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Clinical Trials List

Protocol NumberMK-3475-641
NCT Number(ClinicalTrials.gov Identfier)NCT03834493
Completed

2019-06-01 - 2025-12-31

Phase III

Recruiting5

ICD-10C61

Malignant neoplasm of prostate

ICD-10Z51.12

Encounter for antineoplastic immunotherapy

ICD-9185

Malignant neoplasm of prostate

A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-641)

  • Trial Applicant

    Merck Sharp & Dohme (I.A.) LLC

  • Sponsor

    Merck Sharp & Dohme Corp.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2026/02/01

Investigators and Locations

Principal Investigator Yi-Hsiu Huang Division of Urology
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Chao-Hsiang Chang Division of Urology
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Chia-Yen Lin Division of Urology
Taichung Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Wen-Pin Su Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Yeong-Shiau Pu Division of Urology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Objectives

Primary Objectives To compare pembrolizumab plus enzalutamide versus placebo plus enzalutamide with respect to OS To compare pembrolizumab plus enzalutamide versus placebo plus enzalutamide with respect to rPFS per PCWG-modified RECIST 1.1 as assessed by BICR where soft-tissue will be assessed per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and bone disease will be assessed per PCWG criteria

Test Drug

Keytruda/ Xtandi

Active Ingredient

Enzalutamide
Pembrolizumab

Dosage Form

Injection
Capsule

Dosage

100 mg/4 ml
40mg/cap

Endpoints

Primary Outcome Measures :
Overall Survival (OS) [ Time Frame: Up to approximately 52 months ]
Time from randomization to death due to any cause

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 52 months ]
Time from randomization to radiographic progression, or death due to any cause, whichever occurs first


Secondary Outcome Measures :
Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST) [ Time Frame: Up to approximately 52 months ]
Time from randomization to initiation of the first subsequent anti-cancer therapy or death, whichever occurs first

Prostate-specific Antigen (PSA) Response Rate [ Time Frame: Up to approximately 52 months ]
Percentage of participants in the analysis population who have a negative change (decrease) in PSA level of ≥50% measured twice ≥3 weeks apart

Prostate-specific Antigen (PSA) Undetectable Rate [ Time Frame: Up to approximately 52 months ]
Percentage of participants in the analysis population with PSA <0.2 ng/mL during study treatment

Objective Response Rate (ORR) 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 52 months ]
Percentage of participants in the analysis population who have a best overall response of either confirmed Complete Response (CR) or a confirmed Partial Response (PR) per PCWG-modified RECIST 1.1

Duration of Response (DOR) 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 52 months ]
Time from first documented evidence of confirmed Complete Response (CR) or Partial Response (PR) per PCWG-modified RECIST 1.1 until disease progression or death from any cause, whichever occurs first

Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: Up to approximately 52 months ]
Time from randomization to PSA progression. PSA progression date is defined as the date of 1) ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second value ≥3 weeks later if there is PSA decline from baseline, or 2) ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline

Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of 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 52 months ]
Time from randomization to radiographic soft tissue progression per PCWG-modified RECIST 1.1

Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24 Hours") and Opiate Analgesic Use (Analgesic Quantification Algorithm [AQA] Score) [ Time Frame: Up to approximately 52 months ]
Time from randomization to pain progression. In this study, pain progression will be assessed by participant responses to Item 3 of the BPI-SF and participant AQA Scores which are both assessed by participants daily for 7 consecutive days

Time to First Symptomatic Skeletal-related Event (SSRE) [ Time Frame: Up to approximately 52 months ]
Time from randomization to the first SSRE. SSRE is defined as radiation to prevent or relieve skeletal symptoms, occurrence of new symptomatic pathological fracture, spinal cord compression, or surgery to bone

Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 52 months ]
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment

Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 52 months ]
The number of participants who discontinue study treatment due to an AE will be presented

