Comparison of abiraterone acetate and prednisolone (AAP) or combination enzalutamide (ENZ) + AAP for metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy (ADT): Overall survival (OS) results of 2 randomised phase III trials from the STAMPEDE protocol

ABSTRACT

Background: AAP or ENZ added to ADT improves outcomes for mHSPC. Any benefit of combining ENZ & AAP in this disease setting is uncertain. Methods: STAMPEDE is a multi-arm, multi-stage (MAMS), platform protocol conducted at 117 sites in the UK & Switzerland. 2 trials with no overlapping controls randomised mHSPC patients (pts) 11 to ADT +/- AAP (1000mg od AA + 5mg od P) or AAP + ENZ (160mg od). Treatment was continued to progression. From Jan 2016 docetaxel 75mg/m2 3-weekly with P 10mg od was permitted + ADT. Using meta-analysis methods, we tested for evidence of a difference in OS and secondary outcomes (as described previously failure-free, metastatic progression-free, progression-free & prostate cancer specific survival) across the 2 trials using data frozen 3 Jul 2022. All confidence intervals (CI) 95%. Restricted mean survival times (RMST) restricted to 84 months (m). Results: Between Nov 2011 & Jan 2014, 1003 pts were randomised ADT +/- AAP & between Jul 2014 & Mar 2016, 916 pts were randomised ADT +/- AAP + ENZ. Randomised groups were well balanced across both trials. Pt cohort age, median 68 years (yr), IQR 63, 72;PSA prior to ADT, median 95.7 ng/ml, IQR 26.5, 346;de novo 94%, relapsed after radical treatment, 6%. In AAP + ENZ trial, 9% had docetaxel + ADT. OS benefit in AAP + ENZ trial, HR 0.65 (CI 0.55‒0.77) p = 1.4×10-6;in AAP trial, HR 0.62 (0.53, 0.73) p = 1.6×10-9. No evidence of a difference in treatment effect (interaction HR 1.05 CI 0.83‒1.32, p = 0.71) or between-trial heterogeneity (I2 p = 0.70). Same for secondary end-points. % (CI) of pts reporting grade 3-5 toxicity in 1st 5 yr AAP trial, ADT 38.5 (34.2-42.8), + AAP 54.4 (50.0-58.8);AAP + ENZ trial, ADT 45.2 (40.6 – 49.8), + AAP + ENZ 67.9 (63.5 – 72.2);most frequently increased with AAP or AAP + ENZ = liver derangement, hypertension. At 7 yr in AAP trial (median follow-up 95.8m), % (CI) pts alive with ADT 30 (26, 34) versus with ADT + AAP 48 (43, 52);RMST ADT 50.4m, ADT + AAP 60.6m, p = 6.6 x 10-9. Conclusions: ENZ + AAP need not be combined for mHSPC. Clinically important improvements in OS when adding AAP to ADT are maintained at 7 yr. 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, Janssen, Astellas. Disclosure G. Attard Financial Interests, Personal, Invited Speaker Janssen, Astellas, AstraZeneca;Financial Interests, Personal, Advisory Board Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion;Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone Institute of Cancer Research;Financial Interests, Institutional, Research Grant Janssen, Astellas;Non-Financial Interests, Principal Investigator Janssen, Astellas;Non-Financial Interests, Advisory Role Janssen, AstraZeneca. W.R. Cross Financial Interests, Personal, Invited Speaker, Speaker fee Myriad Genetics, Janssen, Astellas;Financial Interests, Personal, Advisory Board, Advisory Board fee Bayer;Financial Interests, Institutional, Research Grant, Research grant Myriad Genetics. S. Gillessen Financial Interests, Personal, Advisory Board, 2018 Sanofi, Roche;Financial Interests, Personal, Advisory Board, 2018, 2019 Orion;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, 2022 Bayer;Financial Interests, Institutional, Advisory Board, 2020 Janssen Cilag, Roche, MSD Merck Sharp & Dohme, Pfizer;Financial Interests, Institutional, Advisory Board, 2018 AAA International, Menarini Silicon Biosystems;Financial Interests, Institutional, Advisory Board, 2019, 2020 Astellas Pharma;Financial Interests, Institutional, Advisory B ard, 2019 Tolero Pharmaceuticals;Financial