ANDROMEDA: Phase 1/2 Trial of AZD9750 AR Degrader in Metastatic Prostate Cancer

The ANDROMEDA trial, a first-in-human Phase 1/2 study, is evaluating AZD9750, a novel androgen receptor (AR) PROTAC, in men with metastatic castration-resistant prostate cancer (mCRPC). PROTACs represent a paradigm shift in targeted therapy: unlike traditional AR inhibitors that merely block the receptor’s activity, AZD9750 recruits cellular machinery to completely degrade the AR protein, potentially overcoming resistance mechanisms that develop after prolonged AR pathway inhibitor (ARPI) exposure. The trial’s modular design allows systematic assessment of AZD9750 monotherapy across dose escalation, backfill, optimization, and expansion cohorts, followed by combinations with saruparib (AZD5305), a selective PARP1 inhibitor that exploits DNA repair vulnerabilities often present in advanced prostate tumors.

AZD9750 targets the AR, which drives ~80% of prostate cancers even in castration-resistant states through mutations, amplifications, or splice variants. By eliminating the protein entirely, the agent aims to restore sensitivity in resistant disease. The saruparib combination leverages synthetic lethality: PARP1 inhibition impairs DNA repair in cells with underlying homologous recombination deficiencies, common in prostate cancer (especially with BRCA/ATM alterations), while AR degradation may enhance this effect by increasing DNA damage load.

Clinical trial