TALAPRO 1: A Phase 2, Open-Label, Response Rate Study of Talazoparib in Men With DNA Repair Defects and Metastatic Castration-Resistant Prostate Cancer Who Previously Received Taxane-Based Chemotherapy and Progressed on at Least 1 Novel Hormonal Agent (Enzalutamide and/or Abiraterone Acetate/Prednisone)

1.For patients who are at least 18 years of age, there must be evidence of a
personally signed and dated informed consent document indicating that the
patient has been informed of all pertinent aspects of the study.
2.Histologically or cytologically confirmed adenocarcinoma of the prostate
without signet cell, or small cell features. Histologic confirmation may be
based on a de novo tumor biopsy obtained for
purposes of screening. Biopsies of the brain, lung/mediastinum, pancreas, or
endoscopic procedures extending beyond the esophagus, stomach, or bowel may not
be performed for the sole purpose of determining study eligibility.
3.Patients must have measurable soft tissue disease per RECIST1.1.
4.DNA damage repair gene alterations likely to sensitize to PARP inhibition
(DDR positive) as determined by:
•Prospective testing of de novo or archival tumor tissue (via central
laboratory) or prior historical (with Sponsor preapproval) testing of tumor
tissue using the Foundation Medicine, FoundationOne® NGS gene panel test;
Archival or de novo tumor tissue also should be submitted prior to Day 1 if
possible to support concordance analyses and additional molecular profiling.
5.Unless prohibited by local regulations or ethics committee (EC) decision,
consent to a saliva sample collection for retrospective sequencing of DDR genes
used to assess patient eligibility based on tumor tissue, and to serve as a
germline control in identifying tumor mutations.
6.Serum testosterone <= 1.73 nmol/L (50 ng/dL) at screening.
7.Bilateral orchiectomy or ongoing androgen deprivation therapy with a
gonadotropin releasing hormone (GnRH) agonist/antagonist (surgical or medical
castration).
8.Progressive disease at study entry defined as 1 or more of the following 3
criteria:
•A minimum of 3 rising PSA values with an interval of at least 1 week between
determinations. The screening central laboratory PSA value must be >= 2 µg/L (2
ng/mL) if qualifying solely by PSA progression.
•Soft tissue disease progression as defined by RECIST 1.1.
•Bone disease progression defined by PCWG3 with 2 or more new metastatic
lesions on bone scan.
9.Metastatic disease. Patients whose only evidence of metastasis is measurable
soft tissue disease below the aortic bifurcation will be acceptable. Neither
bone metastases on bone scan nor non- measurable soft tissue disease alone will
qualify a patient.
10.Previous treatment with 1 or 2 chemotherapy regimens including at least 1
taxane based regimen for metastatic (non castrate or castrate) prostate cancer.
Patients may have received radium 223 and/or cabazitaxel, or were deemed
unsuitable, declined, or did not have access
to these therapies.
11.Documented disease progression (either radiographic or biochemical) on at
least 1 novel hormonal therapy (enzalutamide and/or abiraterone
acetate/prednisone) for the treatment of metastatic CRPC, irrespective of prior
NHT treatment for non castrate prostate cancer or nonmetastatic (M0) CRPC.
12.Bisphosphonate or denosumab dosage must have been stable for at least 4
weeks before day 1 for patients receiving these therapies.
13.ECOG performance status of 0 to 2.
14.Estimated life expectancy of >= 6 months as assessed by the investigator.
15.Able to swallow the study drug, have no known intolerance to study drugs or
excipients, and comply with study requirements.
16.Must use a condom when having sex with a pregnant woman from the time of the
first dose of study drug through 105 days after last dose of study drug. An
additional highly effective form of contraception (Section 4.3.1) must be used
from the time of the first dose of study drug through
105 days after last dose of study drug when having sex with a non pregnant
female partner of childbearing potential.
17.Must agree not to donate sperm from the first dose of study drug to 105 days
after the last dose of study drug.
18.Patients must be willing and able to comply with scheduled visits, treatment
plan, laboratory tests and other study procedures.

