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Page 56 Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46

in the United States. In 2023, approximately 288,300 diagnoses of prostate cancer and 34,700 deaths were
[1,2]
estimated in the United States . Cancer incidence for prostate cancer increased by 3% annually from 2014
[2]
through 2019 after two decades of decline . Due to a variety of factors including advances in therapeutics,
in addition to widespread prostate-specific antigen (PSA) screening, prostate cancer mortality has declined
by 53% since its peak in 1993 .
[3,4]
[5]
Prostate cancer is an androgen-driven process , and thus, continuous androgen deprivation has remained
the standard of care for patients with metastatic hormone-sensitive disease. Advanced understanding of
testosterone suppression has led to the rise of well-known and universally used hormonal agents. While
most patients initially respond to androgen suppression therapy, over time, castration resistance
[6]
unavoidably occurs, leading to a need for further therapeutic options .

The emergence of immuno-oncology has shifted the landscape and treatment paradigm for many solid
tumor malignancies [7-10] . It aims to augment the body’s innate and humoral immune response, allowing
[10]
enhanced cytotoxic T-cell activity against malignant cells . Despite advances in modern immunotherapy,
to date, the benefits have been modest for patients with prostate cancer [11,12] . The one exception has been for
mismatch-repair-deficient or microsatellite-instability-high tumors, in which pembrolizumab may be
efficacious and has regulatory approval . Overall, there has been limited success with immunotherapy in
[13]
the treatment of prostate cancer and patients with advanced prostate cancer are in need of further
developments within the immuno-oncology field. However, there is reason for optimism in immuno-
oncology based on recent progress. Ongoing investigation into chimeric antigen receptor T-cell therapies
(CAR-T), bispecific T-cell engagers (BiTEs), and cancer vaccines reveals their potential as novel therapies,
offering patients the prospect of benefits. In this review, we outline ongoing immunotherapeutic advances
in prostate cancer with a focus on novel targets for immune activation.

Targeting immune checkpoint blockade
Multiple trials have evaluated the efficacy of immune checkpoint inhibitors (ICIs) in prostate cancer
[Table 1]. Unfortunately, there has yet to be a breakthrough showing significant efficacy or survival benefit
with ICIs for the majority of patients with prostate cancer. The current approval for ICIs in prostate cancer
is limited to patients with tumors that harbor mutations in mismatch repair genes or exhibit microsatellite
instability, which encompasses a minority of patients. The limited efficacy in patients outside of this subset
is likely due in part to the inherently “cold” immunologic microenvironment of prostate stroma compared
to other more immunogenic cancers that classically respond to checkpoint blockade.

Targeting programmed cell death protein 1 and PD - L1
Historically, prostate cancer has been poorly responsive to targeting programmed cell death protein 1
(PD-1) inhibitors. An early phase I trial employing nivolumab in patients with metastatic castrate-resistant
disease did not show objective responses in 17 evaluable patients [14-19] . Similarly, KEYNOTE-199, a phase II
trial evaluating pembrolizumab in patients with metastatic castrate-resistant prostate cancer who had
progressed on prior androgen receptor targeting therapy and prior docetaxel, demonstrated an ORR of 5%
(95%CI: 2%-11%) or lower in multiple cohorts . Pembrolizumab was also studied in combination with
[20]
enzalutamide and olaparib, a poly (ADP-ribose) polymerase inhibitor that previously had success in
metastatic castrate-resistant prostate cancer. In combination with enzalutamide, the ORR was 12.3%
(95%CI: 6.1%-21.5%) . When used in combination with olaparib, the objective response rate (ORR) was
[21]
8.5% (95%CI: 2.8%-1.9%), and 19% of patients benefited from a 50% or greater decrease in PSA (PSA50) .
[22]