1390P Circulating tumor DNA (ctDNA) and prognosis with PSMA-targeted radionuclide therapy (TRT)

Abstract

PSMA-TRT is approved for mCRPC based upon demonstrated overall survival (OS) advantage. However, even after pre-selection by PSMA imaging, not all patients respond (54% without PSA50 response in the VISION study). In addition to dose (which is likely related to both target expression and amount of radioactivity administered), prognostic genomic factors that may relate to radiosensitivity exist. Collection of real-time tissue biopsies in the setting of mCRPC presents challenges that might be overcome with the use of ctDNA. Germline control + plasma DNA were obtained prior to treatment in 2 prospective trials of PSMA-TRT and assayed utilizing the PCF SELECT (Specific Evaluation in Liquid biopsies of Established prostate Cancer Targets) platform. Variables of interest included AR copy number (wild-type vs gain), homologous recombination repair (HRR) gene copy number (wild-type vs loss), and allele-specific ploidy (asP; diploid vs high). asP is a novel metric for genomic instability and loss of heterozygosity, computed as the weighted mean of the allele-specific copy number of homologous chromosomes (Ciani et al. Cell Systems 2022). Cox regression modelling was used to assess the association of these variables with clinical outcome measures of >50% PSA response (PSA50) and OS. 80 patients received PSMA-TRT (177Lu-PSMA-617 n=50; 225Ac-J591 n=30). High asP was associated with poorer OS (HR 2.14, 95% CI 1.15-4, p=0.017) and a trend to lower rates of achieving PSA50 (OR 0.48, 95% CI 0.16-1.47, p=0.20). AR copy number gain was associated with poorer OS (HR 2.69, 95% CI 1.40-5.18, p=0.003) and lower rates of PSA50 (OR 0.47, 95% CI 0.14-1.49, p=0.20). In this study, HRR gene copy number loss was not associated with differential responses or OS. Similar results as this combined study were obtained when individual studies of 177Lu-PSMA-617 or 225Ac-J591 were analyzed for AR copy number and asP. ctDNA analysis, a non-invasive technique, in patients undergoing PSMA-TRT demonstrate that AR copy number gain and high allele-specific ploidy, reflecting genomic instability and complex karyotype, are associated with poorer prognosis.