PMID- 29487219 OWN - NLM STAT- MEDLINE DCOM- 20190919 LR - 20211204 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 23 IP - 6 DP - 2018 Jun TI - 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. PG - 656-e64 LID - 10.1634/theoncologist.2017-0624 [doi] AB - 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/m(2) 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. CI - (c)AlphaMed Press; the data published online to support this summary is the property of the authors. FAU - Wei, Xiao X AU - Wei XX AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA xiaox_wei@dfci.harvard.edu. FAU - Siegel, Adam P AU - Siegel AP AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Aggarwal, Rahul AU - Aggarwal R AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Lin, Amy M AU - Lin AM AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Friedlander, Terence W AU - Friedlander TW AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Fong, Lawrence AU - Fong L AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Kim, Won AU - Kim W AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Louttit, Mirela AU - Louttit M AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Chang, Emily AU - Chang E AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Zhang, Li AU - Zhang L AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. FAU - Ryan, Charles J AU - Ryan CJ AD - Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA. LA - eng SI - ClinicalTrials.gov/NCT02215161 PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180227 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Androstenes) RN - 0 (Benzamides) RN - 0 (Hydrazines) RN - 0 (Nitriles) RN - 0 (Triazoles) RN - 2010-15-3 (Phenylthiohydantoin) RN - 31TZ62FO8F (selinexor) RN - 93T0T9GKNU (enzalutamide) RN - G819A456D0 (abiraterone) SB - IM MH - Aged MH - Androstenes/pharmacology/*therapeutic use MH - Benzamides MH - Humans MH - Hydrazines/pharmacology/*therapeutic use MH - Male MH - Middle Aged MH - Nitriles MH - Phenylthiohydantoin/*analogs & derivatives/pharmacology/therapeutic use MH - Prostatic Neoplasms, Castration-Resistant/*drug therapy MH - Triazoles/pharmacology/*therapeutic use PMC - PMC6067936 EDAT- 2018/03/01 06:00 MHDA- 2019/09/20 06:00 PMCR- 2018/02/27 CRDT- 2018/03/01 06:00 PHST- 2017/11/29 00:00 [received] PHST- 2018/01/02 00:00 [accepted] PHST- 2018/03/01 06:00 [pubmed] PHST- 2019/09/20 06:00 [medline] PHST- 2018/03/01 06:00 [entrez] PHST- 2018/02/27 00:00 [pmc-release] AID - theoncologist.2017-0624 [pii] AID - ONCO12390 [pii] AID - 10.1634/theoncologist.2017-0624 [doi] PST - ppublish SO - Oncologist. 2018 Jun;23(6):656-e64. doi: 10.1634/theoncologist.2017-0624. Epub 2018 Feb 27.