Precision Neoadjuvant Therapy for High Risk Localized Prostate Cancer with PTEN Loss

Portland Va Medical Center, Portland OR

Investigators

Abstract

Project Background: Prostate cancer is the second leading cause of cancer deaths in men in the United States. Prostate cancer treatment options fare historically based on clinical stage, prostate specific antigen (PSA) blood test, and tumor grade. Recent advances in molecular research have shown that a common finding in high-risk cancers prostate cancers that are surgically removed is loss of the phosphatase and tensin homologue (PTEN) tumor suppressor gene, which leads to increased activity of the AKT signaling pathway. PTEN loss is associated with higher rates of prostate cancer recurrence, metastasis, and cancer mortality. Pre- clinical laboratory research has shown a reciprocal feedback regulation between the PTEN/AKT signaling axis and the Androgen Receptor (AR) signaling axis. Manipulation of androgens and AR have been the focus of prostate cancer systemic therapy for decades; however, PTEN loss is a lead mechanism for prostate cancer resistance to AR directed therapy and development of castrate resistant prostate cancer. Project Objectives: This study will change standard localized treatment (radical prostatectomy alone) by conducting a single arm Phase II trial combining intensified androgen deprivation (abiraterone and leuprolide) with an AKT inhibitor (capivasertib) prior to radical prostatectomy among high risk localized prostate cancers with PTEN loss. The goal is that early precision treatment of aggressive disease will result minimal residual cancer at the time of prostatectomy, and subsequently improved cancer outcomes. The response will be compared to a historical control of neoadjuvant intensified androgen deprivation alone. Project Methods This is an integral biomarker (biomarker required) treatment trial with integrated biomarker discovery for mechanisms of resistance and response to therapy. Specific Aim1: Conduct a single arm phase II study to determine efficacy and safety of neoadjuvant capivasertib combined with androgen receptor pathway therapy (leuprolide + abiraterone) prior to radical prostatectomy among high risk localized PCa with PTEN loss. The protocol will include an ADT+ abiraterone run-in (4 weeks) and addition of AKT inhibitor therapy (16 weeks) prior to radical prostatectomy. Specific Aim 2: To investigate molecular signatures of response and adaptive mechanisms of resistance to combined AKT and AR pathway therapies. Aim 2.1 We will interrogate novel mechanisms of resistance and response using `omics profiles and molecular imaging through integrated approaches. On treatment biopsy after abiraterone run-in and prostatectomy tissue will be used to identify tumor adaptation and targetable mechanisms of resistance to therapies. Aim 2.2 Determine the impact of ERG activation on resistance to therapy. We hypothesize that ERG activation will be associated with lower response rates, and persistent activation of AR target genes. The results of the study will have immediate implications for the feasibility of precision oncology trials in non-metastatic PCa, and pending safety and efficacy results we plan to development a phase III trial. Furthermore, knowledge of adaptive mechanisms of resistance will lead to improved development and implementation of targeted therapies in PCa.