A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone- and/or Enzalutamide-Refractory Metastatic Castration-Resistant Prostate Cancer

Abstract

Lessons Learned. In abiraterone‐ and/or enzalutamide‐refractory metastatic castration‐resistant prostate cancer (mCRPC) patients, selinexor led to prostate‐specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice‐a‐week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second‐generation anti‐androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post‐abiraterone and/or post‐enzalutamide mCRPC space.Background.Selinexor is a first‐in‐class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin‐1 (XPO‐1), leading to nuclear accumulation of tumor suppressor proteins.Methods.This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration‐resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide.Results.Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow‐up of 4 months, two patients (14%) had ≥50% prostate‐specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment‐related grade 3–4 AEs. The most common drug‐related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability.Conclusion.Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second‐line anti‐androgenic agents.

Down-regulation of AR splice variants through XPO1 suppression contributes to the inhibition of prostate cancer progression

“…Indeed, we found that SINE in vitro and in vivo potentiated the anti-cancer activity of anti-AR agents, enzalutamide and abiraterone, by inhibition of XPO1 and AR splice variants. Our in vitro and in vivo findings are supported by clinical observations as well [ 20 ]. In this Phase II study (NCT02215161), fourteen patients were 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off with a median treatment duration of 13 weeks.…”

“…In vitro , treatment of prostate cancer cells with selinexor resulted in XPO1 inhibition, which led to the nuclear retention of p53 and Foxo proteins and the degradation of cyclin D1, survivin and XPO1, consequently triggering apoptosis [ 14 , 19 ]. More significantly, in a Phase II study Selinexor demonstrated clinical activity in abiraterone- and/or enzalutamide-refractory mCRPC patients refractory to second-line anti-androgenic agents (NCT02215161) [ 20 ]. However, the detailed molecular mechanisms underlying SINE-inhibited prostate cancer growth are not clear.…”

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

“…The last clinical study on Selinexor published to date (May 2018) is a phase II trial that evaluated its efficacy and tolerability in 14 patients with metastatic, castration-resistant, prostate cancer [201] . Selinexor was administered twice weekly at a dose of 65 mg/m 2 that had to be subsequently reduced to a flat dose of 60 mg to improve tolerability.…”

Nuclear Transport Inhibition in Acute Myeloid Leukemia: Recent Advances and Future Perspectives

“…Apart from AML, selinexor is currently in early phase clinical trials in other malignancies. The efficacy of selinexor was assessed as monotherapy in patients with metastatic castrate-resistant prostate cancer that is refractory to antiandrogen therapies including abiraterone, enzalutamide, apalutamide or other investigational agents [ 32 ]. This Phase II study failed to achieve its primary end point of PFS and was terminated early after enrollment of 14 out of the planned 54 patients.…”