Results of a phase II trial of selinexor, an oral selective inhibitor of nuclear export (SINE), in patients with metastatic castration resistant prostate cancer (mCRPC) refractory to abiraterone or enzalutamide.

Abstract

e16533 Background: Patients (pts) with abiraterone (abi) or enza (enza) refractory mCRPC typically have limited treatment options. Selinexor is a first in class SINE that specifically inhibits the nuclear export protein Exportin-1 (XPO-1) which is overexpressed in prostate cancer (PCa), leading to cytoplasmic mislocalization of tumor suppressor proteins. In preclinical models of PCa, selinexor reduced tumor growth and decreased the incidence of bone metastasis. Methods: Eligibility criteria included progressive mCRPC with primary or acquired resistance to abi, enza, or their combination. Prior chemotherapy for mCRPC was not allowed. All pts must have > 1 bone metastasis. The primary objective was radiographic progression free survival (rPFS). Results: Fourteen pts were enrolled between Oct 2014 and Oct 2016. The median age was 72 years (range 56-79) and median baseline PSA was 73.8 ng/mL (range 12.8-686.9). Eleven pts (79%) had both prior abi and enza. The initial selinexor dose was 65 mg/m2 on Day 1 (D1) and Day 3 (D3) weekly. For toxicity concerns, after the first 2 pts, dose was reduced to 60 mg on D1 and D3 for the first 3 wks followed by a 1-wk rest period (28-day cycle). All pts received ondansetron and olanzapine to prevent nausea and anorexia. The median treatment duration was 3 cycles (range 1-12), and median follow-up was 4 months. One pt (7.1%) had > 50% PSA decline, 5 pts (35.7%) had > 30% PSA decline, and 7 pts (50%) had any PSA decline. Of 10 pts evaluable, 9 pts had stable disease as best radiographic response, and 1 pt had progressive disease on the first radiographic evaluation. The median rPFS was 3.6 months (95% CI 2.1-not reached). The most common AEs of any severity were anorexia (86%), nausea (64%), weight loss (50%), fatigue (50%), thrombocytopenia (50%), anemia (36%), and vomiting (36%). Grade 3/4 AEs included nausea (14%), vomiting (14%), anemia (14%), anorexia (7%), weight loss (7%), thrombocytopenia (7%) and neutropenia (7%). Conclusions: Selinexor demonstrated limited clinical activity in mCRPC. Toxicity, in particular anorexia and weight loss, hinders further development in this pt population. Clinical trial information: NCT02215161.