Abstract 1685: Evaluation of antitumor and molecular responses to abiraterone acetate plus capivasertib in mouse PTEN-deficient prostate cancer

Abstract Inhibition of the androgen receptor (AR) is the primary treatment for metastatic hormone-sensitive prostate cancer (mHSPC). The addition of antiandrogen therapies to androgen deprivation therapy (ADT) has greatly improved patient outcomes. However, loss of the tumor suppressor PTEN is common in prostate cancer (PCa), and the resulting increase in AKT signaling contributes to PCa progression. Capivasertib (AZD5363) is currently being investigated as an oral pan-AKT inhibitor in combination with abiraterone (Abi) and ADT for treating mHSPC in patients with PTEN loss (CAPItello-281). We previously demonstrated the efficacy of targeted AKT inhibition using capivasertib in preclinical mouse models of PTEN-deficient PCa (PMID: 26910118). In this study, we evaluated the antitumor and molecular responses to the combination of Abi and capivasertib in vivo using conditional knockout mouse models with targeted deletions of Pten (KO) and both Pten and Trp53 (DKO). In DKO mice, four weeks of ADT (via surgical castration) followed by four weeks of Abi resulted in a 9.4% tumor growth inhibition (TGI) compared to ADT alone. Additionally, 3/8 (37.5%) mice treated with Abi had tumor burden reductions >20% compared to ADT alone. In a hormone-sensitive model using DKO mice, four-week treatment with ADT/Abi resulted in a 7.4% TGI based on genitourinary tract weight compared with ADT alone. The combination of ADT and Abi+capivasertib further improved the TGI to 21.8%. DKO mice with advanced PCa also exhibited improved antitumor activity with the combination of ADT/Abi+capivasertib compared with ADT/Abi. In survival studies involving DKO mice with advanced PCa, the addition of capivasertib to ADT/Abi reduced metastasis, extended tumor doubling time, and improved OS compared with ADT/Abi alone. Immunohistochemical analysis revealed that mice treated with ADT/Abi+capivasertib exhibited significantly lower proliferation and increased apoptotic rates. Molecular profiling studies revealed that mice treated with Abi exhibited increased AKT signaling, as indicated by increased PRAS40 and S6 phosphorylation, but this enhancement was inhibited by capivasertib. Syngeneic allograft transplantation models using PTEN-expressing TRAMP-C1 and Pten-null-derived PCa cells demonstrated that, while both models responded to capivasertib, the Pten-null allografts exhibited greater sensitivity to the ADT/Abi+capivasertib combination. In conclusion, we provide preclinical evidence that abiraterone-resistant tumors with hyperactivation of AKT due to loss of PTEN are sensitive to AKT inhibition. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Simon T. Barry, Cath Eberlein, Claire Rooney, Kazuto Nishio, Kazutoshi Fujita, Hirotsugu Uemura. Evaluation of antitumor and molecular responses to abiraterone acetate plus capivasertib in mouse PTEN-deficient prostate cancer [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 1685.