Why immunotherapy fails in prostate cancer and what comes next

Abbreviations

ADC

antibody–drug conjugate

CRS

cytokine release syndrome

DLL3

delta‐like canonical Notch ligand 3

ICI

immune checkpoint inhibitor

mCRPC

metastatic castration‐resistant prostate cancer

NEPC

neuroendocrine prostate cancer

ORR

objective response rate

PSMA

prostate‐specific membrane antigen

STEAP

six‐transmembrane epithelial antigen of the prostate

TCE

T‐cell engager

Prostate cancer remains a major therapeutic challenge in the era of immuno‐oncology. Despite transformative success in malignancies such as melanoma and lung cancer, immune checkpoint inhibitors (ICIs) have consistently failed to deliver meaningful clinical benefit in advanced prostate cancer [1]. Multiple phase III trials of ICIs, alone or combined with standard treatments, have not improved overall survival (Table 1). Only a small subset of patients (~5%) with mismatch repair deficiency, high microsatellite instability, or high tumour mutational burden derive limited benefit and responses remain insufficiently durable [2]. This question is not merely academic but has immediate clinical relevance, as ICIs continue to be incorporated into treatment paradigms despite limited efficacy. A clearer understanding of resistance mechanisms is essential to avoid ineffective therapeutic escalation and guide rational biology‐driven strategies.

Table 1.

Clinical trials of failed ICIs and pending ADCs in prostate cancer.

Trail	NCT number	ICIs/ADCs target	Participation	N	Phase	Publication/completion	Status
CA184‐043	NCT00861614	Ipilimumab/placebo	mCRPC post‐docetaxel	799	III	Kwon et al. Lancet Oncol 2014 [10]	Failure
CA184‐095	NCT01057810		mCRPC pre‐docetaxel	399	III	Beer et al. J Clin Oncol 2017 [11]	Failure
CA209‐7DX	NCT04100018	Nivolumab + docetaxel/docetaxel	mCRPC	1030	III	Fizazi et al. Lancet Oncol 2026 [12]	Failure
CO39385	NCT03016312	Atezolizumab + enzalutamide/enzalutamide	mCRPC	759	III	Powles et al. Nat Med 2022 [13]	Failure
CONTACT‐02	NCT04446117	Atezolizumab + cabozantinib/ abiraterone or enzalutamide	mCRPC	575	III	Agarwal et al. Lancet Oncol 2025 [14]	Failure
KEYLYNK‐010	NCT03834519	Pembrolizumab + olaparib/ abiraterone or enzalutamide	mCRPC	793	III	Antonarakis et al. J Clin Oncol 2023 [15]	Failure
KEYNOTE‐641	NCT03834493	Pembrolizumab + enzalutamide/enzalutamide	mCRPC	1244	III	Graff et al. Ann Oncol 2025 [16]	Failure
KEYNOTE‐921	NCT03834506	Pembrolizumab + docetaxel/docetaxel	mCRPC	1030	III	Petrylak et al. J Clin Oncol 2025 [17]	Failure
KEYNOTE‐991	NCT04191096	Pembrolizumab + enzalutamide + ADT/enzalutamide + ADT	mHSPC	1251	III	Gratzke et al. Ann Oncol 2025 [18]	Failure
CA209‐650	NCT02985957	Nivolumab, ipilimumab	mCRPC post‐chemotherapy	351	III	Phase II data published	Failure
MK2400‐001	NCT06925737	B7‐H3	Prostate cancer	1440	III	2031	Pending
MGC‐026	NCT06242470		CRPC	250	I	2028	Pending
FOR46	NCT05011188	CD46	mCRPC	44	I/II	2027	Pending
LY4101174	NCT06238479	Nectin‐4	Prostate cancer	490	I	2027	Pending
ARX‐517	NCT04662580	PSMA	Metastatic prostate cancer	183	I/II	2026	Pending
ABBV‐969	NCT06318273	PSMA + STEAP1	mCRPC	230	I	2027	Pending
ADRX‐0405	NCT06710379	STEAP1	mCRPC	68	I	2026	Pending
RG1123855	NCT06236139		mCRPC	48	I/II	2027	Pending
AZD0516	NCT07181161	STEAP2	Metastatic prostate cancer	177	I/II	2029	Pending
Dato‐DXd	NCT05489211	TROP‐2	mCRPC	454	II	2027	Pending

ADT, androgen deprivation therapy; mHSPC, metastatic hormone‐sensitive prostate cancer; NCT, National Clinical Trial; TROP‐2, trophoblast cell‐surface antigen 2.

