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

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.; ... (2019). A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers. Clinical cancer research, 25(1), pp. 43-51. American Association for Cancer Research 10.1158/1078-0432.CCR-18-1912

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Rubin, Mark Andrew

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1078-0432

Publisher:

American Association for Cancer Research

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

19 Dec 2019 09:48

Last Modified:

19 Dec 2019 09:48

Publisher DOI:

10.1158/1078-0432.CCR-18-1912

PubMed ID:

30232224

BORIS DOI:

10.7892/boris.136263

URI:

https://boris.unibe.ch/id/eprint/136263

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