LBA4 Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol

ABSTRACT

Background: Patients (pts) with high-risk M0 PCa are treated with ADT and when indicated, local radiotherapy (RT). Intensifying hormone treatment with AAP, ENZ or apalutamide continuous to progression improves outcomes of metastatic PCa but its efficacy in M0 PCa starting ADT is unknown. Methods: STAMPEDE is a multi-arm, multi-stage trial that, as part of 2 separate comparisons randomised PCa pts with M0 node positive or high-risk node negative (>1 T3/4, PSA ≥40ng/ml, Gleason 8-10 or relapsing) 11 to ADT (control) vs ADT with AAP (1000mg AA + 5mg P od) or ADT vs ADT with AAP + ENZ (160mg od) for 2 years (y), unless RT was omitted when treatment could be to progression. The primary end-point was metastasis-free survival (MFS, time to death or distant metastases). The sub-group of pts who received ADT +/- AAP was partially reported with metastatic pts in 2017 so one-sided type 1 error rate was set to 1.25%. All analyses were pre-specified, pooled using meta-analyses methods and stratified as described previously. Data frozen 3rd August 2021. Results: 1974 M0 pts at 113 sites in UK & Switzerland were randomised, 914 (Nov 2011 to Jan 2014) to ADT +/- AAP & 1060 (Mar 2016 to Jul 2014) to ADT +/- AAP + ENZ. Groups were well balanced median age 68 y, range 43-86;median PSA 34 ng/ml, range 0.4-2773;Gleason 8-10, 79%;node positive 39%;planned for RT 85%. Median months to stopping AAP, 23.7 (IQR 17.6-24.1);AAP when given with ENZ, 20.7 (IQR 4.4-24);ENZ, 23.2 (IQR 6.3-24). 180 MFS events occurred in the research group and 306 in the control group. AAP-based therapy improved MFS (HR 0.53, 95% CI 0.44-0.64, P=2.9×10- 11) & survival (HR 0.60, 95% CI 0.48-0.73, P=9.3×10-7) 6-y MFS from 69% to 82%, 6-y survival from 77% to 86%. Treatment effect was consistent in major subgroups and between AAP & AAP + ENZ randomisation periods (MFS HR=0.54, 95% CI 0.43-0.68;HR=0.53, 95% CI 0.39-0.71 respectively;interaction HR = 1.02, 95% CI 0.70-1.50, p=0.908). Conclusions: 2 y of AAP-based therapy significantly improves MFS & survival of high-risk M0 PCa starting ADT and should be considered a new standard of care. Clinical trial identification NCT00268476. Legal entity responsible for the study Medical Research Council Clinical Trials Unit at University College London. Funding: Cancer Research UK, Medical Research Council, Astellas, Janssen. Disclosure G. Attard Financial Interests, Personal, Invited Speaker Janssen;Financial Interests, Personal, Advisory Board Janssen;Financial Interests, Personal, Invited Speaker Astellas;Financial Interests, Personal, Advisory Board Astellas;Financial Interests, Personal, Advisory Board Novartis;Financial Interests, Personal, Advisory Board Bayer;Financial Interests, Personal, Invited Speaker AstraZeneca;Financial Interests, Personal, Advisory Board AstraZeneca;Financial Interests, Personal, Advisory Board Pfizer;Financial Interests, Personal, Advisory Board Sanofi;Financial Interests, Personal, Advisory Board Sapience;Financial Interests, Personal, Advisory Board Orion;Financial Interests, Personal, Royalties Janssen;Financial Interests, Institutional, Research Grant Janssen;Financial Interests, Institutional, Research Grant Astellas;Non-Financial Interests, Principal Investigator Janssen;Non-Financial Interests, Advisory Role Janssen;Non-Financial Interests, Advisory Role AstraZeneca;Non-Financial Interests, Principal Investigator Astellas. L.C. Brown Financial Interests, Institutional, Research Grant, FOCUS4-C Trial from June 2017 to Dec 2021 AstraZeneca. N. Clarke Financial Interests, Personal, Invited Speaker Astellas;Financial Interests, Personal, Invited Speaker AstraZeneca;Financial Interests, Personal, Invited Speaker Ferring;Financial Interests, Personal, Invited Speaker Janssen;Financial Interests, Personal, Advisory Board Astellas;Financial Interests, Personal, Advisory Board AstraZeneca;Financial Interests, Personal, Advisory Board Ferring;Financial Interests, Personal, Advisory Board Janssen;Financial Interests, Inst