Abstract
ABSTRACT Aim: Exportin 1 (XPO1) is a nuclear export protein whose inhibition leads to the nuclear accumulation of tumor suppressor proteins (TSPs). XPO1 is overexpressed in many tumors including PrCa. Selinexor is an oral SINE that activates ≥10 TSPs with potent activity against various cancers including CRPC. Methods: Selinexor mediated nuclear localization of TSP & apoptosis induction was evaluated in CRPC cell lines & in pt derived tumors in vitro & xenografts (po 10 mg/kg QoDx3). Oral selinexor was given at 8 doses (twice weekly) 28-day cycle as part of an ongoing Phase 1 study in advanced solid tumors (KCP-330-002, NCT01607905). Response evaluation was every 2 cycles (CT & bone scans). Pts had progressing, chemotherapy refractory CRPC on study entry. Results: Selinexor induced nuclear accumulation of p53, p21, FOXO3a, & p27 in PrCa cells as well as nuclear retention of AR in androgen depleted PrCa cells. Oral selinexor showed strong (∼100%) inhibition of tumor growth in pt derived CRPC xenografts. 11 pts with CRPC (median 65 years; ECOG PS 0/1: 5/6; median prior regimens: 5.5 (range 2-10) received selinexor across 3 dose levels (35-65 mg/m2) & 8 were evaluable for response. All pts received taxanes & 5 pts either abiraterone and/or enzalutamide prior to selinexor. Grade 4 toxicities include leukopenia in 1 pt. The most common AEs (Grade 1/2/3) include: fatigue (18%/27%/18%), nausea (27%/18%/0%), anorexia (18%/27%/0%) & thrombocytopenia (9%/18%/9%). Supportive care with dexamethasone (9 pts, 8-24 mgs/weekly or equivalent), appetite stimulants & anti-emetics improved constitutional symptoms. Pharmacokinetics & pharmacodynamics showed dose-dependent increases in Cmax/AUC0-inf & in XPO1 mRNA. PSA & pain reductions were observed, 7 of 8 evaluable pts achieved prolonged SD (114-300+ days). 1 pt progressed during treatment. Conclusions: Selinexor shows potent activity in preclinical models of CRPC with activation of TSPs & retention of nuclear AR. Single agent oral selinexor induced long-term disease control in pts with chemotherapy-resistant CRPC. Future studies in pts with CRPC are planned in 2014. Disclosure: All authors have declared no conflicts of interest.
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