A Phase 3, Randomized, Double-blind Study of Pembrolizumab (MK-3475) Plus Docetaxel Plus Prednisone versus Placebo Plus Docetaxel Plus Prednisone in Participants with Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC) who have Progressed on a Next Generation Hormonal Agent (NHA) (KEYNOTE-921)

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 androgen deprivation therapy (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
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
antiandrogen 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 received prior treatment with one (but not more than one) NHA (eg,
abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for mHSPC or
CRPC and either
a) progressed through treatment after a minimum of 8 weeks treatment (minimum
14 weeks for those with bone progression)
OR
b) have become intolerant of the drug (minimum 4 weeks treatment)
6. Have ongoing androgen deprivation with serum testosterone <50 ng/dL (<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; all screening labs should be performed
in the 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 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 pembrolizumab or 180 days after the last dose of docetaxel,
whichever is longer:
a) Refrain from donating sperm
PLUS either:
b) 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
a) Must agree to use contraception unless confirmed to be azoospermic
(vasectomized or secondary to medical cause 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 childbearing
potential (WOCBP) who is not currently pregnant
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
15. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1 assessed within 7 days of randomization

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 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 trial, interfere with the
participant*s participation for the full duration of the trial, or is not in
the best interest of the participant, 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
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
current pneumonitis
10. Has a known psychiatric or substance abuse disorder that would interfere
with cooperation with the requirements of the trial
11. Has known active human immunodeficiency virus, hepatitis B virus or
hepatitis C virus. Testing at screening is not required unless mandated by
local regulations
12. Has known active central nervous system metastases and/or carcinomatous
meningitis. Participants with previously treated brain metastases may
participate provided they are stable, have no evidence of new or enlarging
brain metastases, and are not using steroids for at least 7 days prior to
randomization.
13. Has severe hypersensitivity (>=Grade 3) to pembrolizumab and/or any of its
excipients
14. Has CTCAE Grade >=2 peripheral neuropathy, except when due to trauma
15. Has ascites and/or clinically significant pleural effusion
16. Has symptomatic congestive heart failure (New York Heart Association Class
III or IV heart disease)
17. Has received a whole blood transfusion in the last 120 days prior to entry
into the study. Packed red blood cells and platelet transfusions are acceptable
if not given within 28 days of the first dose of study intervention
18. Has received colony-stimulating factors within 28 days prior to the first
dose of study intervention
19. Has had a prior anticancer mAb within 4 weeks prior to randomization or who
has not recovered from AEs due to mAbs administered more than 4 weeks prior to
randomization
20. Has used herbal products that may have hormonal anti prostate cancer
activity and/or are known to decrease PSA levels within 4 weeks prior to
treatment randomization
21. Has received prior treatment with radium or other therapeutic
radiopharmaceuticals for prostate cancer
22. 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
23. Has received prior treatment with docetaxel or another chemotherapy agent
for mCRPC
24. Has hypersensitivity to docetaxel or polysorbate 80
25. Participant is currently receiving either strong or moderate inhibitors of
cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the
study
26. Has received prior targeted small molecule therapy or abiraterone acetate
or enzalutamide within 4 weeks prior to the first dose of study intervention,
or has not recovered from AEs due to a previously administered agent
27. Has received prior radiotherapy within 2 weeks of start of study
intervention. 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
28. Has received a live vaccine within 30 days prior to randomization
29. Has received treatment with 5alfa reductase inhibitors, estrogens, and/or
cyproterone within 4 weeks prior to randomization.
30. Has received prior treatment with ketoconazole for prostate cancer.
31. 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 the first dose of study intervention
32. Has a *superscan* bone scan
33. 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 intervention
34. Has had an allogenic tissue/solid organ transplant