A phase I, first-in-human, open-label, multicenter, trial-in-progress of the safety, tolerability, and preliminary efficacy of JNJ-87189401 (PSMA-CD28 bispecific antibody) combined with JNJ-78278343 (KLK2-CD3 bispecific antibody) for advanced prostate cancer

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis with limited treatment options, especially after the use of androgen receptor (AR) pathway inhibitors. Despite ongoing efforts in developing targeted immunotherapies, the clinical response remains limited with challenging safety profiles. JNJ-78278343 is a bispecific antibody (bsAb) designed to target human Kallikrein 2 (hK2, encoded by the KLK2 gene), a highly prostate-specific antigen, and induce T cell activation via binding to CD3 on T cells. JNJ-87189401 is a costimulatory bsAb directed against prostate-specific membrane antigen (PSMA) on prostate tumor cells and CD28 on T cells. JNJ-78278343 and JNJ-87189401 combination therapy may lead to improved T cell activation and lead to deeper and more durable clinical response.Trial designThis is a first-in-human, open-label, multicenter, ongoing study (NCT06095089) of the safety, tolerability, and preliminary antitumor activity of JNJ-87189401 combined with JNJ-78278343 in mCRPC. Participants (pts; aged ≥18 years) with measurable or evaluable mCRPC per Prostate Cancer Working Group 3 criteria, serum PSA ≥2 ng/mL, and Eastern Cooperative Oncology Group performance status 0 or 1 are eligible. Adenocarcinoma of the prostate with small cell or neuroendocrine (NE) features is permitted; but small cell carcinoma, carcinoid tumor, mixed NE carcinoma, or large cell NE carcinoma is not allowed. Pts are required to have undergone orchiectomy or medical castration or must be receiving ongoing androgen deprivation therapy, and have progressed with at least one AR-targeted agent or systemic chemotherapy. Primary objectives: 1) to determine the recommended phase 2 regimen(s) (RP2Rs) of JNJ-87189401 combined with JNJ-78278343; 2) to evaluate the safety at RP2Rs in pts with advanced prostate cancer. Secondary objectives: preliminary efficacy (objective response rate, duration of response, PSA response rate), pharmacokinetics, and immunogenicity. Enrollment (N≈110) is ongoing.Clinical trial identificationNCT06095089.Legal entity responsible for the studyJanssen Research & Development, LLC.FundingJanssen Research & Development, LLC.DisclosureM.N. Stein: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb/Medarex, Exelixis, Janssen Oncology, Merck Sharp & Dohme, Vaccitech, Xencor; Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb/Medarex, Exelixis, Janssen Oncology, Merck Sharp & Dohme, Vaccitech, Xencor; Financial Interests, Institutional, Research Funding: Advaxis, AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, Exelixis, Genocea Biosciences, Harpoon, Janssen Oncology, Lilly, Medivation/Astellas, Merck Sharp & Dohme, Oncoceutics, Nektar, Regeneron, Seattle Genetics, Suzhou Kintor Pharmaceuticals, Tmunity, Xencor; Financial Interests, Personal, Research Funding: Bellicum Pharmaceuticals. C. Baldini: Financial Interests, Personal, Other, Consulting: 4.UNCAN.eu Consensus meeting, Boxer Capital, EcoR1 capital, Elaia, Guidepoint, Janssen, Rising Tide Fundation; Financial Interests, Personal, Other, Honoraria: Amgen, AZ, BMS, GSK, MSD, Sanofi; Financial Interests, Personal, Other, Travel accommodation: Janssen, MSD; Financial Interests, Personal, Other, As part of the Drug Development Department (DITEP): Principal/sub-Investigator of Clinical Trials: AbbVie, Adaptimmune, Adlai Nortye USA Inc., Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, BicycleTx Ltd., Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals Inc., Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd., Forma Tharapeutics, Gamamabs, Genentech, GSK, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, MedImmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Relay Therapeutics, Inc., Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene S.A, Turning Point Therapeutics, Xencor; Financial Interests, Personal, Other, As part of the Drug Development Department (DITEP): Principal/sub-Investigator of Clinical TrialsAs part of the Drug Development Department (DITEP): Principal/sub-Investigator of Clinical Trials: AstraZeneca Ab; Financial Interests, Institutional, Research Grant, As part of the Drug Development Department (DITEP): Principal/sub-Investigator of Clinical Trials: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Pfizer, Roche, Sanofi; Non-Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP): Principal/sub-Investigator of Clinical Trials: AstraZeneca, BMS, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. A. Vinceneux: Financial Interests, Personal, Other, Principal investigator in the Phase 1 unit at CLB of Clinical Trials: AstraZeneca, BIONTECH RNA, EXSCIENTA Ltd., Exelixis, Hoffmann La Roche Ag, IPSEN, JNJ, Kinnate Biopharma, Lilly France, Loxo Oncology, Novartis, TAKEDA; Financial Interests, Personal, Speaker, Consultant, Advisor, Principal investigator in the Phase 1 unit at CLB of Clinical Trials: BMS; Financial Interests, Personal, Speaker, Consultant, Advisor: IPSEN, MSD; Financial Interests, Personal, Other, Non personal fees and travel accommodation: Bayer, IPSEN, MSD, Recordati. E. Kessler: Financial Interests, Institutional, Research Funding: Astellas, Bristol Meyer Squib, Genentech, Janssen, Lilly, Pfizer, Merck, Seattle Genetics; Financial Interests, Personal, Other, Speaker: Astellas. K. Runcie: Other, Personal, Other, Virtual round table discussing updates in kidney cancer from ASCO 2024: VJ Oncology; Non-Financial Interests, Institutional, Principal Investigator: Amgen, BMS, Novartis, Trisalus Life Sciences, Xencor; Non-Financial Interests, Institutional, Advisory Board: Exelixis; Non-Financial Interests, Personal and Institutional, Steering Committee Member: Janssen. A.Z. Wei: Financial Interests, Personal, Advisory Board: Bicycle Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting: Bicycle Therapeutics, Sanofi. K.P. Papadopoulos: Financial Interests, Institutional, Research Funding: 3D Medicines, AbbVie, ADC Therapeutics, Amgen, AnHeart Therapeutics, Bayer, Bicycle Therapeutics, BioNTech, Daiichi Sankyo, EMD Serono, F-star Therapeutics, Incyte, Kezar Life Sciences Jounce Therapeutics, Lilly, Linnaeus Therapeutics, MedImmune, Merck, Mersana, Mirati Therapeutics, Peloton Therapeutics, Pfizer, Regeneron, Syros Pharmaceuticals, Tempest Therapeutics, Treadwell Therapeutics. A. Bernard-Tessier: Financial Interests, Personal, Other, travel, accommodations and expenses: AAA-Novartis, Orion; Financial Interests, Personal, Other, consultancy or advisory role: AAA-Novartis, Janssen, MSD, AstraZeneca, Roche, Hoopika, Astellas, Bayer, Orion, Bouchara-Recordati. P. Jaiprasart, D. Thaper, F. Shen, L. Cartee, E. Attiyeh, V.M. Villalobos: Financial Interests, Personal, Other, Employee: Janssen; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson. D. Rasco: Financial Interests, Institutional, Research Funding: JNJ, BMS. All other authors have declared no conflicts of interest.