Background: GUNS (NCT04812366) is a multi-centre adaptive phase II trial evaluating 24 weeks of biomarker-selected, neoadjuvant ARPI therapies on depth of pathologic response (<5 mm minimal residual disease [MRD]) in high risk localized prostate cancer (HRLPC). After 8 weeks of an ARPI doublet (LHRHa + apalutamide [APA]), men are assigned to 1 of 4 sub-protocols (SP) combining 16 weeks of an ARPI doublet with drugs defined by specific genomic biomarkers. SP-1 enrolls men with AR-associated genomic^alt (ETS fusions, FOXA1, SPOP) treated with an ARPI doublet +/- abiraterone. SP-2 randomises men with aggressive genomic^alt (RB1, PTEN, TP53, AKT) to an ARPI doublet +/- docetaxel. Biomarkers like PTEN loss are needed to identify men who benefit from ADT-docetaxel, and here we investigate pathologic response to ARPI-docetaxel triplet in a biomarker selected HRLPC setting.

Methods: Diagnostic biopsies underwent Tempus’ CLIA-certified 648-gene panel DNA sequencing (seq) and whole-transcriptome RNA-seq. This analysis focuses genomic analyses on the first 151 biopsies, and pathologic response rates in 48 men enrolled to the 1^st stage of SP-2 who completed neoadjuvant therapy and surgery.

Results: DNA-seq from 129/151 biopsies reveals a genomic landscape dominated by ETS gene fusions (36%), FOXA1 (23%), TP53 (16%), SPOP (14%), PTEN (13%), and BRCA2 (9%) alterations. Overall tumor mutational burden of HRLPC in GUNS is similar to metastatic PC and enriched for the unfavorable luminal PCS1 transcriptomic subtype. PTEN was IHC negative (≤10% positive PC cells) in 18%, half of whom had no reported genomic PTEN^alt. Most PTEN^alt cases, especially HOMDELs, were PTEN-IHC^neg, but 2 PTEN^HOMDEL cases were ≥50% PTEN-IHC^pos, illustrating intra-patient or sampling heterogeneity. PTEN-IHC^neg or TP53 genomic^alt, especially combined with an ETS fusion, was associated with intraductal carcinoma (IDC). SP-2 randomized 48 men with aggressive genomic^alt (TP53, PTEN, AKT) to an ARPI doublet (SP-2a) alone or with 6 cycles of docetaxel (SP-2b). MRD rates were significantly higher in SP-2b (26% vs 0%, p-value = 0.0463). Positive margin (17%) and lymph node (37% vs 28%) status were similar. While genomic PTEN^alt were excluded from SP-1, men assigned to SP-1 who were later found to be PTEN-IHC^neg were more likely to be non-MRD (6/7) than MRD (1/7), suggesting PTEN-IHC^neg may reduce response to ARPI. A detailed report on adverse events, clinical correlates, as well as PTEN status by IHC, genomic, and transcriptomic concordance data, will be presented.

Conclusions: SP-2 associated genomic^alt (TP53, PTEN, AKT) comprise 30% of the alterations in GUNS. Significantly higher rates of MRD in SP-2b patients treated with an ARPI-docetaxel triplet are of interest and support further evaluation with 2^nd stage expansion of SP-2. Clinical trial information: NCT04812366.

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