The study consists of different parts. Depending on the part of the study, treatment may be assigned in different ways.

In Part 1a (dose escalation), the treatment combination of tulmimetostat and JSB462 (luxdegalutamide) will be given at doses determined by the study protocol to find the appropriate dose.

In Part 1b (dose expansion), the treatment combination will be given at the doses identified in Part 1a to further evaluate safety and response.

In Part 2, assignment to treatment will be randomized. This means that either the combination of tulmimetostat and JSB462 or a standard of care treatment will be assigned. The standard of care treatment may include abiraterone, docetaxel, cabazitaxel, or enzalutamide, depending on prior treatments received.

Before starting treatment, imaging scans will be performed. These may include CT scans, MRI scans, or bone scans to document the extent of disease.

Blood tests will be performed to measure PSA (prostate-specific antigen) levels and testosterone levels.

Additional safety assessments will include laboratory tests, vital signs (blood pressure, heart rate, temperature), and electrocardiograms (ECGs, which measure heart activity).

Treatment will begin according to the assigned group.

If assigned to the combination treatment, tulmimetostat and JSB462 (luxdegalutamide) will be taken by mouth as tablets or film-coated tablets.

If assigned to standard of care treatment, the specific medication will depend on prior treatments. Abiraterone and enzalutamide are taken by mouth as tablets. Docetaxel and cabazitaxel are given through a vein (intravenously).

The exact dosage and frequency of administration will be determined by the study protocol and communicated by the study team.

Continuation of androgen deprivation therapy (treatment to keep testosterone levels low) is required throughout the study.

Regular visits will be scheduled to monitor health and response to treatment.

At these visits, blood samples will be collected to measure PSA levels and to assess safety through laboratory tests.

For participants receiving the combination treatment, blood samples will also be collected to measure the levels of tulmimetostat and JSB462 in the bloodstream.

Physical examinations, vital signs measurements, and electrocardiograms may be performed at specified visits.

Any side effects or symptoms experienced will be recorded and assessed according to standard medical criteria.

At approximately 3 months after starting treatment, PSA levels will be assessed to determine if there has been a reduction.

A PSA50 response is defined as a reduction of at least 50% from the baseline PSA level, confirmed by a second measurement at least 3 weeks later.

At approximately 6 months after starting treatment, PSA levels will be assessed again.

This is a key time point for evaluating the biochemical response to treatment.

A PSA50 response at 6 months is one of the main outcomes being measured in this study.

Imaging scans (CT, MRI, or bone scans) will be performed at scheduled intervals to assess whether the disease has progressed, remained stable, or responded to treatment.

The timing of these scans will be determined by the study protocol.

Disease progression is evaluated using standardized criteria that assess changes in tumor size, new lesions, or changes in bone disease.

PSA levels will continue to be monitored at 9 months and 12 months after starting treatment.

These assessments help to track the ongoing response to treatment over time.

Throughout the study, any side effects will be monitored and managed as needed.

Depending on the type and severity of side effects, the study treatment may be temporarily stopped (dose interruption), the dose may be reduced (dose reduction), or treatment may be discontinued.

All side effects will be evaluated and graded according to standard medical criteria.

Treatment will continue as long as there is benefit and side effects are manageable.

If the disease progresses or side effects become unacceptable, treatment may be stopped.

After stopping treatment, follow-up visits will continue to monitor overall health and survival.

The study will track radiographic progression-free survival (time until disease progression or death), overall survival (time until death from any cause), and other long-term outcomes.

Throughout the study, any bone-related complications will be monitored.

These may include new bone fractures, spinal cord compression, need for bone surgery, or need for radiation therapy to relieve bone pain.

The time to the first such event will be recorded as part of the study outcomes.

Participation in the study will end when treatment is discontinued and follow-up assessments are completed.

The total duration of participation will vary depending on how long treatment continues and how long follow-up is required.

The study is estimated to continue until December 2030.