SINGLE-ARM PHASE II STUDY OF NEOADJUVANT INTENSIFIED ANDROGEN DEPRIVATION IN COMBINATION WITH AKT INHIBITION (CAPIVASERTIB) FOR HIGH-RISK LOCALIZED PROSTATE CANCER WITH PTEN LOSS (SNARE)

Abstract

Introduction

High-risk prostate cancers (PCa) treated surgically commonly exhibit loss of the phosphatase and tensin homologue (PTEN) tumor suppressor gene, which leads to increased activity of the protein kinase B (AKT) signaling pathway. PTEN loss is associated with higher rates of PCa recurrence, metastasis, and cancer mortality. Manipulation of androgen receptor (AR) pathway to reduce mortality has been a focus of PCa therapy for decades; however, PTEN loss is a lead mechanism for PCa resistance to AR directed therapy and development of castrate resistant PCa. Pre-clinical research identified a reciprocal feedback regulation between the PTEN/AKT signaling axis and the AR signaling axis that could be overcome by blocking both pathways. This study will perform a single arm Phase II trial combining intensified androgen deprivation (iADT; abiraterone and leuprolide) with AKT inhibition (AKTi, capivasertib) prior to radical prostatectomy among high-risk localized prostate cancers with PTEN loss.

Methods

The SNARE trial (NCT05593497) is a Veterans Affairs (VA) multicenter, single arm phase II study for neoadjuvant iADT with capivasertib with integral biomarker design. Key eligibility includes high-risk PCa defined as ≥1 criterion: resectable cT3; Grade Group ≥4; Memorial Sloan Kettering nomogram 5-year progression free probability ≤50% with either PSA >20 ng/ml or Grade Group 3. Subjects must have ≤10% PTEN staining (central IHC). Intervention includes iADT 4-week run-in, tumor biopsy (for molecular correlates), 16 weeks combined iADT with AKTi, then radical prostatectomy. The primary endpoint is pathological response (pT0 or minimal residual disease ≤5mm, central review). We will screen 160 subjects (estimate PTEN loss in 20%) to enroll 30 participants to compare 20% pathological response vs. null hypothesis of 5% (historical ADT alone). Secondary endpoints include medical and surgical safety and molecular correlates (DNA, RNA, Nanostring DSP protein) with response. SNARE is currently open to enrollment at 4 sites.