DB-1311/BNT324 (a novel B7H3 ADC) in patients with heavily pretreated castrate-resistant prostate cancer (CRPC).

Background: There is a high unmet need for effective therapy for patients (pts) with heavily pretreated CRPC. B7H3 ADCs have reported early clinical activity in CRPC, including DB-1311/BNT324, an investigational B7H3 ADC that received FDA Fast-Track Designation for previously treated CRPC. Methods: This phase 1/2 study (NCT05914116) enrolled pts with advanced/metastatic solid tumors, including previously treated CRPC (post docetaxel/hormonal therapy). Dose optimization cohorts randomized pts to receive 6 mg/kg or 9 mg/kg Q3W DB-1311/BNT324 until progression or unacceptable toxicity. The primary endpoints were objective response rate (ORR, based on investigator assessment per RECIST 1.1 and PCWG3 criteria) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR) and radiographic progression-free survival (rPFS). Results: As of 3 Jan 2025, of 393 pts treated with DB-1311/BNT324, there were 65 pts with CRPC. Median age was 71 years (range 45–84), 49%/34%/14% were White/Asian/Black, 32%/37%/31% from Australia/USA/East Asia, 71% had ECOG PS 1, 29% had bone only disease. Median number of prior lines was 3 (range 1–14) and 28% had ≥5 prior lines. Most pts received prior docetaxel (93.8%) and hormonal therapy (96.9%); other therapies included PARP inhibitors (PARPi, 15.4%), Lutetium-177 (Lu-177, 15.4%), immunotherapy (IO, 13.8%). Among 43 response-evaluable pts (measurable disease at baseline per RECIST 1.1), best overall response was PR in 12 pts and SD in 29 pts for an unconfirmed ORR of 27.9% (95% CI 15.3, 43.7; 12/43, 8 confirmed) and DCR of 95.3% (95% CI 84.2, 99.4). Median DOR was not reached (95% CI 4.2, ne). After a median follow-up of 5.7 months (m) (range 0.6–16.0), median rPFS (N=57) was 8.3 m (95% CI 6.7, ne) with a 6-m rate of 86.6% (95% CI 67.8, 94.8). Outcomes were similar by dose (6 mg/kg [ORR 26.3%, DCR 100%, 6-m rPFS rate 88.7%], 9 mg/kg [ORR 29.2%, DCR 91.7%, 6-m rPFS rate 80.0%]), by line of treatment (≤3L [ORR 33.3%, DCR 77.8%], ≥4L [ORR 26.7%, DCR 100%]), and by type of prior treatment (ORR/DCR: Lu-177 [25.0%/100%], IO [33.3%/100%], albeit lower for PARPi [16.7%/100%]). The CRPC safety profile (N=65) is supported by the safety in the larger overall population (N=393). Treatment-related adverse events (TRAEs) occurred in 56 (86.2%) and 343 (87.3%) pts and were Grade ≥3 (G≥3) in 26 (40.0%) and 156 (39.7%) pts, respectively. TRAEs led to dose reduction in 8 (12.3%) and 39 (9.9%) pts, to discontinuation in 4 (6.2%) and 23 (5.9%) pts, and to death in 0 and 2 (0.5%) pts, respectively. Nausea and hematological events, primarily G1–2, were the most common TRAEs. Hematological TRAEs occurred more frequently with 9 mg/kg vs 6 mg/kg, both in the CRPC and overall populations. Conclusions: DB-1311/BNT324 showed encouraging efficacy and a manageable safety profile in heavily pretreated CRPC and is currently being evaluated in post Lu-177 CRPC and in taxane-naïve CRPC. Clinical trial information: NCT05914116