Martin Gleave, MD, on biomarker-driven neoadjuvant strategies in prostate cancer

In the following video, Martin Gleave, MD, FRCSC, FACS, outlines how the adaptive, biomarker-driven GUNS trial (NCT04812366) is using the neoadjuvant setting to better understand and potentially overcome therapeutic resistance in high-risk prostate cancer.¹ Gleave is a distinguished professor and head of the Department of Urologic Sciences at the University of British Columbia in Canada.

Gleave explains that GUNS was designed in response to the growing role of genomics in guiding prostate cancer treatment, as well as the need to better characterize how tumors develop resistance. By treating patients with high-risk localized disease prior to prostatectomy, the trial enables paired pre- and posttreatment tissue analyses to identify adaptive molecular changes in residual tumors. The study uses an adaptive umbrella design, assigning patients to biomarker-defined sub-protocols testing different combination strategies. This approach allows ineffective regimens to be discontinued early while expanding those that demonstrate activity, effectively moving precision oncology into the presurgical setting.

Key findings from 2 subprotocols highlight the implications of this approach. Subprotocol 1, which enrolls patients with androgen receptor (AR)–driven tumors (eg, ETS fusions, FOXA1, SPOP), showed that intensification with an ARPI triplet (apalutamide plus abiraterone with androgen deprivation therapy) more than doubled pathologic response rates compared with an ARPI doublet (48% vs 16%, respectively), supporting expansion. Subprotocol 2 focused on genomically aggressive tumors harboring TP53, PTEN, or AKT alterations. In this cohort, the addition of docetaxel to an ARPI backbone significantly improved minimal residual disease rates vs doublet (39% vs 0%; P = .016).

Although these findings were conducted in the neoadjuvant setting, Gleave emphasizes that they have implications for advanced disease. The results support the concept that patients with high-risk genomic features, particularly TP53 or PTEN alterations, may benefit from treatment intensification with chemotherapy-containing triplets. Ongoing molecular analyses, including DNA, RNA, and spatial profiling, are expected to further elucidate mechanisms of resistance and refine biomarker-driven treatment strategies across disease states.

REFERENCE

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.