AstraZeneca is initiating a first-in-human clinical trial of AZD9750, a novel androgen receptor (AR) proteolysis targeting chimera (PROTAC), targeting patients with metastatic castration-resistant prostate cancer (mCRPC). The ANDROMEDA trial represents a potentially innovative approach to addressing treatment resistance in advanced prostate cancer.
The Phase I/II open-label, multicenter study will evaluate AZD9750 as a monotherapy and in combination with saruparib, exploring dose escalation, safety, and preliminary efficacy. With a planned enrollment of 300 patients and a primary completion date of 2029, the trial will assess dose-limiting toxicities, prostate-specific antigen (PSA) response rates, radiographic progression-free survival, and objective response rates.
Current standard-of-care therapies, including androgen deprivation therapy and receptor pathway inhibitors, frequently encounter resistance mechanisms. AZD9750’s PROTAC mechanism represents a potential strategy to overcome these limitations by targeting protein degradation rather than traditional inhibition.
The treatment landscape
A wave of targeted and precision therapies is reshaping the treatment landscape for advanced prostate cancer, particularly in biomarker-defined populations.
In the PARP inhibitor class, rucaparib (Rubraca) from Clovis Oncology, now part of pharmaand GmbH, secured full US FDA approval in December 2025 for patients with mCRPC and deleterious BRCA mutations following AR-directed therapy. That converted the drug’s earlier 2020 accelerated approval.
Combination strategies pairing PARP inhibition with androgen-pathway blockade have also advanced. Janssen’s niraparib plus abiraterone acetate (Akeega) gained US approval in December 2025 for BRCA2-mutated metastatic castration-sensitive prostate cancer (mCSPC), following earlier EU clearance in 2023. Meanwhile, olaparib plus abiraterone from AstraZeneca and Janssen was approved in the US and EU in 2023 for mCRPC patients with homologous recombination repair (HRR) gene mutations.
Beyond targeted small molecules, radioligand therapy has moved into earlier lines of care. Novartis’ lutetium Lu 177 vipivotide tetraxetan (Pluvicto), a PSMA-targeted radiopharmaceutical, received US approval in 2022 for post-ARPI mCRPC and saw its label expanded in March 2025 to allow use before chemotherapy.
Next-generation AR inhibitors continue to anchor first-line treatment for metastatic disease. Bayer’s darolutamide (Nubeqa) achieved a major milestone in June 2025 with US FDA approval for mCSPC both with and without chemotherapy, building on its earlier 2022 approval in combination with docetaxel. Janssen’s apalutamide (Erleada) and Astellas-Pfizer’s enzalutamide (Xtandi), although approved earlier, remain key comparators and mainstays across mCSPC, mCRPC, and non-metastatic CRPC.
Research context
AZD9750 enters a small but increasingly important field of AR degraders aimed at overcoming resistance to standard hormonal therapies in mCRPC. The most advanced program to date is bavdegalutamide (ARV-110) from Arvinas, the first AR-directed PROTAC to reach mid-stage clinical development, while Bristol Myers Squibb’s CC-94676 is an oral AR degrader in early clinical testing.
Beyond classical PROTACs, companies such as Harpoon Therapeutics are advancing alternative targeted protein degradation modalities, including AR-directed engager molecules that combine receptor depletion with immune-mediated killing. Meanwhile, groups including Kymera, C4 Therapeutics, and Nurix are pursuing next-generation and dual-pathway degraders in preclinical development, reflecting growing confidence that protein degradation could represent the next major shift in how resistance is tackled in mCRPC.