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Seek and Treat: Targeting B7-H3 in Prostate Cancer

While immune checkpoint inhibition has reshaped the treatment of multiple solid tumors, prostate cancer has remained largely refractory to therapies directed against PD-1, PD-L1, or CTLA-4. In contrast, B7-H3 is highly and consistently expressed in prostate cancer, including advanced and castration-resistant stages, and is implicated in both immune evasion and intrinsic tumor aggressiveness, making it an especially compelling therapeutic target.

B7-H3 is a member of the B7 family of immunoregulatory proteins and is minimally expressed in most normal tissues, yet it is markedly upregulated in many malignancies. In prostate cancer, transcriptomic and immunohistochemical studies have demonstrated B7-H3 expression in the vast majority of primary tumors and metastatic lesions, including more than 90% of metastatic castration-resistant prostate cancer (mCRPC) biopsies.1 Notably, B7-H3 expression often exceeds that of other immune checkpoints such as PD-L1, CTLA-4, and TIM-3, which may partly explain the limited efficacy of existing checkpoint inhibitors in this disease.1 High B7-H3 expression has been associated with adverse clinicopathologic features, including higher Gleason grade, advanced tumor stage, increased PSA levels, and poorer clinical outcomes, supporting its role as both a prognostic marker and a therapeutic target.2

Functionally, B7-H3 contributes to prostate cancer progression through immune-dependent and immune-independent mechanisms. From an immunologic perspective, B7-H3 acts as an inhibitory regulator of antitumor immunity, suppressing cytotoxic T-cell and natural killer cell activity within the tumor microenvironment.3 This is particularly relevant in prostate cancer, which is characterized by a relatively “cold” immune milieu with low baseline T-cell infiltration. Beyond immune suppression, B7-H3 has been shown to promote tumor cell proliferation, migration, invasion, angiogenesis, and resistance to therapy through activation of oncogenic signaling pathways.4 Genetic or pharmacologic disruption of B7-H3 in preclinical prostate cancer models results in slowed tumor growth and partial reversal of immune suppression, further validating its functional importance.5

Interest in B7-H3 as a therapeutic target in prostate cancer has been steadily building over the past several years. I previously highlighted the promise of B7-H3 targeting in a UroToday commentary, emphasizing its high prevalence in prostate cancer and early clinical efforts aimed at exploiting this biology.6 At that time, however, the clinical landscape was relatively limited, with only a small number of ongoing trials and modest human efficacy data. Since that publication, the field has evolved rapidly, with a substantial expansion in the overall number and maturity of B7-H3-directed clinical programs, particularly for advanced prostate cancer.

Early clinical experience with B7-H3-directed therapies has reinforced this biological rationale. Enoblituzumab, a humanized Fc-engineered monoclonal antibody targeting B7-H3, was evaluated in a phase 2 neoadjuvant study in patients with intermediate- and high-risk localized prostate cancer. In this trial, enoblituzumab was administered prior to radical prostatectomy and was generally well tolerated, with no grade 4 adverse events and a low incidence of grade 3 toxicities. At one year following surgery, 66% of treated patients achieved an undetectable PSA; however, efficacy is difficult to determine from a non-randomized trial designed to test safety and feasibility.7

The most compelling recent data have emerged from antibody-drug conjugates (ADCs) directed against B7-H3. DB-1311 (also known as BNT324) is a B7-H3-targeted ADC conjugated to a topoisomerase I inhibitor and is currently being evaluated in a phase 1/2 trial in patients with heavily pretreated mCRPC.

Preliminary results presented at the 2025 American Society of Clinical Oncology Annual Meeting demonstrated confirmed objective responses in approximately 30% of evaluable patients.8 The safety profile was manageable, with gastrointestinal and hematologic toxicities predominating and relatively low treatment discontinuation rates. Based on these findings, DB-1311/BNT324 has received FDA Fast Track designation for mCRPC.

Additional B7-H3-directed ADCs are advancing in clinical development. Ifinatamab deruxtecan (DS-7300), which links an anti-B7-H3 antibody to a topoisomerase I payload, has demonstrated objective responses across multiple solid tumors in early-phase trials, including activity in patients with advanced prostate cancer, where confirmed RECISTv1.1 objective response rates were updated to 25%.9

Beyond antibodies and ADCs, B7-H3 is also being explored as a target for cellular immunotherapies such as chimeric antigen receptor (CAR) T cells. Preclinical studies of B7-H3-directed CAR-T cells have shown potent antigen-dependent cytotoxicity against prostate cancer models.10

Since my early UroToday Clinical Trials Portal article in 2023, the field has progressed substantially, with a growing number of clinical trials now testing B7-H3-targeted strategies with special focus on advanced prostate cancer. Please see below for some actively accruing clinical trials in this area.

Highlighted trials targeting B7-H3 for the treatment or imaging of patients with prostate cancer

  • NCT07115446 – Phase 1b study of HS-20093 (ADC to B7-H3) + HRS-5041 (PROTAC against AR) in advanced prostate cancer
  • NCT07181473 – Phase 1 study of TJ101 (ADC to B7-H3) for advanced metastatic solid tumors, including prostate cancer
  • NCT07198633 – Phase 1/2 study of QLC5508 (ADC to B7-H3) and/or QLH12016 (PROTAC against AR) in combination with other antitumor therapies for advanced prostate cancer
  • NCT06241846 – Phase 2 of YL201 (ADC to B7-H3) in patients with mCRPC
  • NCT06863272 – IDeate-Prostate02: Phase 1/2 of Ifinatamab Deruxtecan (ADC to B7-H3) based combinations or as monotherapy for mCRPC
  • NCT06925737 - IDeate-Prostate01: Randomized phase 3 of Ifinatamab Deruxtecan (ADC to B7-H3) versus docetaxel for mCRPC
  • NCT06454955 – 68GaB7H3 Affibody-BCH PET imaging of solid tumors
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Shi X, et al. Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castration-resistant prostate cancer. NPJ Precis Oncol. 2022; 6:80.
  2. Zang X, et al. B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Proc Natl Acad Sci U S A. 2007; 104:19458–19463.
  3. Picarda E, et al. Molecular pathways: Targeting B7-H3 (CD276) for human cancer immunotherapy. Clin Cancer Res. 2016; 22:3425–3431.
  4. Flem-Karlsen K, et al. B7-H3 in cancer—beyond immune regulation. Trends Cancer. 2018; 4:401–404.
  5. Benzon B, et al. Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis. Prostate Cancer Prostatic Dis. 2017; 20:28–35.
  6. Yu EY. Is B7-H3 the target we need for prostate cancer to come into the antibody drug conjugate era. UroToday. May 2, 2023.
  7. Shenderov E, et al. Neoadjuvant enoblituzumab in localized prostate cancer: a single arm, phase 2 trial. Nat Med. 2023;29:888–897.
  8. Parsonson AO, et al. DB 1311/BNT324 (a novel B7H3 ADC) in patients with heavily pretreated castrate resistant prostate cancer (CRPC). J Clin Oncol. 2025;43(16_suppl):5015.
  9. Patel MR, et al. Ifinatamab deruxtecan (I DXd; DS 7300) in patients with advanced solid tumors: Updated clinical and biomarker results from a phase I/II study. European Society of Medical Oncology 34, Supplement 2:S481 S482 (October 2023).
  10. Majzner RG, et al. CAR-T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors. Clin Cancer Res. 2019; 25:2560-2574.