Abstract 4758: AZD9750, a novel androgen receptor proteolysis targeting chimera (AR-PROTAC) for the treatment of prostate cancer

The androgen receptor (AR) is a member of the nuclear hormone receptor superfamily and a key driver of prostate tumor growth. Several androgen receptor pathway inhibitors (ARPIs) have been developed and approved for the treatment of locally advanced and metastatic prostate cancer, including the androgen synthesis inhibitor, abiraterone and the AR antagonists, enzalutamide, apalutamide and darolutamide. Despite initial success resistance does occur, often involving alterations in the receptor itself, such as AR amplification or point mutations in the ligand binding domain (LBD). Therefore, there remains an urgent need to develop alternative strategies to target the AR. Here we describe the characterization of AZD9750, a novel AR PROTAC that potently degrades AR (DC50 in LNCaP cells = 9.9nM) and shows good cross species oral bioavailability. In a panel of prostate cancer (PC) cells expressing different altered forms of the receptor, AZD9750 was shown to degrade wild type, amplified and LBD mutant AR. The reduced AR levels were confirmed to be a consequence of increased AR degradation with AZD9750 reducing the half-life of AR from 4.9 to 1.0 hr in LNCaP and from 4.6 to 0.4 hr in VCAP PC cells. Degradation was also shown to be mediated via a PROTAC mechanism that required CRBN binding and proteasomal activity. Additionally, AZD9750 decreased AR-regulated gene expression and inhibited the proliferation of AR-dependent PC cell lines with GI50s in the low nM range, which represents a 10-fold increase in potency compared to enzalutamide in the same cell lines. In vivo, in the C901 patient derived xenograft (PDX) model, AZD9750 caused a dose-dependent reduction in tumor AR levels with oral doses of 3, 10 and 30 mg/kg giving a statistically significant reduction of 72, 88 and 95%, respectively. Consistent with this, the mRNA expression of a panel of AR-regulated genes was also decreased. Anti-tumor efficacy studies demonstrated that AZD9750 reduced tumor growth and in some cases caused tumor regression in a range of AR positive PDX models that represent both hormone-sensitive and castration-resistant prostate cancer. The anti-tumor effect was dose-dependent and accompanied by reduced AR levels and AR-regulated gene expression, consistent with the observed efficacy being driven by AR degradation and inhibition of AR signaling. Furthermore, in several models, the efficacy achieved with AZD9750 was superior to the efficacy achieved with a clinical exposure matched dose of enzalutamide. These data confirm that AZD9750 is a potent oral degrader of AR that leads to anti-tumor efficacy in a range of hormone-sensitive and castrate-resistant PDX models. Through degradation of AR, including mutant and amplified forms of the receptor, it has the potential to overcome key resistance mechanisms arising to current standard of care therapies and provide benefit to patients with prostate cancer. Citation Format: Claire Crafter, Antonio Ramos-Montoya, Chrysiis Michaloglou, Ziyanda Shologu, Nuria Galeano-Dalmau, Gemma Hardman Fowler, Ana Quiroga, Pablo Morentin-Gutierrez, Andy Pike, Laura Evans, James S. Scott, Michael Niedbala. AZD9750, a novel androgen receptor proteolysis targeting chimera (AR-PROTAC) for the treatment of 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 4758.