety Analysis
The analyses of safety will include all subjects who receive any study drug (talazoparib or 
active control) throughout the study duration.
All AEs will be coded using MedDRA. The Investigator will classify the severity of AEs 
using the CTCAE v 4.03. A treatment emergent AE (TEAE) is defined as any event with an 
onset date on or after date of first dose of study drug, or any event present before treatment 
that worsens after treatment. Only TEAEs with an onset date prior to date of last dose 
+ 30 days or the date of initiation of a new antineoplastic therapy (whichever occurs first)
will be tabulated in summary tables. 
The number and percentage of subjects with AEs will be summarized by system organ class, 
preferred term, relationship to study drug, and severity for each treatment group. A 
by-subject listing will be provided for those subjects who experience an SAE, including 
death, or experience an AE associated with discontinuation of study drug. 
Clinical laboratory data will be summarized by the type of laboratory test. The number and 
percentage of subjects who experience abnormal (ie, outside of reference ranges) and/or 
clinically significant abnormalities after study drug administration will be presented for each 
clinical laboratory measurement. For each clinical laboratory measurement, descriptive 
statistics will be provided for baseline and all subsequent post-treatment scheduled visits. 
Changes from baseline to the post-treatment visits will also be provided. Descriptive 
statistics of vital signs will also be provided in a similar manner. In addition, shift from 
baseline in CTCAE grade (where applicable) and by high/low flags (where CTCAE grades 
are not defined) will be presented by treatment group.
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14.6
Determination of Sample Size
This study is designed to provide adequate power for PFS and OS.
For PFS, based on 2:1 randomization allocation ratio, a total of 288 events provide the study 
with 90% power for a 2-sided log-rank test with a 0.05 level of significance to detect a 50% 
increase in PFS (hazard ratio [HR]=0.67). Assuming an exponential distribution of PFS, this 
corresponds to an increase in median PFS from 20 weeks to 30 weeks. In the current design, 
the minimum observed effect that would result in statistical significance for PFS is a 28% 
improvement (HR = 0.78) from 20 to 25.6 weeks. 
Up to 429 subjects will be randomized (2:1) and followed to observe the required number of 
events within the planned study duration (approximately 39 months accrual; approximately 
41 months total to observe the required PFS events). 
For OS, approximately 321 events will provide the study with 80% power for a 2-sided 
log-rank test with an overall 0.05 level of significance to detect a 39% increase in OS 
(HR=0.72). Assuming an exponential distribution of OS, this corresponds with an increase in 
median OS from 20 months to 27.8 months. 
14.7
Analysis Populations
The safety analysis population will consist of all subjects who receive any study drug
(talazoparib or protocol-specific physician’s choice therapy).
The ITT population will consist of all randomized subjects.
The PK analysis population will consist of all subjects who receive at least 1 dose of 
talazoparib and provide evaluable PK assessments.
14.8
Statistical Criteria for Termination of the Study 
There are no statistical criteria for the termination of the study.
14.9
Changes in the Conduct of the Study or Planned Analyses
Only the Sponsor may modify the protocol. Any change in study conduct considered 
necessary by the Investigator will be made only after consultation with the Sponsor, who will 
then issue a formal protocol amendment to implement the change. The only exception is 
when an Investigator considers that a subject’s safety is compromised without immediate 
action. In these circumstances, immediate approval of the chairman of the IRB/EC/REB must 
be sought, and the Investigator should inform the Sponsor and the full IRB/EC/REB within 
2 working days after the emergency occurs. 
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With the exception of minor administrative or typographical changes, the IRB/EC/REB must 
review and approve all protocol amendments. Protocol amendments that have an impact on 
subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/EC/REB prior to their implementation.
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by the Sponsor and the 
IRB/EC/REB, and all active subjects must again provide informed consent.
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will 
prevail. 
