Abstract 1686: Enhancing chemotherapy efficacy in PTEN-deficient prostate tumors with targeted AKT inhibition

Abstract Taxane chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). The tumor suppressor PTEN is frequently deleted in advanced prostate cancer (PCa), contributing to cancer progression and poor clinical outcomes. Hyperactivation of AKT resulting from PTEN loss and reciprocal crosstalk between AR and PI3K/AKT signaling may impair the efficacy of taxane therapy. Capivasertib (AZD5363) is a potent oral pan-AKT inhibitor that has shown efficacy against PCa in preclinical and early phase clinical studies. Capivasertib is currently being evaluated in a Phase 3 trial (CAPItello-280) along with docetaxel (Dtx) for the treatment of patients with mCRPC. Here, we assessed the in vivo preclinical efficacy of Dtx plus capivasertib using transgenic mouse models of Pten-null PCa. In an early-stage model of PCa using double knockout mice with conditional inactivation of Pten and Trp53, four weeks of treatment with Dtx resulted in tumor growth inhibition (TGI) of approximately 25% and 7% compared with vehicle-treated control mice in hormone-sensitive PCa (HSPC) and CRPC settings, respectively. Adding capivasertib to Dtx further increased tumor TGI by ∼14% in both settings. More robust improvements were observed with the combination therapy in CRPC compared with HSPC. Namely, 7/10 (70%) and 9/10 (90%) of HSPC mice treated with Dtx and Dtx+capivasertib, respectively, exhibited a >25% reduction relative to the control group. In contrast, 2/15 (13.3%) and 8/18 (44.4%) of CRPC mice treated with Dtx and Dtx+capivasertib, respectively, showed similar reductions. After one week of treatment, capivasertib suppressed the phosphorylation of PRAS40 and S6 downstream molecules of AKT, and this suppression was sustained for four weeks. In HSPC, Dtx+capivasertib resulted in a greater decrease in cancer cell proliferation compared with DTx alone and control mice. One week of administration of Dtx with or without capivasertib in CRPC mice increased cleaved caspase-3 levels to levels higher than those in control mice, whereas both Ki67 and cleaved caspase-3 levels plateaued in atrophic acini during week four suggesting M-phase cell cycle arrest. The therapeutic benefits of Dtx+ capivasertib were further evaluated in a late-stage CRPC model. Mice with tumors treated with Dtx+ capivasertib after progression to androgen deprivation therapy (surgical castration) and apalutamide had longer survival and longer tumor doubling times than those treated with Dtx alone. In conclusion, PTEN-deficient CRPC is less sensitive to Dtx than HSPC. However, our model showed that adding capivasertib to Dtx suppressed tumor growth and improved the therapeutic efficacy of CRPC. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Simon T. Barry, Cath Eberlein, Claire Rooney, Kazuto Nishio, Kazutoshi Fujita, Hirotsugu Uemura. Enhancing chemotherapy efficacy in PTEN-deficient prostate tumors with targeted AKT inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1686.