A central explanation lies in the unique biology of prostate cancer. Unlike immunologically ‘hot’ tumours characterised by high neoantigen burden and robust T‐cell infiltration, prostate cancer is typically an immune ‘cold’ malignancy [3, 4]. The tumour microenvironment is marked by low immunogenicity, limited antigen presentation, and immunosuppressive cell populations. More fundamentally, the prostate represents an immune‐privileged organ similar to the testicles where immune tolerance is essential for physiological function. This intrinsic biology likely constrains the effectiveness of conventional programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) targeted therapies. An important exception is sipuleucel‐T, the first therapeutic cancer vaccine approved for prostate cancer [5]. In the phase III Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial, sipuleucel‐T reduced the risk of death by 22% compared with control in patients with metastatic castration‐resistant prostate cancer (mCRPC), demonstrating that immune intervention can alter disease history but requires context‐dependent strategies. ICI failure therefore reflects a deeper mismatch between therapeutic mechanism and tumour biology, rather than drug selection or trial design alone. Current approaches largely extrapolate from other tumour types through combinations with androgen deprivation therapy, chemotherapy, or targeted agents [2]. As ~95% of patients are not currently eligible for ICIs, future progress will depend on prostate‐specific immune checkpoints and strategies tailored to this microenvironment.

If conventional immunotherapy is unlikely to succeed in its current form, what are the most promising directions for the next decade? Three emerging strategies stand out: focal therapies as systemic immunomodulators, antibody–drug conjugates (ADCs), and T‐cell engagers (TCEs).

First, although focal therapies have historically been regarded as purely local interventions, they are increasingly being reconceptualised as systemic immunomodulators. Techniques such as high‐intensity focused ultrasound, cryotherapy, and irreversible electroporation induce controlled tumour cell death within the prostate. Crucially, this process can trigger immunogenic cell death, leading to the release of tumour‐associated antigens and damage‐associated molecular patterns into the tumour microenvironment. In this context, focal therapy may function as an in situ vaccine, promoting antigen presentation and priming systemic anti‐tumour immune responses. Although the so‐called ‘abscopal effect’ remains rare when focal therapy is used alone, its combination with immunotherapy represents a biologically plausible strategy to convert an immune ‘cold’ tumour into a more responsive ‘hot’ state. Advances in high‐resolution imaging may further improve targeting, preserve organ function, and enable individualised integration of focal therapy into multimodal treatment.

Second, ADCs are rapidly gaining momentum as a targeted therapeutic platform capable of overcoming both antigen heterogeneity and systemic toxicity. Unlike traditional cytotoxic therapies, ADCs combine tumour‐specific targeting with potent payload delivery to provide a rational approach to precision treatment [6]. However, early‐generation ADCs in prostate cancer were limited by unstable linkers, off‐target toxicity, and narrow therapeutic windows. Recent advances in linker chemistry, payload design, and antigen selection are beginning to address these limitations. A growing number of ongoing clinical trials are evaluating next‐generation ADCs targeting diverse surface proteins, including B7‐H3, CD46, Nectin‐4, prostate‐specific membrane antigen (PSMA), trophoblast cell‐surface antigen 2 (TROP‐2), six‐transmembrane epithelial antigen of the prostate 1/2 (STEAP1/2), Tissue Factor (TF), and human epidermal growth factor receptor (HER)2/3 (Table 1). Importantly, the next wave of ADC development is shifting beyond single‐target strategies toward approaches designed to overcome tumour heterogeneity and microenvironmental resistance. Dual‐targeting ADCs, such as PSMA combined with B7‐H3 or STEAP1, may broaden patient coverage and enhance tumour selectivity. These dual‐payload designs integrating complementary cytotoxic mechanisms offer a potential strategy to overcome therapeutic resistance. In parallel, innovations in linker technology including tumour‐specific or hypoxia‐responsive release systems aim to maximise intratumoral drug delivery while minimising systemic toxicity. Moreover, expanding ADC targeting beyond tumour cells to include components of the tumour microenvironment may further improve drug penetration and modulate the immunosuppressive niche. This is particularly relevant in prostate cancer, where stromal richness and immune exclusion contribute to therapeutic resistance. As these platforms mature, ADCs may emerge as a cornerstone of systemic therapy in prostate cancer.

