# Exploratory case series of circulating tumor DNA dynamics during tandem therapy in metastatic castration-resistant prostate cancer

## TL;DR

This study explores how tracking tumor DNA in blood can help monitor treatment response and resistance in prostate cancer patients receiving a new type of radiopharmaceutical therapy.

## Contribution

The study introduces longitudinal ctDNA tumor fraction analysis as a novel biomarker for early detection of treatment response and resistance in actinium-lutetium therapy for mCRPC.

## Key findings

- Patient 1 achieved complete remission with undetectable PSA and ctDNA tumor fraction after two treatment cycles.
- ctDNA tumor fraction increased before PSA levels in some patients, indicating earlier detection of disease progression.
- Patient 4 showed rapid disease progression with increasing ctDNA tumor fraction and PSA levels by the second treatment cycle.

## Abstract

Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy (RPT) with the alpha-emitter actinium-225 (225Ac) has shown promising activity in metastatic castration-resistant prostate cancer (mCRPC), but its use is limited by toxicity. A tandem approach combining [225Ac]Ac-PSMA-617 and [177Lu]Lu-PSMA-617 (actinium-lutetium) has been developed to mitigate adverse effects and optimize efficacy. Given the scarcity of 225Ac and the emergence of resistance, early identification of non-responders is crucial. Circulating tumor DNA (ctDNA), especially tumor fraction (TFx) estimated from ultra-low-pass whole genome sequencing (ULP-WGS) using ichorCNA, may provide a non-invasive biomarker for monitoring treatment response. Blood samples were collected from mCRPC patients treated with actinium-lutetium bimonthly. Cell-free DNA (cfDNA) was extracted and analyzed by ULP-WGS (≤ 7 × coverage). TFx was derived using ichorCNA and compared longitudinally with prostate-specific antigen (PSA) and imaging data.

Patient 1 achieved complete remission with undetectable PSA and TFx after two cycles. Patient 2 showed a strong and sustained therapeutic response; however, after a prolonged treatment hiatus, ctDNA analysis detected genomic progression despite stable PSA levels. Patient 3 initially responded to therapy, but TFx began rising during the third cycle, preceding PSA relapse, indicating early disease progression. Patient 4, classified as a non-responder, showed only transient TFx reduction and experienced rapid disease progression, with increasing PSA and TFx levels already by the second cycle.

Longitudinal ctDNA TFx dynamics enable early detection of response and resistance to actinium-lutetium in mCRPC and may complement PSMA imaging to guide timely, personalized treatment decisions.

The online version contains supplementary material available at 10.1186/s13550-026-01388-x.