PSMA-PET response under [177Lu]Lu-PSMA therapy: Comparison of RECIST, PERCIST, PPP, adapted PCWG4 and RECIP criteria

We aimed to compare various imaging-based response criteria in men with metastatic castration-resistant prostate cancer (mCRPC) treated with [ 177 Lu]Lu-Prostate-specific membrane antigen radioligand therapy (LuPSMA). This retrospective study included 84 men who received a median of 4 [ 177 Lu]PSMA cycles (IQR 2–5) and median of 24.3 GBq (IQR 14.9–32.9 GBq) at the Department of Nuclear Medicine at University Hospital Essen between March 2019 and May 2022. Response assessments were conducted comparing baseline PET/CT and PET/CT at 6–8 weeks after second cycle of LuPSMA using multiple criteria: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the adapted Prostate Cancer Working Group Criteria 4 (aPCWG4) without follow-up confirmation, Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST), the PSMA PET Progression (PPP), and Response Evaluation Criteria in PSMA-Imaging 1.0 (RECIP) with visual assessment or different quantitative volumetry methods (qPSMA, SUV ≥ 4). Responses were categorized as progressive disease (PD) or non-PD. The primary endpoint was the prognostic significance of these response criteria for overall survival, evaluated via Cox regression analysis. Harrell`s C-index was used for concordance of different imaging-based criteria and survival. A total of 34 (40.5%) patients had non-measurable disease according to RECIST. Twenty (40%), 41 (48.8%), 44 (52.4%), 47 (56.0%), 35 (41.7%), 37 (44.0%), and 31 (36.9%) of patients had PD according to RECIST 1.1, aPCWG4, PERCIST, PPP, RECIP qPSMA, RECIP SUV ≥ 4, and visual RECIP respectively. PD patients had a significantly higher risk of death compared to non-PD patients according to all response criteria as follows: RECIST 1.1 (HR = 5.0; 95%CI, 2.5–10.0; p < 0.001), PERCIST (HR = 2.9; 95%CI, 1.8–4.8; p < 0.001), aPCWG4 (HR = 3.6; 95%CI, 2.1–6.0; p < 0.001), PPP (HR = 3.9; 95%CI, 2.3–6.6; p < 0.001), RECIP qPSMA (HR = 2.7; 95%CI, 1.6–4.4; p < 0.001), RECIP SUV ≥ 4 (HR = 2.2; 95%CI, 1.6–3.6; p < 0.001) and visual RECIP (HR = 3.5; 95%CI, 2.1–6.0; p < 0.001). Highest C-indices were observed for PPP: 0.68 (95%CI, 0.58–0.77), and aPCWG4: 0.67 (95%CI, 0.57–0.77) in comparison to PERCIST: 0.65 (95%CI, 0.54–0.75), visual RECIP: 0.63 (95%CI, 0.52–0.73), RECIP qPSMA: 0.62 (95%CI, 0.51–0.74) and, RECIP SUV ≥ 4: 0.62 (95%CI, 0.50–0.73). Disease progression during [ 177 Lu]PSMA in interim PET imaging, as indicated by any of the evaluated criteria, was associated with elevated risk of death. PSMA PET Progression (PPP) and aPCWG4 demonstrated the highest concordance with overall survival whereas RECIP had lowest PD rate. These findings support the prognostic value and consistency of PSMA-PET response assessment during [ 177 Lu]PSMA and highlight the need for standardized, reproducible longitudinal response criteria and support their validation in large, prospective multicenter studies.