Genomic Alterations and Pathologic Responses to Androgen Receptor Pathway Inhibitor Doublets vs. Triplets in the Phase-II Genomic Umbrella Neoadjuvant Study (GUNS) in High-Risk Localized Prostate Cancer
Year: 2026
Type: preprint
Abstract: GUNS (NCT04812366) is a multi-centre adaptive umbrella phase-II neoadjuvant trial evaluating 24 weeks of biomarker-directed therapy on major pathologic response (MPR) and residual cancer burden (RCB) in men with high-risk localized prostate cancer (HR-LPC) undergoing radical prostatectomy. MPR was defined by ≤ 5 mm longest diameter of the dominant focus or viable RCB ≤ 1 mm 2 . Diagnostic biopsies underwent Tempus’ 648-gene DNA and whole-transcriptome RNA sequencing (seq). After 8 weeks of androgen receptor pathway inhibitor (ARPI) doublet therapy with androgen deprivation (ADT) plus apalutamide (APA), men were assigned to sub-protocols (SPs) defined by genomic alterations (alt) for an additional 16 weeks of an ARPI-doublet with or without additional therapy. SP-1 randomized men with AR-associated (ETS fusions, FOXA1 , SPOP ) or otherwise favourable genomic alterations to continue ARPI-doublet (SP-1A) versus triplet therapy that includes another ARPI, abiraterone (SP-1B). SP-2 randomized men with aggressive genomic alterations ( RB1 , PTEN , TP53 , AKT1 ) to ARPI-doublet (SP-2A) versus triplet therapy with docetaxel chemotherapy (SP-2B). This analysis reports genomic and pathologic response data for 100 evaluable men enrolled in SP-1 and 48 in SP-2, out of 322 participants enrolled in GUNS. DNA-seq revealed a genomic landscape dominated by ETS gene fusions (41%), FOXA1 (22%), TP53 (19%), PTEN (15%), and SPOP (12%) alterations. In SP-1, MPR was significantly higher in patients treated with triplet (SP-1B) versus doublet (SP-1A) therapy (58% vs. 32%, p = 0.0045) and overall RCB was lower (median 0.73 vs. 2.79 mm 2 , p = 0.012). In SP-2, MPR was significantly higher with ARPI-docetaxel triplet (SP-2B) versus doublet (SP-2A) therapy (25% vs. 0%, p = 0.011) with a 4.6-fold reduction in median RCB (7.6 vs. 34.6 mm 2 , p = 0.083). Secondary endpoints included ypN1 rates, which trended lower in SP-1B vs. SP-1A (14% vs. 28%) and SP-2B vs. SP-2A (29% vs. 46%). ERG fusions tended to have higher RCB, and SPOP alt and FOXA1 alt lower RCB, in SP-1, while PTEN-deficient tumours with a concurrent ETS fusion had the worst pathologic outcomes in SP-2. Transcriptomically, baseline AR signalling was strongly associated with lower RCB following ARPI-only combinations, while immunological signatures were unfavourable, associations that were not seen with docetaxel in SP-2B. In conclusion, genomic-biomarker-directed ARPI-triplet therapies improve MPR rates and RCB distributions in men with HR-LPC, supporting further validation in trials to evolve selection of treatment intensification strategies.
Source: Research Square
Authors: Martin Gleave, Joshua Scurll, Himisha Beltran, Eric Belanger, Htoo Zarni Oo, Alexander Wyatt, Miles Mannas, Peter Black, Amina Zoubeidi, Jonathan Ma, Doron Berlin, Susan Prendeville, Di Jiang, Brant Inman, Brian Chapin, Todd Morgan, Zachery Reichert, Adam Kibel, Marc Dall’Era, Mamta Parikh, Michael Schweizer, Daniel Lin, Rodney Breau, Lucia Nappi, Neil Fleshner
Institutions: University of British Columbia, Vancouver Prostate Centre, Harvard University, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, University Health Network, London Health Sciences Centre, The University of Texas MD Anderson Cancer Center, University of Michigan, Brigham and Women's Hospital, UC Davis Comprehensive Cancer Center, University of Washington, University of Ottawa
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225330259