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Page 138 Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50

In the KEYNOTE-028 phase Ib study, pembrolizumab showed a 17.4% objective response rate (ORR) in 23
heavily treated mCRPC patients with measurable disease and ≥ 1% PD-L1 expression. The response
included a partial response (PR) in 4 patients, with 3 experiencing a parallel biochemical response. The trial
[259]
had a favorable side effect profile . Subsequently, pembrolizumab was studied in the KEYNOTE-199 trial
across three mCRPC cohorts. Cohort 1 had PD-L1-positive tumors, cohort 2 had PD-L1-negative tumors,
and cohort 3 had non-measurable bone metastatic disease. Median overall survival (OS) was 9.5, 7.9, and
14.1 months for cohorts 1, 2, and 3, respectively. Confirmed PSA response rates were 6%, 8%, and 2% in the
respective cohorts. The observed ORR was modest (about 5%), with a median response duration of 16.8
months. Notably, outcomes were similar regardless of PD-L1 status, and no clear relationship was found
between pembrolizumab responses and DNA damage repair gene mutations [260,261] .

These are a few immune checkpoint inhibitors applied to cure prostate cancer. For the majority of prostate
cancer patients, these medications are ineffective, and they are not approved for all patients with the illness.
Moreover, not all patients with these subtypes will react to immunotherapy, and the reaction to immune
checkpoint inhibitors is still uncertain and variable. The first immunotherapeutic medication to be licensed
by the FDA for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) that is without any
symptoms and with some poor symptoms is sipuleucel-T (Provenge), which increases the overall survival
ratio of the subjects. Limited responses have been observed in mCRPC despite numerous clinical trials
investigating ICIs and combinations of these with different medications. Thus far, ICIs binding with
different molecules, like DNA damage molecules, have only been clinically beneficial for a limited subgroup
[1]
of subjects by CDK12 mutations, MMR deficiency, more MSI, and these conditions . To overcome
resistance and enhance the effectiveness of immunotherapy in treating prostate cancer, further research is
required to uncover biomarkers and assess the efficacy and toxicity of ICIs.

REASONS FOR IMMUNOTHERAPY FAILURE IN PROSTATE CANCER
Some malignancies are more resistant to immunotherapy than others, and it may not always work. One
malignancy that has had a poor response to immunotherapy, particularly in advanced stages, is prostate
cancer. Potential causes for immunotherapy failure in prostate cancer include:

1. Absence of tumor inflammation: Neoantigens, which are novel or changed peptides recognized by the
immune system as foreign molecules, are infrequent in prostate cancer cells. Consequently, immune cells
are less drawn to prostate cancer, and there is little tumor inflammation. Increased tumor inflammation
improves the efficacy of immunotherapy by providing a more conducive environment for immune cells to
target cancer cells [262,263] .

2. Low quantities of antigens, which are chemicals that can elicit an immune response, are present in
prostate cancer cells. This makes it challenging for the immune system to identify and combat them [233,264] .

3. A microenvironment that inhibits or evades the immune system is created by prostate cancer, which
produces immunosuppressive chemicals, attracts regulatory T cells, and expresses checkpoint ligands,
among other things [233,264] .

4. Due to its considerable heterogeneity, prostate cancer might respond differently to immunotherapy and
develop resistance to it. The cancer comprises several clones and subtypes with varying genetic and
molecular properties [233,264] .