Interests, Personal, Invited Speaker, 2021, 2022 SAKK, DESO;Financial Interests, Institutional, Advisory Board, 2021 Telixpharma, BMS, AAA International, Novartis, Modra Pharmaceuticas Holding B.V.;Financial Interests, Institutional, Other, Steering Committee 2021 Amgen;Financial Interests, Institutional, Advisory Board, 2021, 2022 Orion, Bayer;Financial Interests, Personal, Invited Speaker, 2021 SAKK, SAKK, SAMO - IBCSG (Swiss Academy of Multidisciplinary oncology);Financial Interests, Personal, Advisory Board, 2021 MSD Merck Sharp & Dhome;Financial Interests, Personal, 2021 RSI (Televisione Svizzera Italiana);Financial Interests, Institutional, Invited Speaker, 2021 Silvio Grasso Consulting;Financial Interests, Institutional, Other, Faculty activity 2022 WebMD-Medscape;Financial Interests, Institutional, Advisory Board, 2022 Myriad genetics, AstraZeneca;Financial Interests, Institutional, Invited Speaker, 2022 TOLREMO;Financial Interests, Personal, Other, Travel support 2022 AstraZeneca;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, Aranda;Non-Financial Interests, Advisory Role, Continuing ProteoMediX. C. Pezaro Financial Interests, Personal, Advisory Board, Ad board Dec 2020 Advanced Accelerator Applications;Financial Interests, Personal, Advisory Board, Aug 2021 Astellas;Financial Interests, Personal, Advisory Board, Oct 2021 Bayer;Financial Interests, Personal, Invited Speaker, Sept-Oct 2020 AstraZeneca;Financial Interests, Personal, Invited Speaker, Oct 2020 Janssen;Financial Interests, Personal, Advisory Board, July-Sept 2022 Pfizer. Z. Malik Financial Interests, Personal, Advisory Board, advisry board for new hormonal therapy for breast cancer sanofi;Financial Interests, Institutional, Invited Speaker, research grant for CHROME study sanofi;Other, Other, support to attend meetings or advisory boards in the past Astellas,Jaansen,Bayer;Other, Other, Sponsorship to attend ASCO meeting 2022 Bayer. 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, Janssen, Novartis, Pfizer, Sanofi;Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial Clovis Oncology. L.C. brown Financial Interests, Institutional, Research Grant, £170k educational grant for the FOCUS4-C Trial from June 2017 to Dec 2021 AstraZeneca;Financial Interests, Institutional, Funding, Various grants awarded to my institution for work undertaken as part of the STAMPEDE Trial janssen pharmaceuticals;Non-Financial Interests, Other, I am a member of the CRUK CERP funding advisory panel and my Institution also receive grant funding from CRUK for the STAMPEDE and FOCUS4 trials Cancer Research UK. M.K. Parmar Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL Medical Research Council Clinical Trials Unit at UCL;Financial Interests, Institutional, Research Grant AstraZeneca, Astellas, Janssen, Clovis;Non-Financial Interests, Advisory Role, Euro Ewing Consortium University College London;Non-Financial Interests, Advisory Role, rEECur University of Birmingham;Non-Financial Interests, Advisory Role, CompARE Trial University of Birmingham. N.D. James Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors AstraZeneca;Financial Interests, Personal, Advisory Board, Prostate cancer therapies Janssen, Clovis, Novartis;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 facilitate licence extensions internationally for docetaxel Sanofi;Financial Interests, Personal, Advisory Board, Bladder cancer therapy Merck;Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer Bayer;Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer Merck Sharp & Dohme (UK) Limited;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial Janssen, Astellas;Financial Interests, Institutional, Invited Speaker, Funding for RADIO trial bladder cancer AstraZeneca. All other authors have declared no conflicts of interest.