A Phase Ib Trial of Enzalutamide with Oral Decitabine/cedazuridine in Metastatic Castration-Resistant Prostate Cancer (CRPC).

TPS252 Background: Exposure to androgen receptor (AR)-pathway inhibitors like enzalutamide (Enza) is associated with the emergence of AR low subclones that coexist with AR high subclones in CRPC. These AR low cells, including those in neuroendocrine prostate cancer (NEPC), are not critically dependent on AR signaling for survival and proliferation. Alterations in RB1, TP53, and PTEN tend to co-occur in human AR low CRPC and NEPC. These as well as tumors from triple knockout mouse models demonstrate altered expression of epigenetic reprogramming factors, including consistent upregulation of DNA methyltransferase 1 (DNMT1). 1 DNA methylation in CpG islands is increased in human CRPC/NEPC as well as CRPC xenograft models indicating that elevated DNMT activity may correlate with resistance to AR-targeted therapies. 2 Treatment with decitabine (Dec), a DNMT inhibitor, delays the development of AR low NEPC and increases Enza sensitivity in murine models of prostate cancer. 2 Cedazuridine (Ced), an inhibitor of cytidine deaminase which degrades Dec, increases its oral bioavailability. We hypothesize that the combination of Enza with oral Dec/Ced will reverse acquired therapeutic resistance in AR low CRPC/NEPC tumors where DNMT activity is aberrantly elevated by RB1 and/or TP53 loss. Methods: This is a single-center, open-label, non-randomized, dose escalation/de-escalation phase Ib study of fixed drug combination (FDC) oral Dec/Ced [ASTX727, FDC 35mg/100mg] with Enza (160mg/day) in patients with Enza-refractory mCRPC. Three dose levels of ASTX727 will be evaluated using a 3+3 study design - FDC of ASTX727 will be administered on either 4 (cohort 1), 3 (cohort -1) or 5 (cohort 2) consecutive days of a 28-day cycle. The primary endpoint will be safety with determination of the maximum tolerated dose (MTD) and recommended phase II dosing (RP2D). We plan to include an expansion cohort of 10 patients at the MTD, eligibility for which will be restricted to patients with genomic alterations in RB1 and/or TP53. Correlative studies will be aimed at 1) Evaluation of DNMT1 levels and DNA methylation patterns, 2) Analysis of circulating tumor DNA to monitor changes in DNA methylation and emergence of AR low CRPC/NEPC, 3) Evaluation for tissue markers of neuroendocrine lineage, RB1 loss and/or TP53 mutations to examine for treatment emergent AR low CRPC/NEPC and its correlation with RB1 and/or TP53 loss. The study is currently open with 6 patients enrolled. 1) McCabe MT et al. Cancer Res. 2005;65(9):3624-32. 2) Ku SY et al. Science. 2017;355(6320):78-83. 3) Zorn CS et al. Clin Cancer Res. 2007;13(7):2136-43. Clinical trial information: NCT05037500 .