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Clin Cancer Res. 2019 Jan 1;25(1):43-51. doi: 10.1158/1078-0432.CCR-18-1912. Epub 2018 Sep 19.

A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers.

Author information

1
Department of Medicine, Weill Cornell Medicine, New York, New York. hip9004@med.cornell.edu.
2
Englander Institute for Precision Medicine, New York Presbyterian Hospital- Weill Cornell Medicine, New York, New York.
3
Department of Biostatistics, Weill Cornell Medicine, New York, New York.
4
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Weill Cornell Medical College, New York, New York.
6
Department of Medicine, University of Washington, Seattle, Washington.
7
Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
8
Department of Medicine, University of Chicago, Chicago, Illinios.
9
Department of Oncology, Wayne State University/Karmanos Cancer Institute, Detroit, Michigan.
10
Departments of Medicine, Surgery, and Pharmacology and Cancer Biology, Duke Cancer Institute, Duke University, Durham, North California.
11
Division of Medical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
12
Division of Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
13
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
14
Centre for Integrative Biology (CIBIO), University of Trento, Trento Italy.
15
Department of Radiology, Weill Cornell Medicine, New York, New York.
16
Department of Medicine, Weill Cornell Medicine, New York, New York.

Abstract

PURPOSE:

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.

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 RB1 (55%), TP53 (46%), PTEN (29%), BRCA2 (29%), and 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). 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.

PMID:
30232224
PMCID:
PMC6320304
[Available on 2020-01-01]
DOI:
10.1158/1078-0432.CCR-18-1912

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