A Phase II, Randomized, Open-label, Multi-center Study of JSB462 (Luxdegalutamide) in Combination With Lutetium (177Lu) Vipivotide Tetraxetan in Adult Male Patients With PSMA-positive Metastatic Castration Resistant Prostate Cancer (mCRPC)

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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

Key Inclusion Criteria:

* Adult male participants with histologically and/or cytologically confirmed adenocarcinoma of the prostate. Participants with mixed histology (neuroendocrine) are not eligible.

* An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) grade ≤2.

* At least 1 bone or visceral metastatic lesion present on baseline CT, MRI, or bone scan imaging obtained ≤28 days prior to initiation of study treatment.

* Participants must be \[68Ga\]Ga-PSMA-11 PET/CT scan positive and eligible as determined by the sponsor's central reader.

* Participant must have prior exposure to at least one second generation ARPI in the metastatic/advanced setting.

* Previous treatment with a maximum of 2 taxane regimens is allowed.

* Participants eligible for PARPi and/or immune checkpoint inhibitor (per local testing and according to investigator's judgement) are eligible to participate if they have previous exposure to this(these) therapy(ies).

Key Exclusion Criteria:

* Prior treatment with any RLT (approved or investigational) is not allowed

* Prior treatment with a protein degrader compound that targets AR is not allowed

Other protocol-defined inclusion/exclusion criteria may apply.