LBA62 - 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

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) 1:1 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 1^st 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.

Editorial acknowledgement

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 Board, 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.