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DATA MONITORING COMMITTEE
A Data Monitoring Committee (DMC) will be established to monitor the safety of the study 
on a regular basis. The committee will operate independently from the Sponsor and the 
clinical Investigators. The primary responsibilities of the DMC are to review the 
accumulating safety data on a regular and an ad hoc basis and to make recommendations to 
the Sponsor regarding the continued conduct of the study. Safety data will be provided at 
regular intervals to the DMC in the form of unblinded summary reports or data listings from 
an independent statistical center designated by the Sponsor. Details of the composition, role, 
operational considerations, and stopping guidelines will be provided in a separate DMC 
charter.
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BLINDED CENTRAL INDEPENDENT RADIOLOGY FACILITY
An Independent Radiology Facility (IRF) will evaluate imaging data of trial subjects in a 
central, blinded, and independent fashion. Board-certified radiologists will determine 
radiographic response and/or progression following randomization by assessing CT, MRI, 
x-ray, and bone scans according to RECIST v.1.1 with modifications.
16.1
Confirmation of Progression
Subjects will continue to receive treatment until radiographic disease progression or other 
discontinuation criteria are met. Clinical deterioration or radiographic progression 
determined by the Investigator will not be considered progression events for the primary 
analysis; the analysis of PFS (conducted by the Sponsor or designee) will only include 
radiographic disease progression events as determined by the IRF. Radiographic progression 
must be verified centrally before removal of subject from the study drug. For each subject 
whom the site suspects has progressed, a confirmation of progression review will 
radiographically verify that a subject has progressed before discontinuing treatment. Sites 
will quickly be notified of the results. Note: The image review charter will contain further 
detail regarding the confirmation of progression review. 
Details regarding IRF member qualification, training, methods, procedures, and other issues 
relevant to committee operations will be described in the IRF charter.
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COMPENSATION, INSURANCE AND INDEMNITY
There will be no charge to study subjects to be in this study. The Sponsor will pay all costs of 
tests, procedures, and treatments that are part of this study unless otherwise covered by the 
subject’s health insurance company or other third party payer. In addition, after IRB/EC/REB 
approval, the Sponsor may reimburse the cost of travel for study-related visits. The Sponsor 
will not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study subject’s disease, that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected. 
The Investigator should contact the Sponsor immediately upon notification that a study 
subject has been injured by the IP or by procedures performed as part of the study. Any 
subject who experiences a study-related injury should be instructed by the Investigator to 
seek medical treatment at a pre-specified medical institution if possible, or at the closest 
medical treatment facility if necessary. The subject should be given the name of a person to 
contact to seek further information about, and assistance with, treatment for study-related 
injuries. The treating physician should bill the subject’s health insurance company or other 
third party payer for the cost of this medical treatment. If the subject has followed the 
Investigator’s instructions, the Sponsor will pay for reasonable and necessary medical 
services to treat the injuries caused by the IP or study procedures, if these costs are not 
covered by health insurance or another third party that usually pays these costs. In some 
jurisdictions, the Sponsor is obligated by law to pay for study-related injuries without prior 
recourse to third party payer billing. If this is the case, the Sponsor will comply with the law.
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CASE REPORT FORMS AND SOURCE DOCUMENTS
Electronic case report forms will be provided for each subject. The Investigator must review 
and electronically sign the completed eCRF casebook to verify its accuracy before the data 
are locked.
Electronic case report forms must be completed using a validated web–based application. 
Study site personnel will be trained on the application and will enter the clinical data from 
source documentation. Unless explicitly allowed in the eCRF instructions, blank data fields 
are not acceptable. 
In the event of an entry error, or if new information becomes available, the site personnel will 
correct the value by deselecting the erroneous response and then selecting or entering the 
factual response. In compliance with 21 CFR Part 11, the system will require the site 
personnel to enter a reason for changing the value. The documented audit trail will include 
the reason for the change, the original value, the new value, the time of the correction and the 
identity of the operator.
The study data on the eCRFs must be verifiable to the source data, which necessitates access 
to all original recordings, laboratory reports, and subject records. In addition, all source data 
should be attributable (signed and dated). The Investigator must therefore agree to allow 
direct access to all source data. Subjects (or their legally authorized representative) must also 
allow access to their medical records, and subjects will be informed of this and will confirm 
their agreement when giving informed consent. 
