Summary
PSMA-targeted radioligand therapy (RLT) benefits patients with metastatic castration resistant prostate cancer (mCRPC), but up to 40% derive limited benefit. As RLT moves into earlier lines and combination settings, it becomes increasingly important to understand who is most likely to respond, and why resistance develops. Defining the molecular patterns of response and resistance will be essential to improve patient selection, guide therapy sequencing and optimize the use of RLT in clinical practice. This study evaluated baseline clinical and genomic predictors of response to Lu-177-PSMA-617 using harmonized real-world data and liquid biopsy genomics.
Methods
We analyzed 305 patients with mCRPC treated with Lu-177-PSMA-617and standardized Guardant Health (GH) liquid-biopsy genomic profiling from ConcertAI’s Prostate Translational360™ (an integrated EHR, claims, and social determinants of health linked with molecular datasets). Baseline variables included prior ARPI/taxane exposure, metastatic pattern, and labs for prostate-specific antigen (PSA), alkaline phosphatase (ALP), and hemoglobin (Hgb). Baseline genomics were grouped by pathway: AR, PTEN, HRR (limited to commonly reported genes across GH assays), and exploratory (FGFR1/EGFR/CTNNB1). Maximum variant allele fraction (mVAF) and tumor mutational burden (TMB) were evaluated as measures of genomic burden. Outcomes evaluated were PSA50 ≤12 weeks, PSA90 ≤12 weeks, progression free survival (PFS), time to next treatment (TTNT) and overall survival (OS).
Results
The cohort was heavily pre-treated (≥2 ARPIs 60%, ≥2 taxanes 56%) and predominantly bone-dominant (80% bone-only, 15% visceral ±bone). Median baseline PSA = 17.1ng/mL; mVAF= 1.0% [IQR 0.3-5.7]; TMB =8.3mut/Mb [IQR 5.8-11.1]. PSA50≤12w was achieved by 33% and PSA90 by 10%. AR amplification (HR: 1.99 PFS, 2.3 OS) and PTEN (HR: 1.33 PFS, 1.3 OS) were associated with shorted PFS and OS compared with wt-tumors. Similarly, exploratory alterations (HR: 2.56 PFS, 3.21 OS) showed adverse outcomes, whereas HRR mutations (HR: 1.15 PFS, 1.46 OS) were not independently associated with response.
Conclusions
Baseline AR activation, PTEN, and alternative pathway alterations identify mCRPC patients less likely to benefit from PSMA-RLT, while bone dominant disease and wt-profiles show more favorable outcomes. Integrating genomic profiling into RLT eligibility and trial design could optimize patient selection and guide early combination strategies. Subsequent analyses will expand to multi-tested patients to validate these predictors across real world platforms.
