Biomarkers for Neoadjuvant Pembrolizumab in Non-Metastatic Prostate Cancer Positive by 18FDG-PET Scanning

Phase II Clinical and Translational Study of Neoadjuvant Pembrolizumab Before Radical Prostatectomy in Non-metastatic Gleason ≥8 Prostate Cancer Patients Positive by 18FDG-PET Scanning ( PICT-01)

Various approaches are currently being developed for prostate cancer immunotherapy. However, a major challenge facing the development of cancer immunotherapy is the identification of tumors that would best respond to this type of treatment. Different studies suggest that prostate cancer more likely to progress are more infiltrated by exhausted T cells expressing the cell surface protein PD1 (Programmed cell death 1). Therefore, there is a strong rationale for selecting patients at higher risk of progression for testing the efficacy of anti-PD1 therapy.

High glucose metabolism as detected by fludeoxyglucose F18 (FDG)-positron emission tomography (PET) (18FDG-PET) imagery is an innovative biological biomarker-based method to identify patients at higher risk of recurrence and early failure to hormonotherapy. Recent study demonstrated that high intra-prostatic 18-FDG-uptake was associated with higher Gleason grades. Therefore the one third of Gleason ≥ 8 prostate cancer patients with higher 18FDG uptake would be ideal candidates for early immunotherapy treatments based on anti-PD-1 such as pembrolizumab.

The study aimed to identify biomarkers predictive the response to Pembrolizumab given prior to radical prostatectomy in participants with primary prostate cancer at high risk of progression.

This is a Phase II, single-arm and open-label trial of pembrolizumab (MK-3475) in localized prostate cancer patients with newly diagnosed non-metastatic prostate cancer (Gleason grade ≥8 on biopsy) with positive tumor by FDG-PET (SUV max >4) who chose to undergo radical prostatectomy and lymph node dissection as primary treatment.

The trial will meet its endpoint if a reduction in cancer extent, proliferative index and increased apoptosis, as well as an induction of favorable immune cell infiltration and immune checkpoint expression profiles are observed after treatment compare to baseline..

Inclusion Criteria:

• Male Age≥ 18 years old
• Non-metastatic prostate cancer with histologically confirmed Gleason sum ≥8
• Eligible for radical prostatectomy with a delay of 6 to 9 weeks
• Intraprostatic maximum standardized uptake value (SUVmax) ≥4 at 18-FDG-PET/CT exam.
• Not be castrated or under androgen deprivation therapy
• Not have received prior neo adjuvant hormonotherapy.
• Provided archival formalin-fixed, paraffin embedded tumor biopsy of the prostate tumor lesion not previously irradiated
• Performance status of Eastern Cooperative Oncology Group 0 to 1
• Adequate organ function

Exclusion Criteria:

• 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 (Cytotoxic T-lymphocyte-Associated Protein 4), OX-40, CD137).
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation.
• Has received prior radiotherapy to the prostate or other organs within 2 weeks of start of study treatment.
• Has received a live vaccine within 30 days prior to the first dose of study drug.
• Is participating 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 treatment.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Other primary cancer within 3 years
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV).
• Has a known history of Hepatitis B or known active Hepatitis C virus infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is expecting to father children within the projected duration of the study, starting with the screening visit through the date of prostatectomy.