We identified several consistent pretreatment factors linked with inferior outcomes, including prior chemotherapy, poor performance status, visceral metastases—particularly liver involvement—and lower hemoglobin levels. Notably, prior chemotherapy was associated with a 39% higher risk of death, and liver metastases conferred more than a twofold increased risk, highlighting the aggressive biology of such disease subsets. In contrast, patients with higher pre-treatment PSMA uptake (SUVmean) on PET imaging demonstrated significantly better overall survival, reinforcing the biological rationale that PSMA expression directly reflects therapeutic targetability.
Our analysis also confirmed the prognostic value of PSA kinetics. Achieving a ≥50% decline in PSA following PSMA-RLT was strongly correlated with prolonged progression-free and overall survival, underscoring its utility as an early on-treatment biomarker of response.
Collectively, these findings provide an evidence-based framework for patient selection, timing, and treatment monitoring in the era of PSMA theranostics. Importantly, our data support the potential advantage of administering PSMA-RLT earlier in the disease course, before chemotherapy, as ongoing trials such as PSMAfore and ENZA-p are exploring. Furthermore, high pre-treatment PSMA uptake may serve not only as a prognostic marker but also as a predictive biomarker for therapeutic efficacy, guiding treatment personalization.
In summary, our study highlights that disease burden, prior systemic therapy, hematologic condition, and molecular imaging characteristics all shape the clinical benefit derived from PSMA-RLT. By integrating these parameters, clinicians can better identify patients most likely to achieve durable benefit and optimize sequencing strategies in mCRPC management.
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan.
- Theranostics Yokohama, Yokohama, Japan.
- Second Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland.