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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 Publication2019
AuthorsBeltran 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
JournalClin Cancer Res
Volume25
Issue1
Pagination43-51
Date Published2019 Jan 01
ISSN1078-0432
Abstract

PURPOSE: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop 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.

PATIENTS AND METHODS: Sixty men were treated with alisertib 50 mg 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; or elevated serum neuroendocrine markers. The primary endpoint was 6-month radiographic progression-free survival (rPFS). Pretreatment 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 3, and 68% had visceral metastases. Genomic alterations involved (55%), (46%), (29%), (29%), and (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). 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
PubMed Central IDPMC6320304
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
P50 CA092629 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States
Division: 
Biostatistics
Category: 
Faculty Publication