149 Background: FOR46 is a monomethyl auristatin E antibody-drug conjugate targeting a tumor-specific epitope of CD46 that is highly expressed in mCRPC. In pre-clinical models, CD46 cell surface expression is upregulated following treatment with androgen receptor pathway inhibitors (ARPIs), enhancing tumor cell sensitivity to FOR46. We sought to determine the safety and efficacy of FOR46 in combination with enza in mCRPC patients (pts). Methods: Eligible mCRPC pts had progression on ≥ 1 ARPI and no prior chemotherapy for CRPC. The Phase (Ph) 1b dose escalation study to assess adverse events and select a recommended Ph 2 dose (RP2D) utilized a starting dose of FOR46 at 1.8 mg/kg adjusted body weight (ABW) q3 weeks in combination with enza 160 mg daily. The Ph 2 primary endpoint was composite response rate defined as PSA50 response or objective response by RECIST v1.1. Baseline CD46-targeted 89 Zr-DFO-YS5 PET imaging was mandatory in Ph 2 as an exploratory biomarker. Results: 44 pts were enrolled from 3/2022 to 7/2025. 6 pts remain on treatment as of 9/1/25. Median age at study entry was 72 (range 56-93), median baseline PSA was 31.2 ng/mL (range 0.8-1147.7 ng/mL), 61% of pts received ≥ 2 prior ARPIs, and 27% had visceral metastases. In Ph 1b, 17 evaluable pts were enrolled. The RP2D was established at FOR46 2.1 mg/kg ABW with G-CSF primary prophylaxis, in combination with enza 160 mg daily. In the overall study cohort (Ph 1b + 2), the median treatment duration was 3.5 mos (range 0.0-17.8 mos). The composite response rate was 21% (8/39 evaluable pts), with PSA50 response rate of 22% (8/37 evaluable pts) and objective response rate of 9% (1/11 evaluable pts). The median radiographic progression-free survival (rPFS) was 6.6 mos (95% CI 6.1-14.4 mos). Fewer lines of prior ARPI was associated with longer median rPFS 10.1 mos (1 prior ARPI) vs. 6.6 mos (2 prior ARPIs) vs. 5.1 mos (3 prior ARPIs), nominal p=0.048 and higher PSA50 response rate 40% (1 prior ARPI), 10.5% (2 prior ARPIs), 0% (3 prior ARPIs). Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 8 pts (19.5%; n=2 for neutropenia, anemia, and hyponatremia). The most common any-grade TRAEs were fatigue (68%), peripheral neuropathy (56%), anorexia (41%), and dysgeusia (32%). 37% of pts discontinued treatment for TRAEs (17% for neuropathy; 11% for infusion reaction). 89 Zr-DFO-YS5 PET demonstrated tumor uptake in both bone and soft tissue lesions. Conclusions: FOR46 in combination with enza demonstrates anti-tumor activity in mCRPC pts, particularly for pts with one prior line of ARPI. The safety profile was consistent with the prior Ph 1 FOR46 monotherapy study. Cumulative toxicities, especially neuropathy, were dose-limiting for some pts. Predictive imaging and molecular biomarkers are under investigation. Clinical trial information: NCT05011188 .
Cai et al. (Sun,) studied this question.
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