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

Himisha Beltran*, Clara Oromendia, Daniel C. Danila, Bruce Montgomery, Christopher Hoimes, Russell Z. Szmulewitz, Ulka Vaishampayan, Andrew J. Armstrong, Mark Stein, Jacek Pinski, Juan M. Mosquera, Verena Sailer, Rohan Bareja, Alessandro Romanel, Naveen Gumpeni, Andrea Sboner, Etienne Dardenne, Loredana Puca, Davide Prandi, Mark A. RubinHoward I. Scher, David S. Rickman, Francesca Demichelis, David M. Nanus, Karla V. Ballman, Scott T. Tagawa

*Corresponding author for this work
129 Citations (Scopus)


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.

Original languageEnglish
JournalClinical Cancer Research
Issue number1
Pages (from-to)43-51
Number of pages9
Publication statusPublished - 01.01.2019

Research Areas and Centers

  • Research Area: Luebeck Integrated Oncology Network (LION)
  • Centers: University Cancer Center Schleswig-Holstein (UCCSH)


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