A Phase 3, Open-label, Multicenter, Randomized Study of Xaluritamig Plus Abiraterone Versus Investigator's Choice in Participants with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer

The primary objective of this study is to compare overall survival in participants receiving xaluritamig plus abiraterone versus investigator's choice, which includes docetaxel, cabazitaxel, or abiraterone. This endpoint is clinically relevant as overall survival represents the definitive measure of treatment benefit in metastatic castration-resistant prostate cancer, a disease characterized by progression despite androgen deprivation therapy and associated with limited therapeutic options in the chemotherapy-naïve setting.

The secondary objectives include:

• Comparison of radiographic progression-free survival between xaluritamig plus abiraterone and investigator's choice to assess the duration of disease control based on imaging criteria.

• Evaluation of additional efficacy measures to comprehensively characterize the antitumor activity of xaluritamig plus abiraterone compared to investigator's choice.

• Comparison of symptomatic skeletal events in participants treated with xaluritamig plus abiraterone versus investigator's choice, which is clinically significant given the high incidence of bone metastases in this patient population.

• Assessment of safety and tolerability profiles of both treatment regimens to characterize the adverse event spectrum and treatment-emergent toxicities.

• Evaluation of health-related quality of life to determine the impact of treatment on patient-reported functional status and symptom burden.

• Assessment of patient-reported safety and tolerability to capture the patient perspective on treatment-related adverse effects.

• Evaluation of biochemical response to assess treatment efficacy through tumor marker analysis.

• Characterization of the pharmacokinetics of xaluritamig plus abiraterone using intensive and sparse sampling strategies to define drug exposure parameters.

• Evaluation of the immunogenicity of xaluritamig plus abiraterone to assess the development of anti-drug antibodies and their potential clinical impact.

This clinical trial enrolled a total of **455 participants** diagnosed with **metastatic castration-resistant prostate cancer (mCRPC)**. The study population consisted exclusively of **male participants** aged **18 years or older**. All participants were required to have histologically, pathologically, or cytologically confirmed **adenocarcinoma of the prostate** with at least one metastatic lesion documented by baseline imaging. Participants demonstrated evidence of **progressive disease** according to PCWG3-modified RECIST 1.1 criteria and maintained **castrate levels of serum testosterone** (less than 50 ng/dL or less than 1.7 nmol/L) through prior **orchiectomy** and/or ongoing **androgen-deprivation therapy (ADT)**. The selection criteria required prior disease progression on one, and only one, **androgen receptor pathway inhibitor (ARPI)**, specifically **enzalutamide**, **apalutamide**, or **darolutamide**. Participants intended to receive **cabazitaxel** must have previously received no more than 6 cycles of **docetaxel** in the metastatic hormone-sensitive prostate cancer setting. All enrolled participants maintained an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1 and demonstrated adequate organ function at baseline.

This is a phase 3, open-label, multicenter, randomized clinical trial evaluating the efficacy and safety of xaluritamig plus abiraterone acetate compared to investigator's choice in participants with chemotherapy-naïve metastatic castration-resistant prostate cancer. The investigator's choice comparator includes docetaxel, cabazitaxel, or abiraterone acetate. The study employs a randomized design without blinding, allowing for direct comparison between the experimental combination therapy and standard treatment options selected by the investigator based on clinical judgment.

The trial is designed to enroll participants who meet specific eligibility criteria. Key inclusion criteria require participants to be at least 18 years of age or the legal age of majority in their country if older than 18 years. Participants must have histologically, pathologically, or cytologically confirmed adenocarcinoma of the prostate with documented metastatic disease demonstrated by at least one metastatic lesion on baseline imaging studies including computed tomography, magnetic resonance imaging, or bone scan performed within 28 days prior to enrollment. Evidence of progressive disease according to PCWG3-modified RECIST 1.1 criteria is required. All participants must have undergone prior orchiectomy or be receiving ongoing androgen-deprivation therapy with documented castrate levels of serum testosterone below 50 ng/dL or 1.7 nmol/L. Prior disease progression on one, and only one, androgen receptor pathway inhibitor such as enzalutamide, apalutamide, or darolutamide is mandatory. Participants intended to receive cabazitaxel must have previously received no more than 6 cycles of docetaxel in the metastatic hormone-sensitive prostate cancer setting. An Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate organ function are required. All participants must provide informed consent before any study-specific activities or procedures are initiated.