A CRA designated by the Sponsor will compare the eCRFs with the original source 
documents at the study site and evaluate them for completeness and accuracy before 
designating them as “source data verified.” All eCRF data must be source data verified 
before the casebook is approved by the Investigator and locked. If an error is discovered at 
any time or a clarification is needed, the CRA or designee will create an electronic query on 
the associated field. Site personnel will then answer the query by either correcting the data or 
responding to the query. The CRA will then review the response and determine either to 
close the query or re–query the site if the response does not fully address the question. This 
process is repeated until all open queries have been answered and closed. 
Upon completion of the clinical study report, an electronic copy of each site’s casebooks will 
be copied to a compact disk and sent to each site for retention with other study documents.
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STUDY MONITORING AND AUDITING
Qualified individuals designated by the Sponsor will monitor all aspects of the study 
according to GCP and standard operating procedures for compliance with applicable 
government regulations. The Investigator agrees to allow these monitors direct access to the 
clinical supplies, dispensing, and storage areas and to the clinical files, including original 
medical records, of the study subjects, and, if requested, agrees to assist the monitors. During 
the review of these documents, the anonymity of the subject will be respected with strict 
adherence to professional standards of confidentiality. The Investigator and staff are 
responsible for being present or available for consultation during routinely scheduled site 
visits conducted by the Sponsor or its designees.
Members of the Sponsor’s Clinical Quality Assurance Department or designees may conduct 
an audit of a clinical site at any time before, during, or after completion of the study. The 
Investigator will be informed if an audit is to take place and advised as to the scope of the 
audit. Representatives of the FDA or other regulatory agencies may also conduct an audit of 
the study. If informed of such an inspection, the Investigator should notify the Sponsor
immediately. The Investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files.
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RETENTION OF RECORDS
The Investigator must retain all study records required by the Sponsor and by the applicable 
regulations in a secure and safe facility. A file for each subject must be maintained that 
includes the signed informed consent form and copies of all source documentation related to 
that subject. The Investigator must ensure the reliability and availability of source documents 
from which the information on the eCRF was derived. Subject identity information recorded 
will be maintained for at least 15 years on the subject confidentiality log or longer if required 
by local regulations.
The Investigator must consult a Sponsor representative before disposal of any study records, 
and must notify the Sponsor of any change in the location, disposition or custody of the study 
files. The Investigator/institution must take measures to prevent accidental or premature 
destruction of essential documents, that is, documents that individually and collectively 
permit evaluation of the conduct of a study and the quality of the data produced, including 
paper copies of study records (eg, subject charts) as well as any original source documents 
that are electronic as required by applicable regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. Subject files and other source 
data must be kept for the maximum period of time permitted by the hospital, institution or 
private practice, but not less than 15 years. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by a Sponsor 
agreement. The Sponsor must be notified and will assist with retention should 
Investigator/institution be unable to continue maintenance of subject files for the full 
15 years. It is the responsibility of the Sponsor to inform the Investigator/institution as to 
when these documents no longer need to be retained.
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USE OF INFORMATION AND PUBLICATION
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences. 
Written approval from the Sponsor is required before disclosing any information related to 
this clinical trial, and no publications initiated by Investigators may be published until all 
protocol defined primary and secondary endpoints are published in a manuscript. 
Investigators in this study agree to have their name listed as an Investigator in any 
publication reporting results from this study, whether or not they are an author on the 
publication. 
The details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Trial 
Agreement between the Sponsor and the institution of the Investigator.
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REFERENCES
Arun, B, Bayraktar, S, Liu, DD, Gutierrez Barrera, AM et. al. Response to neoadjuvant 
systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-
institution experience. J Clin Oncol 29[28], 3739-3746. 2011.
Atchley, DP, Albarracin, CT, Lopez, A, Valero, V et. al. Clinical and pathologic 
characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin 
Oncol 26[26], 4282-4288. 2008. 
