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    Summary
    EudraCT Number:2017-003295-31
    Sponsor's Protocol Code Number:C3441021
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-003295-31
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study Of Talazoparib With Enzalutamide In Metastatic Castration-resistant Prostate Cancer
    Estudio en Fase III, Aleatorizado, Doble Ciego, Controlado con Placebo de Talazoparib con Enzalutamida en el Cáncer de Próstata Metastásico Resistente a la castración.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study Of Talazoparib With Enzalutamide In Metastatic Castration-resistant Prostate Cancer
    Estudio de Talazoparib con Enzalutamida en el Cáncer de Próstata Metastásico Resistente a la castración.
    A.4.1Sponsor's protocol code numberC3441021
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03395197
    A.5.4Other Identifiers
    Name:US INDNumber:129,642
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials.govcallcenter@pfizer.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTalazoparib
    D.3.2Product code PF-06944076
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalazoparib
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.3Other descriptive nameTALAZOPARIB TOSYLATE
    D.3.9.4EV Substance CodeSUB183862
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Xtandi
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameXtandi 40 mg soft capsules
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENZALUTAMIDE
    D.3.9.1CAS number 915087-33-1
    D.3.9.4EV Substance CodeSUB77412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTalazoparib
    D.3.2Product code PF-06944076
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalazoparib
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.3Other descriptive nameTALAZOPARIB TOSYLATE
    D.3.9.4EV Substance CodeSUB183862
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic Castration-resistant Prostate Cancer
    Cáncer de próstata resistente a la castración metastásico
    E.1.1.1Medical condition in easily understood language
    Metastatic Castration-resistant Prostate Cancer
    Cáncer de próstata resistente a la castración metastásico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10036909
    E.1.2Term Prostate cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10076506
    E.1.2Term Castration-resistant prostate cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging rPFS, in patients with mCRPC unselected for DDR status.
    - To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging rPFS, in patients with mCRPC harboring DDR deficiencies.
    - Mostrar que talazoparib en combinación con enzalutamida es superior a placebo en combinación con enzalutamida para prolongar la SSPr en pacientes con CPRCm no seleccionados en función de la presencia de DRD.
    - Mostrar que talazoparib en combinación con enzalutamida es superior a placebo en combinación con enzalutamida para prolongar la SSPr en pacientes con CPRCm que son portadores de DRD.
    E.2.2Secondary objectives of the trial
    Key Secondary Objectives:
    - To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging OS in patients with mCRPC unselected for DDR status.
    - To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging OS in patients with mCRPC harboring DDR deficiencies.

    Other Secondary Objectives:
    - To evaluate anti-tumor activity in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies with respect to the following:
    - Objective response in measurable soft tissue disease;
    - Duration of response in measurable soft tissue disease;
    - PSA response;
    - Time to PSA progression;
    - Time to initiation of cytotoxic chemotherapy;
    - Time to initiation of antineoplastic therapy;
    - Time to first symptomatic skeletal event;
    - PFS on next line therapy (PFS2);
    Objetivos secundarios clave:
    - Mostrar que talazoparib en combinación con enzalutamida es superior a placebo en combinación con enzalutamida para prolongar la supervivencia general (SG) en pacientes con CPRCm no seleccionados en función de la presencia de DRD.
    - Mostrar que talazoparib en combinación con enzalutamida es superior a placebo en combinación con enzalutamida para prolongar la SG en pacientes con CPRCm que son portadores de DRD.

    Revisar la sinopsis del protocolo adjunto para obtener información sobre "Otros objetivos secundarios"
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
    1. At least 18 years of age. For Japan, at least 20 years of age.
    2. Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features. If the patient does not have a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis and to support biomarker analysis.
    3. Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) (score on BPI-SF Question #3 must be <4).
    4. For enrollment into Part 2 only (optional in Part 1): assessment of DDR mutation status by prospective analysis (de novo or archival tissue), or historical analysis (with Sponsor pre-approval), of most recent tumor tissue per FoundationOne testing. (Note: for patients enrolling in Part 1, DDR deficiency testing is optional).
