Editor’s Note: At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium (GU ASCO), Dr. Martin Gleave from the University of British Columbia presented the latest data from the GUNS study (Genomic Umbrella Neoadjuvant Study). The presentation focused on the pathological responses of high-risk prostate cancer (PCa) patients with aggressive genomic alterations treated with neoadjuvant androgen receptor pathway inhibitor (ARPI) triplet versus doublet regimens.01 GUNS Study Design: A Genome-Driven “Umbrella” Neoadjuvant Exploration
GUNS is a neoadjuvant umbrella clinical trial targeting high-volume, high-grade, high-risk prostate cancer, designed to evaluate pathological responses as a surrogate for “contextual lethality.” The study utilizes a two-stage approach: all enrolled patients first undergo an 8-week Master Protocol treatment consisting of an ARPI doublet (apalutamide + ADT). During this period, genomic profiling is performed via biopsy, and patients are subsequently assigned to one of six sub-protocols based on their specific genomic vulnerabilities.
02 Sub-protocol 2: Focus on Aggressive Tumor Suppressor Gene Loss
The core of this report involves Sub-protocol 2, which enrolled patients harboring aggressive genomic alterations, including TP53 mutations, PTEN copy number loss or mutation, RB1 loss, and AKT gains. Following the initial 8-week phase, these patients were randomized into two arms:
- ARPI Doublet Arm: Abiraterone + prednisone + ADT.
- ARPI Triplet Arm: The doublet regimen plus docetaxel.
Sub-protocol 2 enrolled 48 men, with well-balanced clinicopathological characteristics between the arms. Notably, this cohort demonstrated higher rates of intraductal carcinoma (IDC) and clinical N1 disease compared to the overall study population, highlighting the highly aggressive nature of this subtype.
03 Pathological Response: Triplet Regimen Significantly Elevates MRD Rates
The primary endpoint was minimal residual disease (MRD), defined as a residual cancer burden (RCB) of <5 mm.
- Key Data: The MRD rate was significantly higher in the ARPI-chemo triplet arm compared to the ARPI doublet arm, at 37% (9/23) versus 0% (0/24), respectively.
- Deep Response: One pathologic complete response (pCR) was observed in the triplet arm. Furthermore, average degenerative scores were higher in the triplet group compared to the doublet group.
Based on these results, Sub-protocol 2 met the criteria for expansion to its second stage, with a target enrollment of 45 patients.
04 Genomic Correlation: Predictive Value of SPOP and ETS Fusions
Dr. Gleave presented a correlation analysis between genomic landscapes and MRD status across 202 evaluable pre-treatment biopsies:
- SPOP Mutations: Associated with favorable pathological responses and higher MRD rates.
- ETS Fusions: Associated with a higher likelihood of non-MRD (less favorable) responses.
- Composite Alterations: Loss of PTEN and TP53 was strongly linked to the presence of IDC, a correlation that was even more pronounced when combined with ETS fusions, explicitly linking an aggressive genotype to an aggressive phenotype.
Conclusion and Future Perspectives
A comparison between Sub-protocol 1 (AR-associated alterations without tumor suppressor gene loss) and Sub-protocol 2 revealed that in patients with aggressive tumor suppressor gene (TSG) loss, the MRD rate with ARPI doublet therapy alone was essentially zero.
Dr. Martin Gleave concluded that the GUNS study data demonstrate that for high-risk prostate cancer with aggressive genomic features, a triplet regimen (ARPI + docetaxel) yields a significantly deeper pathological response than a doublet regimen alone. These findings underscore the critical role of genomic stratification in neoadjuvant settings. Moving forward, pre- and post-treatment omics analyses will further refine our understanding of treatment sensitivity and resistance, guiding the evolution of biomarker-targeted combination regimens for high-risk prostate cancer.
