Participants with mCRPC previously treated with docetaxel-based chemotherapy in Cohorts 1 to
3 will receive monotherapy with pembrolizumab. Chemotherapy-naïve subjects with mCRPC either
having failed or showing signs of failure with enzalutamide in Cohorts 4 and 5 will receive
pembrolizumab monotherapy in addition to their current regimen of enzalutamide. In all
cohorts, pembrolizumab administration will occur on Day 1 of each 3-week dosing cycle and
will continue for a maximum of 35 cycles (approximately 2 years) unless specific
withdrawal/discontinuation criteria are met. Participants who discontinue after 35 infusions
of pembrolizumab for reasons other than disease progression or intolerability, or who
discontinue after attaining a complete response may be eligible for up to 17 additional
infusions (approximately 1 year) after they have experienced disease progression.
Inclusion Criteria:
- Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without
small cell histology. Disease must be either metastatic or locally confined inoperable
disease that cannot be treated with definitive intent (no chance for a curative
intervention).
- Has supplied tumor tissue from a newly obtained biopsy or a biopsy obtained ≤12 months
prior to study start and an archival specimen, if available, from a site not
previously irradiated. Participants in Cohorts 1, 2, and 4 with visceral/measurable
lesions must provide a newly obtained biopsy performed after the last line of systemic
therapy or a biopsy obtained ≤12 months prior to study start and an archival specimen,
if available. Participants in Cohorts 3 and 5 must at least provide an archival
specimen.
For Cohorts 1, 2, and 3 only:
- Has been treated with:
- At least 1 targeted endocrine therapy (defined as second generation antiandrogen
therapies that include but are not limited to abiraterone acetate with prednisone,
enzalutamide, and next generation targeted agents such as ARN-509).
- At least 1 regimen/line of chemotherapy that contained docetaxel.
- No more than 2 chemotherapy regimens.
- No more than 3 regimens/lines of the aforementioned treatments (having
failed/progressed on chemotherapy and targeted endocrine therapy).
For Cohorts 4 and 5 only:
- Failing or showing early signs of failure on current pre-chemotherapy enzalutamide
treatment as defined by Prostate Cancer Working Group 3 PCWG3 guidelines. Participants
can have failed prior abiraterone treatment before current enzalutamide treatment.
Participants must have had a clinically meaningful response to enzalutamide treatment.
Enzalutamide must have been initiated no less than 4 weeks prior to the first dose of
trial treatment and be continued throughout the study.
For All Cohorts:
- Has documented prostate cancer progression within 6 months prior to screening, as
determined by the Investigator, by means of one of the following: 1) PSA progression
as defined by a minimum of 3 rising PSA levels with an interval of ≥1 week between
each assessment where the PSA value at screening should be ≥2 ng/mL, OR, 2)
Radiographic disease progression in soft tissue or bone with or without PSA
progression
- Has ongoing androgen deprivation with total serum testosterone <50 ng/dL (<2.0 nM).
- Participants receiving bone resorptive therapy (including but not limited to
bisphosphonate or Receptor activator of nuclear factor kappa-B ligand [RANK-L
inhibitor]) must have been on stable doses for ≥4 weeks prior to first dose of study
drug.
- Has a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale
- Participants of reproductive potential must agree to use an adequate method of
contraception, starting with the first dose of study drug through at least the time
needed to eliminate each study intervention after the last dose of study intervention.
The length of time required to continue contraception after the last dose of
enzalutamide is 30 days.
- Demonstrates adequate organ function.
Exclusion Criteria:
For All Cohorts:
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigation device
within 4 weeks of the first dose of study drug.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of study
drug.
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the
first dose of study drug or who has not recovered (i.e., ≤ Grade 1 or at Baseline)
from AEs due to mAbs administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or external beam
radiation therapy within 4 weeks prior to the first dose of study drug or who has not
recovered (i.e., ≤ Grade 1 or at Baseline) from AEs due to a previously administered
agent.
- Has a known additional malignancy that has had progression or has required active
treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin and
squamous cell carcinoma of the skin that has undergone potentially curative therapy.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis.
- Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs).
- Has evidence of interstitial lung disease and/or a history of (non-infectious)
pneumonitis that required steroids, or current pneumonitis.
- Has an active infection requiring systemic therapy.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Has previously participated in any other pembrolizumab (MK-3475) trial, or received
prior therapy with an anti-programmed cell death 1 (anti-PD-1, anti-PD ligand 1
[anti-PD-L1], and anti-PD-L2 [including ipilimumab or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways]).
- Has a known history of Human Immunodeficiency Virus (HIV).
- Has known active Hepatitis B or Hepatitis C.
- Has received a live vaccine within 30 days of planned start of study drug. Any
licensed coronavirus disease 2019 (COVID-19) vaccine (including for Emergency use) in
a particular country is allowed in the study as long as they are mRNA vaccines,
adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, those not
licensed or approved for Emergency Use) are not allowed.
For Cohorts 4 and 5 only:
- Has received prior chemotherapy (e.g., docetaxel) for mCPRC.
- Has any condition (cardiac, neurologic, absorption) other than clinically failing or
showing early signs of failure on enzalutamide treatment that would require imminent
discontinuation of enzalutamide treatment.
