Early PSA Change after [(177)Lu]PSMA-617 Radioligand Therapy as a Predicator of Biochemical Response and Overall Survival

SIMPLE SUMMARY: Radioligand therapy with [(177)Lu]PSMA-617 (PSMA-RLT) is a promising therapeutic option for metastatic castration-resistant prostate cancers (mCRPC), as its clinical relevance has recently been confirmed in the phase III VISION-trial. As prostate-specific antigen (PSA) plays an important role in the response evaluation of this therapy, and the aim of this study was to prospectively assess the prognostic value of early PSA measurements. We found PSA changes as early as four weeks after the first administration of PSMA-RLT to be predictive of both long-term biochemical and PET imaging response, as well as overall survival. We then evaluated relevant predictive thresholds in PSA change at that time point, as the early detection of long-term (non-)response to PSMA-RLT can be of great benefit in the clinical management of terminally ill mCRPC-patients. ABSTRACT: Purpose: Radioligand therapy with [(177)Lu]PSMA-617 (PSMA-RLT) is a promising therapeutic option for metastatic castration-resistant prostate cancer (mCPRP). This study assessed the prognostic value of early PSA measurements during PSMA-RLT. Methods: 27 patients with mCRPC scheduled for PSMA-RLT were prospectively enrolled for a serial short-interval PSA-assessment. Change in PSA (∆%PSA) during two treatment cycles was correlated with biochemical response (BR) and change in tumor volume on PET (TV) after 16 weeks (w16), as well as overall survival (OS). PCWG3 criteria and the recently recommended threshold of ∆%PSA ≤ −30% were assessed for their predictive value. Results: ∆%PSA first correlated with BR, TV and OS after 4 weeks (c1w4). At c1w4, ∆%PSA ≤ −30% was associated with the biochemical response at w16 (p = 0.003) and a longer median OS (p = 0.025), whereas the PCWG3-derived threshold of ∆%PSA ≤ −50% showed no such correlation. In contrast, ∆%PSA ≥ 25% at c1w4 was associated with biochemical progression at w16 (p = 0.003) and a shorter median OS (p < 0.001). Conclusion: PSA changes as early as four weeks after PSMA-RLT allow a significant prediction of later biochemical and PET-based imaging response, as well as OS. At this early time point, a more lenient threshold for a PSA decrease of at least 30% appears better-suited for the prediction of a positive biochemical response and longer OS. In contrast, the PCWG3-derived threshold for PSA increase (+25%) reliably anticipates biochemical progression and shorter OS.