Analysis of PSMA expression and outcome in patients with advanced Prostate Cancer receiving (177)Lu-PSMA-617 Radioligand Therapy

Rationale: PSMA-PET-CT enables measuring molecular expression of prostate-specific membrane antigen (PSMA) in vivo, which is the target molecule of (177)Lu-PSMA-617 (Lu-PSMA) therapy. However, the correlation of PSMA expression and overall survival (OS) in patients treated with Lu-PSMA therapy is currently unclear; especially with regard to coexistence of high and low PSMA expressing metastases. To this end, this retrospective single arm study elucidates the correlation of PSMA expression and overall survival in patients treated with Lu-PSMA therapy. Additionally, PET based criteria to define low PSMA expression were explored. Methods: Eighty-five patients referred to Lu-PSMA therapy were included in the analysis. Pretherapeutic (68)Ga-PSMA-PET-CT scans were available for all patients. SUV(max) of the highest PSMA expressing metastasis (PSMA(max)), SUV(max) of the lowest PSMA expressing metastasis (PSMA(min)), and average SUV(max) of all metastases (PSMA(average)) amongst other PET parameters were measured for each patient. A log-rank cutoff-finder was used to determine low (lowPSMA(average)) and high (highPSMA(average)) average PSMA expression as well as low (lowPSMA(min)) and high (highPSMA(min)) minimal PSMA expression. Results: PSMA(average) was a significant prognosticator of overall survival in contrast to PSMA(max) (HR: 0.959; p = 0.047 vs. HR: 0.992; p = 0.231). Optimal log rank cut-offs were: PSMA(average) = 14.3; PSMA(min) = 10.2. Patients with low average PSMA expression (lowPSMA(average)) had significantly shorter survival compared to those with high average expression (highPSMA(average)) (5.3 vs. 15.1 months; p < 0.001; HR: 3.738, 95%CI = 1.953-7.154; p < 0.001). Patients with low PSMA expressing metastases (lowPSMA(min)) had shorter survival compared to those without a low PSMA expressing metastasis (highPSMA(min)) (p = 0.003; 7.9 months vs. 21.3; HR: 4.303, 95%CI = 1.521-12.178; p = 0.006). Patients that were classified as highPSMA(average) but with lowPSMA(min) had an intermediate overall survival (11.4 months; longer compared to lowPSMA(average), 5.3 months, p = 0.002; but shorter compared to highPSMA(min), 21.3 months, p = 0.02). Conclusion: Low average PSMA expression is a negative prognosticator of overall survival. Absence of low PSMA expressing metastases is associated with best overall survival and the maximum PSMA expression seems not suited to prognosticate overall survival. Low PSMA expression might therefore be a negative prognosticator for the outcome of patients treated with Lu-PSMA therapy. Future studies are warranted to elucidate the degree of low PSMA expression tolerable for Lu-PSMA therapy.