Investigational Drug
JSB462
HealthScout AI Analysis
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Overview
Luxdegalutamide (JSB462; also known as ARV‑766) is an investigational, oral androgen receptor (AR) degrader being co-developed under a 2024 license agreement between Arvinas and Novartis for prostate cancer. Early human data come from a first‑in‑human phase 1/2 study in metastatic castration‑resistant prostate cancer (mCRPC); randomized phase 2 combination studies in prostate cancer began in 2025. (arvinas.com)
Mechanism of action
Luxdegalutamide is a proteolysis targeting chimera (PROTAC) that recruits the AR to an E3 ubiquitin ligase complex, leading to AR ubiquitination and proteasomal degradation. Preclinical work shows potent AR degradation (DC50 <1 nM in VCaP cells), activity against clinically relevant AR ligand‑binding domain (LBD) mutations (including L702H, H875Y, T878A), and tumor growth inhibition in xenograft models, including enzalutamide‑insensitive models. (aacrjournals.org)
Clinical development
- Monotherapy (phase 1/2, NCT05067140): Oral luxdegalutamide is being evaluated as monotherapy and with abiraterone in metastatic prostate cancer; Novartis lists this study internally as CJSB462A12101, linking ARV‑766 with JSB462/luxdegalutamide. (novartis.com)
- Combination trials (phase 2, 2025 start):
- mHSPC: luxdegalutamide (100 mg or 300 mg QD) + abiraterone vs standard ARPI (abiraterone or enzalutamide). NCT06991556. (novartis.com)
- PSMA‑positive mCRPC: luxdegalutamide (100 mg or 300 mg QD) + lutetium‑177 vipivotide tetraxetan vs lutetium‑177 vipivotide tetraxetan alone. NCT07047118. (novartis.com)
Efficacy
Phase 1/2 monotherapy (mCRPC; initial/updated meeting reports): - In the ASCO 2024 abstract (data cutoff Dec 15, 2023; n=103 treated), among PSA‑evaluable patients with AR LBD mutations (n=28), 50% achieved a ≥50% PSA decline (PSA50). Confirmed and unconfirmed RECIST partial responses were also observed. (ascopubs.org) - Company and independent conference coverage consistent with these findings reported PSA50 rates around 41–50% in AR LBD‑mutated tumors, including activity in L702H‑mutant disease. (ir.arvinas.com)
No randomized efficacy results have been reported yet; the ongoing phase 2 combination studies are designed to select doses and assess comparative activity in mHSPC and mCRPC. (novartis.com)
Safety
Phase 1/2 monotherapy (mCRPC; ASCO 2024 abstract):
- No dose‑limiting toxicities; maximum tolerated dose not reached (20–500 mg QD tested).
- Treatment‑related adverse events (any grade ≥10%): fatigue (36%; grade 3 in 3%), nausea (19%; 1%), diarrhea (15%; 1%), alopecia (14%), increased creatinine (13%), decreased appetite (11%); no grade 4 TRAEs reported. Dose reductions in 7% and discontinuations in 10% across 103 patients. (ascopubs.org)
Additional interim communications have highlighted generally favorable tolerability compared with first‑generation AR degraders; full peer‑reviewed safety datasets are pending. (ir.arvinas.com)
Further reading
- ASCO 2024 meeting abstract (phase 1/2 initial results): ARV‑766 (luxdegalutamide) in mCRPC. (ascopubs.org)
- AACR 2023 discovery abstract: Preclinical characterization of ARV‑766 as an AR‑degrading PROTAC. (aacrjournals.org)
- Novartis trial listings confirming JSB462 = luxdegalutamide and outlining ongoing phase 2 combinations in mHSPC (NCT06991556) and PSMA‑positive mCRPC (NCT07047118). (novartis.com)
- Novartis listing of the phase 1/2 monotherapy study (NCT05067140; internal code CJSB462A12101). (novartis.com)
Notes: As of October 7, 2025, there are no published, peer‑reviewed full manuscripts of human efficacy results for luxdegalutamide; available human data are from meeting abstracts and company/meeting summaries. Randomized phase 2 studies are ongoing. (ascopubs.org)
Last updated: Oct 2025
Active trials using JSB462
Found 3 active trials using this drug:
HealthScout AI summary: Men with progressive metastatic castration-resistant prostate cancer after one prior second‑generation ARPI (taxane‑naive in Phase II; broader prior therapy allowed in Phase I) are enrolled to receive tulmimetostat, a dual EZH2/EZH1 inhibitor, plus luxdegalutamide (JSB462), a PROTAC androgen receptor degrader, versus investigator’s choice standard care. Key exclusions include prior PRC2 inhibitors, AR degraders, and most radioligand therapy.
ClinicalTrials.gov ID: NCT07206056
HealthScout AI summary: Adult men with high‑volume metastatic hormone‑sensitive prostate adenocarcinoma (ECOG 0–2, castrate testosterone) are randomized to luxdegalutamide (JSB462), an oral PROTAC androgen receptor degrader, plus abiraterone (two dose levels) versus standard ARPI therapy (abiraterone or enzalutamide). Prior second‑generation ARPI for advanced/metastatic disease is excluded; limited prior (neo)adjuvant therapy allowed if completed >12 months before randomization.
ClinicalTrials.gov ID: NCT06991556
HealthScout AI summary: PSMA-positive mCRPC after at least one ARPI (and up to two taxanes), no prior PSMA radioligand therapy, randomized to 177Lu-PSMA-617 alone or combined with JSB462 (luxdegalutamide), an oral PROTAC androgen receptor degrader active against LBD resistance mutations. Aims to assess whether adding JSB462 improves antitumor activity and safety versus radioligand alone.
ClinicalTrials.gov ID: NCT07047118
