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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • January 1, 2019

Published In

Volume / Issue

  • 25 / 1

Start / End Page

  • 43 - 51

PubMed ID

  • 30232224

Pubmed Central ID

  • PMC6320304

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-18-1912


  • eng

Conference Location

  • United States