Nivolumab in Prostate Cancer With DNA Repair Defects (ImmunoProst Trial)
Status:
Active, not recruiting
Trial end date:
2022-03-01
Target enrollment:
Participant gender:
Summary
Prostate Cancer (PC) is the most frequent cancer in men, accounting for 21% of new cases of
cancer in men in the United States. Among the four most incident tumors (breast, lung and
colorectal cancer); prostate cancer is the only that does not have any predictive biomarker
to guide the treatment. Even though the molecular heterogeneity of PC is well-documented,
treatment has not been molecularly stratified and the need for genetic prognostic and
predictive markers is critical.
DNA repair defects (DRD), mainly in the Homologous Recombination (HR) pathway (such as BRCA1,
BRCA2, ATM and CHEK2) are emerging as potential biomarkers in prostate cancer. It is well
known BRCA1 and BRCA2 carriers have better Progression-Free Survival (PFS) and Overall
Survival (OS) than non-carriers in ovarian cancer. Differently than ovarian tumors that BRCA
mutations provides a good prognosis, PC patients who harbor HR defects have a higher Gleason
score 6, an increased risk of recurrence and poor prognosis. The predictive role of DRD in PC
was demonstrated in a recent trial using Olaparib, a PARP inhibitor, in DRD carriers. This
trial showed 88% of response rate with Olaparib, a PARP inhibitor that acts in HR pathway by
synthetic lethality.
Recent data demonstrated important association between HR deficient high-grade serous ovarian
cancer (HGSOC), high neoantigen load and high expression of PD-1/PD-L1 compared with HR
proficient HGSOCs 10. This study showed that BRCA1 and BRCA2 mutations increase the number of
tumor-infiltrating lymphocytes (TILs) and confer a better prognosis. The unprecedented
success of immunotherapy in malignant disorders has provided evidence that the patient's
immune system can be improved to attack established tumors, mainly melanoma, non-small cell
lung cancer and kidney cancer. A high mutational burden increases the likelihood of the
development of specific neoepitopes that would confer clinical benefit from CTLA-4 and PD-1
blockade.
These data showed that specific DNA repair defects increase the mutational burden, the
expression of PD-1/PD-L1 and TILs; and could improve the response to immunotherapy in cancer.
This rationale was already tested in a trial that evaluated the PD-1 checkpoint inhibitor
Pembrolizumab in mismatch-repair deficient patients, a kind of DNA repair defect by
definition. This important trial showed that this DRD predicted clinical benefit of immune
checkpoint blockade in many types of cancer, especially colorectal cancer.