tutional, Research Grant AstraZeneca. W. Cross Financial Interests, Personal, Invited Speaker, Speaker fee Myriad Genetics;Financial Interests, Personal, Invited Speaker, Speaker fee Janssen;Financial Interests, Personal, Advisory Board, Advisory Board fee Bayer;Financial Interests, Personal, Invited Speaker, Speaker fee Astellas;Financial Interests, Institutional, Research Grant, Research grant Myriad Genetics. R. Jones Financial Interests, Personal, Advisory Board, advisory board attendance AstraZeneca;Financial Interests, Personal, Advisory Board, advisory board attendance Astellas;Financial Interests, Personal, Invited Speaker, Honoraria for speaking Astellas;Financial Interests, Personal, Advisory Board Bayer;Financial Interests, Personal, Invited Speaker Bayer;Financial Interests, Personal, Advisory Board Clovis;Financial Interests, Personal, Advisory Board Exelixis;Financial Interests, Personal, Advisory Board Ipsen;Financial Interests, Personal, Invited Speaker Ipsen;Financial Interests, Personal, Advisory Board Bristol Myers Squipp;Financial Interests, Personal, Invited Speaker Bristol Myers Squibb;Financial Interests, Personal, Advisory Board Merck Serono;Financial Interests, Personal, Invited Speaker Merck Serono;Financial Interests, Personal, Advisory Board Merck Sharpe Dome;Financial Interests, Personal, Invited Speaker Merck Sharpe Dome;Financial Interests, Personal, Invited Speaker Pfizer;Financial Interests, Personal, Advisory Board Roche;Financial Interests, Institutional, Other, IDMC membership Roche;Financial Interests, Personal, Invited Speaker Roche;Financial Interests, Personal, Advisory Board Janssen;Financial Interests, Personal, Invited Speaker Janssen;Financial Interests, Institutional, Other, IDMC member Stab;Financial Interests, Personal, Advisory Board Novartis / AAA;Financial Interests, Institutional, Invited Speaker Janssen;Financial Interests, Institutional, Invited Speaker Pfizer;Financial Interests, Institutional, Invited Speaker Tail;Financial Interests, Institutional, Invited Speaker AstraZeneca;Financial Interests, Institutional, Invited Speaker BioXcel;Financial Interests, Institutional, Invited Speaker Bristol Myers Squibb;Financial Interests, Institutional, Invited Speaker Novartis / AAA;Financial Interests, Institutional, Invited Speaker Roche;Financial Interests, Institutional, Invited Speaker MSK. S. Gillessen Financial Interests, Personal, Advisory Board, 2018 Sanofi;Financial Interests, Personal, Advisory Board, 2018, 2019 Orion;Financial Interests, Personal, Advisory Board, 2018 Roche;Financial Interests, Personal, Invited Speaker, 2019 Speaker's Bureau Janssen Cilag;Financial Interests, Personal, Advisory Board, 2020 Amgen;Financial Interests, Personal, Invited Speaker, 2020 ESMO;Financial Interests, Personal, Other, Travel Grant 2020 ProteoMEdiX;Financial Interests, Institutional, Advisory Board, 2018, 2019 Bayer;Financial Interests, Institutional, Advisory Board, 2020 Janssen Cilag;Financial Interests, Institutional, Advisory Board, 2020 Roche;Financial Interests, Institutional, Advisory Board, 2018 AAA International;Financial Interests, Institutional, Advisory Board, 2018 Menarini Silicon Biosystems;Financial Interests, Institutional, Advisory Board, 2019, 2020 Astellas Pharma;Financial Interests, Institutional, Advisory Board, 2019 Tolero Pharmaceuticals;Financial Interests, Institutional, Advisory Board, 2020 MSD Merck Sharp & Dohme;Financial Interests, Institutional, Advisory Board, 2020 Pfizer;Financial Interests, Personal, Invited Speaker, 2021 SAKK;Financial Interests, Institutional, Advisory Board, 2021 Telixpharma;Financial Interests, Institutional, Other, Steering Committee 2021 Amgen;Financial Interests, Institutional, Invited Speaker, 2021 DESO;Financial Interests, Institutional, Advisory Board, 2021 BMS;Financial Interests, Institutional, Advisory Board, 2021 AAA International;Financial Interests, Institutional, Advisory Board, 2021 Orion;F nancial Interests, Personal, Invited Speaker, 2021 SAKK;Financial Interests, Personal, Invited Speaker, 