Abstract B046: AZD9750, a novel androgen receptor proteolysis targeting chimera (AR-PROTAC) with monotherapy and combination activity in prostate cancer

Abstract The androgen receptor (AR) is a central driver of prostate cancer and a primary therapeutic target, yet resistance to standard-of-care androgen receptor pathway inhibitors (ARPIs) commonly emerges through mechanisms such as AR amplification and ligand-binding domain mutations. AZD9750 is an AR-directed proteolysis targeting chimera (PROTAC) that co-engages AR and the E3 ligase CRBN to promote AR ubiquitination and degradation. AZD9750 potently and effectively degrades AR across multiple cell lines expressing wild type, amplified and mutant AR, with DC50 values ranging from 1.7 to 29.1 nM. AR degradation was accompanied by reduced expression of KLK3 (PSA) and TMPRSS2. To assess transcriptome-wide changes, RNAseq analysis was performed in LNCaP cells following 24-hour treatment with AZD9750 or enzalutamide. AZD9750 significantly reduced androgen response in LNCaP cells compared to dihydrotestosterone (DHT) control. Pathway enrichment analysis of differentially expressed genes showed broadly similar phenotypic signatures for AZD9750 and enzalutamide versus DHT control. In vivo, AZD9750 demonstrated robust AR degradation and tumour growth inhibition in patient derived xenograft (PDX) models. In the MR041 hormone sensitive PDX model, AZD9750 significantly inhibited tumour growth, with the 10 and 30 mg/kg doses driving tumour regression. Consistent with the anti-tumour efficacy, AZD9750 caused a dose-dependent reduction in AR protein levels and a significant decrease in AR-regulated gene expression. Tumour stasis was also observed in the PCU-012 hormone sensitive PDX model, accompanied by >90% AR degradation. Given pathway crosstalk and tumour heterogeneity that can limit monotherapy efficacy in prostate cancer we evaluated combination strategies. We explored the activity of AZD9750 in combination with capivasertib, an AKT inhibitor with monotherapy activity in prostate cancer cell lines. Combining AZD9750 and capivasertib lead to enhanced antiproliferative activity and induced apoptosis in LNCaP cells. These data support AZD9750 as a potent AR degrader with activity as a monotherapy and in combination with an AKT inhibitor in prostate cancer models. Citation Format: Chrysiis Michaloglou, Antonio Ramos-Montoya, Nuria Galeano-Dalmau, Lynet Nyoni, Ziyanda Shologu, Sara Talbot, Sergio Espeso-Gil, Joshua Armenia, Massimo Squatrito, Simon T. Barry, Michael Niedbala, Claire Crafter. AZD9750, a novel androgen receptor proteolysis targeting chimera (AR-PROTAC) with monotherapy and combination activity in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B046.