Abstract 532: Circulating tumor DNA and outcomes with lutetium-PSMA in advanced prostate cancer: Preliminary results from an Australian study

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Abstract Recent clinical trials have revealed that Lutetium PSMA-617 (Lu-PSMA, a small molecular inhibitor of prostate-specific membrane antigen radiolabelled with the beta emitter 177-Lutetium) significantly improves clinical outcomes including overall survival for patients with metastatic castration resistant prostate cancer (mCRPC). Nevertheless, owing to the highly heterogeneous nature of mCRPC, responses to Lu-PSMA therapy can be variable, with resistance inevitable. Currently, there are no existing data on the genomic landscape of mCRPC in the context of this therapy, with the identification of biomarkers linked to outcomes with Lu-PSMA being a critical unmet need in order to select patients most likely to benefit from treatment and to dissect mechanisms of resistance. mCRPC patients with high PSMA expression on positron emission tomography scans and prior treatment with docetaxel chemotherapy and an androgen receptor pathway inhibitor were enrolled on a compassionate access prospective registry at Peter MacCallum Cancer Centre. Patients received Lu-PSMA every 6 weeks for 4-6 cycles and entered into follow-up. Peripheral blood samples were collected for plasma circulating tumour DNA (ctDNA) analysis at baseline and prior to cycle 2 of therapy. A highly-sensitive targeted next-generation sequencing assay was applied to patient plasma and matched leukocytes. Somatic mutations (single nucleotide variants/indels) and copy number alterations from 43 genes were reported, along with the estimated ctDNA fraction. Current patient numbers preclude formal statistical analysis of genomic aberrations, however dynamic changes in ctDNA were assessed in relation to prostate-specific antigen (PSA) response and clinical and/or radiographic progression. In total, 19 plasma samples were analysed from 13 mCRPC patients with a median age of 71. Patients had between one and four prior lines of therapy for mCRPC and had a median time on Lu-PSMA therapy of 3.7 months. ctDNA was detected in 17/19 plasma samples with a median fraction of 26% (range 0-89%). Overall, a PSA response rate of 54% was observed. Interestingly, patients with higher baseline ctDNA fractions were more likely to experience a PSA response to Lu-PSMA therapy (median ctDNA fraction of responders 49% vs 10% in non-responders, p=0.1). Additionally, no PSA responses were seen in patients who did not attain a reduction in plasma ctDNA from baseline to cycle 2. This is the first targeted assessment of serial plasma samples from patients receiving Lu-PSMA therapy. Using a highly sensitive liquid biopsy assay, ctDNA was detectable in almost all samples. In this preliminary analysis, both baseline ctDNA fraction and early dynamic changes in ctDNA fraction appear to have clinical importance in Lu-PSMA therapy. Recruitment to this registry is proceeding rapidly, with further data available by April 2022. Citation Format: Heidi Fettke, Nicole Ng, Christine Hauser, Patricia Bukczynska, Elizabeth Medhurst, Louise Kostos, James Buteau, Jason Steen, Tu Nguyen-Dumont, Michael Hofman, Arun A. Azad. Circulating tumor DNA and outcomes with lutetium-PSMA in advanced prostate cancer: Preliminary results from an Australian study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 532.

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