Background <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> Graphical abstract <p></p>