Byrski, T, Gronwald, J, Huzarski, T, Grzybowska, E et. al. Pathologic complete response 
rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. 
J Clin Oncol 28[3], 375-379. 2010. 
CPMP/EWP/205/95/Rev.4 Oncology Working Party. Guideline on the Evaluation of 
Anticancer Medicinal Products in Man. 13 December 2012.
De Bono JS, Mina LA, Gonzalez M, Curtin NJ, Wang E, Henshaw JW et al. First-in-Human 
Trial of Novel Oral PARP Inhibitor BMN 673 in patients with Solid Tumors. J Clin Oncol 
31, 2013 (suppl; abstr 2580). Available online at http://chicago2013.asco.org/abstracts.
Eisenhauer, EA, Therasse, P, Bogaerts, J, Schwartz, LH et. al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45[2], 
228-247. 2009.
Food and Drug Administration (US). Guidance for industry. Drug induced liver injury: 
premarketing clinical evaluation [Internet]. 2009 Jul. Available from: 
http://www.fda.gov/downloads/Drugs/Guidance/UCM174090.pdf
Gelmon, KA, Tischkowitz, M, Mackay, H, Swenerton, K et. al. Olaparib in patients with 
recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative 
breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol . 
2011. 
Goodin S, Griffith N, Chen B, Chuk K, Daouphars M, Doreau C, et al. Safe handling of oral 
chemotherapeutic agents in clinical practice: recommendations from an international 
pharmacy panel. J Oncol Pract. 2011 Jan;7(1):7–12.
Harkin, DP, Bean, JM, Miklos, D, Song, YH et. al. Induction of GADD45 and JNK/SAPK-
dependent apoptosis following inducible expression of BRCA1. Cell 97[5], 575-586. 1999. 
Kriege, M, Jager, A, Hooning, MJ, Huijskens, E et. al. The efficacy of taxane chemotherapy 
for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer 118[4], 899-
907. 2012. 
Kriege, M, Seynaeve, C, Meijers-Heijboer, H, Collee, JM et. al. Sensitivity to first-line 
chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin 
Oncol 27[23], 3764-3771. 2009. 
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Lafarge, S, Sylvain, V, Ferrara, M, Bignon, YJ. Inhibition of BRCA1 leads to increased 
chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. 
Oncogene 20[45], 6597-6606. 2001. 
Liebens, FP, Carly, B, Pastijn, A, Rozenberg, S. Management of BRCA1/2 associated breast 
cancer: a systematic qualitative review of the state of knowledge in 2006. Eur J Cancer 43[2], 
238-257. 2007. 
Quinn, JE, Carser, JE, James, CR, Kennedy, RD et. al. BRCA1 and implications for response 
to chemotherapy in ovarian cancer. Gynecol Oncol 113[1], 134-142. 2009. 
Quinn, JE, Kennedy, RD, Mullan, PB, Gilmore, PM et. al. BRCA1 functions as a differential 
modulator of chemotherapy-induced apoptosis. Cancer Res 63[19], 6221-6228. 2003. 
Rennert, G, Bisland-Naggan, S, Barnett-Griness, O, Bar-Joseph, N et. al. Clinical outcomes 
of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 357[2], 115-
123. 2007. 
Everardo D. Saad. Endpoints in advanced breast cancer: methodological aspects & clinical 
implications. Indian J Med Res. 2011 October; 134(4): 413–418. Available at: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237237
Sledge, GW, Neuberg, D, Bernardo, P, Ingle, JN et. al. Phase III trial of doxorubicin, 
paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for 
metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21[4], 588-592. 2003. 
Tassone, P, Tagliaferri, P, Perricelli, A, Blotta, S et. al. BRCA1 expression modulates 
chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer 
88[8], 1285-1291. 2003. 
Tutt A, Ellis P, Kilburn L, Gilett C, Pinder S, Abraham J, et al. The TNT trial: a randomized 
phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or 
recurrent locally advanced triple negative or BRCA 1/2 breast cancer. Abstract presented at: 
37th Annual San Antonio Breast Cancer Symposium; 2014 Dec 09-13; San Antonio, TX. 
