Integrative analysis of capivasertib mediated AKT blockade with AR inhibition in mouse PTEN-deficient prostate cancer

Background: PTEN-deficient prostate tumors have poor prognosis and limited response to AR-targeted therapies. PI3K/AKT activation compensates for AR inhibition, reducing the efficacy of androgen deprivation therapy (ADT) and agents such as abiraterone (Abi). Capivasertib (Capiva, AZD5363), a potent pan-AKT inhibitor, is the first to demonstrate clinical benefit when combined with Abi and ADT in PTEN-deficient metastatic hormone-sensitive prostate cancer (HSPC), as shown in the Phase 3 CAPItello-281 trial. Objective: To investigate biological responses and therapeutic outcomes of AKT inhibition with capivasertib plus AR-targeted therapy in HSPC using an integrative approach with a clinically relevant PTEN-deficient mouse model, enabling simultaneous assessment of cancer cell signaling and the tumor microenvironment. Methods: Gene expression profiling, quantitative immunohistochemistry, and flow cytometry were combined with computational analysis to characterize molecular responses to ADT (A, n=13), ADT plus abiraterone (AA, n=14), and ADT plus Abi with Capiva (AAC, n=15) in an aged PTEN-deficient mouse model of locally invasive prostate adenocarcinoma. Treatment response was classified by tumor burden (TB) relative to the population median: ≥20%, high TB; <20% and >-20%, moderate TB; ≤-20%, low TB-serving as surrogates for progressive disease, stable disease, and partial response. Progressive disease was considered unfavorable; stable disease and partial response were favorable. Results: Favorable outcomes occurred in 8/13 (61.5%), 7/14 (50%), and 12/15 (80%) of A, AA, and AAC groups. Approximately 70 markers related to signal transduction, AR signaling, DNA damage, epigenetic regulation, proliferation/apoptosis, angiogenesis, and immune composition were analyzed. Unfavorable AA outcomes correlated with high AKT signaling, PMN accumulation, and vascularization. AAC favorable responders showed sustained AKT inhibition, increased DNA damage, and reduced PMN infiltration; poor responders exhibited persistent AR signaling. Conclusion: Capiva improved response to ADT and Abi in PTEN-deficient prostate cancer. Favorable outcomes were associated with sustained AKT inhibition, reduced pro-tumor immune infiltration, and decreased vascularization. These findings underscore the importance of targeting PI3K/AKT to overcome AR therapy resistance and highlight the value of integrative approaches for biomarker discovery and optimizing therapeutic outcomes.