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Sooi et al. Cancer Drug Resist 2023;6:656-73 https://dx.doi.org/10.20517/cdr.2023.48 Page 664

of cabozantinib with atezolizumab (anti-PD1) in mCRPC patients who have had disease progression
following treatment with novel hormonal agents such as abiraterone or enzalutamide. An ORR of 32% was
observed in 132 patients treated with the combination, with a disease control rate (DCR) of more than 80%.
[82]
This effect was consistent in patients with visceral disease as well . Due to promising results from this
study, this combination is now being evaluated in a phase 3 clinical trial for mCRPC patients. Other
ongoing studies looking at combination anti-VEGF therapy with ICIs are listed in Table 1.

Combination ICIs
CheckMate-650 is a phase 2 study looking at various dosing combinations of nivolumab with ipilimumab in
asymptomatic or minimally symptomatic mCRPC patients who have progressed on novel hormone therapy
in two cohorts (chemotherapy-naive and chemotherapy-exposed). In the chemotherapy-naive cohort,
nivolumab/ipilimumab achieved an ORR of 25% with a median radiological PFS of 5.5 months and a
median OS of 19.0 months. In the chemotherapy-exposed cohort, the ORR was 10%, with a median
[83]
radiological PFS of 3.8 months and a median OS of 15.2 months . Exploratory analyses revealed that
PD-L1 ≥ 1%, the presence of DDR or homologous recombination deficiency (if at least one gene in the
[83]
relevant gene panel had a deleterious mutation/homozygous deletion) were associated with higher ORR .
In this study, 44 patients had quality-controlled whole-exome sequencing data, giving rise to a median TMB
of 74.5 mutations/patient. Tumours harbouring TMB exceeding this median were associated with higher
ORR, PSA response rate, radiologic PFS, and median OS .
[83]

Combination nivolumab and ipilimumab has been examined in AR-V7 expressing mCRPC patients as well.
Androgen receptor splice variant 7 (AR-V7) expression is found in approximately 20% of mCRPC patients
and is associated with alterations in a greater number of DDR genes, which could increase susceptibility to
ICIs . The STARVE-PC trial is a phase 2 non-randomised study that evaluated the activity of nivolumab
[84]
and ipilimumab in 15 AR-V7 expression mCRPC patients, showing an ORR of 25%, PSA response rate of
13% and OS of 8.2 months . Responses were more pronounced in six of the patients who were found to
[85]
have mutations in DDR genes (three in BRCA2, two in ATM, and one in ERCC4) . Lastly, an ongoing
[86]
phase 2 randomised study is looking at mCRPC patients following progression on novel hormonal agents,
randomising them to receive durvalumab or combination durvalumab plus ipilimumab. The ORR with
combination ICI was 16% vs. 0% with durvalumab monotherapy in this study . Other ongoing trials
[87]
evaluating the efficacy of combination ICIs are listed in Table 1.

Androgen receptor antagonists and ICIs
How prostate cancer treatment impacts the immune response is variable. ADT enhances lymphopoiesis,
which can mitigate immune tolerance to prostate cancer antigens . On the other hand, androgen receptor
[88]
[89]
antagonists have been shown to inhibit T cell responses .
ADT and anti-androgens can both target the AR signalling pathway and have been shown to result in an
increase in the number of TILs, and a decrease in the number of regulatory T cells supporting an
antitumour response to ADT [90,91] . Animal models confirm that while ADT induces pro-inflammatory
conditions initially, the subsequent development of castration resistance and immune tolerance to prostate
cancer antigens reduces this [92,93] . Therefore, the combination of AR-signalling blockade with ICIs, especially
during its pro-inflammatory state, may be beneficial in the treatment of advanced prostate cancer.

The phase 2 IMbassador250 trial examined 759 advanced CRPC patients who had progressed on
abiraterone and docetaxel, randomising them to receive combination enzalutamide and atezolizumab vs.
enzalutamide alone. The study was closed prematurely due to futility (combination therapy vs.
enzalutamide monotherapy, 15.2 vs. 16.6 months; HR 1.12, 95% CI 0.91-1.37). However, pre-planned