PSMA-positive circulating tumor cell detection and outcomes with abiraterone or enzalutamide treatment in men with metastatic castrate resistant prostate cancer.

BACKGROUND: In men with mCRPC, PSMA-targeted radioligand therapy has drastically improved clinical outcomes. A liquid biopsy characterizing PSMA expression could be useful in guiding optimal therapy.

METHODS: We conducted a retrospective analysis of the prospective multicenter PROPHECY trial of men with mCRPC (n=118) treated with abiraterone (abi) or enzalutamide (enza). CTCs were enriched (CTC/mL) and characterized for PSMA protein expression/heterogeneity at baseline and progression. We utilized proportional hazards modeling of the association between PSMA+ CTC enumeration with overall survival(OS) and progression free survival(PFS).

RESULTS: Overall, 97 men with mCRPC had evaluable blood samples for baseline CTC PSMA detection; 78 men (80%) had detectable CTCs. Of these, 55%(43/78) men had any PSMA CTC detection, 21%(16/78) had ≥2 PSMA+ CTCs/mL, and 19%(8/43) were 100% PSMA positive. At progression on abi/enza, 88%(50/57) of men had detectable CTCs, 68%(34/50) had any PSMA CTCs, and 12%(4/34) had 100% PSMA+ CTCs. Among paired cases (n=57), PSMA+ CTC detection increased slightly after abi/enza progression. Using an optimal cut-off of ≥2 PSMA+ CTCs/mL, median OS was 26, 21, and 11 mo for men without CTCs, PSMA- CTCs, and PSMA+ CTCs. Adjusting for prior abi/enza therapy, Halabi clinical risk-score, and CTC enumeration, the hazard ratios for OS and PFS for PSMA+ CTC+ were 3.0 (95% CI=1.1-7.8) and 2.3 (95%CI=0.9-5.8).

CONCLUSIONS: We observed PSMA CTC heterogeneity between and within patients with mCRPC over time during abi/enza progression. CTC PSMA enumeration was adversely prognostic independent of clinical factors and disease burden. Further validation is warranted in the context of PSMA-targeted therapies.