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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04191096




Registration number
NCT04191096
Ethics application status
Date submitted
5/12/2019
Date registered
9/12/2019
Date last updated
5/06/2024

Titles & IDs
Public title
Efficacy and Safety of Pembrolizumab (MK-3475) Plus Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (MK-3475-991/KEYNOTE-991)
Scientific title
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) (KEYNOTE-991)
Secondary ID [1] 0 0
MK-3475-991
Secondary ID [2] 0 0
3475-991
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Hormone-Sensitive Prostate Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Prostate
Inflammatory and Immune System 0 0 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Pembrolizumab
Treatment: Drugs - Enzalutamide
Treatment: Drugs - Androgen Deprivation Therapy (ADT)
Other interventions - Placebo

Experimental: Pembrolizumab + Enzalutamide + ADT - Starting on Day 1 of each 21-day cycle, participants receive 200 mg pembrolizumab IV every 3 weeks (Q3W) for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a luteinizing-hormone releasing hormone (LHRH) agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

Placebo Comparator: Placebo + Enzalutamide + ADT - Starting on Day 1 of each 21-day cycle, participants receive placebo IV Q3W for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a LHRH agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.


Other interventions: Pembrolizumab
Pembrolizumab is administered as an IV infusion at 200 mg on Day 1 of each 21-day cycle for up to 35 cycles.

Treatment: Drugs: Enzalutamide
Enzalutamide is administered orally as capsules/tablets at a dosage of 160 mg daily. Enzalutamide is administered continuously until criteria for discontinuation are met.

Treatment: Drugs: Androgen Deprivation Therapy (ADT)
Stable regimen of ADT (LHRH agonist or antagonist) at a dose and frequency of administration that is consistent with the local product label.

Other interventions: Placebo
Placebo infusion solution is administered as an IV infusion on Day 1 of each 21-day cycle for up to 35 cycles.
Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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 (BICR)
Timepoint [1] 0 0
Up to approximately 32 months
Primary outcome [2] 0 0
Overall Survival (OS)
Timepoint [2] 0 0
Up to approximately 32 months
Secondary outcome [1] 0 0
Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)
Timepoint [1] 0 0
Up to Approximately 32 months
Secondary outcome [2] 0 0
Time to First Symptomatic Skeletal-related Event (TTSSRE)
Timepoint [2] 0 0
Up to Approximately 32 months
Secondary outcome [3] 0 0
Time to Prostate-specific Antigen (PSA) Progression
Timepoint [3] 0 0
Up to Approximately 32 months
Secondary outcome [4] 0 0
Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of PCWG-Modified RECIST 1.1 as Assessed by BICR
Timepoint [4] 0 0
Up to Approximately 32 months
Secondary outcome [5] 0 0
Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item #3 ("Worst Pain in 24 Hours") and Opiate Use
Timepoint [5] 0 0
Up to Approximately 32 months
Secondary outcome [6] 0 0
Time From Randomization to Disease Progression as Determined by Investigator Assessment After Next-line of Therapy or Death From Any Cause, Whichever Occurs First (PFS2)
Timepoint [6] 0 0
Up to Approximately 32 months
Secondary outcome [7] 0 0
Prostate-specific Antigen (PSA) Response Rate
Timepoint [7] 0 0
Up to Approximately 32 Months
Secondary outcome [8] 0 0
Prostate-specific Antigen (PSA) Undetectable
Timepoint [8] 0 0
Up to Approximately 32 Months
Secondary outcome [9] 0 0
Objective Response Rate (ORR) Per PCWG-Modified RECIST 1.1 as Assessed by BICR
Timepoint [9] 0 0
Up to Approximately 32 Months
Secondary outcome [10] 0 0
Duration of Response (DOR) Per PCWG- Modified RECIST 1.1 as Assessed by BICR
Timepoint [10] 0 0
Up to Approximately 32 Months
Secondary outcome [11] 0 0
Number of Participants Who Experience an Adverse Event (AE)
Timepoint [11] 0 0
Up to Approximately 59 Months
Secondary outcome [12] 0 0
Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
Timepoint [12] 0 0
Up to Approximately 59 Months

Eligibility
Key inclusion criteria
- 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 Androgen Deprivation Therapy (ADT) with a
luteinizing-hormone releasing hormone (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
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
- 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-programmed cell death-ligand
2 (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:

