TAMARACK: Randomized Phase II trial of the B7-H3 targeting antibody drug conjugate (ADC) vobramitamab duocarmazine (vobra duo) in metastatic castration-resistant prostate cancer (mCRPC)

BackgroundVobra duo (MGC018) is a B7-H3-targeting ADC with a duocarmycin-based DNA-alkylating payload. Phase 1 testing (NCT03729596) of vobra duo demonstrated anti-tumor activity in mCRPC, with adverse events at 3.0 mg/kg Q3W resulting in frequent early treatment discontinuation.MethodsTAMARACK (NCT05551117) is a randomized, open-label, Phase 2 dose selection study assessing efficacy and tolerability of two dose levels of vobra duo (2.0 mg/kg and 2.7 mg/kg IV Q4W) in pts with mCRPC previously treated with abiraterone, enzalutamide, or apalutamide; prior docetaxel was allowed. The primary endpoint is investigator-assessed PFS at 6 months.ResultsAs of 12Apr2024, 181 patients (pts) enrolled and 176 received vobra duo. Thirty (13.8%) had liver or lung disease and 104 (57.5%) had received docetaxel. Pts received a median of 5 (range 1-10) cycles of vobra duo with a median of 5.4 months (range 1-10) on study treatment. Treatment is ongoing in 99 (56.3%) pts. In PSA-evaluable pts, confirmed PSA50 response was 43.9% (36/82) in the low dose and 36.6% (26/71) in the high dose arm. Confirmed objective response rate (ORR) in pts with measurable disease was 17.8% (8/45) in the low dose and 25.0% (8/32) in the high dose arm. ORR was higher in pts who did not receive prior taxane (23.5% vs 14.3% in the low dose and 35.7% vs 16.7% in the high dose arm). In pts on study for ≥ 6 months or discontinued (n=123), the 6-month rPFS rate was 51% in the low dose and 59% in the high dose arm. Tolerability data are below (Table). Table: 1654P 2.0 mg/kg (n=90) 2.7 mg/kg (n=86) Any TEAE 89 (98.9%) 86 (100%) TEAE grade 3-5 49 (54.4%) 44 (51.2%) Serious TEAE 25 (27.8%) 30 (34.9%) TEAE leading to drug interruption 38 (42.2%) 48 (55.8%) TEAE leading to dose reduction 39 (43.3%) 44 (51.2%) TEAE leading to discontinuation 10 (11.1%) 13 (15.1%) Fatal TEAE 1 (1.1%) 4 (4.7%) Pleural effusion 16 (17.8%) all grade 1-2 25 (29.1%) all grade 1-2 except 1 grade 3 event Pericardial effusion 8 (8.9%) all grade 1-2 8 (9.3%) all grade 1-2 Palmar-plantar erythrodysesthesia 14 (15.6%) all grade 1-2 20 (23.3%) all grade 1-2 except 1 grade 3 event ConclusionsVobra duo had acceptable tolerability and anti-tumor activity in mCRPC meriting further evaluation in later phase trials.Clinical trial identificationNCT05551117.Legal entity responsible for the studyMacroGenics, Inc.FundingMacroGenics, Inc.DisclosureJ.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Menarini Silicon Biosystems, ImCheck Therapeutics, Crescendo, MetaCurUm, Myricx, Nurix Therapeutics, Oncternal Therapeutics; Financial Interests, Institutional, Advisory Board: Harpoon, Dark Blue Therapeutics, Novartis, Takeda, Tango Therapeutics; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi Sankyo, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics, Menarini Silicon Biosystems, Immunic Therapeutics, MetaCurUm, Myricx, Nurix Therapeutics, Oncternal Therapeutics; Financial Interests, Institutional, Local PI: Amgen; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Crescendo, ImCheck Therapeutics, Immunic Therapeutics; Non-Financial Interests, Institutional, Product Samples: Daiichi Sankyo, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. C. Helissey: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca, MSD, BMS, Viatris, ACCORD, Bayer, Ipsen, GSK, Eisai; Financial Interests, Personal, Advisory Board: Macrogenics; Non-Financial Interests, Principal Investigator: Janssen, Sanofi, Roche, Astellas, Macrogenics, Regeneron, GILEAD. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Personal, Advisory Board, February 2022: Arvinas; Financial Interests, Personal, Advisory Board, April 2022: Macrogenics; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the CAPITELLO 281 phase 3 trial: AstraZeneca; Non-Financial Interests, Principal Investigator, Chair of the TALAPRO-2 and TALAPRO-3 phase 3 trials: Pfizer; Non-Financial Interests, Principal Investigator, Chair of the RADIANT phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the TRITON-3 phase 3 trial: Clovis. J.P. Maroto Rey: Financial Interests, Personal, Advisory Board, Participation in Ad boards: Bayer; Financial Interests, Personal, Advisory Board, Participation in ad boards: Astellas, Merck, Pfizer, MSD; Financial Interests, Personal, Invited Speaker: Janssen; Non-Financial Interests, Principal Investigator, Collaboration as PI in trials: AstraZeneca. G. Roubaud: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer; Financial Interests, Institutional, Advisory Board: Pfizer, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Coordinating PI: Bayer. E.S. Antonarakis: Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis, MacroGenics, Merck, Novartis, Seagen; Non-Financial Interests, Principal Investigator: Orion; Non-Financial Interests, Advisory Role: Aadi Bioscience, Amgen, AstraZeneca, Bayer, Blue Earth Diagnostics, Curium, EcoR1, Hookipa Pharma, Janssen, Lilly, Menarini Silicon Biosystems, Merck, Pfizer, Sanofi, Tango Therapeutics, Tempus, z-Alpha, Orion. S.K. Sandhu: Financial Interests, Institutional, Advisory Board, I have served on advisory boards for BMS. The contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Bristol Myer Squib; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for MSD. The e contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Merck Sharp and Dohme; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for AstraZeneca. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: AstraZeneca; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for Novartis. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Novartis; Financial Interests, Institutional, Advisory Board, I have served on an advisory board for Merck Serono. The contracts for my service are set up with the institution and funds go into a research fund at the Peter MacCallum Cancer Centre.: Merck Serono; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead.: Novartis, Genentech, Amgen, AstraZeneca, Merck Serono, Merck Sharp and Dohme; Financial Interests, Institutional, Funding, Pfizer are providing funding to my institution for the conduct of an investigator initiated clinical trial.: Pfizer; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Janssen sponsored studies and don't receive any renumeration for this.: Janssen; Non-Financial Interests, Principal Investigator, I am a principal investigator on several Novartis sponsored studies and don’t receive any renumeration for this.: Novartis; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Genentech sponsored studies and don't receive any renumeration for this.: Genentech; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Bristol Myer Squibb sponsored studies and don't receive any renumeration for this.: Bristol Myer Squibb; Non-Financial Interests, Other, I serve on the Independent Safety and Data Monitoring committee for 2 of Novartis sponsored studies and don’t receive any compensation for this.: Novartis; Non-Financial Interests, Principal Investigator, I am the Priincipal Investigator for several AstraZeneca sponsored studies and am not remunerated for this.: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for several Janssen sponsored trials and i do not receive compensation for this.: Janssen; Non-Financial Interests, Other, I serve on the steering committee for one AstraZeneca sponsored trial and I do not receive compensation for this.: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for one Genentech sponsored trials and I do not receive compensation for this.: Genentech; Non-Financial Interests, Other, I serve on the steering committee for a Bristol Myer Squibb sponsored trial and I do not receive renumeration for this.: Bristol Myer Squibb. N.D. Shore: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Cold Genesys, Dendreon, Exact Imaging, Genesis Care Us, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Propella, Sanofi Genzyme, Speciality Networks, Tolmar, Urogen, Clarity, Lantheus, Lilly, Photocure, Telix, Photocure, Asieris, Alessa Therapeutics, Arquer, Fize medical, GConcology, Guardant, Ferring, Foundation Medicine, Immunitybio, Incyte, Minomic, NGM, Nonagen, Novartis, PlatformQ, Promaxo, Protara, Accord, Antev, Aura biosciences, Sumitomo; Financial Interests, Personal, Member of Board of Directors: Photocure, Alessa Theraputics; Financial Interests, Personal and Institutional, Local PI: AstraZeneca, Bayer, Aura, Exact Imaging, Janssen, Merck, Myovant, Novartis, Pfizer, Propella, Bristol Myers Squibb, Dendreon, Pfizer, Urogen; Financial Interests, Institutional, Local PI: Alessa, GC oncology, FORMA therapeutics, Pacific edge, Point Biopharma, The MT group, Theralase, Verity, Astellas, Palette Life Sciences, Steba, Zenflow. R. Ratta: Financial Interests, Personal, Invited Speaker: Ipsen, Astellas; Financial Interests, Personal, Advisory Board: Pfizer, Merck, Bristol Meyer Squibb, AstraZeneca, Janssen. B. Perez Valderrama: Financial Interests, Personal, Advisory Board: Pfizer, Astellas Pharma, Bristol-Myers-Squibb, Ipsen, EUSA Pharma, Merck, MSD, AstraZeneca, AAA, Recordati; Financial Interests, Personal, Invited Speaker: Bristol-Myers-Squibb, Bayer, MSD, Merck, Pfizer, Astellas Pharma, AAA, Almirall pharma; Other, Travel/accommodations: Bristol--Myers-Squibb, Pfizer. C. Vulsteke: Financial Interests, Personal, Advisory Board: MSD, Janssen-Cilag, GSK, Astellas Pharma, BMS, Leo Pharma, Bayer, AstraZeneca, Pfizer, Merck; Financial Interests, Institutional, Research Grant, Funding for research project on immune related toxicities: MSD. L. Schafer: Financial Interests, Institutional, Full or part-time Employment: MacroGenics; Financial Interests, Institutional, Stocks/Shares: MacroGenics; Non-Financial Interests, Project Lead: MacroGenics; Non-Financial Interests, Institutional, Proprietary Information: MacroGenics. G. Marr: Financial Interests, Personal, Full or part-time Employment, Currently employed, since April 2023: MacroGenics; Financial Interests, Personal, Full or part-time Employment, Employed December 2015 - April 2023: AstraZeneca; Financial Interests, Personal, Stocks/Shares: MacroGenics, AstraZeneca. E. Zhao: Financial Interests, Personal, Full or part-time Employment: Macrogenics Inc.; Financial Interests, Personal, Stocks/Shares: Macrogenics Inc. A.F. Ward: Financial Interests, Personal, Full or part-time Employment: MacroGenics; Financial Interests, Personal, Stocks/Shares: MacroGenics; Non-Financial Interests, Personal, Leadership Role: MacroGenics. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca, Immunocore, Novartis; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati, Immunocore, Regeneron.