    5. For enrollment into Part 2 only (optional for Part 1): Unless prohibited by local regulations or ethics committee decision, consent to a saliva sample collection for retrospective sequencing of the same DDR genes tested on tumor tissue, or a subset thereof, and to serve as a germline control in identifying tumor mutations.
    6. Surgically or medically castrated, with serum testosterone ≤50 ng/dL (≤1.73 nmol/L) at screening. Or ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist for patients who have not undergone bilateral orchiectomy must be initiated at least 4 weeks before Day 1 (Part 1) or randomization (Part 2) and must continue throughout the study.
    7. Metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI scan. Scans obtained as part of standard of care in the 6 weeks (42 days) prior to Day 1 (Part 1) or randomization (Part 2) can be used if they meet study requirements (Table 2). Measurable soft tissue disease is not required. (Adenopathy below the aortic bifurcation alone does not qualify).
    8. Progressive disease at study entry in the setting of medical or surgical castration as defined by 1 or more of the following 3 criteria:
    - Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 consecutive assessments with an interval of at least 7 days between assessments. The screening laboratory PSA value must be ≥2 g/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 Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan.
    9. Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before Day 1 (Part 1) or randomization (Part 2) for patients receiving these therapies.
    10. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
    11. Life expectancy 12 months as assessed by the investigator.
    12. Able to swallow the study treatment and have no known intolerance to study treatments or excipients.
    13. Sexually active participants that in the opinion of the investigator are capable of ejaculating, must agree to use a condom when having sex with a partner (female or male) from the time of the first dose of study treatment through 4 months after last dose of study treatment. Must also agree for female partner of childbearing potential to use an additional highly effective form of contraception (Section 4.4.1) from the time of the first dose of study treatment through 4 months after last dose of study treatment when having sex with a non-pregnant female partner of childbearing potential. 14. Must agree not to donate sperm from the first dose of study treatment to 4 months after the last dose of study treatment.
    15. Evidence of a personally signed and dated informed consent document (and molecular prescreening consent if appropriate) indicating that the patient [or a legally acceptable representative/legal guardian] has been informed of all pertinent aspects of the study.
    16. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    1. Tener al menos 18 años de edad.
    2. Adenocarcinoma de próstata confirmado por medios histológicos o citológicos sin características microcíticas ni de células en anillo de sello. Si el paciente carece de un diagnóstico histológico previo, deberá utilizarse una biopsia inicial de novo para confirmar el diagnóstico y respaldar el análisis de biomarcadores.
    3. Cáncer de próstata resistente a la castración metastásico (CPRCm) asintomático o levemente sintomático (la puntuación de la pregunta n.º 3 del BPI-SF debe ser <4).
    4. Solo para la inscripción en la parte 2 (opcional en la parte 1): evaluación del estado mutacional relativo a DRD mediante análisis prospectivo (tejido de novo o de archivo), o análisis histórico (previa aprobación del promotor) del tejido tumoral más reciente según la prueba FoundationOne (R). (Nota: para los pacientes incluidos en la parte 1, las pruebas de DRD son opcionales).
    - No se podrán realizar biopsias de cerebro, pulmón/mediastino, páncreas ni procedimientos endoscópicos que se extiendan más allá del esófago, el estómago o el intestino con el único objeto de determinar la aptitud para el estudio.
    5. Solo para la inclusión en la parte 2 (opcional para la parte 1): a menos que lo prohíba la normativa local o por decisión del comité de ética, dar el consentimiento para obtener una muestra de saliva para la secuenciación retrospectiva de los mismos genes de DRD analizados en el tejido tumoral, o un subgrupo de ellos, para servir como control de estirpe germinal a la hora de detectar mutaciones tumorales.