(Abstract S3-01.) 
Tutt, A, Robson, M, Garber, JE, Domchek, SM et. al. Oral poly(ADP-ribose) polymerase 
inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: 
a proof-of-concept trial. Lancet 376[9737], 235-244. 2010. 
U.S. Department of Health and Human Services. Food and Drug Administration. Center for 
Drug Evaluation and Research. Center for Biologics Evaluation and Research. Guidance for 
Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
May 2007. 
Verhoog, LC, Brekelmans, CT, Seynaeve, C, Dahmen, G et. al. Survival in hereditary breast 
cancer associated with germline mutations of BRCA2. J Clin Oncol 17[11], 3396-3402. 
1999. 
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SIGNATURE PAGE
Protocol Title: A Phase 3, Open-Label, Randomized, Parallel, 2-Arm, Multi-Center Study of 
Talazoparib (BMN 673) versus Physician’s Choice in Germline BRCA Mutation Subjects 
with Locally Advanced and/or Metastatic Breast Cancer, Who Have Received Prior 
Chemotherapy Regimens for Metastatic Disease
Protocol Number: 673-301, Amendment 1
I have read the forgoing protocol and agree to conduct this study as outlined. I agree to 
conduct the study in compliance with all applicable regulations and guidelines, including 
ICH E6, as stated in the protocol, and other information supplied to me.
Investigator Signature
Date
Printed name:
Accepted for the Sponsor:
On behalf of Medivation, Inc., I confirm that Medivation, Inc., as a Sponsor will comply with 
all obligations as detailed in all applicable regulations and guidelines. I will ensure that the 
Investigator is informed of all relevant information that becomes available during the conduct 
of this study. 
Medical Monitor Signature
Date
Printed name:
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APPENDICES
24.1
ECOG Performance Status
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
24.2
Common Terminology Criteria for Adverse Events
Please refer to:
http://ctep.cancer.gov/reporting/ctc.html
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24.3
Response Assessment using RECIST v.1.1 Criteria with Modifications
Tumor response will be assessed according to the revised Response Evaluation Criteria in 
Solid Tumor guideline (RECIST v.1.1) (Eisenhauer, Eur. J. Cancer. 2009). Modifications to 
the criteria, regarding progression by bone metastasis will be employed account for the 
enrollment of subjects with only bone lesions at study entry (documented in the table notes 
for Overall Visit Response). Another modification is a requirement for progression by 
imaging (omitting progression by digital photography or physical examination for superficial 
lesions), as described in Section 24.3.1. Computed tomography (CT), magnetic resonance 
imaging (MRI), X-ray, and nuclear medicine whole body bone scans will be reviewed at an 
independent review facility by radiologists trained in RECIST v.1.1 for this trial (Section 16), 
and blinded to subject demographics, treatment, and clinical status. Full details will be 
provided as a separate imaging charter.
24.3.1 Image Included in the Assessment
!
CT is the preferred method of assessment. Intravenous contrast is required, unless the 
subject has an allergy to contrast that cannot be controlled with premedications. 
Anatomy scanned should include the chest (starting above the lung apices), abdomen, 
and pelvis (coverage to include the symphysis pubis). Slice thickness should be no 
greater than 5 mm, with no gaps. Details of the imaging protocols will be provided to 
sites in an imaging manual.
!
If subjects are unable to receive iodinated CT contrast, the preferred imaging is non-
contrast CT of the chest, and MRI of the abdomen and pelvis with contrast.
!
For non-infiltrative and distinct skin nodules, CT or MRI remains the preferred 
method of assessment. Digital photography will not be acceptable as a method of 
radiographic assessment of skin lesions. Discrete skin nodules that are not visible 
using CT or MRI should be considered non-measurable, non-target lesions. 
!
