ASCO 2022: On-Treatment Plasma ctDNA Fraction and Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer

(UroToday.com) Androgen receptor pathway inhibitors (ARPIs) are highly active in both castration sensitive prostate cancer, where they are the standard of care, and in castration resistant disease, the clinical state where they were previously typically applied. Despite their activity, rapid development of resistance can occur, including in 20-30% of ARPI-naïve patients with metasetatic CRPC according to this study’s authors. Identification of treatment resistance early, prior to standard forms of objective progression, would allow more timely treatment augmentation.


Tolmeijer and colleagues hypothesized that plasma ctDNA fraction (ctDNA%) as measured after 4 weeks on treatment will identify the patients with mCRPC who will have non-durable responses to first ARPI. To test this, the authors measured ctDNA% using integrated deep- and shallow whole genome sequencing. Samples were considered as detected (≥1%) or undetected (<1%). Radiographic and/or clinical progression-free survival (rcPFS) and overall survival (OS) were outcome measures. All rcPFS ≤6 months were declared non-durable. Samples were collected from plasma ctDNA samples from 81 patients with mCRPC collected at baseline and following 4 week following initiation of ARPI from two prospective multi-center observational studies (NCT02426333; NCT02471469).

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Of the 81 patients with evaluable samples, 33 patients did not have ctDNA detected at both baseline and 4 weeks. 19 patients converted from detected to undetected and 29 has detected ctDNA at both time points. Among these groups, those with ctDNA at both time points experienced the shortest rcPFS (HR 4.79, p<0.001) and OS (HR 5.49, p<0.001). the association between ctDNA% change and outcome data were independent of alkaline phosphatase, LDH, and PSA, as well as baseline ctDNA%.

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Expanding on these data, the authors calculated positive predictive value (PPV) and negative predictive values (NPV) for ctDNA% at 4 weeks. Change in ctDNA% at 4 weeks for predicting non-durable response had a PPV of 88% and NPV of 92%.

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The authors concluded that ctDNA% as early as 1 month on treatment are strongly linked to duration of first-line ARPI treatment benefit in mCRPC. Such metrics could have powerful utility for informing patient trajectory.

Presented by: Sofie H. Tolmeijer, PhD, Department of Medical Oncology, Radboud Institute of Molecular Sciences, Radboud University Medical Center, Nijmegen, Netherlands

Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at NewYork-Presbyterian Hospital. @DrJonesNauseef on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.