Matching Neoadjuvant Therapy to Tumor Genomics in High-Risk Prostate Cancer

In an interview with CancerNetwork® at the 44th Annual Chemotherapy Foundation Symposium (CFS), Martin Gleave, CM, MD, FRCSC, FACS, distinguished professor in the Department of Urologic Sciences at the University of British Columbia in Vancouver, Canada, discussed what the Genomic Umbrella Neoadjuvant Study (GUNS; NCT04812366) has shown about biomarker-directed neoadjuvant therapy in high-risk localized prostate cancer.

GUNS is a multicenter, adaptive phase 2 trial evaluating 24 weeks of biomarker-selected neoadjuvant androgen receptor pathway inhibitor (ARPI)–based therapy before radical prostatectomy, with depth of pathologic response as the primary measure.¹ Subprotocol 1 enrolls patients with androgen receptor–associated alterations, such as ETS fusions, FOXA1, and SPOP, who receive an ARPI doublet with or without abiraterone. Subprotocol 2 randomly assigns patients with aggressive alterations, such as TP53, PTEN, RB1, and AKT, to an ARPI doublet with or without docetaxel. Among 48 patients in the first stage of subprotocol 2, minimal residual disease rates were 26% with the docetaxel triplet vs 0% with the doublet (P = .0463).

The trial builds on the phase 3 PROTEUS trial (NCT03767244), in which perioperative apalutamide plus androgen deprivation therapy (ADT) improved metastasis-free survival vs placebo plus ADT in patients with high-risk localized or locally advanced prostate cancer undergoing radical prostatectomy (HR, 0.80; 95% CI, 0.67-0.96).² Gleave is the principal investigator of GUNS and a coauthor of the PROTEUS publication.

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CancerNetwork: What has the GUNS trial taught us about biomarker-directed neoadjuvant therapy, and how close is molecular profiling to guiding perioperative decisions?

Gleave: Right now, what PROTEUS, ENZARAD, and the DASL-HiCaP high-risk trials are teaching us is that we are using clinicopathologic risk stratification to decide who would benefit from treatment intensification with an ARPI doublet vs ADT alone. We know that in advanced prostate cancer, we can improve outcomes by building on an ARPI doublet: adding a PARP inhibitor for BRCA-altered disease, adding an AKT inhibitor for PTEN-altered disease, and potentially adding chemotherapy for aggressive phenotypes. The question is whether we can improve outcomes if we further stratify high-risk localized prostate cancer into genomic baskets where we understand the biology, or at least have a therapeutic tool that exploits that underlying biology.

PROTEUS accepts and treats all high-risk phenotypes the same, but we know that not all high-risk prostate cancers share the same genomics, so they do not share the same vulnerabilities to androgen receptor (AR)-pathway inhibition alone. Some subgroups are more sensitive to AR pathway inhibitors, and that is one area GUNS is testing. If you enroll only patients with genomic alterations that drive AR biology, such as SPOP and FOXA1 alterations, and exclude the alterations that drive an aggressive biology, such as TP53 and PTEN, you may identify a group of patients who are more sensitive to AR pathway inhibition. That is what the subprotocol 1 analysis from GUNS is demonstrating: by intensifying from an ARPI doublet to a triplet with abiraterone, we are seeing a greater depth of pathologic response.

The next question is whether that depth of pathologic response translates into something clinically meaningful, such as a delay in metastasis-free survival. That will require a hypothesis-testing trial. GUNS is a hypothesis-generating trial designed to provide sufficient information to justify a much larger study of clinically meaningful end points.

The other segment of GUNS reported thus far is subprotocol 2, the aggressive genotype. We know that TP53 alteration, PTEN loss, AKT gain, and RB1 loss are associated with an aggressive phenotype, one that responds poorly, or at least only briefly, to an ARPI doublet. We asked whether we could deepen the pathologic response by intensifying that doublet to a triplet with docetaxel chemotherapy. Subprotocol 2 is showing that patients with an aggressive genotype do not have any deep pathologic responses to an ARPI doublet alone. When you add docetaxel as a triplet, we see a shift in residual cancer burden toward lower volumes, as well as a major pathologic response in about 25% of patients.

That suggests that when we treat patients with aggressive genomic alterations, we should be thinking about how to intensify therapy, at least in more advanced disease. That is ultimately what is being done with the addition of chemotherapy in the PEACE trials and the addition of an AKT inhibitor for PTEN-altered disease. In the future, we have to ask whether we can bring that into a hypothesis-testing study. That will hopefully be the next wave of neoadjuvant studies.

References

1. Gleave M, Scurll J, Belanger E, et al. Genomic alterations and pathologic responses to neoadjuvant androgen receptor pathway inhibitor (ARPI) doublets vs docetaxel triplets in the Genomic Umbrella Neoadjuvant Study (GUNS). J Clin Oncol. 2026;44(suppl 7):309. doi:10.1200/JCO.2026.44.7_suppl.309
2. Taplin ME, Gleave M, Shore ND, et al. Perioperative apalutamide in high-risk localized prostate cancer. N Engl J Med. 2026;395(6):546-560. doi:10.1056/NEJMoa2603878