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

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.