Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer

Sofie H. Tolmeijer; Emmy Boerrigter; Takayuki Sumiyoshi; Edmond M. Kwan; Sarah W.S. Ng; Matti Annala; Gráinne Donnellan; Cameron Herberts; Guillemette E. Benoist; Paul Hamberg; Diederik M. Somford; Inge M. van Oort; Jack A. Schalken; Niven Mehra; Nielka P. van Erp; Alexander W. Wyatt

doi:10.1158/1078-0432.CCR-22-2998

Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer

Sofie H. Tolmeijer, Emmy Boerrigter, Takayuki Sumiyoshi, Edmond M. Kwan, Sarah W.S. Ng, Matti Annala, Gráinne Donnellan, Cameron Herberts, Guillemette E. Benoist, Paul Hamberg, Diederik M. Somford, Inge M. van Oort, Jack A. Schalken, Niven Mehra, Nielka P. van Erp, Alexander W. Wyatt

TAYS Cancer Centre

Research output: Contribution to journal › Article › Scientific › peer-review

14 Citations (Scopus)

Abstract

PURPOSE: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes. EXPERIMENTAL DESIGN: Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months. RESULTS: ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62-8.77 and univariate HR, 5.49; 95% CI, 2.76-10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses. CONCLUSIONS: Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification. See related commentary by Sartor, p. 2745.

Original language	English
Pages (from-to)	2835-2844
Number of pages	10
Journal	Clinical Cancer Research
Volume	29
Issue number	15
DOIs	https://doi.org/10.1158/1078-0432.CCR-22-2998
Publication status	Published - 1 Aug 2023
Publication type	A1 Journal article-refereed

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Publication forum level 3

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General Medicine

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

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10.1158/1078-0432.CCR-22-2998

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Tolmeijer, S. H., Boerrigter, E., Sumiyoshi, T., Kwan, E. M., Ng, S. W. S., Annala, M., Donnellan, G., Herberts, C., Benoist, G. E., Hamberg, P., Somford, D. M., van Oort, I. M., Schalken, J. A., Mehra, N., van Erp, N. P., & Wyatt, A. W. (2023). Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer. Clinical Cancer Research, 29(15), 2835-2844. https://doi.org/10.1158/1078-0432.CCR-22-2998

@article{5d6c4f7882404b7ebfd20664650be011,

title = "Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer",

abstract = "PURPOSE: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-na{\"i}ve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes. EXPERIMENTAL DESIGN: Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months. RESULTS: ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62-8.77 and univariate HR, 5.49; 95% CI, 2.76-10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses. CONCLUSIONS: Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification. See related commentary by Sartor, p. 2745.",

author = "Tolmeijer, {Sofie H.} and Emmy Boerrigter and Takayuki Sumiyoshi and Kwan, {Edmond M.} and Ng, {Sarah W.S.} and Matti Annala and Gr{\'a}inne Donnellan and Cameron Herberts and Benoist, {Guillemette E.} and Paul Hamberg and Somford, {Diederik M.} and {van Oort}, {Inge M.} and Schalken, {Jack A.} and Niven Mehra and {van Erp}, {Nielka P.} and Wyatt, {Alexander W.}",

note = "Publisher Copyright: {\textcopyright}2023 American Association for Cancer Research.",

year = "2023",

month = aug,

day = "1",

doi = "10.1158/1078-0432.CCR-22-2998",

language = "English",

volume = "29",

pages = "2835--2844",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research",

number = "15",

}

Tolmeijer, SH, Boerrigter, E, Sumiyoshi, T, Kwan, EM, Ng, SWS, Annala, M, Donnellan, G, Herberts, C, Benoist, GE, Hamberg, P, Somford, DM, van Oort, IM, Schalken, JA, Mehra, N, van Erp, NP & Wyatt, AW 2023, 'Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer', Clinical Cancer Research, vol. 29, no. 15, pp. 2835-2844. https://doi.org/10.1158/1078-0432.CCR-22-2998

Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer. / Tolmeijer, Sofie H.; Boerrigter, Emmy; Sumiyoshi, Takayuki et al.
In: Clinical Cancer Research, Vol. 29, No. 15, 01.08.2023, p. 2835-2844.

Research output: Contribution to journal › Article › Scientific › peer-review

TY - JOUR

T1 - Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer

AU - Tolmeijer, Sofie H.

AU - Boerrigter, Emmy

AU - Sumiyoshi, Takayuki

AU - Kwan, Edmond M.

AU - Ng, Sarah W.S.

AU - Annala, Matti

AU - Donnellan, Gráinne

AU - Herberts, Cameron

AU - Benoist, Guillemette E.

AU - Hamberg, Paul

AU - Somford, Diederik M.

AU - van Oort, Inge M.

AU - Schalken, Jack A.

AU - Mehra, Niven

AU - van Erp, Nielka P.

AU - Wyatt, Alexander W.

PY - 2023/8/1

Y1 - 2023/8/1

N2 - PURPOSE: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes. EXPERIMENTAL DESIGN: Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months. RESULTS: ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62-8.77 and univariate HR, 5.49; 95% CI, 2.76-10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses. CONCLUSIONS: Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification. See related commentary by Sartor, p. 2745.

AB - PURPOSE: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes. EXPERIMENTAL DESIGN: Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months. RESULTS: ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62-8.77 and univariate HR, 5.49; 95% CI, 2.76-10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses. CONCLUSIONS: Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification. See related commentary by Sartor, p. 2745.

U2 - 10.1158/1078-0432.CCR-22-2998

DO - 10.1158/1078-0432.CCR-22-2998

M3 - Article

C2 - 36996325

AN - SCOPUS:85166385051

SN - 1078-0432

VL - 29

SP - 2835

EP - 2844

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 15

ER -

Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer

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