The primary endpoint of the study is overall survival, defined as the time from randomization to death from any cause. Secondary endpoints include radiographic progression-free survival per PCWG3-modified RECIST 1.1 criteria as assessed by the investigator, objective response per modified RECIST 1.1, duration of response, disease control, progression-free survival 2, time to response, time to first subsequent therapy, and time to symptomatic skeletal events. Safety endpoints encompass treatment-emergent adverse events, treatment-emergent serious adverse events, and fatal adverse events. Additional secondary endpoints include patient-reported outcomes measuring pain and quality of life using the Brief Pain Inventory-Short Form worst pain score, pain intensity scale, pain interference scale, and Functional Assessment of Cancer Therapy-Prostate total score and subscale scores. Time to worsening and time to improvement in these patient-reported outcome measures are also evaluated. The study assesses prostate-specific antigen responses including PSA 50 and PSA 90 responses, time to PSA responses, duration of PSA response, and time to PSA progression. Pharmacokinetic parameters for xaluritamig including maximum serum concentration, time to maximum concentration, minimum serum concentration, area under the concentration-time curve over the dosing interval, accumulation following multiple dosing, and half-life if feasible, as well as abiraterone pharmacokinetic concentrations at end of dosing interval are measured. The incidence of anti-xaluritamig antibody formation is monitored. Quality of life is further assessed using the EQ-5D-5L utility score and visual analogue scale, and symptomatic adverse events are captured using selected questions from the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events item library and the GP5 question on overall bother of side effects from the FACT-P questionnaire.

Xaluritamig, also known as AMG 509, is a humanized bispecific antibody targeting STEAP1 and CD3, administered as a solution for infusion via intravenous use. Abiraterone acetate is administered orally as film-coated tablets. Docetaxel and cabazitaxel are administered as concentrate for solution for infusion via intravenous use. Siltuximab, marketed as SYLVANT, is included as an auxiliary medicinal product and is administered as a powder for concentrate for solution for infusion via intravenous use. All investigational medicinal products are classified as antineoplastic agents or of biological or biotechnological origin.

The estimated recruitment start date for the trial is November 15, 2025, with an estimated study completion date of August 30, 2032. The maximum treatment period for all medicinal products is set at 9999 days, indicating that treatment may continue as long as participants derive clinical benefit and do not meet discontinuation criteria. Participants may be withdrawn from the study due to disease progression, unacceptable toxicity, withdrawal of consent, or at the discretion of the investigator or sponsor based on safety or efficacy considerations. The study duration encompasses the screening period, treatment period, and follow-up period to assess long-term outcomes including overall survival.

The experimental medication xaluritamig (AMG 509) is a humanised bispecific antibody against STEAP1 and CD3 of biological or biotechnological origin. This investigational product is supplied as a solution for infusion and is administered via the intravenous route. Xaluritamig is dosed in milligrams and is used in combination with abiraterone acetate in the experimental treatment arm of this clinical trial.

Abiraterone acetate is an antineoplastic agent available in multiple pharmaceutical formulations, including film-coated tablets and film coated tablets. The medication is administered via the oral route with dosing expressed in milligrams. Abiraterone acetate functions both as part of the experimental treatment regimen in combination with xaluritamig and as a comparator treatment option selected by the investigator.

Docetaxel is an antineoplastic agent provided as a concentrate for solution for infusion. This comparator medication is administered via intravenous use with dosing measured in milligrams. Docetaxel represents one of the investigator's choice options in the comparator arm of the study.

Cabazitaxel is an antineoplastic agent supplied as a concentrate for solution for infusion. The medication is administered intravenously with dosing expressed in milligrams. Cabazitaxel serves as another investigator's choice comparator treatment option in this trial.

Siltuximab is supplied as SYLVANT 400 mg powder for concentrate for solution for infusion. This protein-based substance is administered via intravenous use and serves as an auxiliary medicinal product in the study. Siltuximab is a marketed product with European Union marketing authorization.

The primary efficacy endpoint is overall survival, defined as the time from randomization until death from any cause. This endpoint will be used to compare outcomes between participants receiving xaluritamig plus abiraterone and those receiving investigator's choice therapy (docetaxel, cabazitaxel, or abiraterone).

Secondary efficacy endpoints include radiographic progression-free survival per Prostate Cancer Working Group 3-modified Response Evaluation Criteria in Solid Tumors version 1.1, assessed by the investigator. Objective response, duration of response, and disease control will be evaluated using modified RECIST 1.1 criteria per investigator assessment. Additional secondary endpoints include progression-free survival 2, time to response per modified RECIST 1.1, time to first subsequent therapy, and time to symptomatic skeletal events. Prostate-specific antigen response rates (PSA 50 and PSA 90), time to PSA response, duration of PSA response, and time to PSA progression will also be assessed.

Patient-reported outcomes will be measured using several validated instruments. Time to worsening and time to improvement will be evaluated using the Brief Pain Inventory-Short Form worst pain score, pain intensity scale, and pain interference scale, as well as the Functional Assessment of Cancer Therapy-Prostate total score. Changes from baseline over time will be assessed using these same instruments, along with the EQ-5D-5L utility score and visual analogue scale. Selected questions on symptomatic adverse events from the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events item library and the GP5 question on overall bother of side effects from the FACT-P questionnaire will be used to evaluate patient-reported outcomes summary scores over time.

Pharmacokinetic parameters for xaluritamig, including maximum serum concentration, time to maximum concentration, minimum serum concentration, area under the concentration-time curve over the dosing interval, accumulation following multiple dosing, and half-life, will be assessed. Abiraterone pharmacokinetic concentrations at end of dosing interval will also be measured. The incidence of anti-xaluritamig antibody formation will be evaluated as part of the immunogenicity assessment.