PET-Based Outcome Prediction in Patients with Prostate Cancer Scheduled for [ ²²⁵ Ac]Ac-PSMA Radiopharmaceutical Therapy

²²⁵Ac-labeled prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy (RPT) has emerged as a promising treatment option in advanced metastatic castration-resistant prostate cancer. We aimed to identify predictors for outcome including established clinical and PSMA-directed imaging parameters at baseline. <b>Methods:</b> Twenty-six patients with metastatic castration-resistant prostate cancer who were receiving [²²⁵Ac]Ac-PSMA-I&T RPT were included in this retrospective monocentric study. In each patient, all metastases on pretherapeutic [¹⁸F]F-PSMA-1007 PET/CT were segmented, enabling assessment of averaged SUV_max, SUV_mean, as well as summed PSMA tumor volume (PSMA-TV) and PSMA-total lesion quotient (PSMA-TLQ; defined as PSMA-TV divided by SUV_mean). PET parameters were then correlated with the relative prostate-specific antigen (PSA) change after 2 cycles of [²²⁵Ac]Ac-PSMA-I&T RPT. In addition, the predictive values for early progressive disease (PD; defined as a PSA increase of more than 25% or PD according to RECIP 1.0) after 2 cycles, progression-free survival (PFS), and overall survival (OS) were explored. <b>Results:</b> SUV_max (<i>r</i> = -0.42, <i>P</i> = 0.031) and SUV_mean (<i>r</i> = -0.4, <i>P</i> = 0.046) correlated significantly with PSA change after 2 cycles, but PSMA-TV (<i>P</i> = 0.51) and PSMA-TLQ (<i>P</i> = 0.83) did not. Eleven patients (42%) demonstrated early PD. SUV_max (odds ratio, 0.769; <i>P</i> = 0.032) and SUV_mean (odds ratio, 0.427; <i>P</i> = 0.041) were predictive for early PD. SUV_mean emerged as the strongest predictor for prolonged PFS (hazard ratio [HR], 0.501; <i>P</i> = 0.006) with SUV_max also trending toward significance (HR, 0.914; <i>P</i> = 0.054). Patients with a high SUV_mean achieved a longer median PFS of 134 d compared with 39 d in patients with low SUV_mean (HR, 0.369; <i>P</i> = 0.041). PSMA-TLQ (HR, 1.007; <i>P</i> = 0.027) and PSMA-TV (HR, 1.001; <i>P</i> = 0.037) were predictive for OS. Patients with a low PSMA-TLQ (reflecting low PSMA-TV in combination with high SUV_mean) achieved a longer median OS of 375 d compared with 148 d in patients with high PSMA-TLQ (HR, 2.84; <i>P</i> = 0.043). <b>Conclusion:</b> In patients scheduled for [²²⁵Ac]Ac-PSMA-I&T RPT, SUV_mean on pretherapeutic [¹⁸F]F-PSMA-1007 PET/CT is predictive for early treatment response by identifying individuals prone to early PD and shorter PFS. In addition, PSMA-TLQ is associated with OS. As such, pretherapeutic PSMA PET-based quantification may optimize patient selection for targeted α-RPT.