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


Authors: Beltran, H.; Oromendia, C.; Danila, D. C.; Montgomery, B.; Hoimes, C.; Szmulewitz, R. Z.; Vaishampayan, U.; Armstrong, A. J.; Stein, M.; Pinski, J.; Mosquera, J. M.; Sailer, V.; Bareja, R.; Romanel, A.; Gumpeni, N.; Sboner, A.; Dardenne, E.; Puca, L.; Prandi, D.; Rubin, M. A.; Scher, H. I.; Rickman, D. S.; Demichelis, F.; Nanus, D. M.; Ballman, K. V.; Tagawa, S. T.
Article Title: A phase II trial of the aurora kinase A inhibitor alisertib for patients with castration-resistant and neuroendocrine prostate cancer: Efficacy and biomarkers
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.
Keywords: docetaxel; genomics; design; recommendations; clinical-trials; n-myc; lineage plasticity
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 1
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-01-01
Start Page: 43
End Page: 51
Language: English
ACCESSION: WOS:000455001100008
DOI: 10.1158/1078-0432.Ccr-18-1912
PROVIDER: wos
PMCID: PMC6320304
PUBMED: 30232224
Notes: Article -- Source: Wos
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MSK Authors
  1. Howard Scher
    792 Scher
  2. Daniel C Danila
    77 Danila