213 - Circulating Tumor Cell-Based Molecular Biomarkers of ¹⁷⁷Lu-PSMA-617 Treatment Efficacy in Metastatic Prostate Cancer

Y. Miyazawa¹, A. Konik², K. Otani¹, R. Pittie¹, E. Chung¹, D. J. Rodden¹, J. P. Kelly¹, M. Shan³, K. H. Xu³, Y. Otani¹, X. Gao⁴, B. Kako⁵, A. OShea⁵, P. Heidari⁵, J. Dejan⁴, N. Chevalier⁴, M. A. Miller⁶, L. Nieman³, T. S. C. Ng⁵, and D. T. Miyamoto^1,3; ¹Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ²Dana-Farber Cancer Institute, Boston, MA, ³Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, ⁴Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ⁵Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ⁶Center for Systems Biology, Massachusetts General Hospital, Boston, MA

Purpose/Objective(s): Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (¹⁷⁷Lu-PSMA-617) has demonstrated clinical efficacy for metastatic castration-resistant prostate cancer (mCRPC) with PSMA-PET positive disease. However, not all mCRPC patients with PSMA-avid disease benefit, and there is an unmet need for novel biomarkers to predict treatment efficacy. We evaluated whether circulating tumor cell (CTC) molecular analyses may provide biomarkers of ¹⁷⁷Lu-PSMA-617 treatment efficacy. Materials/

Methods: This single-institution biomarker study enrolled men with mCRPC initiating ¹⁷⁷Lu-PSMA-617. Informed consent was obtained (DF-HCC 13-416). A microfluidic device (CTC-iChip) was used to isolate CTCs from blood samples before starting ¹⁷⁷Lu-PSMA-617. For each patient, half of CTCs were immunostained using antibodies against cytokeratin, EpCAM, and PSMA, counterstained for CD45 to exclude leukocytes, and imaged using Vectra Polaris multispectral microscopy. The remaining CTCs were analyzed using droplet digital polymerase chain reaction for gene expression profiling of 8 prostate-specific genes (FAT1, KLK2, STEAP2, TMPRSS2, AGR2, FOLH1, HOXB13, KLK3) used to calculate a previously validated CTC_M score, as well as the androgen receptor splice variant AR-V7. The algorithm of Contal-OQuigley was applied using leave-one-out jackknife resampling to determine the optimal division point within the CTC_M score for PSA progression-free survival (PFS), calculated using the Kaplan-Meier method.
Results: Blood samples were analyzed from 14 enrolled patients with a median follow-up of 6.1 months (range 3-13). The median age was 71.5 years (range 53-79). Median CTC count was 10.3 cells/7.5 mL, and median % of PSMA-negative CTCs was 23.9%. Patients with more CTCs (>10.3 cells/7.5 mL) and a higher proportion of PSMA-negative cells (>23.9%) had a significantly worse median PSA-PFS compared to other patients (116 days vs. not yet reached; log-rank p = 0.0383). Pre-treatment CTC_M score correlated with the best %PSA response during treatment (r = 0.73, p = 0.0033). The low CTC_M score group had significantly better PSA-PFS than the high CTC_M score group (median PSA-PFS not yet reached for low CTC_M score vs. 56 days for high CTC_M score; log-rank p = 0.0011). Pre-treatment AR-V7 positivity was associated with significantly poorer PSA-PFS than AR-V7 negative patients (median PSA-PFS not yet reached for AR-V7 negative vs. 56 days for AR-V7 positive; log-rank p = 0.0223).
Conclusion: Our preliminary results suggest that molecular analyses of CTCs may predict ¹⁷⁷Lu-PSMA-617 treatment efficacy in mCRPC patients, complementary to PSMA-PET metrics. This motivates continued validation of these findings.