PSMA-positive Circulating Tumor Cell Detection and Outcomes with Abiraterone or Enzalutamide Treatment in Men with Metastatic Castrate-resistant Prostate Cancer

Purpose: In men with metastatic castration-resistant prostate cancer (mCRPC), prostate-specific membrane antigen (PSMA)targeted radioligand therapy has drastically improved clinical outcomes. A liquid biopsy characterizing PSMA expression could be useful in guiding optimal therapy. Experimental Design: We conducted a retrospective analysis of the prospective multicenter PROPHECY (Prospective CiRculating PrOstate Cancer Predictors in HighEr Risk mCRPC StudY) trial of men with mCRPC (n = 118) treated with abiraterone (abi) or enzalutamide (enza). Circulating tumor cells (CTC) 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-positive (PSMAþ) 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) of men had any PSMA CTC detection, 21% (16/78) had ≥2 PSMAþ CTCs/mL, and 19% (8/43) were 100% PSMAþ. 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% PSMAþ CTCs. Among paired cases (n = 57), PSMAþ CTC detection increased slightly after abi/enza progression. Using an optimal cutoff of ≥2 PSMAþ CTCs/mL, median OS was 26, 21, and 11 months for men without CTCs, PSMA- CTCs, and PSMAþ CTCs. Adjusting for prior abi/enza therapy, Halabi clinical risk score, and CTC enumeration, the HRs for OS and PFS for PSMAþ CTCþ were 3.0 [95% confidence interval (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.