Phase I/II safety and pharmacokinetic (PK) study of ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase I results of a Prostate Cancer Clinical Trials Consortium study.

• DOI: 10.1200/jco.2012.30.5_suppl.43
• Publication Date: 2017-02-23T18:53:34Z
• Authors: Dana E. Rathkopf; Daniel Costin Danila; Michael J. Morris; Susan F. Slovin; Jill Elise Steinb...; Gabrielle Arauz; Peter J. Rix; Edna Chow Maneval; Isan Chen; Josef J. Fox; Martin Fleisher; Steven M. Larson; Howard I. Scher
• Keywords: Bicalutamide

43 Background: In CRPC, androgen receptor (AR) overexpression is associated with resistance to first-generation anti-androgen therapy such as bicalutamide. ARN-509 a novel small molecule AR antagonist that impairs nuclear translocation and binding DNA, inhibiting tumor growth promoting apoptosis, no partial agonist activity. Preclinical data shows binds 5-fold greater affinity than bicalutamide, induces regression in hormone-sensitive CRPC xenograft models. Methods: this open-label, Phase 1/2 study, mCRPC patients received orally on continuous daily dosing schedule. 1 , 7 doses (30, 60, 90, 120, 180, 240, 300 mg) were tested using standard 3x3 dose escalation criteria assess safety, PK, determine the recommended 2 (RP2D). Preliminary anti-tumor activity was assessed by PSA kinetics, radiographic responses, circulating cells (CTCs), FDHT-PET imaging. Results: Twenty-four (median age 68 yrs, Gleason Score 8; prior docetaxel 13%) enrolled. The most common Grade 1-2 treatment-related adverse events fatigue (38%), nausea (29%), pain (24%). There only 3 event (abdominal pain) at mg, possibly related higher pill burden, which led an additional being enrolled highest further limiting toxicities. PK shown be linear dose-dependent. Twelve (55%) had ≥ 50% declines. To date, have discontinued study due progression, longest patient still for more year. imaging demonstrated blockade 4 weeks across multiple levels. Based preclinical assessment of maximum efficacious dose, promising all doses, 240 mg selected RP2D. Conclusions: safe well tolerated, preliminary based pharmacodynamic evidence antagonism. portion will enroll up 90 treatment-naïve non-metastatic mCRPC.