MMR-deficient cancers of any histologic type appear to be very sensitive to PD-1 blockade
with pembrolizumab, and similar data are also beginning to emerge for nivolumab and other
immune checkpoint inhibitors. Among the MMR-deficient cancers, the best antitumor responses
are often associated with high microsatellite instability (MSI-H status), higher tumor
mutational burden (TMB), and higher predicted neoantigen load. Prevalence estimates of MMR
deficiency across solid tumor types range from 1% to 20% depending on the type of malignancy.
In prostate cancer, 1-3% of unselected cases harbor MMR deficiency and/or microsatellite
instability.
For men who previously received definitive treatment for prostate cancer and subsequently
develop detectable prostate specific antigen (PSA) levels, the clinical state is known as
biochemically recurrent prostate cancer. The current standard of care treatment for patients
with biochemically recurrent prostate cancer is either surveillance or androgen deprivation
therapy (ADT). ADT has not been shown to provide a survival benefit in this setting, and the
decision to initiate ADT will depend on patient preference and perceived risks of the
disease. A non-hormonal therapy such as nivolumab would provide an alternative to ADT in
patients with biomarker selected (i.e. dMMR, MSI-H, high TMB, or CDK12-altered) biochemically
recurrent prostate cancer.
Inclusion Criteria:
- Willing and able to provide signed informed consent and HIPAA authorization for the
release of personal health information
- Males aged 18 years and above
- Prior local therapy with prostatectomy or EBRT/brachytherapy is required
- Prior salvage or adjuvant radiation therapy is allowed but not mandated. Radiation
therapy must have been completed for at least 6 months.
- Absolute PSA >=1.0 ng/mL at screening
- Must have at least one of the following genetic alterations identified using archival
tissue (i.e. prostate needle biopsy prior to radiation therapy or prostatectomy
specimen):
- Microsatellite instability (MSI-high) status by clinical grade testing
- MMR protein loss (MSH2, MSH6, MLH1, PMS2) by immunohistochemistry
- Inactivating mutation of MSH2, MSH6, MLH1 or PSM2 by clinical grade genomic
testing
- Tumor mutational burden >= 20 mutations/megabase (TMB >=20 muts/Mb) by clinical
grade testing
- Inactivating mutation (at least monoallelic of CDK12 by clinical grade testing
- Serum testosterone >= 150 ng/dL
- No radiographic evidence of metastatic disease by CT scan and bone scan, performed
within the prior 4 weeks.
- Karnofsky Performance Status (KPS) >= 70% within 14 days before start of study
treatment (ECOG <=1)
- Participants must have normal organ and bone marrow function measured within 28 days
prior to administration of study treatment as defined below:
- Hemoglobin >= 9.0 g/dL with no blood transfusion in the past 28 days
- Absolute neutrophil count (ANC) >= 1.0x10^9 / L
- Platelet count >= 100 x 10^9 /L
- Total bilirubin within institutional upper limit of normal (ULN) (in patients
with Gilbert's syndrome, total bilirubin <1.5x institutional ULN will be
acceptable)
- Aspartate aminotransferase (AST), Serum Glutamic Oxaloacetic Transaminase (SGOT)
/ Alanine aminotransferase (ALT), Serum Glutamic Pyruvate Transaminase (SGPT)
within institutional ULN
- Participants must have creatinine clearance estimated using the Cockcroft-Gault
equation of >=40 mL/min:
Estimated creatinine clearance = [(140 - age (years)) x weight (kg)] / [serum creatinine
(mg/dL) x 72]
- Participants must have a life expectancy of >= 6 months
- Male participants and their partners who are sexually active and of childbearing
potential must agree to the use of two highly effective forms of contraception in
combination, throughout the period of taking study treatment and for 7 months after
the last dose of nivolumab to prevent pregnancy in a partner.
- No evidence (within 5 years) of prior malignancies (except successfully treated basal
cell or squamous cell carcinoma of the skin)
Exclusion Criteria:
- Metastatic disease or currently active second malignancy
- Prior androgen deprivation therapy (ADT) in the past 6 months. Prior ADT in context of
neoadjuvant/adjuvant primary; prior ADT for biochemical recurrence is allowed, as long
as no ADT has been administered in past 6 months and testosterone has recovered (>150
ng/dL)
- Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide),
or androgen synthesis inhibitor (e.g. abiraterone, orteronel) within the past 2 weeks
is not permitted. 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride)
is allowed, as long as subject has been stable on medication for past 6 months.
- Involvement in the planning and/or conduct of the study (applies to both BMS staff
and/or staff at the study site)
- Participation in another clinical study with an investigational product during the
last 4 weeks/28 days
- Patients should be excluded if they have had prior systemic treatment with an
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell costimulation or immune checkpoint pathways
- Patients should be excluded if they have an active, known or suspected autoimmune
disease (e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis,
lupus, celiac disease). Subjects are permitted to enroll if they have vitiligo, type I
diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring
hormone replacement, psoriasis not requiring systemic treatment, or conditions not
expected to recure in the absence of an external trigger.
- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (>10 mg daily prednisone daily equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses >10mg daily prednisone equivalents are
permitted in the absence of active autoimmune disease
- Permitted therapies include topical, ocular, intra-articular, intranasal, and
inhalational corticosteroids (with minimal systemic absorption). Physiologic
replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day
prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g.
contrast dye allergy) or for treatment of nonautoimmune conditions (e.g. delayed-type
hypersensitivity reaction caused by contact allergen) is permitted.
- As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition
to hepatotoxicity should be used with caution in patients treated with
nivolumab-containing regimen.
- Patients should be excluded if they have a positive test for hepatitis B virus surface
antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute
or chronic infection
- Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- History of allergy to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
- Any other serious illness or medical condition that would, in the opinion of the
investigator, make this protocol unreasonably hazardous, including but not limited to:
- Any uncontrolled major infection
- Cardiac failure NYHA (New York Heart Association) III or IV
- Crohn's disease or ulcerative colitis
- Bone marrow dysplasia
- Known allergy to any of the compounds under investigation
- Unmanageable fecal incontinence
- Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant
systemic disease or active, uncontrolled infection. Examples include, but are not
limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial
infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung
disease, or any psychiatric disorder that prohibits obtaining informed consent.
