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

BACKGROUND

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.

RESULTS

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.

CONCLUSIONS

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.