    6. Sometido a castración quirúrgica o médica, con unas concentraciones de testosterona en suero <=50 ng/dl (<=1,73 nmol/l) en la selección. O el tratamiento en curso de privación de andrógenos con un agonista o antagonista de la hormona liberadora de gonadotropina (GnRH) para los pacientes no sometidos a orquiectomía bilateral debe haberse iniciado al menos 4 semanas antes del día 1 (parte 1) o de la aleatorización (parte 2), y debe mantenerse a lo largo del estudio.
    7. Metástasis ósea documentada mediante gammagrafía ósea o en las partes blandas mediante TAC/RMN. Las imágenes obtenidas como parte de la práctica clínica habitual en las 6 semanas (42 días) anteriores al día 1 (parte 1) o a la aleatorización (parte 2) se podrán utilizar si cumplen los requisitos del estudio (Tabla 2). No es necesario que exista enfermedad medible de partes blandas. (No será suficiente la presencia únicamente de adenopatía por debajo de la bifurcación aórtica).
    8. Progresión de la enfermedad al entrar en el estudio en el marco de una castración médica o quirúrgica, definida según 1 o más de los 3 criterios siguientes:
    - Progresión del antígeno prostático específico (PSA), definida por un mínimo de 2 valores del PSA en aumento obtenidos en 3 evaluaciones consecutivas con un intervalo mínimo de 7 días entre ellas. El valor del PSA en la selección debe ser >=2 µg/l (>=2 ng/ml) si solo se establece la aptitud mediante la progresión del PSA.
    - Progresión de la enfermedad en las partes blandas según la definición de los criterios RECIST 1.1.
    - Progresión de la metástasis ósea definida según el Grupo de trabajo 3 sobre el cáncer de próstata (PCWG3) con 2 o más lesiones óseas metastásicas nuevas en una gammagrafía ósea de cuerpo entero.
    9. La pauta posológica del bisfosfonato o de denosumab debe haberse mantenido estable durante al menos 4 semanas antes del día 1 (parte 1) o de la aleatorización (parte 2) en los pacientes que reciban estos tratamientos.
    10. Estado funcional según el Grupo Oncológico Cooperativo de la Costa Este (Eastern Cooperative Oncology Group, ECOG) <=1.
    11. Esperanza de vida >=12 meses según la evaluación del investigador.
    12. Ser capaz de tragar el tratamiento del estudio y no presentar intolerancia conocida a los tratamientos del estudio o a sus excipientes.
    13. Los participantes sexualmente activos que, en opinión del investigador, tengan capacidad de eyacular, deben comprometerse a usar un preservativo cuando mantengan relaciones sexuales con una pareja (hombre o mujer) desde el momento de la primera dosis del tratamiento del estudio hasta 4 meses después de la última dosis del este. También deben comprometerse a que la pareja de sexo femenino con capacidad de concebir utilice un método anticonceptivo adicional altamente eficaz (Sección 4.4.1) desde el momento de la primera dosis del tratamiento del estudio hasta 4 meses después de recibir la última dosis de este, cuando mantengan relaciones sexuales con una mujer con capacidad de concebir que no esté embarazada.
    14. Compromiso de no donar esperma desde el momento de la primera dosis del tratamiento del estudio hasta 4 meses después de la última dosis de este.

    (Revisar el protocolo para ver la lista completa de criterios de inclusión)
    E.4Principal exclusion criteria
    Patients with any of the following characteristics/conditions will be excluded:
    1. Any prior systemic cancer treatment initiated in the non-metastatic CRPC and mCRPC disease state. This includes prior treatment with taxane-based chemotherapy or NHT of enzalutamide, apalutamide, or darolutamide initiated after onset of castration resistance setting.
    2. Patients whose only evidence of metastasis is adenopathy below the aortic bifurcation.
    3. Prior treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.
    4. Prior treatment with platinum-based chemotherapy within 6 months prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease progression on platinum-based therapy at any time in the past.
