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

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


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.

Trial registration: ClinicalTrials.gov NCT01799278.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / genetics*
  • Azepines / administration & dosage*
  • Azepines / adverse effects
  • Carcinoma, Neuroendocrine / drug therapy*
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / pathology
  • Disease Progression
  • Humans
  • Male
  • Middle Aged
  • N-Myc Proto-Oncogene Protein / genetics*
  • Orchiectomy
  • Prostate / pathology
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Pyrimidines / administration & dosage*
  • Pyrimidines / adverse effects
  • Receptors, Androgen / genetics
  • Signal Transduction / drug effects


  • Azepines
  • MLN 8237
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Pyrimidines
  • Receptors, Androgen
  • Aurora Kinase A

Associated data

  • ClinicalTrials.gov/NCT01799278