ASCO GU 2023: Evaluation of ctDNA in Patients Treated with Lutetium-177-PSMA-617

( The agent most recently approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) is 177Lu-PSMA-617. This agent represents as a small molecule which targets prostate specific membrane antigen (PSMA), a transmembrane cell surface protein highly conserved on prostate cells with significant increase following transformation and castration resistance. The payload for 177Lu-PSMA-617 emits beta particles to PSMA-expressing cells, as well as in select healthy tissues. Responses are common yet not uniform and causes of sensitivity and resistance are incompletely understood.

The authors sought to evaluate the ctDNA from patients treated with 177Lu-PSMA-617, with comparison between those with and without PSA response to identify genomic mediators of response and resistance. To do so, Dr. Lanka and colleagues retrospectively evaluated 31 patients treated with 177Lu-PSMA-617 at Tulane Cancer Center. PSA responses were judged by PCWG3 and binned into responders (n=18) and non-responders (n=13). ctDNA data were derived from commercial Guardant360 assays and mutational results were limited to those with at least 0.1% variant allele fraction and those deemed pathogenic or likely pathogenic by consensus. All patients had pre-treatment samples and 7 had paired pre- and post-treatment assessments.

No significant differences were detected in the ctDNA profile in the pre-treatment samples between responders and non-responders, with common alterations in known drivers of mCRPC, including AR, CDK12, and TP53. In contrast, a significant increase in copy number amplifications (CNAs) was noted in the pretreatment samples from non-responders (11/13, 84.6% v 7/1, 61.1%, OR 8.64, 95% C.I. [1.46, 51.25], p=0.025).


The most frequently amplified genes in non-responders included AR (8/13), CCNE1 (6/13), EGFR (4/13), and FGFR1 (4/13), with those in FGFR1 and CCNE1 significantly enriched versus responders.

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In those patients with paired ctDNA assessments, the association of amplifications with lack of response in pre-treatment samples was observed to continue, with amplifications increasing in detection.

The authors provide the conclusions that the presence of CNA, in particular in CCNE1 and FGFR1, in ctDNA correlate with a lack of PSA response following treatment with 177Lu-PSMA-617. Further analysis with larger cohorts and matched tissue samples may validate these data and allow more precise patient selection and also consideration of rational addition of a second therapeutic agent based on genomic targets to re-sensitize a patient with mCRPC to this beta-emitting radioligand therapy.

Presented by: Sree M. Lanka, MD, Tulane University School of Medicine, New Orleans, Louisiana

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 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.