Page 44 - Read Online

Sooi et al. Cancer Drug Resist 2023;6:656-73 https://dx.doi.org/10.20517/cdr.2023.48 Page 660

checkpoints has been reported to be dynamic, and various agents such as ipilimumab, sipuleucel-T and
enzalutamide can increase T cell infiltration into the TME and modulate response to anti-PD(L)1
[44]
therapy . This sets the stage for combination of various therapies with ICIs to improve immunotherapeutic
response in prostate cancer.

ONGOING STRATEGIES TO OVERCOME IMMUNE RESISTANCE
Several strategies have been examined to modulate antitumour immunity in advanced prostate cancer.

PARP inhibitors and ICIs
PARP inhibitors are small molecules that prevent the repair of single-strand DNA breaks. Pathogenic DDR
[45]
gene alterations are found in 23% of mCRPCs , with BRCA2, ATM, CHEK2, and BRCA1 being the most
frequently implicated genes . The resulting homologous recombination deficiency (HRD) leads to
[46]
sensitivity to PARP inhibition as a result of synthetic lethality . Presently in mCRPC patients, the FDA has
[47]
approved rucaparib for use in those with germline/somatic BRCA mutation and olaparib for those with
germline/somatic homologous recombination repair (HRR) gene mutations. This is based on a high ORR of
50.8% seen with rucaparib use in the phase 2 TRITON2 study and improved radiologic PFS with olaparib
use over enzalutamide/abiraterone in the phase 3 PROfound study [48,49] . The phase 3 TRITON3 study
[50]
showed similar results . Furthermore, efforts made in examining PARP inhibition in unselected patients
have been successful as well, with the phase 3 PROpel trial showing improvement in radiologic PFS with
combination abiraterone plus olaparib over abiraterone plus placebo as first-line treatment of mCRPC
[51]
patients, overall suggesting an increasing role in PARP inhibition .
Increased micronuclei and cytosolic double-stranded DNA release after PARP inhibitor treatment as a
result of PARP-DNA trapping and DNA damage leads to increased neoantigen formation, increased PD-L1
expression, increased intra-tumoural CD8 T cell infiltration and increased interferon production in the
TME, forming the basis for ICI-PARP inhibitor combinations, and potentially expanding the benefit of
PARP inhibitors beyond tumours harbouring alterations [52,53] . A phase 2 open-label clinical trial combining
durvalumab with olaparib in men with mCRPC showed a response (radiographic or biochemical) in 9 out
of 17 patients. Five of the 9 responders were found to have dysfunctional DDR genes based on genomic
analysis and the presence of mutated DDR genes was associated with significantly higher 12-month PFS
than those without (83.3% vs. 36.4%). Interestingly, patients with fewer peripheral MDSCs were more likely
to respond . This study showed early evidence of combining PARP inhibitors and ICIs, and other ongoing
[54]
studies looking at similar combinations are listed in Table 1.

As mentioned, CDK12-altered prostate cancers typically carry poor prognosis and do not respond well to
PARP inhibition, yet they present increased neoantigen load and lymphocytic infiltration, which may
increase responsiveness to anti-PD1 therapy [25,27] . A retrospective study of 60 men with CDK12-altered
advanced prostate cancer showed that of the 9 men who received PD-1 inhibitor therapy, 33% had a PSA
response and the median PFS was 5.4 months [27,55] . Similarly, the ongoing phase 2 IMPACT trial has shown a
21.4% PSA response with ipilimumab-nivolumab combination in these patients .
[55]

Vaccines and ICIs
Anti-cancer vaccines can be classified into four groups: cell-based, viral-based, DNA/RNA-based, and
peptide-based vaccines [56,57] . The goal of vaccine therapy is to stimulate the host’s adaptive immune response
against tumour-associated antigens (TAA). Prostate cancer is suitable for vaccine therapy because it has
many TAAs such as PSA, prostate-specific membrane antigen (PSMA), prostate acid phosphatase (PAP),
prostate stem cell antigen (PSCA), prostate cancer antigen 3 (PCA3), mucin-1, and six-transmembrane
epithelial antigens of the prostate (STEAP) .
[58]