Note:we cannot be 100% sure, but it looks like JSB462 is the new name for ARV-766.

A new investigational drug called luxdegalutamide, also known as JSB462 (or even ARV-766), offers a glimmer of hope in the fight against this challenging disease. Luxdegalutamide is a proteolysis targeting chimera (PROTAC), a novel class of drugs designed to tackle prostate cancer by degrading the androgen receptor (AR), a key driver of tumor growth.
Unlike traditional therapies like abiraterone or enzalutamide, which block AR signaling, luxdegalutamide takes a more direct approach by binding to the AR and recruiting the body’s ubiquitin-proteasome system to break it down entirely, including resistant mutants like T878, H875, and L702H, which are found in up to 24% of patients with metastatic castration-resistant prostate cancer (mCRPC). This ability to target both wild-type and mutant AR makes it a promising candidate for mHSPC patients, particularly those at risk of developing resistance to standard treatments.
The mechanism of luxdegalutamide is both innovative and precise. By acting as a molecular bridge, it connects the AR to an E3 ubiquitin ligase, marking the receptor for degradation in the proteasome, the cell’s protein disposal system. In animal models, such as LNCaP and VCaP xenografts, luxdegalutamide has demonstrated dose-dependent tumor growth inhibition, even in enzalutamide-insensitive tumors, suggesting it could offer significant benefits for mHSPC patients where maintaining hormonal control is critical.

Currently, luxdegalutamide is being evaluated in a Phase II, randomized, open-label, multi-center clinical trial (EudraCT 2024-520156-22) for men with mHSPC. The study tests luxdegalutamide at two doses—100 mg or 300 mg taken orally once daily—in combination with abiraterone (1000 mg daily), compared to standard AR pathway inhibitors (abiraterone or enzalutamide). The goal is to assess efficacy, safety, tolerability, and pharmacokinetics to determine the optimal dose for a future Phase III trial.

While specific data for mHSPC are still forthcoming, insights from a related Phase 1/2 trial (NCT05067140) for mCRPC provide early clues about luxdegalutamide’s potential. In that study, patients with AR mutations like L702H showed a 43% PSA50 response rate (a 50% or greater reduction in prostate-specific antigen levels), with 5 out of 7 patients achieving this benchmark at doses of 100–600 mg daily. Common side effects included fatigue (25%), nausea (22%), and vomiting (11%), which were generally mild (grade 1 or 2), indicating a manageable safety profile. These findings are encouraging for mHSPC patients, as the combination with abiraterone, which reduces androgen production, could enhance luxdegalutamide’s AR degradation, potentially delaying disease progression and improving quality of life.

For mHSPC patients, who often face the challenge of disease progression despite initial hormonal sensitivity, luxdegalutamide’s ability to target resistant AR mutants could be a game-changer. The drug’s oral administration also offers convenience, allowing patients to take it at home without the need for hospital visits, which is a significant advantage for those managing a chronic condition. Moreover, its targeted mechanism may result in fewer off-target effects compared to traditional therapies, though the ongoing trial will clarify the extent of any toxicities at the tested doses.
The broader context of luxdegalutamide’s development highlights its potential to address unmet needs in prostate cancer treatment. Resistance to AR-targeted therapies is a major hurdle, particularly as patients progress to more advanced stages like mCRPC. By degrading the AR, luxdegalutamide could restore sensitivity to hormonal therapies, offering a new lifeline for men with mHSPC before their disease becomes castration-resistant.

Clinical trial.