A Phase 3 Randomized, Double-blind, Placebo-controlled Study of JNJ-78278343, a T-cell-redirecting Agent Targeting Human Kallikrein 2 Versus Placebo for Metastatic Castration-resistant Prostate Cancer

The primary objective of this phase 3 randomized, double-blind, placebo-controlled trial is to determine if pasritamig combined with best supportive care (BSC) compared to placebo combined with BSC is superior in overall survival (OS) in patients with late-line metastatic castration-resistant prostate cancer (mCRPC). Pasritamig (JNJ-78278343) is a T-cell-redirecting agent targeting human kallikrein 2. The evaluation of overall survival as the primary endpoint is clinically relevant for establishing the therapeutic benefit of this novel immunotherapeutic approach in patients with advanced disease who have limited treatment options.

This clinical trial enrolled a total of **416 participants** diagnosed with **metastatic castration-resistant prostate cancer (mCRPC)**. The study population consisted exclusively of **male subjects** with **histologically confirmed adenocarcinoma of the prostate**. Participants included **adults** and **elderly individuals** who had disease metastatic to bone, lymph nodes, or both, without visceral organ metastasis at screening. The trial population was selected based on extensive prior treatment history, requiring participants to have progressed on at least one **androgen receptor pathway inhibitor (ARPI)** and to have received at least two previous **taxane-based regimens**, with certain exceptions for unavailability or intolerance. Participants were also expected to have received **PSMA-targeted lutetium radioligand therapy** unless unavailable or clinically contraindicated, and those with known **germline or somatic BRCA mutation** should have been previously treated with **PARP inhibitors** if available. All participants were required to have ongoing **androgen deprivation therapy (ADT)** with a **GnRH analog** or prior **orchiectomy**, and to maintain castration throughout the study. Eligible participants had an **ECOG performance status** of 0 to 2, demonstrating adequate functional capacity. Laboratory requirements included **estimated glomerular filtration rate (eGFR)** ≥30 mL/min, **absolute neutrophil count (ANC)** ≥1.0 x 10⁹/L, **hemoglobin** ≥8.0 g/dL, **platelet count** ≥75 x 10⁹/L, **alanine aminotransferase (ALT)** and **aspartate aminotransferase (AST)** ≤5 times the upper limit of normal, and serum **total bilirubin** ≤3 times the upper limit of normal. Participants were required to have a **prostate-specific antigen (PSA)** level ≥2 ng/mL at screening. The selection process ensured that participants had exhausted life-prolonging therapies for which they were clinically eligible and to which they had access, with the investigator determining that the next best treatment option was participation in a clinical trial.

This is a **Phase 3**, **randomized**, **double-blind**, **placebo-controlled** clinical trial evaluating **pasritamig** (JNJ-78278343), a **T-cell-redirecting agent** targeting **human kallikrein 2**, versus **placebo** in participants with **metastatic castration-resistant prostate cancer** (mCRPC). The study aims to determine if pasritamig combined with **best supportive care** (BSC) is superior to placebo combined with BSC in terms of **overall survival**, which serves as the **primary endpoint**. The trial is designed as a therapeutic exploratory and confirmatory study in patients with mCRPC who have exhausted standard treatment options.