Inclution Criteria

1. Have histologically- or cytologically-confirmed (if acceptable according to local
health authority regulations) adenocarcinoma of the prostate without small cell
histology. Diagnosis must be stated in a pathology report and confirmed by the
investigator.
2. Have prostate cancer progression while on ADT (or post bilateral orchiectomy)
within 6 months prior to screening, as determined by the investigator, by means of
one of the following:
a. PSA progression using local laboratory values as defined by a minimum of
2 consecutive rising PSA levels with an interval of ≥1 week between each
assessment where the PSA value at screening should be ≥1 ng/mL. See Section
8.2.2 – Prostate-specific Antigen Assessment for further details.
b. Radiographic disease progression in soft tissue based on RECIST 1.1 criteria with
or without PSA progression.
c. Radiographic disease progression in bone based on PCWG defined as the
appearance of 2 or more new bone lesions on bone scan with or without PSA
progression.
3. Have progression under the following conditions if the participant received
anti-androgen therapy prior to enrollment:
a. Evidence of progression >4 weeks since last flutamide treatment.
b. Evidence of progression >6 weeks since last bicalutamide or nilutamide
treatment.
4. Have current evidence of metastatic disease documented by either bone lesions on
bone scan and/or soft tissue disease by CT/MRI. Participants whose disease spread is
limited to regional pelvic lymph nodes are not eligible.
5. Have met one of the following criteria with regards to abiraterone acetate exposure:
a. not received prior abiraterone acetate (ie, abiraterone naïve)
b. received prior abiraterone acetate for the treatment of mHSPC, for a minimum of
4 weeks and must not have progressed while on treatment.
c. received prior abiraterone acetate for the treatment of mCRPC and either
progressed on treatment after a minimum of 8 weeks treatment (minimum 14
weeks for those with bone progression) or become intolerant of the drug after a
minimum of 4 weeks treatment.
6. Have ongoing androgen deprivation with serum testosterone <50 ng/mL (<2.0 nM). If
the participant is currently being treated with luteinizing hormone-releasing hormone
agonists or antagonists (participants who have not undergone an orchiectomy) this
therapy must have been initiated at least 4 weeks prior to randomization and
treatment must be continued throughout the study.
7. Participants receiving bone resorptive therapy (including, but not limited to,
bisphosphonate or denosumab) must have been on stable doses for ≥4 weeks prior to
randomization.
8. Demonstrate adequate organ function as defined in Table 1; all screening labs should
be performed in central laboratory within 10 days of the first dose of study
intervention.
9. Participant is male.
10. Participant is ≥18 years of age on day of signing the informed consent.
11. Male participants are eligible to participate if they 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 as their preferred and usual lifestyle (abstinent
on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception, unless confirmed to be azoospermic (vasectomized or
secondary to medical cause [Appendix 5]), as detailed below:
• Agree to use a male condom plus partner use of an additional contraceptive method
when having penile-vaginal intercourse with a woman of child-bearing potential
(WOCBP) who is not currently pregnant. Note: Men with a pregnant or breastfeeding
partner must agree to remain abstinent from penile-vaginal intercourse or use a male
condom during each episode of penile-vaginal penetration.
12. 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.
13. The participant (or legally acceptable representative if applicable) provides written
informed consent/assent for the study. The participant may also provide consent/assent
for future biomedical research. However, the participant may participate in the main
study without participating in future biomedical research.
14. Have 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; other exceptions may be considered after Sponsor
consultation). Participants with bone only or bone predominant disease may provide a
bone biopsy sample. However, if obtaining a fresh biopsy is not feasible, then
participants may provide an archival tumor tissue sample after Sponsor consultation
(SCF). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
Newly obtained biopsies are preferred to archive tissue.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the
testing laboratory within 14 days from the date slides are cut (details pertaining to tumor
tissue submission can be found in the Procedures Manual).
15. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
assessed within 7 days of randomization.

