The androgen receptor (AR) is a key therapeutic target in prostate cancer, being an important tumor driver in patients with metastatic hormone-sensitive prostate cancer (mHSPC), and AR alterations are a key mechanism of acquired resistance to androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) in those with metastatic castration resistant prostate cancer (mCRPC). JSB462 (Luxdegalutamide, formerly ARV-766) is an orally bioavailable proteolysis targeting chimera (PROTAC®) that induces a protein-protein interaction between AR and the Cereblon (CRBN) E3 substrate receptor, resulting in the ubiquitination of AR and its subsequent degradation via the proteasome. JSB462 is efficacious against wild type AR as well as clinically relevant AR ligand binding domain (LBD) mutants that confer resistance to ADT and ARPIs, including AR L702H, H875Y, and T878A mutations. AR degradation overcomes limitations of conventional AR antagonists that only inhibit AR activity and cannot compensate for the feedback loop leading to AR upregulation. JSB462 demonstrates potent AR degradation at sub-nanomolar concentrations in vitro and dose-dependent tumor growth inhibition in mouse xenograft models, including those resistant to enzalutamide and with high levels of AR. In addition to degrading the androgen receptor, JSB462 also exhibits direct antagonistic activity against AR signaling, inhibiting AR-driven transcriptional programs independent of receptor abundance. Beyond single agent activity, we have also explored biology-guided combination opportunities to maximize JSB462 efficacy. Abiraterone inhibits AR activity by targeting CYP17A1 and reducing synthesis of androgen receptor ligands, and combination with JSB462 leads to sustained AR pathway inhibition and improved in vivo efficacy. JSB462 treatment leads to sustained upregulation of PSMA in multiple prostate cancer cell lines, and pre-treatment of prostate tumor xenografts with JSB462 in combination with a sub-efficacious single dose of the PSMA-targeting radioligand therapy (RLT) Lutetium ( 177 Lu) Vipivotide Tetraxetan (Pluvicto®) led to sustained tumor growth inhibition. In a phase I/II trial, JSB462 was well tolerated and showed encouraging antitumor activity in pretreated patients with mCRPC. Here, we show preclinical combination data of JSB462 with abiraterone and Pluvicto® that support further investigation of these regimens. Towards that end, two phase 2 trials of JSB462 in combination with abiraterone in patients with high-volume mHSPC (NCT06991556) as well as in combination with Pluvicto® in patients with mCRPC (NCT07047118) are ongoing.