Loading
Prostate Cancer Treatment and Research / Prostate Cancer Diagnosis and Treatment · Journal article
Clinical Cancer Research · August 13, 2026
Well-designed and adequately powered for the question it asks.
This clinico-genomic study identifies SPEN inactivation as a biomarker of resistance to androgen receptor pathway inhibitors across multiple analytical levels. In a large metastatic prostate cancer cohort, SPEN mutations are associated with significantly shorter time to next treatment (6.4 vs 29.7 months), and low SPEN protein expression predicts reduced benefit from abiraterone in a separate rapid autopsy validation cohort.
Retrospective clinico-genomic cohort study with functional cell line screening and independent rapid autopsy validation. Primary cohort: patients from a nationwide prostate cancer clinico-genomic database with metastatic disease and ARPI exposure. Validation cohort: metastatic prostate cancer patients (both hormone-sensitive and castration-resistant) in a rapid autopsy tissue microarray.. Intervention: SPEN mutation status (presence vs absence) or SPEN protein expression level (H-score) measured in patients receiving ARPI therapy (enzalutamide, abiraterone, or other ARPIs).. Compared with: Comparison between SPEN-mutant and SPEN wild-type patients (genomic analysis); comparison between low and high SPEN H-score (protein expression analysis).. n = 6,828. Nationwide clinico-genomic database (country not specified); rapid autopsy cohort (location not specified)..
SPEN mutations enriched post-ARPI treatment: 2.1% to 3.6% (p=0.001) SPEN mutations correlate with shorter TTNT on ARPI: 6.4 vs 29.7 months, HR 2.67, p=0.02 in metastatic hormone-sensitive prostate cancer Low SPEN H-score associated with shorter time on abiraterone: 5.0 vs 7.9 months, p=0.023 in metastatic castration-resistant prostate cancer
Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.
SPEN inactivation status may have utility as a predictive biomarker to identify metastatic prostate cancer patients at high risk of early ARPI treatment failure. However, the authors appropriately note this is an association requiring prospective validation before clinical implementation; current evidence does not yet support routine SPEN testing to guide treatment decisions.
Rigorous multi-level evidence (functional screens, large clinico-genomic cohort analysis with survival endpoints, and independent rapid autopsy validation) demonstrating SPEN inactivation as a biomarker associated with reduced ARPI benefit in metastatic prostate cancer.
As stated by the source record.
Quoted from the source exactly as published.
SPEN inactivation status may have utility as a predictive biomarker to identify metastatic prostate cancer patients at high risk of early ARPI treatment failure. However, the authors appropriately note this is an association requiring prospective validation before clinical implementation; current evidence does not yet support routine SPEN testing to guide treatment decisions.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract Purpose: Treatment intensification with androgen receptor pathway inhibitors (ARPIs) has become the standard of care for patients with metastatic prostate cancer. However, there remains an unmet need to identify biomarkers for treatment resistance. Here, we identify SPEN inactivation as a driver of ARPI resistance. Experimental Design: Pre-clinical studies were performed in LNCaP and VCaP cell lines. Data from a nationwide prostate cancer clinico-genomic database were extracted. Log-rank test and Cox proportional hazards models were used to compare time to next treatment (TTNT) on ARPI with/without SPEN mutations. SPEN immunohistochemistry was performed on a rapid autopsy metastatic tissue microarray. Results: SPEN was identified as a top enzalutamide resistance hit in an unbiased genome-wide loss-of-function screen. SPEN inactivation results in upregulation of cell cycle proliferation and basal/stem cell activity as well as increased translation of pro-oncogenic genes. In a large patient cohort (N=6828), SPEN mutations are enriched following treatment with ARPIs (2.1% to 3.6%, p=0.001) and correlate with shorter TTNT on ARPI in patients with metastatic hormone-sensitive prostate cancer (6.4 vs 29.7 months, HR 2.67, p=0.02). In a metastatic rapid autopsy cohort (N=181), low SPEN H-score is associated with shorter time on abiraterone (5.0 vs 7.9 months, p=0.023) in metastatic castration-resistant prostate cancer. Conclusions: In real-world cohorts, loss of SPEN function across genomic, transcriptomic, and protein levels is associated with reduced benefit from ARPI therapy in metastatic prostate cancer. These findings identify SPEN inactivation as a clinically relevant biomarker of ARPI resistance that warrants prospective evaluation to guide treatment selection.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.