An Open-label Study of JSB462 (Luxdegalutamide) in Combination With Abiraterone in Adult Male Patients With Metastatic Hormone-sensitive Prostate Cancer (mHSPC)

The study for each participant consists of a Screening period (28 days), a treatment period, a post-treatment safety follow-up (30 days) followed by a long-term follow-up period.

During the treatment period:

• JSB462 is administered from randomization, orally, daily and continuously (100 mg or 300 mg QD) until disease progression per PCWG3-modified RECIST 1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision.
• Abiraterone 1000 mg or enzalutamide 160 mg are administered from randomization, orally, daily, and continuously until disease progression per PCWG3-modified RECIST 1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision.

During the post-treatment follow up period:

• Safety follow-Up: After discontinuation of study treatment, all participants will be followed for at least 1 safety follow-up visit (30 days \[+/- 7 days\] after treatment discontinuation). Subsequent lines of therapy may be administered according to investigator's discretion after treatment discontinuation.
• Long-term follow-up: Starts after the Safety follow-up period and lasts until the end of study. Safety, efficacy and survival information may be collected from participants during this period.

JSB462 100 mg QD + abiraterone 1000 mg QD

Drug: JSB462 · Drug: Abiraterone

JSB462 300 mg QD + abiraterone 1000 mg QD

Drug: JSB462 · Drug: Abiraterone

abiraterone 1000 mg QD or enzalutamide 160 mg QD

Drug: Abiraterone · Drug: Enzalutamide

JSB462 is administered orally, daily and continuously (100 mg or 300 mg QD) until disease progression per PCWG3-modified RECIST 1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision.

Abiraterone 1000 mg is administered orally, daily and continuously until disease progression per PCWG3-modified RECIST 1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision.

Enzalutamide 160 mg is administered orally, daily and continuously until disease progression per PCWG3-modified RECIST 1.1 as assessed by the investigator, the occurrence of unacceptable toxicities, death, participant decision or investigator decision.

Plazo: From date of randomization till 30 days safety fup, assessed up to approximately 75 months

Prostate Specific Antigen 90 (PSA90) Rate is defined as the proportion of participants who achieve a ≥90% decrease in PSA from baseline at any timepoint, confirmed by a second PSA measurement ≥3 weeks without any PSA progression in between.

Plazo: From date of randomization till 30 days safety fup, assessed up to approximately 75 months

The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.

Plazo: From date of randomization till 30 days safety fup, assessed up to approximately 75 months

The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.

Plazo: From date of randomization till 30 days safety fup, assessed up to approximately 75 months

The duration of exposure in weeks to study treatment and for each study treatment component (JSB462, abiraterone and enzalutamide) will be summarized for each study treatment component by means of descriptive statistics using the SAS.

Plazo: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 83 months

Radiographic Progression Free Survival (rPFS) is defined as the time between randomization and the first occurrence of disease progression (per PCWG3-modified RECIST 1.1 as assessed by the investigator) or death due to any cause

Plazo: From date of randomization until date of death from any cause, assessed up to approximately 83 months

Overall Survival (OS) is defined as the time between randomization and death due to any cause

Plazo: From date of randomization till 30 days safety fup, assessed up to approximately 83 months

The analysis of adverse events and laboratory abnormalities will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.

Plazo: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 83 months

Overall Response Rate (ORR) is defined as the proportion of participants achieving a confirmed complete response (CR) or partial response (PR) per PCWG3-modified RECIST 1.1 as assessed by the investigator

Plazo: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 83 months

Disease Control Rate (DCR) is defined as the proportion of participants achieving a CR, PR or stable disease (SD) per PCWG3-modified RECIST 1.1 as assessed by the investigator

Plazo: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 83 months

Duration of Response (DOR) is defined as the time between first documented CR/PR and disease progression or death due to any cause per PCWG3-modified RECIST 1.1 as assessed by the investigator

Plazo: From date of randomization until date of first documented Complete Response (CR) or Partial Response (PR), assessed up to approximately 83 months

Time to response (TTR) is defined as the time from randomization to the date of first documented CR or PR per PCWG3-modified RECIST 1.1 as assessed by the investigator

Plazo: From date of randomization until date of soft tissue radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 83 months

Time to soft tissue progression (TTSTP) is defined as the time from randomization to the date of first documented radiographic soft tissue progression per PCWG3-modified RECIST 1.1 as assessed by the investigator

Plazo: From date of randomization till 30 days safety fup, assessed up to approximately 75 months

Prostate Specific Antigen 30 (PSA30) Rate is defined as the proportion of participants who achieve a ≥30% decrease from baseline at any timepoint, confirmed by a second PSA measurement ≥3 weeks without any PSA progression in between

Plazo: From date of randomization till 30 days safety fup, assessed up to approximately 75 months

Prostate Specific Antigen 50 (PSA50) Rate is defined as the proportion of participants who achieve a ≥50% decrease from baseline at any timepoint, confirmed by a second PSA measurement ≥3 weeks without any PSA progression in between

Plazo: From date of randomization till 30 days safety fup, assessed up to approximately 75 months

Prostate Specific Antigen 0 (PSA0) Rate is defined as the proportion of participants who achieve a PSA level \<0.2 ng/ml at any timepoint after start of treatment, confirmed by a second PSA measurement ≥3 weeks without any PSA progression in between

Plazo: From date of date of first PSA50 response until date of PSA progression or death from any cause, assessed up to approximately 83 months

Duration of biochemical response (DBR) is defined as the time between PSA90 and/or PSA0 and PSA progression (increase ≥25% in PSA and an absolute increase of ≥2 ng/mL from NADIR) or death due to any cause

Plazo: From date of randomization till EOT or death, whichever happens first, assessed up to approximately 83 months

Time to first symptomatic skeletal event (TTSSE) is defined as the date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first

Plazo: Day 1 of Cycles 1 and 2: Pre-dose/0h and Post-dose 4h +/- 1h. Day 1 of Cycles 3 to 8: Pre-dose/0h. End of Treatment Visit (EOT): Anytime. 1 cycle = 28 days.

JSB462 pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels in JSB462 treatment arms.

Plazo: From randomization up till 30 day safety Follow-up, assessed up to approximately 83 months

The PRO-CTCAE is a patient-reported outcomes measurement system developed by the National Cancer Institute as a companion to the CTCAE. It includes items covering participant-reported symptomatic adverse events (AEs) from the CTCAE. Each symptomatic AE concept has up to three items evaluating frequency, severity, or interference, focused on the study population and treatment regimens.

Participants respond on a 5-point scale for each item:

• Frequency: Never, Rarely, Occasionally, Frequently, Almost constantly
• Severity: None, Mild, Moderate, Severe, Very severe
• Interference: Not at all, A little bit, Somewhat, Quite a bit, Very much

The past 7-day recall version is used, focusing on relevant symptoms like fatigue, diarrhea, and hot flashes.

A Phase II, Randomized, Open-label, Multi-center Study of JSB462 (Luxdegalutamide) in Combination With Abiraterone in Adult Male Patients With Metastatic Hormone-sensitive Prostate Cancer (mHSPC)