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A phase II trial of the aurora kinase A inhibitor alisertib for patients with castration resistant and neuroendocrine prostate cancer: efficacy and biomarkers.

TitleA phase II trial of the aurora kinase A inhibitor alisertib for patients with castration resistant and neuroendocrine prostate cancer: efficacy and biomarkers.
Publication TypeJournal Article
Year of Publication2018
AuthorsBeltran H, Oromendia C, Danila DC, Montgomery B, Hoimes C, Szmulewitz RZ, Vaishampayan U, Armstrong AJ, Stein M, Pinski J, Mosquera JMiguel, 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
JournalClin Cancer Res
Date Published2018 Sep 19
ISSN1078-0432
Abstract

BACKGROUND: 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.

EXPERIMENTAL DESIGN: Sixty men were treated with alisertib50mg 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.

RESULTS: 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.

CONCLUSIONS: 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.

DOI10.1158/1078-0432.CCR-18-1912
Alternate JournalClin. Cancer Res.
PubMed ID30232224