The Prognostic Value of Posttreatment 68Ga-PSMA-11 PET/ CT and 18F-FDG PET/CT in Metastatic Castration-Resistant Prostate Cancer Treated with 177Lu-PSMA-617 and NOX66 in a Phase I/II Trial (LuPIN)

Lu-PSMA-617 therapy has shown high prostate-specific antigen (PSA) response rates in men with metastatic castration-resistant pros-tate cancer. However, early treatment resistance is common. This LuPIN substudy aimed to determine the prognostic value of posttreatment quantitative PET for PSA progression-free survival (PFS) and overall survival (OS) with 177Lu-PSMA-617 therapy.Methods: Fifty-six men with progressive metastatic castration-resistant prostate cancer were enrolled in the LuPIN trial and received up to 6 doses of 177Lu-PSMA-617 and a radiation sensitizer (NOX66). 68Ga-PSMA-11 and 18F-FDG PET/CT, diagnostic CT, and bone scanning were performed at study entry and exit. Quantitative analysis tracked change in total tumor vol-ume (TTV) and SUV. Univariable and multivariable analyses were con-ducted to examine the association of change in TTV (continuous and >30%), SUVmax, PSA, and radiographic progression with PSA PFS and OS.Results: All men (37/56) who underwent both screening and post-treatment molecular imaging were analyzed; 70% (26/37) had a PSA response of more than 50%. Median PSA PFS was 8.6 mo, and median OS was 22 mo. Clinical progression had occurred at trial exit in 54% (20/37). In response to treatment, a reduced PSMA SUVmax was demon-strated in 95% (35/37) and a reduced PSMA TTV in 68% (25/37). An increase in PSMA TTV by at least 30% was associated with worse OS (median, 10.2 vs. 23.6 mo; P = 0.002). Change in PSMA SUVmax was not associated with PSA PFS or OS. 18F-FDG SUVmax was reduced in 51% (18/35) and 18F-FDG TTV in 67% (22/35). An increased 18F-FDG SUVmax was associated with worse OS (median, 20.7 vs. 25.7 mo; P < 0.01). An 18F-FDG TTV increase by more than 30% was associated with a short PSA PFS (median, 3.5 vs. 8.6 mo; P < 0.001) but not OS. Both PSA and radiographic progression were associated with shorter OS (median, 14.5 vs. 25.7 mo [P < 0.001] and 12.2 vs. 23.6 mo [P = 0.002]). On multivariable analysis, only increased PSMA TTV and PSA progression remained independently prognostic of OS (hazard ratio, 5.1 [95% CI, 1.5-17.1; P = 0.008] and 3.5 [95% CI, 1.1-10.9; P = 0.03], respectively).Conclusion: Change in quantitative PSMA TTV has strong potential as a prognostic biomarker with 177Lu-PSMA-617 therapy, independent of 18F-FDG PET parameters, PSA, or radiographic progres-sion. Further research into the value of posttreatment PET as an imaging biomarker is warranted.

Automated summary

Lu-PSMA-617 therapy has shown high PSA response rates in men with metastatic castration-resistant prostate cancer, but early treatment resistance is common. This study aimed to determine the prognostic value of posttreatment quantitative PET for PSA progression-free survival and overall survival with 177Lu-PSMA-617 therapy.