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. Rubin; Howard I. Scher; David S. Rickman; Francesca Demichelis; David M. Nanus; Karla V. Ballman; Scott T. Tagawa

doi: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

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

Institute of Pathology

233 Citations (Scopus)

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.

Original language	English
Journal	Clinical Cancer Research
Volume	25
Issue number	1
Pages (from-to)	43-51
Number of pages	9
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.CCR-18-1912
Publication status	Published - 01.01.2019

Funding

We are grateful to our patients and their families for participation in this study. We appreciate all the work of the site coordinators, data managers, and investigators. In particular, we would like to acknowledge Irene Karpenko, Gillian Hodes, Olivera Calukovic, Michael Sigouros, Danielle Pancirer, Jessica Padilla, Theresa MacDonald, and Terra McNary for their help with regulatory, tissue, and data coordination for this study. This work was supported by Millennium Pharmaceuticals, Inc and the Prostate Cancer Foundation. Additional funding sources include the Department of Defense PC131961 (to D.M. Nanus, S.T. Tagawa, and H. Beltran), PC121341 (to H. Beltran), PC160264 (to H. Beltran and D.S. Rickman), PC121111 (to H.I. Scher), and PC131984 (to H.I. Scher); NIH/NCI SPORE in Prostate Cancer P50-CA211024 (to H. Beltran, J.M. Mosquera, M.A. Rubin, and D.S. Rickman) and P50-CA92629 (to H.I. Scher); NIH/NCI Cancer Center Support Grant P30-CA008748 (to H.I. Scher); and the Ann and William Bresnan Foundation (to H. Beltran and D.M. Nanus). H. Beltran reports receiving commercial research grants from Millenium Pharmaceuticals. M. Stein reports receiving commercial research grants from Oncoceutics, Merck Sharpe Dohme, Janssen Oncology, and Advaxis, and is a consultant/advisory board member for Merck Sharpe Dohme. H.I. Scher reports receiving commercial research grants from Janssen and is a consultant/advisory board member for Janssen Research Development. D.M. Nanus is a consultant/ advisory board member for Roche Genentech. K.V. Ballman reports receiving other remuneration from Janssen. No potential conflicts of interest were disclosed by the other authors.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

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

Access to Document

10.1158/1078-0432.CCR-18-1912

Cite this

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., ... Tagawa, S. T. (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), 43-51. https://doi.org/10.1158/1078-0432.CCR-18-1912

@article{011c50a52d064601828f1b0cdae3ae68,

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.",

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

note = "Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2019",

month = jan,

day = "1",

doi = "10.1158/1078-0432.CCR-18-1912",

language = "English",

volume = "25",

pages = "43--51",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "1",

}

Beltran, H, Oromendia, C, Danila, DC, Montgomery, B, Hoimes, C, Szmulewitz, RZ, Vaishampayan, U, Armstrong, AJ, Stein, M, Pinski, J, Mosquera, JM, Sailer, V, Bareja, R, Romanel, A, Gumpeni, N, Sboner, A, Dardenne, E, Puca, L, Prandi, D, Rubin, MA, Scher, HI, Rickman, DS, Demichelis, F, Nanus, DM, Ballman, KV & Tagawa, ST 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, vol. 25, no. 1, pp. 43-51. https://doi.org/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. / Beltran, Himisha; Oromendia, Clara; Danila, Daniel C. et al.
In: Clinical Cancer Research, Vol. 25, No. 1, 01.01.2019, p. 43-51.

Research output: Journal Articles › Journal articles › Research › peer-review

TY - JOUR

T1 - A phase II trial of the aurora kinase a inhibitor alisertib for patients with castration-resistant and neuroendocrine prostate cancer

T2 - Efficacy and biomarkers

AU - Beltran, Himisha

AU - Oromendia, Clara

AU - Danila, Daniel C.

AU - Montgomery, Bruce

AU - Hoimes, Christopher

AU - Szmulewitz, Russell Z.

AU - Vaishampayan, Ulka

AU - Armstrong, Andrew J.

AU - Stein, Mark

AU - Pinski, Jacek

AU - Mosquera, Juan M.

AU - Sailer, Verena

AU - Bareja, Rohan

AU - Romanel, Alessandro

AU - Gumpeni, Naveen

AU - Sboner, Andrea

AU - Dardenne, Etienne

AU - Puca, Loredana

AU - Prandi, Davide

AU - Rubin, Mark A.

AU - Scher, Howard I.

AU - Rickman, David S.

AU - Demichelis, Francesca

AU - Nanus, David M.

AU - Ballman, Karla V.

AU - Tagawa, Scott T.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85054925867

U2 - 10.1158/1078-0432.CCR-18-1912

DO - 10.1158/1078-0432.CCR-18-1912

M3 - Journal articles

C2 - 30232224

AN - SCOPUS:85054925867

SN - 1078-0432

VL - 25

SP - 43

EP - 51

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 1

ER -

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

Abstract

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Research Areas and Centers

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