The Prognostic Value of Posttreatment 68 Ga-PSMA-11 PET/CT and 18 F-FDG PET/CT in Metastatic Castration-Resistant Prostate Cancer Treated with 177 Lu-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 prostate 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 Lu-PSMA-617 therapy. Fifty-six men with progressive metastatic castration-resistant prostate cancer were enrolled in the LuPIN trial and received up to 6 doses of Lu-PSMA-617 and a radiation sensitizer (NOX66). Ga-PSMA-11 and F-FDG PET/CT, diagnostic CT, and bone scanning were performed at study entry and exit. Quantitative analysis tracked change in total tumor volume (TTV) and SUV. Univariable and multivariable analyses were conducted to examine the association of change in TTV (continuous and >30%), SUV , PSA, and radiographic progression with PSA PFS and OS. All men (37/56) who underwent both screening and posttreatment 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 SUV was demonstrated 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; = 0.002). Change in PSMA SUV was not associated with PSA PFS or OS. F-FDG SUV was reduced in 51% (18/35) and F-FDG TTV in 67% (22/35). An increased F-FDG SUV was associated with worse OS (median, 20.7 vs. 25.7 mo; < 0.01). An F-FDG TTV increase by more than 30% was associated with a short PSA PFS (median, 3.5 vs. 8.6 mo; < 0.001) but not OS. Both PSA and radiographic progression were associated with shorter OS (median, 14.5 vs. 25.7 mo [ < 0.001] and 12.2 vs. 23.6 mo [ = 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; = 0.008] and 3.5 [95% CI, 1.1-10.9; = 0.03], respectively). Change in quantitative PSMA TTV has strong potential as a prognostic biomarker with Lu-PSMA-617 therapy, independent of F-FDG PET parameters, PSA, or radiographic progression. Further research into the value of posttreatment PET as an imaging biomarker is warranted.