    5. Treatment with cytotoxic chemotherapy, biologic therapy including sipuleucel-T (other than approved bone-targeting agents and GnRH agonist/antagonist therapy), or radionuclide therapy in the 28 days prior to Day 1 (Part 1) or randomization (Part 2). Hormonal therapy (eg, bicalutamide, nilutamide, flutamide, estrogens, 5 alpha reductase inhibitors are not exclusionary if discontinued prior to randomization. *Corticosteroid use of >10 mg/day is exclusionary. (The concomitant use of systemic glucocorticoid administration such as “stress dose” glucocorticoid is permitted when clinically indicated for a life threatening medical condition).
    6. Treatment with any investigational agent within 4 weeks or 5 half-lives of the drug (whichever is longer) before Day 1 (Part 1) or randomization (Part 2).
    7. Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to Day 1 (Part 1) or randomization
    (Part 2) unless no pain related to prostate cancer has been reported in the 28 days prior to Day 1 (Part 1) or randomization (Part 2).
    8. Current use within 7 days prior to Day 1 (Part 1) or randomization (Part 2) or anticipated use during the study of the following medications:
    - Potential DDI with talazoparib: 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).
    - Potential DDI with enzalutamide: strong cytochrome P450 2C8 (CYP2C8) inducers (eg, rifampin), strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin and rifapentine), moderate CYP3A4 inducers (eg, bosentan, efavirenz, etravirine, modafinil and nafcillin), and substrates of CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (eg, phenytoin), or CYP2C19 (eg, S mephenytoin) with a narrow therapeutic index.
    9. Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2).
    10. Clinically significant cardiovascular disease, including any of the following:
    - Myocardial infarction or symptomatic cardiac ischemia within 6 months before Day 1 (Part 1) or randomization (Part 2).
    - Congestive heart failure New York Heart Association class III or IV.
    - History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1 year before screening.
    - History of Mobitz II second degree or third degree heart block unless a permanent pacemaker is in place.
    - Hypotension as indicated by systolic blood pressure <86 mm Hg at screening.
    - Bradycardia as indicated by a heart rate of <45 beats per minute on the screening electrocardiogram.
    - Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at screening. However, patients can be rescreened after adequate control of blood pressure is achieved.

    Please refer to protocol for the full list of exclusion criteria.
    Se excluirá a los pacientes que presenten alguna de las características o afecciones siguientes:
    1. Cualquier tratamiento oncológico sistémico previo iniciado en el estado de CPRC no metastásico y CPRCm. Esto es, tratamiento previo con quimioterapia a base de taxanos o NTH con enzalutamida, apalutamida o darolutamida iniciado tras la aparición de resistencia a la castración.
    2. Pacientes cuyo único indicio de metástasis sea adenopatía por debajo de la bifurcación aórtica.
    3. Tratamiento previo con un inhibidor de la PARP, ciclofosfamida o mitoxantrona para el cáncer de próstata.
    4. Quimioterapia previa a base de platino en los 6 meses anteriores al día 1 (parte 1) o a la aleatorización (parte 2), o antecedentes de progresión de la enfermedad con tratamientos a base de platino en algún momento del pasado.
    5. Tratamiento con quimioterapia citotóxica, tratamientos biológicos como sipuleucel-T (distintos de los fármacos autorizados dirigidos al hueso y del tratamiento con agonistas o antagonistas de la GnRH) o tratamiento con radionúclidos en los 28 días anteriores al día 1 (parte 1) o a la aleatorización (parte 2). Los tratamientos hormonales (p. ej., bicalutamida, nilutamida, flutamida, estrógenos, inhibidores de la 5 alfa reductasa) no son motivo de exclusión si se suspenden antes de la aleatorización. *El uso de corticoesteroides a una dosis >10 mg/día sí es motivo de exclusión. (Se permite la administración concomitante de un glucocorticoide sistémico, por ejemplo a una “dosis de estrés”, cuando esté clínicamente indicado para un trastorno médico potencialmente mortal).
