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

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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 <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
.