2021 SAKK;Financial Interests, Institutional, Advisory Board, 2021 Bayer;Financial Interests, Personal, Advisory Board, 2021 MSD Merck Sharp & Dhome;Financial Interests, Personal, Other, 2021 RSI (Televisione Svizzera Italiana);Financial Interests, Personal, Invited Speaker, 2021 SAMO - IBCSG;Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator Astellas;Non-Financial Interests, Advisory Role, 2019 Menarini Silicon Biosystems;Non-Financial Interests, Advisory Role, 2019 Aranda;Non-Financial Interests, Advisory Role, Continuing ProteoMediX. S. Chowdhury Financial Interests, Personal, Advisory Board Astellas;Financial Interests, Personal, Advisory Board Janssen;Financial Interests, Personal, Invited Speaker Janssen;Financial Interests, Personal, Advisory Board Huma;Financial Interests, Personal, Invited Speaker AstraZeneca;Financial Interests, Personal, Advisory Board Bayer;Financial Interests, Personal, Invited Speaker Bayer;Financial Interests, Personal, Advisory Board Novartis/AAA;Financial Interests, Personal, Advisory Board Beigene;Financial Interests, Personal, Advisory Board Remedy Bio;Financial Interests, Personal, Advisory Board Athenex;Financial Interests, Personal, Advisory Board Telix;Financial Interests, Personal, Advisory Board Clovis Oncology;Financial Interests, Personal, Stocks/Shares Curve Life;Financial Interests, Institutional, Research Grant Clovis Oncology;Non-Financial Interests, Advisory Role, Non-compensated advice NHS England;Non-Financial Interests, Advisory Role NICE NHS England. Z. Malik Financial Interests, Personal, Advisory Board, advisry board for new hormonal therapy for breast cancerSanofi;Other, support to attend meetings or advisory boards in the past Astellas, Jaansen, Bayer. C. Parker Financial Interests, Personal, Advisory Board, Education Steering Committee Bayer;Financial Interests, Personal, Invited Speaker, Speaker at prostate cancer educational events Janssen;Financial Interests, Personal, Advisory Board, Advisory board on apalutamide Janssen;Financial Interests, Personal, Advisory Board, Advisory board Clarity Pharmaceuticals;Financial Interests, Personal, Advisory Board, Advisory board on relugolix Myovant;Financial Interests, Personal, Advisory Board, Advisory board ITM Oncologics. M.R. Sydes Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training sessions for clinicians (no discussion of particular drugs) Janssen;Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training session for clinicians (no discussion of particular drugs) Eli Lilly;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial Astellas;Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial Clovis Oncology;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial Janssen;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial Novartis;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial Pfizer;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial Sanofi. M.K. Parmar Financial Interests, Institutional, Research Grant AstraZeneca, Astellas, Janssen, Clovis. N.D. James Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors AstraZeneca;Financial Interests, Personal, Advisory Board, Prostate cancer therapies Janssen;Financial Interests, Institutional, Expert Testimony, Assisted with submissions regarding licencing for abiraterone Janssen;Financial Interests, Personal, Advisory Board, Docetaxel Sanofi;Financial Interests, Institutional, Expert Testimony, Providing STAMPEDE trial data to facili ate licence extensions internationally for docetaxel Sanofi;Financial Interests, Personal, Advisory Board, Prostate cancer therapies Clovis;Financial Interests, Personal, Advisory Board, Prostate cancer therapies Novartis;Financial Interests, Personal, Advisory Board, Bladder cancer therapy Merck;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial Janssen;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial Astellas;Financial Interests, Institutional, Invited Speaker, Funding for RADIO trial bladder cancer AstraZeneca. All other authors have declared no conflicts of interest.