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

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

来源：Clinical Cancer Research, 2019, 25(1): 43-51.

DOI：10.1158/1078-0432.CCR-18-1912

• N-MYC
• LINEAGE PLASTICITY
• CLINICAL-TRIALS
• RECOMMENDATIONS
• DOCETAXEL
• GENOMICS
• DESIGN

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.

• 出版日期2019-1-1