Galeterone monotherapy in advanced pancreatic ductal adenocarcinoma: Results from a phase two trial.

744 Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited treatment options. Dysregulated MAPK and PI3K signaling in PDAC activates the eukaryotic translational initiation complex, promoting cell growth, chemoresistance and metastatic spread (PMID 25593033). Galeterone, a novel steroidal anti-androgen, downregulates critical mediators of this complex including Mnk1/2 and phosphorylated eIF4E, thereby blocking epithelial-to-mesenchymal transition and NF-kB activity. In-vitro, galeterone exhibits anti-tumor activity both alone and in combination with gemcitabine and slows tumor growth in a MiaPaCa-2 xenograft murine model (PMID 28881737). We present results of the monotherapy arm from an ongoing phase two trial evaluating galeterone +/- gemcitabine for patients with advanced PDAC. Methods: Patients with locally advanced or metastatic PDAC, an ECOG performance status of 0-2 and adequate organ function, who progressed on two prior lines of systemic therapy were eligible. Galeterone was administered orally at 2550mg daily and gemcitabine intravenously at 1000mg/m 2 weekly for three weeks on 28-day cycle. The primary endpoint was radiographic response rate per RECIST v1.1 and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. We used a Simon’s optimal two-stage design with a null hypothesis of p 0 =0.05 and one-sided alternative of p 1 =0.20 with an early stopping rule for futility in each arm. Due to poor accrual and no signal of activity, the galeterone alone arm closed after enrollment of four patients. Results: Four patients were evaluable for the primary endpoint. Ages ranged from 43 to 68. Two patients were male and two were female. Two patients were white and two were black; one patient was Hispanic/Latino. All patients had ECOG PS of 1. No patients had a radiographic response; the best response was progressive disease (PD). PFS from cycle 1 day 1 ranged from 0.9 – 1.7 months and overall survival between 1.8 – 3.6 months. The only treatment-related adverse events (TRAEs) were grade 1 dizziness and grade 3 fatigue in one patient each. There were no treatment-related serious adverse events. No patients required dose modification or discontinued due to TRAEs. Conclusions: Galeterone showed no clinical activity, but with a favorable safety profile, as a single-agent in heavily pre-treated patients with advanced PDAC. Activation of the Mnk-eIF4E axis mediates chemoresistance in PDAC and galeterone may prove more efficacious with gemcitabine. This combination arm is currently open to enrollment. Clinical trial information: NCT04098081 . Clinical outcomes with galeterone monotherapy in PDAC. Pt # Age Prior lines of Therapy Time on Treatment (days) Best Response PFS (months) OS(months) 1 68 4 46 PD 1.5 3.6 2 59 2 54 PD 1.7 3.8 3 55 2 47 PD 1.4 2 4 43 2 35 PD 0.9 1.8