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Multicenter Study
. 2024 Mar 15;30(6):1152-1159.
doi: 10.1158/1078-0432.CCR-23-3017.

The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide

Susan Halabi #  1   2 , Siyuan Guo #  1 , Joseph J Park  2 , David M Nanus  3 , Daniel J George  2 , Emmanuel S Antonarakis  4 , Daniel Costin Danila  3   5 , Russell Zelig Szmulewitz  6 , Donald P McDonnell  2   7 , John D Norris  2   7 , Changxue Lu  8 , Jun Luo  8 , Andrew J Armstrong  2   7
Affiliations
Multicenter Study

The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide

Susan Halabi et al. Clin Cancer Res. .

Abstract

Purpose: HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated with abiraterone or enzalutamide.

Experimental design: We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (NCT02269982, n = 118) treated with abiraterone/enzalutamide. CTC detection and HOXB13 complementary DNA (cDNA) expression was measured using a modified Adnatest, grouping patients into 3 categories: CTC 0 (undetectable); CTC+ HOXB13 CTC low (<4 copies); or CTC+ HOXB13 CTC high. The HOXB13 threshold was determined by maximally selected rank statistics for prognostic associations with overall survival (OS) and progression-free survival (PFS).

Results: We included 102 men with sufficient CTC HOXB13 cDNA, identifying 25%, 31%, and 44% of patients who were CTC 0, CTC+ HOXB13 low, and CTC+ HOXB13 high, respectively. Median OS were 25.7, 27.8, and 12.1 months whereas the median PFS were 9.0, 7.7, and 3.8 months, respectively. In subgroup analysis among men with CellSearch CTCs ≥5 copies/mL and adjusting for prior abi/enza treatment and Halabi clinical risk score, the multivariate HR for HOXB13 CTC detection was 2.39 (95% CI, 1.06-5.40) for OS and 2.78 (95% CI, 1.38-5.59) for PFS, respectively. Low HOXB13 CTC detection was associated with lower CTC PSA, PSMA, AR-FL, and AR-V7 detection, and more liver/lung metastases (41% vs. 25%).

Conclusions: Higher CTC HOXB13 expression is associated with AR-dependent biomarkers in CTCs and is adversely prognostic in the context of potent AR inhibition in men with mCRPC.

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Conflict of interest statement

Conflict of interest:

Susan Halabi

Consulting Role from ASCO, AVEO, BMS, Janssen, Sanofi

Research Funding: ASCO, Astellas

David M. Nanus

Advisory Boards: Janssen Oncology, Telix

Research support: Exelixis, Zenith Epigenetics, Plantable, Sagimet Biosciences

Daniel J. George

Advanced Accelerator Applications SA/Novartis – Personal/Financial – 06/2019

American Association for Cancer Research – Sr Editor – Personal/Financial – 11/2013

Astellas – Consultant, Research, Advisory Board – Institutional and Personal/Financial – 04/2010

Astrazeneca – Research, Consultant, Advisory Board, CAPI-281 Steering Committee member - Institutional and Personal/Financial – 10/2018

AVEO Pharmaceuticals – Personal/Financial – 01/2012

Bayer H/C Pharmaceuticals – Consultant, Speaker, Honorarium, Travel accommodations, SC – Personal/Financial – 04/2019

BMS – Research - Institutional

Calithera – Research – Institutional

Eisai – Personal/Financial – 02/2021

Exelixis, Inc – Research, Consultant, Speaker, Honorarium, Travel accommodations - Institutional and Personal/Financial – 11/2015

IdeoOncology (formerly Nexus) – Consultant – 12/2020

Janssen Pharmaceuticals – Research, Consultant, Independent Data Monitoring Committee (IDMC) - Institutional and Personal/Financial – 03/2015

Medscape Education – Personal/Financial – 02/2017

Merck Sharp & Dohme – Consultant – Personal/Financial – 07/2015

Michael J Hennessey Associates – Honorarium, Consultant – Personal/Financial – 05/2017

Millennium Medical Publishing, Clinical Advances in Hematology & Oncology – Co-Editor-in-Chief – Personal/Financial – 11/2013

