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. 2020 Oct 28:4:PO.20.00200.
doi: 10.1200/PO.20.00200. eCollection 2020.

Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer

Andrew J Armstrong  1 , Jun Luo  2 , David M Nanus  3 , Paraskevi Giannakakou  3 , Russell Z Szmulewitz  4 , Daniel C Danila  3   5 , Patrick Healy  1   2   3   4   5   6   7   8 , Monika Anand  1 , William R Berry  1 , Tian Zhang  1 , Michael R Harrison  1 , Changxue Lu  2 , Yan Chen  2 , Giuseppe Galletti  3 , Joseph D Schonhoft  7 , Howard I Scher  5 , Richard Wenstrup  7 , Scott T Tagawa  3 , Emmanuel S Antonarakis  2   8 , Daniel J George  1 , Susan Halabi  8
Affiliations

Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer

Andrew J Armstrong et al. JCO Precis Oncol. .

Abstract

Purpose: Androgen receptor splice variant 7 (AR-V7) detection in circulating tumor cells (CTCs) is associated with a low probability of response and short progression-free (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide or abiraterone. However, it is unclear whether such men benefit from taxane chemotherapy.

Patients and methods: PROPHECY is a multicenter prospective blinded study of patients with poor-risk mCRPC starting abiraterone or enzalutamide and observed through subsequent progression and taxane chemotherapy. We assessed AR-V7 status using the Johns Hopkins modified AdnaTest CTC AR-V7 messenger RNA assay and the Epic Sciences CTC nuclear-localized AR-V7 protein assay before treatment. The primary objective was to validate the independent prognostic value of CTC AR-V7 status based on radiographic/clinical PFS. OS, confirmed prostate-specific antigen (PSA), and objective radiologic responses were secondary end points.

Results: We enrolled 118 men with mCRPC treated with abiraterone or enzalutamide, 51 of whom received subsequent docetaxel or cabazitaxel. Pretreatment CTC AR-V7 status by the Johns Hopkins and Epic Sciences assays was independently associated with worse PFS (hazard ratio [HR], 1.7; 95% CI, 1.0 to 2.9 and HR, 2.1; 95% CI, 1.0 to 4.4, respectively) and OS (HR, 3.3; 95% CI, 1.7 to 6.3 and HR, 3.0; 95% CI, 1.4 to 6.3, respectively) and a low probability of confirmed PSA responses, ranging from 0% to 11%, during treatment with abiraterone or enzalutamide. At progression, subsequent CTC AR-V7 detection was not associated with an inferior PSA or radiographic response or worse PFS or OS with subsequent taxane chemotherapy after adjusting for CellSearch CTC enumeration and clinical prognostic factors.

