Randomized, noncomparative, phase II trial of early switch from docetaxel to cabazitaxel or vice versa, with integrated biomarker analysis, in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer

TAXYNERGY Investigators

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23 Citations (Scopus)

Abstract

Purpose: The TAXYNERGY trial (ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods: Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve $ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed $ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results: Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor–targeted therapy. Overall, 35 patients (55.6%) had confirmed $ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had $ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve $ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved $ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of $ 50% PSA decrease at C4 (P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion: The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.

Original languageEnglish (US)
Pages (from-to)3181-3188
Number of pages8
JournalJournal of Clinical Oncology
Volume35
Issue number28
DOIs
StatePublished - Oct 1 2017

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docetaxel
Castration
Prostatic Neoplasms
Prostate-Specific Antigen
Biomarkers
Drug Therapy
Circulating Neoplastic Cells
Taxoids
cabazitaxel
taxane
Febrile Neutropenia
Androgen Receptors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{0c4fc5bbeae44d78a7bf62e6ad5f292e,
title = "Randomized, noncomparative, phase II trial of early switch from docetaxel to cabazitaxel or vice versa, with integrated biomarker analysis, in men with chemotherapy-na{\"i}ve, metastatic, castration-resistant prostate cancer",
abstract = "Purpose: The TAXYNERGY trial (ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-na{\"i}ve, metastatic, castration-resistant prostate cancer. Patients and Methods: Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve $ 30{\%} prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed $ 50{\%} PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization ({\%}ARNL) and increased microtubule bundling. Results: Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4{\%} received prior potent androgen receptor–targeted therapy. Overall, 35 patients (55.6{\%}) had confirmed $ 50{\%} PSA responses, exceeding the historical control rate of 45.4{\%} (TAX327). Of 61 treated patients, 33 (54.1{\%}) had $ 30{\%} PSA declines by C4 and did not switch taxane, 15 patients (24.6{\%}) who did not achieve $ 30{\%} PSA declines by C4 switched taxane, and 13 patients (21.3{\%}) discontinued therapy before or at C4. Of patients switching taxane, 46.7{\%} subsequently achieved $ 50{\%} PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in {\%}ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of $ 50{\%} PSA decrease at C4 (P = .009). Median composite progression-free survival was 9.1 months (95{\%} CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1{\%}) and febrile neutropenia (11.5{\%}). Conclusion: The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in {\%}ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.",
author = "{TAXYNERGY Investigators} and Antonarakis, {Emmanuel S.} and Tagawa, {Scott T.} and Giuseppe Galletti and Daniel Worroll and Karla Ballman and Marie Vanhuyse and Guru Sonpavde and Scott North and Costantine Albany and Tsao, {Che Kai} and John Stewart and Atef Zaher and Ted Szatrowski and Wei Zhou and Ada Gjyrezi and Shinsuke Tasaki and Luigi Portella and Yang Bai and Lannin, {Timothy B.} and Shalu Suri and Gruber, {Conor N.} and Pratt, {Erica D.} and Kirby, {Brian J.} and Eisenberger, {Mario A.} and Nanus, {David M.} and Fred Saad and Paraskevi Giannakakou",
year = "2017",
month = "10",
day = "1",
doi = "10.1200/JCO.2017.72.4138",
language = "English (US)",
volume = "35",
pages = "3181--3188",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "28",

}

TY - JOUR

T1 - Randomized, noncomparative, phase II trial of early switch from docetaxel to cabazitaxel or vice versa, with integrated biomarker analysis, in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer

AU - TAXYNERGY Investigators

AU - Antonarakis, Emmanuel S.

AU - Tagawa, Scott T.

AU - Galletti, Giuseppe

AU - Worroll, Daniel

AU - Ballman, Karla

AU - Vanhuyse, Marie

AU - Sonpavde, Guru

AU - North, Scott

AU - Albany, Costantine

AU - Tsao, Che Kai

AU - Stewart, John

AU - Zaher, Atef

AU - Szatrowski, Ted

AU - Zhou, Wei

AU - Gjyrezi, Ada

AU - Tasaki, Shinsuke

AU - Portella, Luigi

AU - Bai, Yang

AU - Lannin, Timothy B.

AU - Suri, Shalu

AU - Gruber, Conor N.

AU - Pratt, Erica D.

AU - Kirby, Brian J.

AU - Eisenberger, Mario A.

AU - Nanus, David M.

AU - Saad, Fred

AU - Giannakakou, Paraskevi

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Purpose: The TAXYNERGY trial (ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods: Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve $ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed $ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results: Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor–targeted therapy. Overall, 35 patients (55.6%) had confirmed $ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had $ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve $ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved $ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of $ 50% PSA decrease at C4 (P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion: The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.

AB - Purpose: The TAXYNERGY trial (ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods: Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve $ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed $ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results: Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor–targeted therapy. Overall, 35 patients (55.6%) had confirmed $ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had $ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve $ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved $ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of $ 50% PSA decrease at C4 (P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion: The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.

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U2 - 10.1200/JCO.2017.72.4138

DO - 10.1200/JCO.2017.72.4138

M3 - Article

C2 - 28632486

AN - SCOPUS:85029444456

VL - 35

SP - 3181

EP - 3188

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 28

ER -