    6. Tratamiento con algún fármaco en investigación en las 4 semanas o 5 semividas del fármaco (lo que suponga más tiempo) antes del día 1 (parte 1) o de la aleatorización (parte 2) .
    7. Tratamiento previo con opioides para el dolor relacionado con el cáncer de próstata primario o con las metástasis en los 28 días anteriores al día 1 (parte 1) o a la aleatorización (parte 2), a menos que no se haya declarado ningún dolor relacionado con el cáncer de próstata en los 28 días anteriores al día 1 (parte 1) o a la aleatorización (parte 2).
    8. Uso en los 7 días anteriores al día 1 (parte 1) o a la aleatorización (parte 2) o uso previsto durante el estudio de los siguientes medicamentos:
    - Posible IF con talazoparib: Inhibidores de la P-gp (amiodarona, carvedilol, claritromicina, cobicistat, darunavir, dronedarona, eritromicina, indinavir, itraconazol, ketoconazol, lapatinib, lopinavir, propafenona, quinidina, ranolazina, ritonavir, saquinavir, telaprevir, tipranavir, verapamilo y valspodar).
    - Posible IF con enzalutamida: inductores potentes del citocromo P450 2C8 (CYP2C8) (p. ej., rifampicina), inductores potentes del CYP3A4 (p. ej., carbamazepina, fenobarbital, fenitoína, rifabutina y rifapentina), inductores moderados del CYP3A4 (p. ej., bosentán, efavirenz, etravirina, modafinilo y nafcilina) y sustratos del CYP3A4 (p. ej., alfentanilo, ciclosporina, dihidroergotamina, ergotamina, fentanilo, pimozida, quinidina, sirolimus y tacrolimus), CYP2C9 (p. ej., fenitoína) o CYP2C19 (p. ej., S mefenitoína) con un índice terapéutico estrecho.
    9. Cirugía mayor (definida por el investigador) en las 2 semanas anteriores al día 1 (parte 1) o la aleatorización (parte 2).
    10. Enfermedad cardiovascular de importancia clínica, incluidas cualquiera de las siguientes:
    - Infarto de miocardio o isquemia cardíaca sintomática en los 6 meses anteriores al día 1 (parte 1) o la aleatorización (parte 2).
    - Insuficiencia cardíaca congestiva de clase III o IV según la Asociación de Cardiología de Nueva York (New York Heart Association, NYHA).
    - Antecedentes de arritmias ventriculares de importancia clínica (p. ej., taquicardia ventricular mantenida, fibrilación ventricular, torsade de pointes) en el año anterior a la selección.
    - Antecedentes de bloqueo Mobitz II de segundo o de tercer grado, a menos que lleve puesto un marcapasos permanente.
    - Hipotensión, manifestada por una presión arterial sistólica <86 mm Hg en la selección.
    - Bradicardia, manifestada por una frecuencia cardíaca <45 latidos por minuto en el electrocardiograma de la selección.
    - Hipertensión incontrolada, manifestada por una presión arterial sistólica >170 mm Hg o una presión arterial diastólica >105 mm Hg en la selección. Sin embargo, se puede reseleccionar a los pacientes tras conseguir un control adecuado de la presión arterial.

    (Revisar el protocolo para ver la lista completa de criterios de exclusión)
    E.5 End points
    E.5.1Primary end point(s)
    - rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) in patients with mCRPC unselected for DDR status.
    - rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) in patients with mCRPC harboring DDR deficiencies.
    - SSPr según los Criterios de Evaluación de la Respuesta en Tumores Sólidos (Response Evaluation Criteria in Solid Tumors, RECIST) 1.1 (afectación de partes blandas) y del Grupo de Trabajo en el Cáncer de Próstata (Prostate Cancer Working Group, PCWG3) (afectación ósea) en pacientes con CPRCm no seleccionados en función de la presencia de DRD.