Myovant Sciences, Inc – Consultant – Personal/Financial – 08/2017

NCI Genitourinary Steering Committee member (Leidos Biomedical Research Inc) – Personal/Financial – 02/2015

Novartis – Research - Institutional

Pfizer – Research, Consultant, Steering Committee, Honorarium - Institutional and Personal/Financial – 10/2016

Propella TX – Consultant (formerly Vizuri) – Personal/Financial – 03/2021

RevHealth, LLC (David Winkler) – Consultant – 01/2021 – Personal/Financial

Sanofi – Research, Consultant, Speaker, Honorarium, Travel accommodations - Institutional and Personal/Financial – 09/2011

Seattle Genetics – Consultant – 10/2020

UroGPO – Honorarium – Personal/Financial – 04/2018

UroToday (Digital Science Press) – Honorarium, Travel accommodations – Personal/Financial – 06/2018

WebMD – Consultant – 05/2011

WilmerHale Attorneys – Personal/Finance – 04/2021

Xcures – Consultant – 8/2021

Emmanuel S. Antonarakis reports grants and personal fees from Janssen, Sanofi, Bayer, Bristol Myers Squibb, Curium, Merck, Pfizer, AstraZeneca, Clovis, Constellation; personal fees from Astellas, Amgen, Blue Earth, Exact Sciences, Invitae, Eli Lilly, and Foundation Medicine; grants from Novartis, Celgene, and grants from Orion outside the submitted work; and has a patent for an AR-V7 biomarker technology that has been licensed to Qiagen.

Daniel Danila

Research support from US Department of Defense, American Society of Clinical Oncology, Prostate Cancer Foundation, Stand Up 2 Cancer, Amgen, Janssen Research & Development, Astellas, Medivation, Agensys, Genentech, CreaTV. Consultant for Angle LLT, Janssen Research & Development, AstraZeneca, BioView LTD, Clovis, Astellas, Medivation, Pfizer, Agensys, Merck.

Russell Zelig Szmulewitz

Honoraria: Astellas Pharma, Pfizer/Astellas

Consulting or Advisory Role: AstraZeneca, Abbvie, Exelixis, Merck, Amgen, Janssen Oncology, Sanofi, Astellas Pharma, Pfizer, Novartis, Eisai

Research Funding (to institution): Abbvie, Astellas Pharma, Macrogenics, Janssen Oncology, Plexxikon, Harpoon therapeutics, Merck, Novartis, Progenics Patent licensed by University of Chicago of which I am co-inventor to Corcept Therapeutics for combination AR/GR inhibition in prostate cancer

Travel, Accommodations, Expenses; Corcept Therapeutics

Jun Luo is the lead inventor of AR-V7 and CTC technologies that are owned by the Johns Hopkins University and licensed to Qiagen and A & G.

Changxue Lu is a co-inventor of AR-V7 and CTC technologies that are owned by the Johns Hopkins University and licensed to Qiagen.

Andrew J. Armstrong

Research support (to Duke) from the NIH/NCI, PCF/Movember, DOD, Astellas, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Amgen, Novartis

Consulting or advising relationships with Astellas, Epic Sciences, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Clovis, Exact Sciences, Myovant, Exelixis, Go

The other authors declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Kaplan Meier plot of OS in men with mCRPC based on CTC and HOXB13 CTC detection.
Figure 2.
Figure 2.
Kaplan Meier plot of PFS in men with mCRPC based on CTC and HOXB13 CTC detection.
See this image and copyright information in PMC

References

    1. de Bono JS, Logothetis CJ, Molina A, et al. : Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005, 2011 - PMC - PubMed
    1. Beer TM, Armstrong AJ, Rathkopf DE, et al. : Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 371:424–33, 2014 - PMC - PubMed
    1. Ryan CJ, Smith MR, Fizazi K, et al. : Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 16:152–60, 2015 - PubMed
    1. Armstrong AJ, Lin P, Tombal B, et al. : Five-year Survival Prediction and Safety Outcomes with Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer from the PREVAIL Trial. Eur Urol 78:347–357, 2020 - PubMed
    1. Armstrong AJ, Azad AA, Iguchi T, et al. : Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 40:1616–1622, 2022 - PMC - PubMed

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