AZD9750 / AstraZeneca - LARVOL DELTA

Phase I/II study to evaluate AZD9750, a novel androgen receptor proteolysis-targeting chimera, alone and in combination with other anticancer agents in patients with metastatic prostate cancer (ANDROMEDA). (ASCO 2026) - P1/2 | "Preclinical data also showed significant antitumor benefit with AZD9750 as monotherapy and combined with the PARP1 selective inhibitor saruparib (AZD5305). This study is currently recruiting for monotherapy dose escalation. aRecommended doses determined in Module 1 Part A; bTo be opened once recommended phase II dose identified in Module 1 Part B1; cTo be opened once combination dose identified in Module 2 Part A."

Clinical • Combination therapy • First-in-human • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR

The combination of the AR PROTAC AZD9750 and AKT inhibitor capivasertib delivers improved efficacy over monotherapy in prostate cancer (AACR 2026) - P3 | "Consistent with this, in the Phase III CAPItello-281 trial (NCT04493853), capivasertib plus abiraterone and ADT achieved a statistically significant improvement in radiographic progression-free survival versus abiraterone and ADT in patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC). In PTEN-null patient-derived xenograft prostate tumor models (both HSPC and CRPC), the combination consistently delivered significantly greater efficacy than either monotherapy, including 73% tumor growth inhibition (TGI) in TM00298 (vs AZD9750 52% TGI and capivasertib 14% TGI) and >100% TGI with 25% regression in MR041 (vs AZD9750 90% TGI and capivasertib 61% TGI), with similar benefits observed in other models. These findings indicate that in PTEN-null prostate cancer AZD9750 mediated AR degradation synergizes with AKT inhibition by capivasertib to enhance antitumor efficacy and support clinical evaluation of the AR-PROTAC-AKT inhibitor..."

Clinical • Monotherapy • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • AKT1S1 • CRBN • KLK3 • PTEN

Application of mechanistic preclinical PK/PD/efficacy modeling to support combination strategy for AZD9750, a novel oral androgen receptor degrader (PROTAC) (AACR 2026) - "AZD9750 is a novel potent oral selective AR Proteolysis-targeting chimera (PROTAC) with a suitable pharmacological profile to be used in combination with a variety of other therapeutics such as capivasertib, a potent pan-AKT kinase inhibitor with anti-tumor activity in tumors with PIK3CA and PTEN mutations, and saruparib, a PARP1-selective inhibitor especially effective against tumors with mutations in genes like BRCA1 and BRCA2. The study enriches our understanding of biomarkers relevant to AR-PROTACs, PARP inhibitors, and AKT inhibitors, informing the selection of biomarkers for monitoring in clinical trials. Additionally, it quantifies the extent of biomarker modulation required to achieve maximal antitumor activity and supports rational combination strategies, as well as dose and schedule optimization for clinical development."

PK/PD data • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BRCA1 • BRCA2 • PIK3CA • PTEN

ANDROMEDA: A Trial to Learn How Safe AZD9750 is and How Well it Works in People With Metastatic Prostate Cancer When Given With or Without Other Anticancer Drugs (clinicaltrials.gov) - P1/2 | N=300 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • First-in-human • Monotherapy • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Preclinical mechanistic PK/PD-efficacy modeling for AZD9750, a novel oral androgen receptor degrader (PROTAC), to support dose selection during early clinical development (AACR 2025) - "This study provides quantitative mechanistic insights into the links between compound exposure, biomarker modulation (AR) and anti-tumor responses, supporting our understanding of the required target modulation needed for maximal anti-tumor effects in these two hormone sensitive patient-derived tumor models. This mechanistic understanding is valuable to contextualize compound-induced PD modulation in patients, for given doses and schedules."

PK/PD data • Preclinical • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • AR

AZD9750, a novel androgen receptor proteolysis targeting chimera (AR-PROTAC) for the treatment of prostate cancer (AACR 2025) - "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. 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."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CRBN

D7270C00001: A trial to learn how safe AZD9750 is and how well it works in people with metastatic prostate cancer when given with or without other anticancer drugs (clinicaltrialsregister.eu) - P1/2 | N=52 | Not yet recruiting | Sponsor: AstraZeneca AB

Monotherapy • New P1/2 trial • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer. (PubMed, J Med Chem) - "This compound inhibited AR signaling in vitro and was able to inhibit tumor growth in vivo in a mouse prostate cancer xenograft model. Extensive profiling in terms of drug-like properties allowed this to be progressed into development as AZD9750."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR

ANDROMEDA: A Trial to Learn How Safe AZD9750 is and How Well it Works in People With Metastatic Prostate Cancer When Given With or Without Other Anticancer Drugs (clinicaltrials.gov) - P1/2 | N=300 | Not yet recruiting | Sponsor: AstraZeneca

First-in-human • Monotherapy • New P1/2 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor