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)

1. Histologically- or cytologically-confirmed adenocarcinoma of the prostate
without small cell histology.
2. Have prostate cancer progression while on ADT (or post bilateral
orchiectomy) within 6 months prior to randomization, as determined by the
investigator.
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 must have been on stable
doses for >=4 weeks prior to randomization.
8. Demonstrate adequate organ function as defined in the protocol
9. Participant is male.
10. Participant is >=18 years of age on day of signing the informed consent.
11. Participants are eligible to participate if they agree to the following
during the intervention period and for at least 45 days after the last dose
of enzalutamide:
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, documented from the site
personnel's review of the participant's medical records, medical
examination, or medical history interview) as detailed below:
*Agree to use a male condom plus partner use of an additional
contraceptive method when having penile-vaginal intercourse with a
WOCBP who is not currently pregnant.
*Contraceptive use by men should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies. If the contraception requirements in the local label for any of
the study interventions is more stringent than the requirements above,
the local label requirements are to be followed.
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.
15. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1 assessed within 7 days of randomization.

Digital proficiency is recommendable (in order to complete digital
questionnaires).

Inclusion criteria for 2nd course retreatment:
Either:
- Stopped initial study intervention after CR, and
- Treated with at least 8 cycles of study intervention before discontinuing
treatment, and
- Received at least 2 treatments with pembrolizumab beyond the date initial CR
was declared

OR:
- Had SD, PR, or CR and stopped study intervention after completion of 35
cycles of study intervention for reasons other than disease progression or
intolerability

AND:
- Experienced radiographic disease progression after stopping initial
treatment, and
- Upon unblinding at the time of centrally verified disease progression, were
found to have received pembrolizumab, and
- No new anticancer treatment was administered after the last dose of study
intervention (exception: enzalutamide study treatment), en
- Meet all safety parameters listed in the inclusion criteria and none of the
safety parameters listed in the exclusion criteria, and
- the study is ongoing

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. Replacement therapy 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 HIV, active hepatitis B virus (HBsAg positive and/or
detectable HBV DNA) or known active hepatitis C virus (HCV) (defined as anti
HCV Ab positive and detectable HCV RNA infection). 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.
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 end/or enzalutamide
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, OX- 40, 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.
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.
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.