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.

A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers / 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.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 25:1(2019), pp. 43-51. [10.1158/1078-0432.CCR-18-1912]

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

Romanel A.;Sboner A.;Prandi D.;Demichelis F.;
2019-01-01

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.
2019
1
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.
A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers / 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.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 25:1(2019), pp. 43-51. [10.1158/1078-0432.CCR-18-1912]
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