BNT324-03: Phase 3, randomized, open-label trial of BNT324/DB-1311, a B7H3 ADC, versus docetaxel in patients with taxane-naïve metastatic castration-resistant prostate cancer (mCRPC).

Abstract

TPS5137 Background: B7H3 is highly expressed in various human cancers, including mCRPC, and overexpression is associated with a poor patient prognosis. BNT324/DB-1311 is an investigational B7H3 ADC comprised of a topoisomerase-I-inhibitor-based payload with a cleavable linker and a drug-to-antibody ratio of ~6 that received FDA Fast-Track Designation for previously treated CRPC. A phase 1/2 study (DB-1311-O-1001, NCT05914116) is currently enrolling several prostate cancer cohorts: post Lutetium-177 [¹⁷⁷Lu]-PSMA-617 radioligand (RLT) (Lu 177-RLT) mCRPC, taxane-naïve mCPRC, and castration-sensitive prostate cancer (CSPC) with suboptimal PSA response, with patients receiving BNT324/DB-1311 alone or with abiraterone or enzalutamide. This study has reported encouraging activity (median radiographic PFS 11.3 months) and a manageable safety profile in heavily pretreated mCRPC (Parsonson A, ASCO 2025 #5015), and in Lu 177-RLT pretreated mCRPC (Stein M, ASCO GU 2026 #176). The treatment landscape of mCRPC has been evolving. As first use of an androgen receptor pathway inhibitor (ARPI) has shifted to the mCSPC setting, more patients will receive docetaxel in early-line mCRPC. The use of Lu 177-RLT in taxane-naïve mCRPC has been increasing; however, outcomes with subsequent docetaxel appear suboptimal. Docetaxel remains the first-line treatment option for symptomatic or rapidly progressive mCRPC, but outcomes are poor. Overall, there is a high unmet need for novel effective and better tolerated treatment options in the post-ARPI and emerging post-RLT settings. Methods: BNT324-03 is an open-label, randomized, Phase 3 trial (NCT07365995) designed to determine the efficacy and safety of BNT324 compared with docetaxel in patients ( > 18 years, ECOG PS 0–1) with mCRPC previously treated with 1 or 2 prior ARPIs. Patients may have received prior Lu 177-RLT but must not have received prior taxane for mCRPC (allowed in mCSPC if ≥6 months since completion without disease progression). Prior treatment with B7H3 targeted therapy is not allowed. Approximately 736 patients will be randomized 1:1 to receive either BNT324 or docetaxel (+ prednisone/prednisolone). Unless there is unacceptable toxicity or withdrawal of consent, BNT324 will be administered until PCWG3-modified RECIST v1.1-defined progressive disease and docetaxel will be administered for up to 10 cycles. Randomization will be stratified by prior Lu 177-RLT, prior taxane use, and site of metastasis. The dual primary endpoints are to assess the efficacy of BNT324 in terms of radiographic PFS and OS when compared with docetaxel. Secondary endpoints include time to first subsequent therapy, ORR and DOR by BICR, time to pain progression, time to first symptomatic skeletal-related event, PSA response and time to PSA progression, and safety. Enrollment is ongoing globally. Clinical trial information: NCT07365995 .