In parallel with the development of ADCs, TCEs have emerged as another most important next‐generation immunotherapeutic platform in prostate cancer [7]. By simultaneously binding CD3 on T cells and a tumour‐associated antigen on prostate cancer cells, TCEs can bypass conventional major histocompatibility complex (MHC)‐dependent antigen presentation and directly trigger T‐cell‐mediated tumour cell killing. Early PSMA‐directed TCEs, including pasotuxizumab, JNJ‐63898081, and acapatamab, achieved PSA50 (defined as a ≥50% decline in PSA value from baseline) responses in patients with mCRPC. However, their clinical development has been hampered by a high incidence of cytokine release syndrome (CRS), antidrug antibody formation, and a lack of durable responses. In contrast, a STEAP1‐directed TCE (xaluritamig) has shown encouraging activity in patients with mCRPC. In a phase I study, 49% of PSA‐evaluable patients achieved a confirmed PSA50 response, and 28% achieved a PSA90 (defined as a ≥90% decline in PSA value from baseline) response. Although CRS occurred in 72% of patients, only 2% experienced Grade 3 CRS, indicating a lower severity than that reported with PSMA‐directed TCEs. Further phase III registration trials of xaluritamig are being planned. The experience with tarlatamab also highlights the promise and limitations of TCEs in prostate cancer. Tarlatamab is a delta‐like canonical Notch ligand 3 (DLL3) × CD3 bispecific TCE with clear activity in small‐cell lung cancer and has also been evaluated in neuroendocrine prostate cancer (NEPC). In the DeLLpro‐300 trial, tarlatamab showed preliminary antitumor activity, with an overall objective response rate (ORR) of 10.5% [8], lower than the 24% ORR reported with xaluritamig. This difference may reflect the relatively high and tumour‐enriched expression of STEAP1, whereas NEPC is heterogeneous and DLL3 expression varies across lesions and over time. Consistent with this, the ORR of tarlatamab increased to 22.2% among patients with DLL3‐positive tumours, suggesting that the modest activity observed in the overall population may partly reflect insufficient biomarker enrichment. Future studies may therefore need to incorporate DLL3 expression as an eligibility or enrichment criterion. Many patients with NEPC also have aggressive disease and may have impaired T‐cell fitness after multiple prior lines of therapy. Additional factors may include greater immune exclusion in NEPC and unoptimised dosing. Collectively, these findings underscore that TCE efficacy depends not only on target expression, but also on antigen density, tumour heterogeneity, immune contexture, treatment timing, and biomarker‐driven patient selection.

Taken together, these insights point toward a broader paradigm shift in prostate cancer therapy. The next decade is unlikely to be defined by incremental improvements in checkpoint inhibition. Instead, progress will depend on the integration of multiple complementary strategies, including biologically informed local therapies, targeted drug delivery, and precision treatment. In this emerging framework, treatment is no longer viewed as a single‐modality intervention but as a coordinated and multimodal approach tailored to the biological characteristics of each patient's disease [9].

In conclusion, the limited success of ICIs in prostate cancer reflects a fundamental misalignment between therapeutic strategy and tumour biology. Overcoming this challenge will require moving beyond conventional paradigms and embracing innovative approaches that address the unique immunological features of the prostate. The emergence of immunomodulatory focal therapies and next‐generation ADCs and TCEs offers a compelling path forward. As the field transitions to a multimodal precision era, the ultimate goal is not only to improve survival but also to achieve durable disease control with minimal toxicity.

Disclosure of Interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author Contributions

Conception of the work, data collection, wrote and revised the paper: Chuzhong Wei, Qiang Wei, and Shi Qiu. All authors contributed to the work and approved the final submitted version.

Funding

This work was supported by National Natural Science Foundation of China (Grant number: 82170784, 82370775, 82503729), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD23001), the Programs from Science and Technology Department of Sichuan Province (2026NSFSC1901, 2025ZNSFSC0746), Chengdu Science and Technology Program (2024‐YF05‐00475‐SN), National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z2024LC007), Postdoctoral Fellowship Program of CPSF (GZC20241158), and Qimingxing Research Fund for Young Talents, West China Hospital, Sichuan University (HXQMX0059).

Ethics Approval and Consent to Participate

Not applicable.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.