Exclusion Criteria

1. Has a known additional malignancy that is progressing or has required active treatment in
the last 3 years. Participants with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or carcinoma in situ that have undergone potentially curative
therapy are not excluded.
2. Has an active autoimmune disease that has required systemic treatment in past 2 years
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment.
3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study intervention.
4. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant’s participation
for the full duration of the study, or is not in the best interest of the participant to
participate, in the opinion of the treating investigator.
5. 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.
6. Has a gastrointestinal disorder affecting absorption (eg, gastrectomy, active peptic ulcer
disease within last 3 months).
7. Is unable to swallow tablets/capsules.
8. Has an active infection (including tuberculosis) requiring systemic therapy.
9. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
10. Has known active human immunodeficiency virus (HIV), hepatitis B virus (eg, hepatitis
B surface antigen reactive) or hepatitis C virus (HCV) (eg, HCV RNA [qualitative] is
detected). Testing is not required unless mandated by local regulation.
11. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Participants with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least 4 weeks prior to
randomization and any neurologic symptoms have returned to baseline), have no
evidence of new or enlarging brain metastases, and are not using steroids for at least 7
days prior to randomization. This exception does not include carcinomatous meningitis,
which is excluded regardless of clinical stability.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the study.
13. Has a history of seizure or any condition that may predispose to seizure (including, but
not limited to prior cerebrovascular accident, transient ischemic attack, or brain
arteriovenous malformation; or intracranial masses such as a schwannoma or
meningioma that is causing edema or mass effect).
14. Has a history of loss of consciousness within 12 months of the Screening Visit.
15. Has had myocardial infarction or uncontrolled angina within 6 months prior to
randomization.
Note: Participants with recent history of revascularization for acute coronary syndrome
within 3 months prior to randomization are included.
16. Has a history of clinically significant ventricular arrhythmias (eg, ventricular tachycardia,
ventricular fibrillation, torsades de pointes).
17. Has a history of Mobitz II second degree or third degree heart block without a permanent
pacemaker in place.
18. Has hypotension as indicated by systolic blood pressure <86 millimeters of mercury
(mmHg) at the Screening Visit.
19. Has bradycardia as indicated by a heart rate of <50 beats per minute on the Screening
electrocardiogram (ECG).
20. Has uncontrolled hypertension as indicated by systolic blood pressure >170 mmHg or
diastolic blood pressure >105 mmHg at the Screening visit.
21. Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients.
22. Has history of prostate cancer progression on ketoconazole.
23. Has had prior treatment with any second-generation androgen receptor inhibitor (eg,
enzalutamide, apalutamide, darolutamide).
24. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).
25. Has received prior treatment with radium or other therapeutic radiopharmaceuticals for
prostate cancer.
26. Has had prior chemotherapy for mCRPC. Prior docetaxel for mHSPC is allowed if more
than 4 weeks have elapsed from the last dose of docetaxel.
27. Has received prior targeted small molecule therapy or abiraterone treatment within 4
weeks prior to randomization or who has not recovered (ie, Grade ≤1 or at baseline), with
the exception of Grade ≤2 neuropathy or Grade ≤2 alopecia from AEs due to a previously
administered agent.
28. Has received an anticancer mAb within 4 weeks prior to randomization or has not
recovered (ie, Grade ≤1 or at baseline) from AEs due to mAbs administered more than 4
weeks prior to randomization.
Note: Treatment with denosumab as standard of care for bone metastases is permitted.
29. Has used herbal products that may have hormonal anti-prostate cancer activity and/or are
known to decrease PSA levels (eg, saw palmetto) within 4 weeks prior to randomization.
30. Has received treatment with 5-α reductase inhibitors (eg, finasteride, dutasteride),
estrogens, and/or cyproterone within 4 weeks prior to randomization.
31. Has received a live vaccine within 30 days prior to randomization. Examples of live
vaccines include, but are not limited to, the following: measles, mumps, rubella,
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG),
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live
attenuated vaccines and are not allowed.
32. Has received prior radiotherapy within 2 weeks of randomization. Participants must have
recovered from all radiation-related toxicities, not require corticosteroids, and not have
had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2
weeks of radiotherapy) to non- CNS disease.
33. Is currently participating in or has participated in a study of an investigational agent or
has used an investigational device within 4 weeks prior to randomization.
Note: Participants who have entered the non-treatment follow-up phase of an
investigational study may participate as long as it has been 4 weeks after the last dose of
the previous investigational agent.
34. Has a “superscan” bone scan. This is defined as an intense symmetric activity in the
bones and diminished renal parenchymal activity on baseline bone scan such that the
presence of additional metastases in the future could not be evaluated.
35. Is to father children within the projected duration of the study, starting with the screening
visit through 120 days after the last dose of study intervention.
36. Has had an allogenic tissue/solid organ transplant.

The Estimated Number of Participants

  • Taiwan

    30 participants

  • Global

    1240 participants

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