PROSTest: Blood mRNA Assay Predicts 177Lu-PSMA Success in mCRPC After One Cycle

A study presented at the 2025 Society of Urologic Oncology (SUO) Annual Meeting has introduced PROSTest, a novel blood-based mRNA assay that accurately predicts treatment outcomes for 177Lu-PSMA radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC) patients. The multi-center investigation analyzed 268 PET-positive mCRPC patients from centers in Munster, Basel, and Essen, all with median age 73 years who received a median of two cycles of therapy, revealing that PROSTest score changes after just one cycle strongly correlate with progression-free survival (PFS) and overall survival (OS). This 27-gene qPCR assay, measuring prostate cancer-specific transcripts from whole blood and processed via machine learning for a 0-100 score (cutoff ≥50 positive), offers a minimally invasive tool to identify early responders, potentially enabling personalized treatment decisions beyond current PSMA-PET eligibility criteria that fail to predict responses reliably.​

In the study, 50% of patients (133/268) achieved PSA nadir responses greater than 50%, with median PFS of 15 months (95% CI: 8.7-15) versus 4.4 months (95% CI: 3.4-6.1) in non-responders; prostate cancer deaths occurred in 49% (130 patients), with median OS of 8.6 months (95% CI: 7.4-11.2) among deceased cases. All patients had positive baseline PROSTest scores, but post-first-cycle decreases marked superior outcomes: 90% of responders showed score reductions, while 75% of progressors had increases, yielding hazard ratios of 0.37 (95% CI: 0.36-0.71) for PFS and 0.26 (95% CI: 0.18-0.37) for OS—indicating 63% and 74% lower risks, respectively, for those with declining scores. Validated previously with 94% sensitivity and 88% specificity (AUROC 0.97) across 143 patients versus controls, PROSTest’s reproducibility and concordance with tumor tissue biology position it as a sensitive biomarker capturing circulating tumor RNA dynamics reflective of therapy response.​

Developed from public tumor mRNA databases using machine learning to select a minimal 27-gene signature including prostate lineage transcripts like KLK3 and FOLH1, PROSTest outperforms PSA kinetics alone by providing molecular insights after minimal exposure, addressing a key gap in 177Lu-PSMA management where early discontinuation could avoid toxicity in non-responders. Compared to urine-based assays like SelectMDx or kallikrein panels (AUC 0.77-0.90), its whole-blood approach and therapy-monitoring utility stand out, complementing nomograms incorporating hemoglobin or metastases status (C-index 0.70).

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