758O - Selinexor (KPT-330), an oral, selective inhibitor of nuclear export (SINE) shows anti-prostate cancer (PrCa) activity preclinically & disease contr...

Date 29 September 2014
Event ESMO 2014
Session Genitourinary tumours, prostate 2
Topics Drug Development
Prostate Cancer
Translational Research
Presenter Hemchandra Mahaseth
Citation Annals of Oncology (2014) 25 (suppl_4): iv255-iv279. 10.1093/annonc/mdu336
Authors H. Mahaseth1, S.N. Maity2, N.Y. Gabrail3, A. Mahipal4, J.F. Gericitano5, S. Shacham6, T. Rashal7, B. Klebanov7, R. Carlson6, E. Shacham7, D. Vincent8, M. Kauffman7, A.F. Shields9, M.R. Mirza6, J.C. Araujo10
  • 1., Karmanos Cancer Center, Wayne State University, 48201 - Detroit/US
  • 2., Memorial Sloan Kettering Cancer Center, New York/US
  • 3., Gabrail Cancer Center, Canton/US
  • 4Medical Oncology, Moffitt Cancer Center, 33612 - Tampa/US
  • 5., Memorial Sloan Kettering Cancer, New York/US
  • 6., Karyopharm Therapeutics, Inc., 01760 - Natick/US
  • 7., Karyopharm Therapeutics, 01760 - Natick/US
  • 8., Ozmosis Research, Toronto/CA
  • 9Oncology, Karmanos Cancer Center, Wayne State University, 48201 - Detroit/US
  • 10., MD Anderson Cancer Center, Houston/US

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.