A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers.
A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers.
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DOI：
10.1158/1078-0432.ccr-18-1912
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Tagawa ST
中科院分区：
文献类型：
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作者：
Beltran H;Oromendia C;Danila DC;Montgomery B;Hoimes C;Szmulewitz RZ;Vaishampayan U;Armstrong AJ;Stein M;Pinski J;Mosquera JM;Sailer V;Bareja R;Romanel A;Gumpeni N;Sboner A;Dardenne E;Puca L;Prandi D;Rubin MA;Scher HI;Rickman DS;Demichelis F;Nanus DM;Ballman KV;Tagawa ST
Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. Sixty men were treated with alisertib 50mg twice daily for 7 days every 21-days. Eligibility included metastatic prostate cancer and at least one: small cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; elevated serum neuroendocrine markers. The primary endpoint was six-month radiographic progression free survival (rPFS). Pre-treatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed. Median PSA was 1.13 ng/ml (0.01–514.2), number of prior therapies was three, and 68% had visceral metastases. Genomic alterations involved RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%), AR (27%), and there was a range of androgen receptor signaling and NEPC marker expression. Six-month rPFS was 13.4% and median overall survival was 9.5 months (7.3–13). Four exceptional responders were identified, including complete resolution of liver metastases and prolonged stable disease, with tumors suggestive of N-myc and Aurora-A overactivity. Patient organoids exhibited concordant responses to alisertib and allowed for the dynamic testing of Aurora-N-myc complex disruption. Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.
