Combining PSMA-PET metrics and circulating tumor cell RNA sequencing to predict LuPSMA response.

261 Background: Metastatic castrate-resistant prostate cancer (mCRPC) is a deadly and incurable disease. Targeted radioligand therapies such as 177 Lu-PSMA-617 (LuPSMA) are a promising new class of treatment for men with mCRPC progressing after standard therapy. There remain challenges in patient selection and predictive biomarkers for clinical response. Circulating tumor cells (CTCs) are a minimally invasive source of tumor material to explore biomarkers. We previously reported the largest CTC RNA sequencing cohort of patients with mPC to date and defined four CTC transcriptional phenotype associated with prognosis in mCRPC, and found that the poor prognosis Luminal-B like (LumB) CTC phenotype was associated with early progression on LuPSMA. Here we evaluate the intersection between CTC and imaging biomarkers for LuPSMA to elucidate a biomarker-driven framework for stratifying mCRPC patients most likely to benefit from LuPSMA therapy. Methods: Pretreatment CTCs were isolated from a prospective cohort of 37 patients with mCRPC undergoing LuPSMA therapy using automated microfluidic technology. CTCs were captured via immune-magnetics and analyzed via RNA-seq, followed by CTC transcriptional phenotype classification and quantification of FOLH1 gene expression. The following features were extracted from pretreatment PSMA PET scans available for 25/37 patients: whole-body PSMA-positive disease volume, tumor mean and tumor maximum SUV. Association between CTC phenotypes and PSMA PET metrics and impact on clinical response was evaluated. Results: CTC FOLH1 expression was significantly higher in patients with PSMA-positive disease volume above median (p = 0.0324). CTC FOLH1 expression and pretreatment PSMA PET metrics were not different between patients with LumB versus non-LumB CTC phenotypes. Patients with early progression within the first 3 cycles (18 weeks) of treatment had higher PSMA-positive disease volume compared to patients who did not (p = 0.04). 5/8 patients with early progression had a LumB CTC phenotype compared to 2/16 patients without early progression (p=0.0207). 0/6 patients with a pretreatment tumor PSMA SUVmax above the median and a non-LumB CTC phenotype experienced early progression, while 2/2 patients with pretreatment tumor PSMA SUVmax below the median and a LumB CTC phenotype experienced early progression (p=0.0196). Conclusions: Combining functional imaging with CTC transcriptional phenotype shows potential for refining the selection of patients for LuPSMA therapy to maximize likelihood of response.