Objective response of the dual CYP17-Lyase (L) inhibitor / androgen receptor (AR) antagonist, VT-464, in patients with CRPC.
273 Background: VT-464 is an oral, CYP17-L inhibitor and non-clinically an antagonist of the AR and its variants associated with clinical resistance to enzalutamide (ENZ) and abiraterone (AA). The safety, tolerability and initial pharmacodynamic effects (tumor responses, PSA and testosterone (T) decreases) of VT-464 given without steroid supplementation either bid with food or QD at night with dinner were evaluated in the Phase (Ph) 1/2 studies INO-VT-464-CL-001 (NCT02012920) and INO-VT-464-CL-004 (NCT02361086), respectively. Patients were either treatment-naïve (TN), or had failed AA or ENZ or AA/ENZ/chemotherapy (at least 2 out of the three). Preliminary objective response results from both studies are presented herein. Methods: Target lesions were assessed at baseline and during therapy using CT or MRI. Target lesion responses were categorized as a complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) using RECIST 1.1. Patients with ≥ 1 target lesion and ≥ 1 post-baseline scan following VT-464 BID (INO-VT-464-CL-001) or QD (INO-VT-464-CL-004) were included in the analysis. Results are reported through a data cutoff of 01 Sep 2015. Results: Combined, 23 patients (8 TN, 4 AA, 7 ENZ, 4 AA/ENZ/chemotherapy) from both Ph 1/2 studies had ≥ 1 target lesion and ≥ 1 post-baseline scan. Of 15 patients included who were treated BID (Study 001), 1 had PD, 12 had SD and 2 had a PR. Of 8 patients who were treated QD (Study 004), 2 had PD, 5 had SD and 1 had a PR. No patient had a CR in either study. For the 3 patients with PRs one patient had a prior response to ENZ but failed taxane-based chemotherapy, another was de novo resistant to ENZ, while the third was TN. For the 3 PRs, one was confirmed with a repeat scan 8-weeks later and the others have repeat scans pending. Conclusions: Potent and selective CYP17-L inhibition, PSA reductions, and objective tumor responses in TN and ENZ-failure patients have been observed with oral VT-464 administered bid (de Bono et al, GU ASCO 2015) or QD (Shore et al, GU ASCO 2016). Preliminary results demonstrate that the QD regimes are as efficacious as BID regimens. All Ph 2 CRPC studies now utilize a 750 mg QD regimen. Clinical trial information: NCT02012920 and NCT02361086.
Nordquist, LT; Shore, ND; De Bono, JS; Gupta, S; Berry, WR; Gillessen, S; Liu, G; Vogelzang, NJ; Efstathiou, E; Fleming, MT; George, DJ; Araujo, JC; Zhang, J; Kurman, MR; Eisner, JR; Moore, WR
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