Conclusion: Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7-positive disease still experience clinical benefits from taxane chemotherapy.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Andrew J. ArmstrongHonoraria: Dendreon, Janssen Oncology Consulting or Advisory Role: Bayer, Sanofi, Dendreon, Medivation, Janssen Biotech, Pfizer, Astellas Scientific and Medical Affairs, Clovis Oncology, AstraZeneca Speakers’ Bureau: Dendreon, Bayer Research Funding: Dendreon (Inst), Sanofi (Inst), Bayer (Inst), Pfizer (Inst), Novartis (Inst), Janssen Oncology (Inst), Medivation (Inst), Astellas Pharma (Inst), Gilead Sciences (Inst), Roche/Genentech (Inst), Active Biotech (Inst), Bristol Myers Squibb (Inst), Constellation Pharmaceuticals (Inst), Merck (Inst) Patents, Royalties, Other Intellectual Property: Circulating tumor cell novel capture technology (Inst) Travel, Accommodations, Expenses: Dendreon, Janssen Biotech, Bayer, Astellas Scientific and Medical AffairsJun LuoConsulting or Advisory Role: Sun Pharma, Janssen Oncology, Tolero Pharmaceuticals Research Funding: Sanofi (Inst), Orion Pharma (Inst), Mirati Therapeutics (Inst), Gilead Sciences (Inst), Astellas Pharma (Inst), Constellation Pharmaceuticals (Inst), Calibr (Inst), Cardiff Oncology (Inst) Patents, Royalties, Other Intellectual Property: Coinventor of a technology assigned to Johns Hopkins University, which licensed to Tokai Pharmaceuticals (Inst); coinventor of a technology licensed to Qiagen (Inst); coinventor of a technology licensed to A&G Pharmaceuticals (Inst)David M. NanusConsulting or Advisory Role: Roche/Genentech Research Funding: Novartis (Inst), Boehringer Ingelheim (Inst), Zenith Epigenetics (Inst), AstraZeneca (Inst), Immumedics (Inst), Janssen (Inst), Clovis Oncology (Inst), Pfizer (Inst)Paraskevi GiannakakouEmployment: Novartis (I) Stock and Other Ownership Interests: Novartis (I) Patents, Royalties, Other Intellectual Property: Coinventor on international patent application docket No. 1676.083WO1“Identifying taxane sensitivity in prostate cancer patients”Russell Z. SzmulewitzHonoraria: Astellas Pharma Consulting or Advisory Role: AstraZeneca, AbbVie, Exelixis, Merck, Amgen, Janssen Oncology, Sanofi, Astellas Pharma, Pfizer Research Funding: AbbVie, Astellas Pharma, Incyte, Macrogenics, Janssen Oncology Patents, Royalties, Other Intellectual Property: Coinventor on patent licensed by University of Chicago to Corcept Therapeutics for combination AR/GR inhibition in prostate cancer Travel, Accommodations, Expenses: Corcept TherapeuticsDaniel C. DanilaHonoraria: Angle, Bayer, ScreenCell, Janssen Oncology, Pfizer, AxImmune, Pfizer, Clovis Oncology, Astellas Pharma Consulting or Advisory Role: Angle, Bayer, Sanador, AxImmune, Pfizer, Clovis Oncology, Astellas Pharma, Janssen Scientific Affairs Research Funding: Prostate Cancer Foundation, Genentech, Janssen Research & Development (Inst) Patents, Royalties, Other Intellectual Property: Gene expression profile associated with prostate cancer Travel, Accommodations, Expenses: Cambridge Healthtech Institute, Prostate Cancer Foundation, ScreenCell, StopCancer, American Austrian Open Medical Institute, Janssen Biotech, Genzyme, Pfizer, Janssen Scientific Affairs, Astellas PharmaPatrick HealyConsulting or Advisory Role: ParexelWilliam R. BerryHonoraria: Pfizer, Merck, Genomic Health, Janssen Oncology Consulting or Advisory Role: Merck, Pfizer, Genomic Health, Janssen Oncology Research Funding: Merck (Inst) Travel, Accommodations, Expenses: Merck, Pfizer, Genomic Health, Janssen OncologyTian ZhangLeadership: Capio BioSciences (I), Archimmune Therapeutics (I) Stock and Other Ownership Interests: Capio Biosciences (I), Archimmune Therapeutics (I), Nanorobotics (I) Honoraria: Exelixis, Genentech/Roche, MJH Life Sciences, Pacific Genuity Consulting or Advisory Role: Janssen, Genentech/Roche, Sanofi, Exelixis, AstraZeneca, Pfizer, Bristol Myers Squibb, Foundation Medicine, Pharmacyclics, Amgen, Merck, Seattle