(UroToday.com) The 2026 American Society of Clinical Oncology (ASCO) Annual Meeting was host to a prostate, testicular, and penile cancers poster session. Dr. Johann S. De Bono presented BNT324-03, an ongoing, randomized, open-label phase III study evaluating the DLL3-targeted bispecific antibody BNT324/DB-1311 versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on a novel hormonal agent (NHA). BNT324/DB-1311 is being developed as a potential first-in-class immunotherapeutic strategy targeting delta-like ligand 3 (DLL3), a protein highly expressed in neuroendocrine prostate cancer and increasingly recognized in treatment-emergent aggressive prostate cancer phenotypes.
DLL3 has emerged as a promising therapeutic target in advanced prostate cancer. While normal tissue expression is limited, DLL3 expression has been identified in approximately one-third of mCRPC tumors and appears enriched in patients with treatment-emergent neuroendocrine differentiation. The rationale for targeting DLL3 is supported by findings from the phase 1/2 BNT324-01 study, which demonstrated encouraging antitumor activity and a manageable safety profile in heavily pretreated patients with advanced solid tumors, including mCRPC.
Among patients with mCRPC treated in BNT324-01, objective responses were observed and durable disease control was achieved in a subset of patients. The poster highlights encouraging efficacy signals in the DLL3-positive population, with improvements in both progression-free and overall survival outcomes compared with historical expectations. These findings provided the basis for advancement into the phase III BNT324-03 trial.
BNT324-03 is an international, randomized, open-label study designed to compare BNT324/DB-1311 with docetaxel in patients with mCRPC who have progressed following treatment with an androgen receptor pathway inhibitor. Approximately 470 patients will be randomized 1:1 to receive:
- BNT324/DB-1311 administered intravenously every 3 weeks
- Docetaxel 75 mg/m² intravenously every 3 weeks
Patients in both treatment groups continue androgen deprivation therapy throughout study participation.
Key eligibility criteria include:
- Histologically confirmed adenocarcinoma of the prostate
- Metastatic castration-resistant prostate cancer
- Progression during or after treatment with an NHA
- ECOG performance status 0–1
- Adequate organ function
- Availability of tumor tissue for DLL3 biomarker assessment
The study specifically enrolls patients who are taxane-naïve in the mCRPC setting and are considered appropriate candidates for docetaxel therapy.
Key exclusion criteria include:
- Prior chemotherapy for mCRPC
- Prior DLL3-directed therapy
- Active or untreated central nervous system metastases
- Significant cardiovascular disease
- Active autoimmune disease requiring systemic immunosuppression
Patients are stratified according to:
- Presence versus absence of visceral metastases
- Prior use of androgen receptor pathway inhibitors
- Geographic region
The primary endpoint is radiographic progression-free survival (rPFS) assessed by blinded independent central review according to PCWG3-modified RECIST v1.1 criteria.
Key secondary endpoints include:
- Overall survival (OS)
- Objective response rate (ORR)
- Duration of response (DOR)
- Time to PSA progression
- PSA response rate
- Safety and tolerability
- Patient-reported outcomes
The study includes extensive translational and biomarker analyses, including prospective assessment of DLL3 expression and correlation with clinical outcomes. Investigators aim to better define the prevalence and prognostic significance of DLL3 in mCRPC and identify patient populations most likely to benefit from DLL3-targeted therapy.
The poster also summarizes results from the phase 1/2 BNT324-01 program that informed development of BNT324-03. In the efficacy-evaluable mCRPC population, BNT324/DB-1311 demonstrated antitumor activity with objective responses and disease stabilization observed across multiple dose levels. Kaplan-Meier analyses presented for progression-free survival and overall survival suggested encouraging durability of benefit, while the safety profile was characterized predominantly by manageable treatment-related adverse events. Cytokine release syndrome was reported but was generally low grade and manageable with established mitigation strategies.
At the time of presentation, BNT324-03 was actively recruiting patients globally across North America, Europe, Asia-Pacific, and additional international regions. Enrollment is ongoing at multiple participating centers worldwide.
BNT324-03 represents one of the first phase III studies evaluating DLL3-directed immunotherapy in prostate cancer. By comparing BNT324/DB-1311 directly against docetaxel in patients progressing after NHA therapy, the study will determine whether DLL3-targeted treatment can improve outcomes in a population with significant unmet need and potentially establish a new biomarker-driven therapeutic approach for advanced prostate cancer.
Presented by: Johann S. De Bono, MD, MSc, PhD, FRCP, Regius Professor of Cancer Research and a Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK
Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center, Tucson, AZ – @rksayyid on X during the American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL between May 29th and June 1st, 2026