A phase 1b dose escalation study of FOR46, a novel antibody-drug conjugate targeting a tumor-specific epitope of CD46, in combination with enzalutamide (Enza) in patients with metastatic castration resistant prostate cancer (mCRPC).

5066 Background: FOR46 is an MMAE-containing antibody-drug conjugate (ADC) targeting a tumor-specific conformational epitope on the extracellular domain of CD46 on prostate cancer and other cancer tissues in a lineage independent fashion. A prior phase 1, first-in-human trial of FOR46 demonstrated encouraging preliminary activity in mCRPC. In pre-clinical models, androgen receptor blockade with enzalutamide enhances CD46 epitope expression and achieves additive activity in combination with the CD46 ADC. We sought to evaluate the combination of FOR46 plus enza in mCRPC patients (pts). Methods: Pts with mCRPC with progression on ≥ 1 androgen receptor pathway inhibitor (ARPI) were enrolled. No prior chemotherapy for mCRPC was allowed. A 3+3 dose escalation design was utilized with a starting dose of FOR46 of 1.8 mg/kg adjusted body weight (ABW) in combination with enza 160 mg/day. Dose escalation was explored with and without prophylactic granulocyte colony-stimulating factor (G-CSF) support. The primary endpoint was determination of the maximally tolerated dose (MTD) of FOR46 in combination with enza. A baseline CD46-directed PET imaging probe utilizing the same antibody backbone as FOR46 ( 89 Zr-DFO-YS5) was obtained in a subset of pts. Results: Seventeen pts were enrolled. Median age was 71 years (range 58 – 91) and median PSA was 43.8 ng/mL (range 2.1 – 379.6) at study entry. Twelve pts (70.6%) had ≥ 2 lines of prior ARPI. The median duration of treatment was 5.0 months (range 1– 18). Dose-limiting toxicities (DLTs) included grade 4 neutropenia at a dose of 2.1 mg/kg without G-CSF (n = 2), grade 4 hyponatremia at 2.4 mg/kg (n = 1), and grade 3 elevated transaminases at 2.4 mg/kg (n = 1). The MTD of FOR46 was established at 2.1 mg/kg ABW, with primary G-CSF prophylaxis, in combination with enza 160 mg/day. Grade ≥ 3 treatment-related adverse events (trAEs) were observed in 29.4% of pts. The most common trAEs of any grade were fatigue (n = 11, 64.7%), peripheral sensory neuropathy (n = 8, 47.1%), elevated transaminases (n = 3, 17.6%), alopecia (n = 4, 23.5%), decreased appetite (n = 7, 41.2%), neutropenia (n = 3, 17.6%), and weight loss (n = 3, 17.6%). Grade 2 neuropathy was observed in 2 patients (11.8%). Preliminary anti-tumor activity was observed with PSA declines in 13/16 (81.3%) of evaluable pts, and a disease control rate (stable disease ≥ 6 months) of 41.2%. 89 Zr-DFO-YS5 demonstrated tumor uptake on whole body PET with pharmacokinetics typical for an IgG radiopharmaceutical. Conclusions: In combination with enza, the established MTD of FOR46 with primary G-CSF prophylaxis was safe and demonstrated preliminary evidence of efficacy. 89 Zr-DFO-YS5 PET demonstrates tumor-specific uptake and will be employed in the ongoing Phase 2 portion of the study as a potential predictive biomarker of response. Clinical trial information: NCT05011188 .