For bone lesions, CT or MRI remains the preferred method of assessment. For lesions 
that cannot be quantified by CT or MRI, nuclear medicine bone scan may be used to 
assess metastases to bone. Whole body acquisition with planar spot views of areas of 
concern is acceptable. Single-photon emission computed tomography (SPECT) 
imaging, if acquired, is also acceptable.
!
Chest X-ray is permitted by the RECIST v.1.1 guidelines to assess lung lesions, but 
CT of the chest is strongly preferred.
24.3.2 Overview of Assessment Process
The tumor burden will be documented at baseline. First, a reviewer will determine which 
lesions are appropriate for repeated quantitative assessment (measurable lesions). From the 
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measurable lesions, the reviewer will choose a set of lesions to be followed quantitatively 
throughout the trial (target lesions). Target lesions will be selected based on size, 
reproducibility of measurement, and whether the group of lesions represents the disease 
distribution. A value for the target tumor burden (sum of diameters) will be calculated. All 
tumor lesions that are not chosen for quantitative assessment will be documented and 
followed qualitatively as non-target lesions.
At each follow-up visit, the reviewer will assess the target lesions by making measurements 
that correspond to measurements made at baseline. The Reviewer will verify the calculated
sum of diameters, and the comparison of that sum to the baseline value (for determining 
partial response) and to the nadir, the smallest value seen until that point (to look for 
progression). The Reviewer will assess the non-target lesions qualitatively, and will search 
for new lesions. Information about target, non-target, and new lesions will be combined to 
produce an overall visit response for the subject. After all visit assessments are completed, 
the Reviewer will verify each visit response, and the visit responses will be used to derive 
information relevant to the endpoints (such as the date of progression and the best overall 
response).
24.3.3 Measurable and Non-Measurable Disease
Eligibility of lesions for quantitative assessment will be determined at baseline, with target 
lesions selected from the measurable lesions identified. After baseline, target lesions will 
always be assessed quantitatively, and non-target lesions will be assessed qualitatively, with 
no further evaluation of measurability according to these definitions.
Measurable Disease
!
A lesion is considered measurable if it has a diameter of ≥ 10 mm in the axial plane 
on CT or MRI, assuming that the slice thickness is 5 mm or less. If the slice thickness 
is greater than 5 mm, the minimum size increases to two times the slice thickness
(slice thickness is the total distance between the tops of two adjacent slices, including 
any gap).
!
Malignant lymph nodes are considered measurable if the short axis (greatest 
dimension perpendicular to the longest diameter) is ≥ 15 mm at baseline.
!
If chest X-ray is used, a lesion is considered measurable if it is completely surrounded 
by aerated lung with clear boundaries, and has a diameter of 20 mm. In the unlikely 
event that a non-spiral CT scanner is used, the minimum size for measurability is 
20 mm.
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Non-Measurable Disease
!
A lesion is considered evaluable, but not measurable, if it does not meet the 
measurability criteria described above, but which is a manifestation of malignancy 
that can be followed qualitatively as an indicator of disease progression or treatment 
response. 
o
By RECIST v.1.1 definitions, a lymph node that has a short axis diameter of 
10-14 mm is considered evaluable, but not measurable. Nodes with a short 
axis diameter of <10 mm are considered normal.
o
Palpable skin nodules that are not discernible using CT or MRI are considered 
evaluable but not measurable for this study
!
Non-measurable lesions are those the reviewer strongly believes to be malignant, but 
which do not meet the definitions above.
o
Bone lesions that are blastic are non-measurable by definition. Bone lesions 
that are lytic or mixed lytic-blastic, which have soft tissue components seen 
on CT or MRI, and which meet size criteria above, may be measurable.
o
Simple cysts are considered benign by default. Cystic metastases may be 
considered measurable, but solid lesions are preferred for selection as target.
o
Malignant ascites or pleural/pericardial effusions, lymphangitic infiltration of 
skin or lung, leptomeningeal disease, inflammatory breast disease, and 
infiltrative disease without clear borders are all examples of disease 
considered intrinsically non-measurable.
!
