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

Abstract

Rationale: PSMA-PET-CT enables measuring molecular expression of prostate-specific membrane antigen (PSMA) in vivo, which is the target molecule of ¹⁷⁷Lu-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 ⁶⁸Ga-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.

Keywords: PSMA PET; PSMA radioligand therapy; prognosticator; prostate cancer.

Figure 1

Survival stratified by quartiles of PSMA-PET parameters. Estimated median overall survival (OS) in months (mo.) is shown together with the 95% Confidence Interval (in parentheses). Log rank test was used to compare OS between quartiles.

Figure 2

Survival stratified by high, intermediate and low PSMA expression. There was no relevant correlation between PSMA_min and PSMA_average (A, linear regression and 95% CI interval). Therefore, the combination of both PET parameters enabled an optimized stratification according to overall survival (B). Exemplary patients of the high (C), intermediate (D) and low (E) overall survival group were shown additionally.

Figure 3

Relations of baseline PSMA-PET parameters. PSMA-PET parameters were grouped by history of Cabazitaxel chemotherapy (= Caba; A+B) or presence of liver metastases (= Liv. mets; C+D); there were no statistically significant differences. There was a high correlation of PSMA_std and PSMA_average and a moderate correlation of PSMA_max and PSMA_average (E+F, linear regression and 95% CI interval).