1.Use of systemic chemotherapeutic (including but not limited to taxanes),
hormonal, biologic, or radionuclide therapy for treatment of metastatic
prostate cancer (other than approved bone targeting agents and GnRH
agonist/antagonist) or any other investigational agent within
4 weeks before day 1.
2.Prior treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone
chemotherapy. Patients who discontinued prior platinum based chemotherapy 6
months prior to screening or whose disease previously progressed on platinum
based therapy at any time in the past
are also excluded.
3.Treatment with any concurrent cytotoxic chemotherapy or investigational
drug(s) within 4 weeks or 5 half lives of the drug (whichever is longer) before
Day 1 and/or during study participation.
4.Radiation therapy within 3 weeks (within 2 weeks, if single fraction of
radiotherapy) before day 1.
5.Major surgery within 2 weeks before day 1.
6.Clinically significant cardiovascular disease, including any of the following:
•Myocardial infarction or symptomatic cardiac ischemia within 6 months before
screening.
•Congestive heart failure New York Heart Association class III or IV.
•History of clinically significant ventricular arrhythmias (eg, sustained
ventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1
year before screening.
•History of Mobitz II second degree or third degree heart block unless a
permanent pacemaker is in place.
•Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening.
•Bradycardia as indicated by a heart rate of < 45 beats per minute on the
screening electrocardiogram.
•Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg
or diastolic blood pressure > 105 mm Hg at screening.
7.Significant organ dysfunction as defined by any one of the following
laboratory abnormalities:
•Renal: eGFR < 30 mL/min /1.73 m2 by the MDRD equation (Modification of Diet in
Renal Disease [available via www.mdrd.com]).
•Hepatic:
•Total serum bilirubin > 1.5 times the upper limit of normal (ULN) (> 3 × ULN
for patients with Gilbert syndrome or for whom indirect bilirubin
concentrations suggest an extrahepatic source of elevation);
•Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >= 2.5 times
ULN (if liver test abnormalities are due to hepatic metastasis, then AST or ALT
>= 5 × ULN);
•Albumin < 2.8 g/dL.
•Bone marrow reserve: absolute neutrophil count < 1500/µL, platelets <
100,000/µL, or hemoglobin < 9 g/dL (NOTE: may not have received growth factors
or blood transfusions within 14 days before obtaining the hematology values at
screening).
8.Known or suspected brain metastasis or active leptomeningeal disease.
9.Symptomatic or impending spinal cord compression or cauda equina syndrome.
10.Diagnosis of myelodysplastic syndrome.
11.History of another cancer within 3 years before enrollment with the
exception of nonmelanoma skin cancers, or American Joint Committee on Cancer
stage 0 or stage 1 cancer that has a remote probability of recurrence in the
opinion of the investigator and the sponsor.
12.Gastrointestinal disorder affecting absorption.
13.Current or anticipated use of the following P gp inhibitors (amiodarone,
carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin,
indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone,
quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir,
verapamil, and valspodar), P gp inducers (avasimibe, carbamazepine, phenytoin,
rifampin, and St. John's
wort), or BCRP inhibitors (curcumin, cyclosporine, elacridar [GF120918] and
eltrombopag).
14.Any other acute or chronic medical or psychiatric condition (concurrent
disease, infection, or comorbidity) that interferes with ability to participate
in the study, causes undue risk, or complicates the interpretation of data, in
the opinion of the investigator or medical monitor, including recent (within
the past year) or active suicidal ideation or behavior or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation
of study results and, in the judgment of the investigator, would make the
patient inappropriate for entry into this study.
15.Investigator site staff members directly involved in the conduct of the
study and their family members, site staff members otherwise supervised by the
investigator, or patients who are Pfizer employees, including their family
members, directly involved in the conduct of the
study.
16.Fertile male subjects who are unwilling or unable to use a highly effective
method of contraception as outlined in this protocol for the duration of the
study and for at least 105 days after the last dose of investigational product.