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Review
. 2025 Jul 3:17:17588359251347857.
doi: 10.1177/17588359251347857. eCollection 2025.

Immunotherapy in metastatic prostate cancer

Liam Dwyer  1   2 , Claudia Leslie  1 , Rhiannon Mellor  1   3   4 , Tahlia Scheinberg  1   2   4 , Renea A Taylor  5   6   7   8 , Lisa G Horvath  9   2   3   4
Affiliations
Review

Immunotherapy in metastatic prostate cancer

Liam Dwyer et al. Ther Adv Med Oncol. .

Abstract

Over the last 15 years, immunotherapy has revolutionised treatment paradigms and improved outcomes in a range of malignancies. Despite these advances, the role of immunotherapy in standard prostate cancer (PCa) management is limited, and Sipuleucel-T is the only approved immunotherapeutic agent. This article reviews the role of checkpoint inhibitors (ICIs), T-cell engagers (TCEs) and chimeric antigen receptor (CAR)-T cells in PCa treatment. Phase II/III trials of ICIs as monotherapy or combination treatment have been negative to date. Early phase data for TCE are promising, but the feasibility of adoption of TCEs into the clinic will depend on overcoming neutralising anti-drug antibodies and limiting toxicities. CAR-T cells have demonstrated feasibility and acceptable safety profiles in early phase clinical trials, and it is hoped that the ongoing development of later-generation constructs and therapeutic combinations will enhance outcomes.

Keywords: BiTE; CAR-T cell; T cell engager therapy; bispecific T cell engager; checkpoint inhibitor; chimeric antigen receptor-T cell; immunotherapy; prostate cancer.

Plain language summary

The current and future role of immunotherapy in prostate cancer Over the past 15 years, traditional forms of immunotherapy have revolutionised survival from some ‘hot’ cancers, such as melanoma and other skin cancers. Immune cell ‘cold’ cancers, such as prostate cancer, are resistant to traditional immunotherapy. Here, we explain some of the reasons behind the failure of traditional immunotherapy in prostate cancer. We also review new types of immunotherapy which look promising as ways to overcome resistance and harness the immune system against prostate cancer cells. We suggest that newer forms of immunotherapy are worthy of ongoing development in the treatment of prostate cancer.

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Conflict of interest statement

Liam Dwyer declares no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Claudia Leslie declares no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Rhiannon Mellor declares no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Renea A. Taylor has research collaborations with Pfizer, Astellas, Zenith Epigenetics and AstraZeneca. Lisa Horvath: Site investigator on PRINCE, KEYNOTE-991, Checkmate 9KD, COSMIC021, NCT03792841 (AMG160), NCT04221542 (phase 1 AMG509), NCT06691984 (AMG509 phase III). Received research funding from Bayer and RedHill Biopharma (through ANZUP) and Astellas (through COBLH institution). Received travel and honoraria (all through COBLH institution) from Bayer, Astellas, Janssen, MSD and Pfizer. Advisory boards for Amgen, Astellas, Bayer and Janssen. Tahlia Scheinberg received research funding from Bayer (paid to ANZUP) and conference travel support from Bayer. She is a named inventor for a patent (PCT/AU2023/050849).

Figures

Figure 1.
Figure 1.
Categories of immunotherapeutic strategies. (a) TCEs are MHC-independent constructs directly linking a range of target TAAs with an immune effector. Current TCEs are ‘off-the-shelf’ constructs typically linking TAAs with CD-3+ T cells. (b) ICIs facilitate MHC-dependent T-cell activation by blocking immunosuppressive signalling pathways. ICIs are antigen-agnostic, nonspecific immunotherapies dependent on the net immunogenicity of the TIME rather than a specific TAA. (c) CAR-T cell therapy is also MHC-independent. Current CAR-T cell constructs are manufactured by ex vivo activation and expansion of patient-derived effector T cells, which have been genetically modified to recognise a target TAA of choice. (d) Sipuleucel-T is an autologous APC vaccine produced by ex vivo exposure of APCs to prostatic acid phosphatase, facilitating MHC-dependent T-cell activation. Source: Created in BioRender. Mellor (2025) https://BioRender.com/9s5k725 Anti-CTLA-4, anti-cytotoxic T lymphocyte-associated protein-4; Anti-PD-1, anti-programmed cell death protein-1; Anti-PD-L1, anti-programmed cell death ligand-1; APC, antigen-presenting cell; CAR-T, chimeric antigen receptor-T cell; ICI, immune checkpoint inhibitor; MHC, major histocompatibility complex; TAA, tumour-associated antigen; TCEs, T-cell engager; TCR, T-cell receptor; TIME, tumour immune micro-environment.
Figure 2.
Figure 2.
BiTEs and prostate cancer TAAs. Source: Created in BioRender. Mellor (2025) https://BioRender.com/yy40itc BiTE, bispecific T-cell engager; hK2, human kallikrein 2; MHC, major histocompatibility complex; PSCA, prostate stem cell antigen; PSMA, prostate-specific membrane antigen; STEAP1, six transmembrane epithelial antigens of the prostate 1; TAA, tumour-associated antigen; TMEFF2, transmembrane protein with EGF-like and two follistatin-like domains 2.
Figure 3.
Figure 3.
Timeline of key immunotherapy trials and drugs. Source: Created in BioRender. Mellor (2025) https://BioRender.com/gh44i6p aKantoff et al.; bBrahmer et al.; cFriedrich et al.; dJunghans et al.; eBeer et al.; fHummel et al.; gGraff et al.; hGratzke et al.; iPowles et al.; jAntonarakis et al.; kAgarwal et al.; l[ClinicalTrials.gov identifier: NCT06691984]. ADAs, anti-drug antibodies; anti-PD-1, anti-programmed cell death protein-1; ARPI, androgen receptor pathway inhibitor; B-ALL, B-cell acute lymphoblastic leukaemia; BiTE, bispecific T-cell engager; CAR-T, chimeric antigen receptor-T; CD3, cluster of differentiation 3; FDA, U.S. Food and Drug Administration; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PCa, prostate cancer; PSMA, prostate-specific membrane antigen; pts., participants; rPFS, radiographic progression-free survival.
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