1. Up to 3 months of ADT or orchiectomy with or without concurrent first-generation
antiandrogens, if patient was not treated with docetaxel

2. 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

3. 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

4. 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
12/02/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
15/06/2026
Actual
Sample size
Target
Accrual to date
Final
1251
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
Chris OBrien Lifehouse ( Site 0300) - Camperdown
Recruitment hospital [2] 0 0
Port Macquarie Base Hospital ( Site 0301) - Port Macquarie
Recruitment hospital [3] 0 0
Riverina Cancer Care Center ( Site 0302) - Wagga Wagga
Recruitment hospital [4] 0 0
Gallipoli Medical Research Foundation ( Site 0309) - Greenslopes
Recruitment hospital [5] 0 0
John Flynn Hospital & Medical Centre ( Site 0308) - Tugun
Recruitment hospital [6] 0 0
Box Hill Hospital ( Site 0304) - Box Hill
Recruitment hospital [7] 0 0
Monash Health ( Site 0305) - Clayton
Recruitment hospital [8] 0 0
Peter MacCallum Cancer Centre ( Site 0306) - Melbourne
Recruitment hospital [9] 0 0
Fiona Stanley Hospital ( Site 0311) - Murdoch
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2444 - Port Macquarie
Recruitment postcode(s) [3] 0 0
2650 - Wagga Wagga
Recruitment postcode(s) [4] 0 0
4120 - Greenslopes
Recruitment postcode(s) [5] 0 0
4224 - Tugun
Recruitment postcode(s) [6] 0 0
3128 - Box Hill
Recruitment postcode(s) [7] 0 0
3168 - Clayton
Recruitment postcode(s) [8] 0 0
3000 - Melbourne
Recruitment postcode(s) [9] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alaska
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California
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Colorado
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Connecticut
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Slaskie
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Zachodniopomorskie
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Russian Federation
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Krasnoyarskiy Kray
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Russian Federation
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Moskva
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Russian Federation
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Nizhegorodskaya Oblast
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Russian Federation
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Omskaya Oblast
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Spain
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Barcelona
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Spain
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Gerona
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Spain
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Lugo
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Spain
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Madrid
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Spain
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Grisons
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Vaud
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Zurich
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Taiwan
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Kaohsiung
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Taiwan
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Tainan
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Taiwan
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Taipei
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Taiwan
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Taoyuan
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Thailand
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Krung Thep Maha Nakhon
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Thailand
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Khon Kaen
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Turkey
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Adana
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Turkey
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Ankara
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Turkey
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Istanbul
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Turkey
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Izmir
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Turkey
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Konya
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United Kingdom
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Aberdeen City
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United Kingdom
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Cornwall
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United Kingdom
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London, City Of
Country [151] 0 0
United Kingdom
State/province [151] 0 0
Cardiff

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus
Androgen Deprivation Therapy (ADT) versus placebo plus enzalutamide plus ADT in participants
with mHSPC. The primary hypothesis is that in participants with mHSPC, the combination of
pembrolizumab plus enzalutamide plus ADT is superior to placebo plus enzalutamide plus ADT
with respect to 1) radiographic progression-free survival (rPFS) per Prostate Cancer Working
Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed
by blinded independent central review (BICR) and 2) overall survival (OS). As of 19-JAN-2023,
the study was unblinded and all study participants stopped ongoing treatment with
pembrolizumab/placebo and will continue to receive Standard of Care treatment until meeting
protocol-specified discontinuation criteria if deriving clinical benefit. Safety analysis
will be performed at the end of the study; there will be no further analyses for efficacy and
electronic patient-reported outcome (ePRO) endpoints collected from participants beyond the
IA1 cutoff date. All study participants will stop ongoing treatment with
pembrolizumab/placebo. Exceptions may be requested for study participants who, in the
assessment of their study physician, are benefitting from the combination of enzalutamide and
pembrolizumab, after consulting with the Sponsor. All other study participants should be
discontinued from study and be offered standard of care (SOC) treatment as deemed necessary
by the Investigator. If enzalutamide as SOC is not accessible off study to the participant,
central sourcing may continue. As of Amendment 04, disease progression will no longer be
centrally verified, participants will only be assessed locally. As of Amendment 4, Second
Course treatment is not an option for participants. There are currently no participants in
the Second Course Phase.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04191096
Trial related presentations / publications
Public notes

Contacts
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Merck Sharp & Dohme LLC
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