Genetics Speakers’ Bureau: Exelixis, Genentech/Roche, Genomic Health, Sanofi Research Funding: Janssen (Inst), Acerta Pharma (Inst), Pfizer (Inst), Merrimack (Inst), Stem CentRx (Inst), Novartis (Inst), OmniSeq (Inst), Personal Genome Diagnostics (Inst), Regeneron (Inst), Merck (Inst), Mirati Therapeutics (Inst), Astellas Pharma Patents, Royalties, Other Intellectual Property: Circulating tumor cell novel capture by c-MET technology (Inst); prochelators as targeted prodrugs for prostate cancer (Inst) Travel, Accommodations, Expenses: Acerta Pharma, Genomic Health, AstraZenecaMichael R. HarrisonConsulting or Advisory Role: Bayer, Sanofi, Exelixis, Genentech, Argos Therapeutics, Fujifilm, Janssen Oncology, AstraZeneca, Pfizer, Bristol Myers Squibb Speakers’ Bureau: Genentech, Exelixis Research Funding: Argos Therapeutics (Inst), Bristol Myers Squibb (Inst), Genentech (Inst), Pfizer (Inst), Medivation/Astellas Pharma (Inst), Merck (Inst), Clovis Oncology (Inst), Acerta Pharma (Inst), AstraZeneca (Inst)Changxue LuPatents, Royalties, Other Intellectual Property: Inventor of the patent that was licensed to Qiagen and received royaltyJoseph D. SchonhoftEmployment: Epic Sciences Stock and Other Ownership Interests: Epic SciencesHoward I. ScherLeadership: Asterias Biotherapeutics Stock and Other Ownership Interests: Asterias Biotherapeutics Honoraria: Research to Practice Consulting or Advisory Role: Janssen Biotech, Amgen, Janssen Research & Development, Menarini Silicon Biosystems, WIRB-Copernicus Group, ESSA, Sanofi, Ambry Genetics, Konica Minolta, Pfizer, Bayer Research Funding: Janssen (Inst), Illumina (Inst), Epic Sciences (Inst), Menarini Silicon Biosystems (Inst), Thermofisher Scientific Biomarkers (Inst) Travel, Accommodations, Expenses: Asterias Biotherapeutics, Menarini Silicon Biosystems, Amgen, WIRB-Copernicus Group, Konica Minolta, ESSA, Prostate Cancer Foundation, Sanofi, Bayer, Phosplatin TherapeuticsRichard WenstrupEmployment: Epic Sciences Leadership: Epic Sciences Stock and Other Ownership Interests: Epic Sciences Consulting or Advisory Role: Blueprint Genetics, Resolys Patents, Royalties, Other Intellectual Property: Patent royalties from AssurexHealth Travel, Accommodations, Expenses: Epic SystemsScott T. TagawaConsulting or Advisory Role: Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, POINT Biopharma Research Funding: Lilly (Inst), Sanofi (Inst), Janssen (Inst), Astellas Pharma (Inst), Progenics (Inst), Millennium Pharmaceuticals (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Dendreon (Inst), Rexahn Pharmaceuticals (Inst), Bayer (Inst), Genentech (Inst), Newlink Genetics (Inst), Inovio Pharmaceuticals (Inst), AstraZeneca (Inst), Immunomedics (Inst), Novartis (Inst), AVEO (Inst), Boehringer Ingelheim (Inst), Merck (Inst), Stem CentRx (Inst), Karyopharm Therapeutics (Inst), AbbVie (Inst), Medivation (Inst), Endocyte (Inst), Exelixis (Inst), Clovis Oncology (Inst) Travel, Accommodations, Expenses: Sanofi, Immunomedics, Amgen Uncompensated Relationships: Telix Pharmaceuticals, ATLAB Pharma, Phosplatin TherapeuticsEmmanuel S. AntonarakisHonoraria: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology Consulting or Advisory Role: Sanofi, Dendreon, Janssen Biotech, ESSA, Merck, AstraZeneca, Clovis Oncology, Lilly, Bayer Research Funding: Janssen Biotech (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst), Millennium Pharmaceuticals (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Constellation Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: Coinventor of a biomarker technology that has been licensed to Qiagen Travel, Accommodations, Expenses: Sanofi, Dendreon, MedivationDaniel J. GeorgeLeadership: Capio BioSciences Honoraria: Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, UroToday, Acceleron Pharma, American Association for Cancer Research, Axess Oncology, Janssen Oncology, Millennium Medical Publishing Consulting or Advisory Role: Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, Innocrin