Lesions seen on nuclear medicine bone scan, or modalities other than CT or MRI 
(plain X-ray [with the exception for lung lesions noted above], positron emission 
tomography [PET], etc.) cannot be measured. These modalities can be used only to 
determine whether a lesion is present or absent.
!
Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
previous treatment.
24.3.4 Baseline Lesion Selection and Documentation
!
Target lesions will be chosen from among the measurable lesions. The lesions chosen 
should be the largest, most reproducible, and most representative of the overall 
disease distribution. 
!
All measurable lesions up to a maximum of 5 lesions total, and 2 lesions per organ, 
should be selected as target lesions. Paired organs (lungs, kidneys, adrenals, ovaries) 
are considered one organ. The lymph nodes collectively are considered one organ.
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!
Non-nodal target lesions are measured in the longest diameter in the axial plane (on 
CT or MR). Malignant lymph nodes are always measured in the short axis diameter 
(greatest dimension perpendicular to the longest diameter). The appropriate 
measurements for all target lesions chosen at baseline will be added to produce the 
recorded sum of diameters, which will be recorded.
!
Other disease present at baseline should be recorded as ‘Non-target lesions’. Multiple 
non-target lesions in a single organ can be recorded as one entry during assessment, 
as non-target lesions are assessed as a whole during follow-up.
24.3.5 Assessment of Response
The overall response for each visit is a combination of target lesion response, non-target 
lesion response, and the presence or absence of new lesions. 
!
Target lesions measurements should be performed in the same manner as at 
baseline. The sum of diameters of all target lesions must be calculated, and compared 
to the baseline value and to the nadir value (the smallest value previously seen during 
the trial, which may be the same as baseline). The following special rules apply to 
lesion measurements:
o
If two target lesions coalesce the longest diameter measurement of the 
coalesced mass is used. If a large target lesion splits, the longest diameter of 
each fragment is measured, and the sum is used.
o
Measurements for target lesions that become small should continue to be 
recorded, as long as the Reviewer is confident in the accuracy. If a target 
lesion is considered to have completely disappeared, 0 mm should be 
recorded. If it is too small to measure accurately, but is still present, a default 
value of 5 mm should be recorded.
o
When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
!
Target lesion response categories are defined as follows
o
Complete response (CR): Disappearance of all non-nodal target lesions. 
Target lymph nodes must reduce to < 10 mm in short axis
o
Partial response (PR): At least a 30% decrease in the sum of diameters of 
target lesions, compared to the sum at baseline.
o
Progressive disease (PD): At least a 20% increase in the sum of target lesion 
measurements, compared to the smallest sum on study (including baseline). 
Also, the absolute increase in the sum has to be at least 5 mm.
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o
Stable disease (SD): Neither PR nor PD criteria are met. 

SD can follow PR only in rare cases, when the sum increases by less 
than 20% from the nadir, but enough that a previously seen 30% 
decrease from baseline no longer holds. 
o
Non Evaluable (NE): One or more target lesions cannot be assessed because 
assessment methods are not comparable to baseline (e.g., change of modality), 
lesion visibility is poor due to image quality or lesion features (except where 
the lesion is too small to measure), or one or more lesions that were excised or 
locally irradiated have not reappeared or increased; and the other lesions do 
not show sufficient growth to qualify for PD on their own.
!
Non-target lesion response assessment is qualitative. Categories are defined as 
follows
o
CR: Disappearance of all non-nodal non-target lesions. Non-target lymph 
nodes must reduce to < 10 mm in short axis
o
PD: Unequivocal progression of non-target lesions, evaluated as a whole, 
such that it is clear that treatment has failed and disease is progressing, 
regardless of the status of the target lesions
o
Non-CR/Non-PD: Neither CR nor PD criteria are met.
o
NE: One or more non-target lesions cannot be assessed because assessment
methods are not comparable to baseline (e.g., change of modality), lesion 
visibility is poor due to image quality or lesion features (except where the 
lesion is too small to measure), or one or more lesions that were excised or 
locally irradiated have not reappeared or increased; and the other lesions do 
not show sufficient growth to qualify for PD on their own.
