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Lessons LearnedIn 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.BackgroundSelinexor 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.MethodsThis 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.ResultsFourteen 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.ConclusionSelinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti-androgenic agents.

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.

Oral inhibitors of androgen synthesis are a new class of therapy for castration resistant prostate cancer. Their development supports the concept of secondary hormonal manipulation in castration resistant prostate cancer. Abiraterone acetate, the first in class of these therapies to receive multi-national regulatory approval and widespread clinical use, has become a new standard of care in patients with prior docetaxel chemotherapy as well as for a large proportion of patients worldwide who have not received chemotherapy. Considerations in the use of these therapies include the clinical and hormonal milieu of the patient as well as the composition and outcome with prior therapies. While generally non-toxic, there are safety, tolerability, and monitoring issues that must be adhered to by the clinician, and in general there is a requirement for concomitant corticosteroid use. Further research into these agents focuses on their role in combination therapy, earlier disease states, and the mechanisms of resistance to them.

e16042 Background: Prostate cancer progression and development of resistance to abiraterone acetate (AA) is associated with loss of PTEN-mediated negative regulation of the PI3K and mammalian targe...