Background: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles., Methods: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m 2 intravenously on days 1-3), doxorubicin (35 mg/m 2 intravenously on day 1), and cyclophosphamide (1250 mg/m 2 intravenously on day 1), and standard doses of bleomycin (10 mg/m 2 intravenously on day 8), vincristine (1·4 mg/m 2 intravenously on day 8), procarbazine (100 mg/m 2 orally on days 1-7), and prednisone (40 mg/m 2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503)., Findings: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively., Interpretation: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma., Funding: Takeda Oncology., Competing Interests: Declaration of interests PB reports consulting fees from Takeda, BMS, Roche, Amgen, Novartis, Celgene, Miltenyi Biotech, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, Novartis, BMS, Roche, MSD, Celgene, Miltenyi Biotech, Gilead, and AbbVie; and funding for scientific research from Takeda Oncology, MSD, and Novartis. JF reports funding and consulting fees from Takeda Oncology and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda Oncology and Roche Pharma. RG reports consulting fees from Celgene, Novartis, Roche, Takeda, AbbVie, Astra Zeneca, MSD, Merck, Gilead, Daiichi Sanko, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, and Sanofi; support for attending meetings or travel from Roche, Amgen, Janssen, Astra Zeneca, Novartis, BMS, AbbVie, and Daiichi Sankyo; participating on a data safety monitoring board or advisory board for Celgene, Novartis, Roche, BMS, Takeda, AbbVie, Astra Zeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo, and Sanofi; and stock or stock options from Novo Nordisk and Lilly. MHe reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. AH reports payment for speakers bureau, funding, and travel support from, and participation on an advisory board for Takeda. FK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and support for attending meetings or travel from Takeda. MHä reports consulting fees from Pfizer, Incyte, Roche, Amgen, Sanofi/Aventis, Sobi, Kite/Gilead, Janssen, and BMS and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sobi, Novartis, Kite/Gilead, Falk Foundation, and BMS. UN reports consulting fees for the institution from Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, BeiGene, Kyowa Kiin, Gileag, and Pierre Fabre; payment or honoraria for lectures, presentations, speakers bureaus, manuscript, writing or educational events for the institution from Celgene (BMS), Novartis, Takeda, and Gilead; support to the institution for attending meetings or travel from Janssen, Roche, Gilead, and Takeda; and participating on a data safety monitoring board or advisory board for Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, BeiGene, Kyowa Kiin, Gileag, and Pierre Fabre. JM reports consulting fees from MSD. AZi reports payment for presentations from Novartis, Oncopeptides, Takeda, Incyte, and Roche and travel support from Oncopeptides, Roche, and Novartis. AF reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. AV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, BMS, and AbbVie; support for attending meetings or travel from Janssen, Kite/Gilead, BMS, and AbbVie; and participation on a data safety monitoring board or advisory board from Roche, BMS, AbbVie, and Kite/Gilead. SS reports travelling support from AbbVie and Jazz and reports support for attending meetings or travel from and having a leadership or fiduciary role in another board, society, committee or advocacy group (paid or unpaid) with Pfizer, Amgen, and Novartis. VV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda and participation on an advisory board for Takeda and MSD. AK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Celgene, AbbVie, Sobi, BMS, and Takeda and support for attending meetings or travel from AbbVie, BeiGene, Sobi, Takeda, EUSA Pharma, Novartis, and Alexion. KT-G reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. PK reports travel support from Roche Pharmaceuticals and Takeda. BvT reports institutional grants or contracts from Esteve, Merck Sharp & Dohme, Novartis, and Takeda; consulting fees from Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Roche, Sobi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Lilly, Merck Sharp & Dohme, Novartis, Roche, and Takeda; support for attending meetings or travel from AbbVie, AstraZeneca, Gilead, Kite, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis; payment from Takeda and Regeneron (INSIGHTFUL study); payment to institution from the Olympia 3 study; and participation on a data safety monitoring board or advisory board for Takeda and Regeneron. SB reports consulting fees from Galapagos; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events and consultation from Takeda; support for attending meetings or travel from Takeda; having a leadership role in another board, society, committee, or advocacy group (paid or unpaid), and holding stock or stock options for Liqomics. KB reports funding and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda Oncology. MF reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Celgene, BMS, Takeda, and Janssen. AZo reports Takeda stocks and being an employee of Takeda Oncology. SK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, payment for expert testimony, and support for attending meetings or travel from, and participating on a data safety monitoring board or advisory board for Takeda. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)