Genomic alterations and their pathologic responses in high-risk localized prostate cancer (HRLPC) in subprotocol 1 of the Genomic Umbrella Neoadjuvant study (GUNS).
Authors: Martin Gleave, Eric Belanger, Joshua Scurll, Htoo Zarni Oo, Lucia Nappi, Himisha Beltran, Alexander William Wyatt, Miles Mannas, Peter Colin Black, Amina Zoubeidi, Jonathan Ma, Doron Berlin, Tiiu Sildva, Theo Van Der Kwast, Neil Eric Fleshner
Journal: Journal of Clinical Oncology (2025)

403 Background: GUNS (NCT04812366) is a multicenter adaptive phase II trial evaluating 24 weeks of biomarker-selected, neoadjuvant androgen receptor pathway inhibitor (ARPI) combination therapies on depth of pathologic response (complete response [pCR] or &lt;5 mm minimal residual disease [MRD]) in HRLPC. After 8 weeks of LHRHa + apalutamide (APA), participants are assigned to 1 of 4 sub-protocols (SP) combining 16 weeks of an ARPI doublet with drugs defined by specific genomic alterations (e.g. SP-2, docetaxel for RB1 , PTEN , TP53 loss; SP-3, niraparib for DNA-repair def ; SP-4, atezolizumab for mismatch-repair def ). SP-1 randomises men without these aggressive genomic alt and includes those that enhance AR activity (ETS fusions, FOXA1 , SPOP ) to either SP-1a (LHRHa + APA) or SP-1b (LHRHa + APA + abiraterone acetate/prednisone). SP-1 tests the hypothesis that ARPI triplet intensification, in cancers with AR-associated genomic alt , will increase depth of pathologic response. Methods: From 9/2021 to 8/2024, GUNS enrolled 95 and 30 men at University of BC and Toronto, respectively. Diagnostic biopsies underwent Tempus’ CLIA-certified 648-gene panel DNA sequencing (seq) and whole-transcriptome RNA-seq. This analysis focuses on 46 men enrolled to the 1 st stage of SP-1 who completed neoadjuvant therapy and surgery. Results: DNA-seq from 105/125 patients reveals a genomic landscape dominated by AR-associated alterations ( 36% ETS fusion, 23% FOXA1, 13% SPOP ). Other frequently altered genes were TP53 (14%), PTEN (12%), and BRCA2 (9%). Transcriptomes largely cluster in alignment with ETS fusions and SPOP status. ETS fusions were associated with PCS2-luminal-subtype and decreased proliferative signatures, whereas most other genomic alt were associated with PCS1-luminal-subtype. AR signatures associated with SPOP and FOXA1 mutations but not ETS fusions. 46 men, equally balanced for high-risk features and genomic alt , were randomized to SP-1a or SP-1b. Undetectable pre-surgery PSA levels trended higher in SP-1b (16/23) vs. SP-1a (11/23), but was not statistically significant (p = 0.12). While there were no pCR, MRD rates were significantly higher in SP-1b compared to SP-1a (43% vs 13%, p=0.012, odds ratio = 5.9). Degenerative scores (morphologic indicators of treatment stress) also averaged higher in SP-1b vs. SP-1a. Positive margin (17%) and lymph node (35% vs 26%) status were similar in both arms. Although genomic PTEN alt were assigned to SP-2, 7 patients in SP-1 were found to be PTEN neg by IHC and 6 were non-MRD; PTEN-IHC neg trended more common in non-MRD (21%) than MRD (8%) cases. Conclusions: SP-1 associated genomic alt (ETS fusion, FOXA1, SPOP) are the most frequent alterations in GUNS. Significantly higher rates of MRD in SP-1 patients treated with an ARPI triplet vs. doublet are of interest and support further evaluation with 2 nd stage expansion. Clinical trial information: NCT04812366 .