    - SSPr según los criterios RECIST 1.1 (afectación de partes blandas) y del PCWG3 (afectación ósea) en pacientes con CPRCm portadores de DRD.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • rPFS (both unselected and DDR-postive mCRPC): Screening (-42 to -1 day of the study), then every 8 weeks through Week 25 and then every 12 weeks until radiographic progression is determined by BICR (Part 2) regardless of initiation of subsequent antineoplastic therapy. RECIST 1.1 and PCWG3 assessments are to be completed when radiographic imaging tests are done; and documented on the CRF.
    • SSPr (ya sea no seleccionado o DRD-CPRCm positivo): Selección (-42 a -1 día del estudio), a partir de entonces cada 8 semanas hasta la semana 25 y, a partir de entonces, cada 12 semanas hasta la determinación de la progresión radiológica por RCIE (parte 2), independientemente del inicio de un tratamiento antineoplásico posterior. Una vez adquiridas las imágenes radiológicas, se deberán efectuar evaluaciones según los criterios RECIST 1.1 y el PCWG3 y documentarse en el CRD.
    E.5.2Secondary end point(s)
    Key Secondary Endpoints:
    - OS in patients with mCRPC unselected for DDR status (alpha-protected).
    - OS patients with mCRPC harboring DDR deficiencies (alpha-protected).
    Other Secondary Endpoints:
    - Proportion of patients with measurable soft tissue disease at baseline with an objective response per RECIST 1.1 in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - Duration of soft tissue response per RECIST 1.1 in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - Proportion of patients with PSA response ≥50% in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - Time to PSA progression in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - Time to initiation of cytotoxic chemotherapy in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - Time to initiation of antineoplastic therapy in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - Time to first symptomatic skeletal event in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - PFS2 based on investigator assessment separately in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - Time to opiate use for prostate cancer pain in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
    - Incidence of adverse events characterized by type, severity (graded by NCI CTCAE version 4.03), timing, seriousness and relationship to study treatment.
    - PK characterized by pre-dose trough and post-dose plasma concentrations of talazoparib, enzalutamide and its N-desmethyl metabolite.
    - PROs in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies:
    - Change from baseline in patient-reported pain symptoms per BPI-SF;
    - Change from baseline in patient-reported general health status per EQ-5D-5L;
    - Change from baseline in patient-reported cancer-specific global health status/QoL, functioning, and symptoms per EORTC QLQ-C30;
    - Time to deterioration in patient-reported pain symptoms per BPI-SF;
    - Time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30;
    - Time to definitive deterioration in patient-reported disease-specific urinary symptoms per EORTC QLQ-PR25.
    Criterios de valoración secundarios :
    - SG en pacientes con CPRCm no seleccionados en función de la presencia de DRD (con protección frente a α).
    - SG en pacientes con CPRCm portadores de DRD (con protección frente a α).

    Otros criterios de valoración secundarios
    - Proporción de pacientes con enfermedad medible en partes blandas al inicio con una respuesta objetiva según RECIST 1.1, en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - Duración de la respuesta en partes blandas según RECIST 1.1 en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - Proporción de pacientes con respuesta del PSA >=50 %, en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - Tiempo hasta la progresión del PSA en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - Tiempo hasta el inicio de quimioterapia citotóxica en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - Tiempo hasta el inicio de tratamiento antineoplásico en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - Tiempo hasta la primera complicación ósea sintomática en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - SSP2 según la evaluación del investigador en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - Tiempo hasta el uso de opiáceos para el dolor del cáncer de próstata en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD.
    - Incidencia de acontecimientos adversos caracterizados por tipo, intensidad (clasificada según los Criterios Terminológicos Comunes para Acontecimientos Adversos [Common Terminology Criteria for Adverse Events, CTCAE] del Instituto Nacional del Cáncer estadounidense [National Cancer Institute, NCI] versión 4.03), momento de aparición, gravedad y relación con el tratamiento del estudio.
    - FC caracterizada por las concentraciones plasmáticas mínimas anteriores a la dosis y las concentraciones plasmáticas posteriores a la dosis de talazoparib, enzalutamida y su metabolito N-desmetil.
