Early changes in PROSTest, a blood-based mRNA assay, as a predictor of outcomes of ¹⁷⁷ LuPSMA radioligand therapy and chemotherapy in metastatic castration-resistant prostate cancer.

Abstract

e17067 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains associated with heterogeneous responses to systemic therapies, including chemotherapy and PSMA-targeted radioligand therapy (RLT). PROSTest is a novel blood-based molecular assay designed to quantify prostate cancer–associated transcriptional activity. This study (NCT06872619) evaluated whether early changes in PROSTest following initiation of 177 Lu-PSMA or Taxotere therapy predict sustained treatment benefit, as assessed by progression-free survival (PFS) and overall survival (OS). Methods: Sixty-five patients with mCRPC (median age 73 years; range 58–89) treated with ¹⁷⁷Lu-PSMA RLT ( n = 46) or docetaxel ( n = 19) were investigated. Samples for PSA were collected prior to every cycle and PSA measured (standard clinical assays). Response (PFS) was categorized by PSA nadir (> -50% decreases from baseline). Changes in PROSTest (directly after 1 cycle vs baseline) were correlated with PFS or OS using AUROC, Kaplan-Meier survival analysis and hazard ratios. Results: Thirty-six patients (55%) achieved treatment response, while 29 (45%) were non-responders. Median PFS was 5.7 months (95% CI: 3.8–9.1), and median OS was 12.0 months (95% CI: 10.2–20). PROSTest was positive in all subjects at baseline (100% sensitivity). Early decreases in PROSTest scores following one treatment cycle were strongly associated with improved outcomes. Patients demonstrating score reductions exhibited markedly prolonged PFS (median not reached) compared with those with increased scores (median PFS 3.3 months [95% CI: 2.1–3.9]). PROSTest score decreases were significantly associated with both PFS (HR = 0.18 [0.08–0.39]) and OS (HR = 0.23 [0.11–0.46]). Overall, early PROSTest changes predicted treatment response with 80.0% accuracy (52/65) and OS with 66.1% accuracy (43/65). Conclusions: Early molecular changes measured by PROSTest were significantly associated with both PFS and OS in patients with mCRPC receiving chemotherapy or PSMA-targeted RLT. Importantly, PROSTest reflects tumor-associated molecular activity distinct from PSA and provided early response stratification after one treatment cycle, supporting its potential utility as a complementary pharmacodynamic biomarker beyond conventional PSA-based assessment. These findings suggest that PROSTest may enable earlier identification of therapeutic benefit, inform patient stratification, and support adaptive treatment strategies. Prospective validation is warranted to define its role in optimizing clinical management and guiding combination approaches. Clinical trial information: NCT06872619 .