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A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Plus ADT Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) - MK3475-991 (KEYNOTE-991)

Studio Clinico

Patologia: Carcinoma della prostata

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico


Fase di studio: III

Richiesta mandatoria di tessuto: 

Linee di trattamento: Non applicabile

Criteri di inclusione: 

- Male participants with histologically - or cytologically -confirmed adenocarcinoma of the prostate without small cell histology
- Has metastatic disease assessed by investigator and verified by BICR by either ≥2 bone lesions on bone scan and/or visceral disease by computed tomography/magnetic resonance imaging (CT/MRI)
- Willing to maintain continuous ADT with a LHRH agonists or antagonists during study treatment or have a history of bilateral orchiectomy
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 10 days of randomization
- Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
- Has adequate organ function
- Has provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed). Participants with bone only or bone predominant disease may provide a bone biopsy sample
- Male participants must agree to the following during the intervention period and for at least 120 days after the last dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse and agree to remain abstinent OR agree to use contraception, unless confirmed to be azoospermic
- Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.

Criteri di esclusione: 

- Has a known additional malignancy that is progressing or has required active treatment in the last 3 years
- Has an active autoimmune disease that has required systemic treatment in past 2 years
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
- Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications
- Has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules
- Has an active infection (including tuberculosis) requiring systemic therapy
- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
- Has known or suspected central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has a history of seizure or any condition that may predispose to seizure
- Has a history of loss of consciousness within 12 months of screening
- Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization, or has New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure
- Has hypotension (systolic blood pressure <86 millimeters of mercury [mmHg]) or uncontrolled hypertension (systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg) at the screening visit
- Has a history of clinically significant ventricular arrhythmias
- Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
- Has received prior ADT as neoadjuvant/adjuvant therapy for non-metastatic prostate cancer for >39 months in duration or within 9 months prior to randomization or with evidence of disease progression while receiving ADT
- Has had prior treatment with a next generation hormonal agent (eg, abiraterone, enzalutamide, apalutamide, darolutamide)
- Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
- Has received a live vaccine within 30 days prior to randomization
- Has a 'superscan' bone scan
- Has had an allogenic tissue/solid organ transplant
- Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
- Has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer with the following exceptions:
    - Up to 3 months of ADT or orchiectomy with or without concurrent first-generation antiandrogens, if patient was not treated with docetaxel
    - May have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to randomization
    - For participants with low volume metastatic disease, may have 1 course of definitive radiotherapy if it was administered at least 4 weeks prior to randomization
    - Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of randomization and no evidence of disease progression. In these participants up to 6 months of ADT permitted.

Trattamento sperimentale: 

Pembrolizumab + Enzalutamide

Trattamento di controllo: 

PLACEBO + Enzalutamide

Obiettivi primari dello studio: 

- Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review [ Time Frame: Up to approximately 77 months ]
    rPFS is defined as the time from randomization to radiographic progression, or death due to any cause, whichever occurs first. rPFS according to PCWG-modified RECIST 1.1 as assessed by Blinded Independent Central Review will be reported for each study arm.

- Overall Survival (OS) [ Time Frame: Up to approximately 77 months ]
    OS is defined as the time from randomization to death due to any cause. OS will be reported for each study arm.

Centri partecipanti

Nord Italia

Via P. Maroncelli 40 - 47014 Meldola - FC

Riferimento: Dr. Ugo De Giorgi
Telefono: 0543739100


IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI

Riferimento: Dr. Giuseppe Procopio
Telefono: 0223904450


Istituto Clinico Humanitas Rozzano
Via Manzoni 56 - 20089 Rozzano - MI


Centro di Riferimento Oncologico
Via Franco Gallini 2 - 33081 Aviano - PN


AOUI Verona - Borgo Trento
Piazzale Aristide Stefani 1 - 37126 Verona - VR


Centro Italia

Fondazione Policlinico A. Gemelli
Largo Agostino Gemelli 8 - 00168 Roma - RM

Telefono: 0630155202


AO S. Maria Terni
Via Tristano di Joannuccio 1 - 05100 Terni - TR

Riferimento: Dr. Sergio Bracarda
Telefono: 0744205631


Sud Italia e isole

Istituto Tumori “Giovanni Paolo II” IRCCS
Viale Orazio Flacco 65 - 70124 Bari - BA


A.O. per l’Emergenza Cannizzaro di Catania
Via Messina 829 - 95126 Catania - CT


Istituto Nazionale Tumori IRCCS Fondazione Pascale
Via Mariano Semmola - 80131 Napoli - NA
SC Oncologia Medica Uro-Ginecologica

Riferimento: Dr. Sandro Pignata
Telefono: 0815903637

Informazioni Generali


Numero di iscrizione a registro: 2019-003633-41

Data di inserimento: 14.04.2021


Merck Sharp & Dohme Corp.



Principal Investigator ITALIA

Istituto Nazionale Tumori IRCCS - Fondazione Pascale, Napoli

Riferimento: Dr. Sandro Pignata

Telefono: 0815903409


Localita: Napoli


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