!
New lesion response is classified as present or not (“Yes” or “No”). The response is 
“Yes” if there is at least one lesion that the reviewer considers unequivocal new 
tumor.
o
Lesions that are equivocal (for example, due to small size) should not be 
considered new until they are confirmed by later scanning. Once confirmed, 
they can be retrospectively called new lesions at the time they were first seen.
o
A lesion identified in an area not previously scanned is considered a new 
lesion.
o
New lesions seen on nuclear medicine bone scans should be confirmed using 
anatomical imaging, whenever possible. If bone lesions are confirmed on later 
CT or MRI scan, progression should be assigned to the visit in which new 
lesion(s) were first seen on bone scan (in a manner similar to other equivocal 
new lesions). In the absence of structural confirmation, the pattern of lesions 
must clearly indicate metastasis, usually with at least two new lesions present.
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!
Overall visit response is determined by combining the target, non-target, and new 
lesion responses using a table.
For Subjects with Target Disease
Target 
Lesions
Non-Target Lesions
New Lesions
Overall Visit 
Response
CR
CR
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-CR/Non-PD or NE
No
PR
SD
Non-CR/Non-PD or NE
No
SD
PD
Any
Yes or No
PD
Any
PD†
Yes‡ or No
PD
Any
Any
Yes
PD
†   Worsening of bone metastasis seen on bone scan alone, in the best 
judgment of the reader, must be such that the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. 
‡   Progression based on new bone scan lesions should be confirmed using 
CT or MRI whenever possible. If bone lesions are confirmed on later CT 
or MRI scan, progression should be assigned to the visit in which new 
lesion(s) were first seen on bone scan (in a manner similar to other 
equivocal new lesions). In the absence of structural confirmation, the 
pattern of lesions must clearly indicate metastasis, usually with at least 
two new lesions present.
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For Subjects with Non-Target Disease ONLY
Non-Target Lesions
New Lesions
Overall Visit 
Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-
PD*
NE
No
NE
Unequivocal PD†
Yes‡ or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment of 
efficacy so to assign this category when no lesions can be measured is 
not advised
†   Worsening of bone metastasis seen on bone scan alone, in the best 
judgment of the reader, must be such that the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. 
‡   Progression based on new bone scan lesions should be confirmed using 
CT or MRI whenever possible. If bone lesions are confirmed on later CT 
or MRI scan, progression should be assigned to the visit in which new 
lesion(s) were first seen on bone scan (in a manner similar to other 
equivocal new lesions). In the absence of structural confirmation, the 
pattern of lesions must clearly indicate metastasis, usually with at least 
two new lesions present.
!
After all visits have been evaluated, the sequence of overall visit responses is used to 
derive progression-free survival (PFS), best overall response (BOR), and duration of 
response (DOR).
o
PFS is defined as the time from randomization until the date of radiologic 
progressive disease (per RECIST v.1.1 with modifications) as determined by 
the IRF or death from any cause, whichever occurs first.
o
BOR is defined as the best visit response recorded from the start of the 
treatment until disease progression/recurrence. 

RECIST v.1.1 states that confirmation of a BOR of PR or CR is 
required only for non-randomized trials in which response rate is the 
primary endpoint. Thus, confirmation is not required in this trial.

If SD is the best visit response seen on the trial, the SD must be 
maintained for at least 6 weeks from the start of treatment for SD to be 
the BOR.
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o
DOR is measured from the time of first radiographic documentation of CR or 
PR to disease progression by RECIST v.1.1 with modifications or death due to 
any cause, whichever occurs first 

The duration of overall CR is measured from the time of first 
radiographic documentation of CR to disease progression by RECIST 
v.1.1 or death from any cause, whichever occurs first.
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24.4
EORTC QLQ-C30/ 
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Pa
F
EORTC QLQ-BR-23
age 112
FINAL 14Dec2015
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Proprietary and Confidential
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Pa
F
age 113
FINAL 14Dec2015
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age 114
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Pa
F
age 115
FINAL 14Dec2015
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