    - Resultados notificados por el paciente (RNP) en pacientes con CPRCm no seleccionados en función de la presencia de DRD y en pacientes con CPRCm portadores de DRD:
    - Cambio con respecto al inicio en los síntomas de dolor notificados por el paciente según el Inventario breve de dolor en su versión abreviada (brief pain inventory short form, BPI-SF).
    - Cambio con respecto al inicio en el estado de salud general notificado por el paciente según la Escala europea de calidad de vida de 5 dimensiones y 5 niveles (European Quality of Life 5 dimension, 5 level scale, EQ-5D 5L).
    - Cambio con respecto al inicio en el estado de salud global/CdV, la funcionalidad y los síntomas específicos del cáncer notificados por el paciente, de acuerdo el cuestionario QLQ-C30 de la Organización Europea para la Investigación y el Tratamiento del Cáncer (European Organisation for Research and Treatment of Cancer, EORTC).
    - Tiempo hasta el empeoramiento de los síntomas de dolor notificados por el paciente según el BPI-SF.
    - Tiempo hasta el empeoramiento definitivo del estado de salud global/CdV, la funcionalidad y los síntomas específicos del cáncer notificados por el paciente, de acuerdo con el cuestionario de salud global de la EORTC específico para el cáncer (QLQ-C30 de la EORTC).
    - Tiempo hasta el empeoramiento definitivo de los síntomas urinarios específicos de la enfermedad notificados por el paciente, de acuerdo con el cuestionario de la EORTC de síntomas urinarios específicos de la enfermedad (QLQ-PR25 de la EORTC).
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS: Every 8 weeks (wks) until wk 25, then every 12 wks until withdrawal of consent or end of study (EoS)
    ORR/DoR: as for rPFS (see E.5.1.1)
    PSA response: every 8 wks until radiographic progression (RP)
    Time to initiation of cytotoxic chemo, PFS2: Record info for new subsequent antineoplastic therapy start
    Time to 1st symptomatic skeletal event: Every 4 wks until wk 25, then every 12 wks
    Time to opiate use for prostate cancer pain: Every 2 wks until week 21, then 4 wks until wk 25, then every 12 wks
    AEs: from signed informed consent until a min of 28dafter the last dose of study treatment
    PK: blood samples collected pre-dose and 2 hours post-dose at wks 3, 5 & 9, & pre-dose at wks 13 & 17
    PROs: Before RP: every 4 wks until wk 53, then every 8 wks; After RP: every 12 wks until EoS
    SG: Cada (C) 8 semanas (s) hasta s25, luego C 12s hasta retirar consentimiento o fin de estudio (FdE).
    TRO / DR: como para SSPr (ver E.5.1.1)
    Respuesta PSA: C 8s hasta progresión radiológica (PR)
    Tiempo hasta iniciar quimio-citotóxica, SSP2: Registrar info de tratamientos (trat.) posteriores a nuevo trat. antineoplásico
    Tiempo 1ª complicación ósea sintomática: C 4s hasta s25, luego C 12s
    Tiempo del uso de opiáceos para dolor de cáncer de próstata: C 2s hasta s21, luego C 4s hasta s25, luego C 12s
    AA: desde la firma del CI hasta un mín. de 28d tras la última dosis del trat. del estudio
    FC: Extrac. muestras de sangre pre-dosis y 2h tras la dosis en s3,5 y 9 y post-dosis en s13 y 17
    Cuestionarios de paciente: Antes de PR: C 4s hasta s53, luego C 8s tras PR: C 12s hasta FdE
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Parte 1 y Parte 2. Parte 2 cohortes secuenciales
    Part 1 and Part 2. Part 2 sequential cohorts
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    Chile
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    New Zealand
    Norway
    Peru
    Poland
    Portugal
    South Africa
    Spain
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 800
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 240
    F.4.2.2In the whole clinical trial 872
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Ninguno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-30
    P. End of Trial
    P.End of Trial StatusOngoing
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