Nivolumab as a Non-Castrating Therapy for MMR-deficient and CDK12- Altered Prostate Cancer With PSA Recurrence After Local Therapy
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.
• 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)