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Clinical Trial
. 2024 Sep 13;30(18):4115-4122.
doi: 10.1158/1078-0432.CCR-24-1096.

Circulating Tumor DNA Assessment for Treatment Monitoring Adds Value to PSA in Metastatic Castration-Resistant Prostate Cancer

Christopher J Sweeney  1 , Russell Petry  2 , Chang Xu  2 , Merrida Childress  2 , Jie He  2 , David Fabrizio  2 , Ole Gjoerup  2 , Samantha Morley  2 , Timothy Catlett  2 , Zoe J Assaf  3 , Kobe Yuen  3 , Matthew Wongchenko  3 , Kalpit Shah  3 , Pratyush Gupta  3 , Priti Hegde  2 , Lincoln W Pasquina  2 , Sanjeev Mariathasan  3 , Ryon P Graf  2 , Thomas Powles  4
Affiliations
Clinical Trial

Circulating Tumor DNA Assessment for Treatment Monitoring Adds Value to PSA in Metastatic Castration-Resistant Prostate Cancer

Christopher J Sweeney et al. Clin Cancer Res. .

Abstract

Purpose: Enzalutamide after abiraterone progression is commonly used in metastatic castration-resistant prostate cancer despite a low rate of clinical benefit. Analyzing IMbassador250, a phase III trial assessing enzalutamide with or without atezolizumab after abiraterone, we hypothesized that baseline and early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients more likely to exhibit survival benefit from enzalutamide.

Experimental design: ctDNA was quantified from plasma samples using a tissue-agnostic assay without buffy coat sequencing. Baseline ctDNA TF, changes in ctDNA TF from baseline to cycle 3 day 1 (C3D1), and detection at C3D1 alone were compared with overall response rate, radiographic progression-free survival (rPFS), median OS (mOS), and 50% reduction in PSA.

Results: ctDNA TF detection at baseline and/or C3D1 was associated with shorter rPFS and OS in 494 evaluable patients. Detection of ctDNA TF at C3D1, with or without detection at cycle 1 day 1, was associated with worse rPFS and mOS than lack of detection. When ctDNA TF and PSA response at C3D1 were discordant, patients with (ctDNA TF undetected/PSA not reduced) had more favorable outcomes than (ctDNA TF detected/PSA reduced; mOS 22.1 vs. 16 months; P < 0.001).

Conclusions: In a large cohort of patients with metastatic castration-resistant prostate cancer receiving enzalutamide after abiraterone, we demonstrate the utility of a new tissue-agnostic assay for monitoring molecular response based on ctDNA TF detection and dynamics. ctDNA TF provides a minimally invasive, complementary biomarker to PSA testing and may refine personalized treatment approaches.

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Conflict of interest statement

C.J. Sweeney reports grants and personal fees from Roche/Genentech, Astellas, and Pfizer, as well as personal fees from Merck, Bayer, BMS, Janssen, and Foundation Medicine Inc. during the conduct of the study. M. Childress reports other support from Foundation Medicine Inc. during the conduct of the study and from Foundation Medicine Inc. outside the submitted work, as well as stock in Roche. J. He reports other support from Foundation Medicine Inc. during the conduct of the study and from Foundation Medicine Inc. outside the submitted work, as well as stock ownership in Roche. D. Fabrizio reports other support from Foundation Medicine and Roche outside the submitted work. O. Gjoerup reports personal fees from Foundation Medicine Inc. and other support from Roche during the conduct of the study. S. Morley reports other support from Foundation Medicine Inc. during the conduct of the study and from Foundation Medicine Inc. outside the submitted work, as well as stock ownership in Roche Holdings AG. T. Catlett reports personal fees from Foundation Medicine Inc. during the conduct of the study and other support from Roche outside the submitted work. Z.J. Assaf reports other support from Roche/Genentech during the conduct of the study. K. Yuen reports personal fees from Genentech during the conduct of the study. M. Wongchenko reports other support from Genentech/Roche during the conduct of the study and from Genentech/Roche outside the submitted work. K. Shah reports other support from Genentech during the conduct of the study. P. Gupta reports other support from Roche/Genentech outside the submitted work. P. Hegde reports personal fees from Roche outside the submitted work. L.W. Pasquina reports other support from Foundation Medicine Inc. during the conduct of the study and from Foundation Medicine Inc. outside the submitted work, as well as stock ownership in Roche Holdings AG. S. Mariathasan reports employment at Genentech, a subsidiary of Roche. R.P. Graf reports other support from Foundation Medicine Inc. during the conduct of the study and from Foundation Medicine Inc. outside the submitted work. T. Powles reports grants and personal fees from AstraZeneca, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Merck Serono, Seattle Genetics, Astellas, Johnson & Johnson, Eisai, and Roche, as well as personal fees from Incyte and from Mashup outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Lack of ctDNA TF detection at C3D1 is associated with more favorable outcomes. A, OS. B, rPFS for patients with ctDNA TF detected versus undetected at C3D1. BEP is represented. Index date is the time from initiation of therapy. Seven patients with a progression event prior to C3D1 were excluded from B. Gray boxes indicate the time from C1D1 to C3D1 required for inclusion in the analysis. CI, confidence interval; D, detected; HR, hazard ratio; ND, not detected.
Figure 2.
Figure 2.
Combined baseline and on-treatment ctDNA TF status further stratifies patient risk. A, OS. B, rPFS for patients stratified by baseline and C3D1 ctDNA TF status. BEP is represented. Index date is the time from initiation of therapy. Seven patients with a progression event prior to C3D1 were excluded from B. Gray boxes indicate the time from C1D1 to C3D1 required for inclusion in the analysis. D, detected; ND, not detected; NR, not reached.
Figure 3.
Figure 3.
Comparison of PSA, RECIST, and ctDNA TF as intermediate clinical endpoints. Multivariable model assessing ctDNA TF status at C3D1, ctDNA TF status at C1D1, PSA at C1D1, PSA response, PTEN loss, and DDR gene alterations for associations with (A) OS and (B) rPFS. C, C-index comparison of model performance for predicting OS. Error bars indicate standard error. TF and PSA values are categorical. “TF C1D1 and TF C3D1” includes the categorical response values at both timepoints in addition to a combination term. Axis of the C-index is displayed as starting at 0.5, consistent with the possible values of a C-index calculation.
Figure 4.
Figure 4.
ctDNA TF is more correlated with survival than PSA response in discordant cases. A, OS. B, rPFS for patients stratified by ctDNA TF and PSA response at C3D1. BEP is represented. Index date is the time from initiation of therapy. Seven patients with a progression event prior to C3D1 were excluded from B. TF D, ctDNA TF detected; TF ND, ctDNA TF not detected; PSA R, PSA reduced by >50%; PSA NR, PSA not reduced by >50%.
Figure 5.
Figure 5.
Patients with discordant imaging and PSA results can be stratified by TF. OS for patients without radiographic progression but lacking a PSA response (>50% reduction) stratified by TF response. Index date is the time from initiation of therapy. Gray box indicates the time from C1D1 to C3D1 required for inclusion in the analysis.
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