Pharma, Bristol Myers Squibb, Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, AstraZeneca, Michael J. Hennessy Associates, Vizuri Health Sciences Speakers’ Bureau: Sanofi, Bayer, Exelixis Research Funding: Exelixis (Inst), Janssen Oncology (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Acerta Pharma (Inst), Bayer (Inst), Dendreon (Inst), Innocrin Pharma (Inst), Calithera Biosciences (Inst), Sanofi (Inst) Travel, Accommodations, Expenses: Bayer, Exelixis, Merck, Pfizer, Sanofi, Janssen Oncology, UroTodaySusan HalabiEmployment: ASCO Targeted Agent and Profiling Utilization Registry Consulting or Advisory Role: Eisai, Ferring Pharmaceuticals, Bayer No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Kaplan-Meier plot of outcomes in men with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide in PROPHECY: (A) progression-free survival (PFS) and (B) overall survival (OS) by pretreatment Johns Hopkins circulating tumor cell (CTC) androgen receptor splice variant 7 (AR-V7) detection criteria and (C) PFS and (D) OS by pretreatment Epic Sciences CTC AR-V7 detection criteria. Time (months) is defined from date of registration to event of interest (PFS or OS).
FIG 2.
FIG 2.
Kaplan-Meier plot of outcomes in men with metastatic castration-resistant prostate cancer treated with taxane chemotherapy after progression with abiraterone (abi) or enzalutamide (Enza) in PROPHECY: (A) progression-free survival (PFS) and (B) overall survival (OS) by Johns Hopkins (JHU) circulating tumor cell (CTC) androgen receptor splice variant 7 (AR-V7) detection criteria after abiraterone or enzalutamide but before taxane therapy and (C) PFS and (D) OS by Epic Sciences CTC AR-V7 detection criteria after abiraterone or enzalutamide but before taxane therapy. Time (months) is defined from the date of taxane chemotherapy to event of interest (PFS or OS). (E) Forest plot of hazard ratios for PFS and OS according to treatment and pretreatment AR-V7 status. NOTE. The abiraterone or enzalutamide–treated and taxane-treated men are the same patients who received sequential therapies, and AR-V7 status for taxane prediction was updated and assessed at progression during abiraterone or enzalutamide and pretaxane treatment.
FIG 3.
FIG 3.
Bar plot demonstrating heterogeneity of androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) by either the Johns Hopkins (JHU) messenger RNA assay or the Epic Sciences nuclear protein assay collected from men in the PROPHECY study at one of three time points: (A) before abiraterone (abi) or enzalutamide (Enza) therapy, (B) at progression during abiraterone or enzalutamide treatment, and (C) at progression during subsequent taxane chemotherapy. CTC enumeration is provided by CellSearch criteria. For the Epic Sciences nuclear protein assay, approximately 1 mL of blood is analyzed, and total and nuclear-localized AR-V7–positive CTCs are expressed per 1 mL of blood. CTC enumeration is provided by CellSearch criteria and expressed as the total count detected per 7.5 mL of blood. (*) No data.
FIG A1.
FIG A1.
CONSORT diagram.
FIG A2.
FIG A2.
Waterfall plots of best overall prostate-specific antigen (PSA) decline from pretaxane baseline during therapy with docetaxel or cabazitaxel according to (A) Epic Sciences and (B) Johns Hopkins androgen receptor splice variant 7 (AR-V7) status. (*) Indicates that PSA decline was confirmed with second subsequent value per Prostate Cancer Working Group 2/3 guidelines.
See this image and copyright information in PMC

References

    1. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–433. - PMC - PubMed
    1. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 2010;376:1147–1154. - PubMed
    1. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013 [Erratum: N Engl J Med 368:584, 2013] - PMC - PubMed
    1. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–1512. - PubMed
    1. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381:2506–2518. - PubMed