Eligible participants must have histologically confirmed **adenocarcinoma of the prostate** with metastatic disease to bone, lymph nodes, or both, without visceral organ metastasis at screening. Participants must have a **prostate-specific antigen** (PSA) level of at least 2 ng/mL and must be receiving ongoing **androgen deprivation therapy** (ADT) with a **gonadotropin-releasing hormone** (GnRH) analog or have undergone prior orchiectomy. In the investigator's opinion, the next best treatment option for eligible participants should be enrollment in a clinical trial. Prior therapy requirements include progression on at least one **androgen receptor pathway inhibitor** (ARPI) with unlikely benefit from retreatment with another ARPI, receipt of at least two previous taxane-based regimens (or one regimen if cabazitaxel is unavailable or deemed unsuitable), and prior treatment with at least one dose of **PSMA-targeted lutetium radioligand therapy** unless unavailable, inaccessible, or clinically contraindicated. Participants with known germline or somatic **BRCA mutation** should have received prior **PARP inhibitor** (PARPi) therapy if available. Participants must have an **Eastern Cooperative Oncology Group** (ECOG) performance status of 0 to 2 and adequate organ function, including **estimated glomerular filtration rate** (eGFR) of at least 30 mL/min, **alanine aminotransferase** (ALT) and **aspartate aminotransferase** (AST) levels not exceeding 5 times the **upper limit of normal** (ULN), serum total **bilirubin** not exceeding 3 times ULN, **absolute neutrophil count** (ANC) of at least 1.0 x 10⁹/L, **hemoglobin** of at least 8.0 g/dL, and **platelet count** of at least 75 x 10⁹/L, with no transfusion or growth factor usage within 28 days of randomization.

The investigational product JNJ-78278343 is administered as a **solution for injection/infusion**, while the comparator is a matched placebo. The study is conducted as a therapeutic confirmatory trial evaluating the efficacy and safety of pasritamig in a late-line mCRPC population. The estimated recruitment start date is November 2025, with an estimated study completion date of May 2029, indicating an overall trial duration of approximately 42 months. The maximum treatment period for participants is 999 days, though individual participant involvement may vary based on treatment response, disease progression, and tolerability.

Participants will undergo a **screening visit** to assess eligibility according to the inclusion and exclusion criteria outlined in the protocol. Following randomization, participants will receive either pasritamig or placebo in combination with best supportive care. **Follow-up visits** will be conducted at regular intervals to monitor treatment efficacy, safety parameters, disease progression, and overall survival. The sequence and frequency of study visits will be determined according to the protocol schedule, with assessments including physical examinations, laboratory evaluations, imaging studies, and adverse event monitoring. An **end-of-study visit** will be conducted upon treatment discontinuation or study completion.

Participant involvement in the study will continue until disease progression, unacceptable toxicity, withdrawal of consent, death, or study termination by the sponsor. **Early termination** from the study may occur under several conditions, including the development of unacceptable adverse events, significant protocol violations, participant withdrawal of consent, loss to follow-up, investigator decision that continued participation is not in the participant's best interest, pregnancy, or administrative reasons including sponsor decision to terminate the trial. Participants who discontinue study treatment will be followed for survival status and subsequent anticancer therapies as specified in the protocol.

The experimental treatment under investigation is **JNJ-78278343**, a T-cell-redirecting agent targeting human kallikrein 2. This investigational medicinal product is manufactured by JANSSEN-CILAG INTERNATIONAL N.V. and is classified as a protein-based therapeutic agent. JNJ-78278343 is supplied as a **solution for injection/infusion** in a ready-to-use pharmaceutical form. The active substance is JNJ-78278343, which is administered via **intravenous infusion**. The treatment period may extend up to 999 days. JNJ-78278343 is administered in combination with best supportive care in participants with metastatic castration-resistant prostate cancer.

The comparator treatment consists of **placebo** matching JNJ-78278343. The placebo is administered to maintain the double-blind design of the study and is given in combination with best supportive care. The placebo formulation is designed to match the appearance and administration characteristics of the active investigational product to ensure blinding integrity throughout the trial. Participants randomized to the placebo arm receive the comparator treatment according to the same schedule as those receiving the active investigational medicinal product.

Efficacy will be assessed using overall survival as the primary endpoint. The study objective is to determine if pasritamig in combination with best supportive care compared to placebo in combination with best supportive care demonstrates superiority in overall survival. The trial is designed as a randomized, double-blind, placebo-controlled Phase 3 study in participants with metastatic castration-resistant prostate cancer. Participants must have a prostate-specific antigen level of at least 2 ng/mL at screening and must have progressed on prior life-prolonging therapies including at least one androgen receptor pathway inhibitor and at least two taxane-based regimens, unless specific criteria for exemption apply. The treatment period is planned for up to 999 months with an estimated study end date in May 2029.