1596O - Decipher mRNA score for prediction of survival benefit from docetaxel at start of androgen deprivation therapy (ADT) for advanced prostate cancer (PC): An ancillary study of the STAMPEDE docetaxel trials

Background

Docetaxel (Doce) is effective for metastatic (M1) PC but its effect is heterogeneous. Combining Doce with hormone therapy can improve overall survival (OS) but may not be appropriate for all. We hypothesised that the Decipher 22-gene mRNA score (DS) predicts Doce benefit.

Methods

DS were generated from whole transcriptome profiling with a clinical test (Veracyte) on tumor index cores from patients (pts) randomised 1:1 to ADT or ADT + Doce +/- zoledronic acid (ZA) in the STAMPEDE protocol (Oct 2005 - Mar 2013). We followed a pre-defined statistical analysis plan to fit Cox models individually in M1 and very high-risk non-metastatic (M0) pts dichotomised by DS ( 0.8) adjusted for age, WHO PS, pre-ADT PSA, Gleason score, T-stage, N stage (N0, N1), metastatic volume if M1 (CHAARTED definition, high [M1HV] or low [M1LV]). Likelihood ratio tests were used to test the hypotheses that Doce effect was larger in DS high vs lower. Primary endpoint was OS. Updated OS (Feb 2024) included record linkage to national datasets. Hazard ratios (HR) provided with 95% confidence intervals.

Results

895 pts (539 M1, 356 M0, 639 [71%] reported to have died) were included and representative of the full trial cohort (N = 2369). DS were significantly lower in M0N0 (adjusted p<0.001) but showed the same distribution across M0N1, M1LV, M1HV. DS were prognostic: each 0.1 increment increased the hazards of death by 11% (HR = 1.11 [1.06-1.16], p<0.001) for M1, 9% (HR = 1.10 [1.02-1.18], p = 0.012) for M0. DS predicted Doce efficacy in M1: high DS, HR = 0.64 [0.48-0.86]; lower DS, HR = 0.96 [0.71-1.30]. This interaction effect was statistically significant (p = 0.039). The effect was consistent in M1LV (high DS, HR = 0.53 [0.32-0.88]; lower DS, HR = 0.78 [0.47-1.30]) and M1HV (high DS, HR = 0.72 [0.49-1.07]; lower DS, HR = 1.16 [0.77-1.74]). In M0 there was no evidence of an interaction effect (p=0.302; high DS, HR = 0.75 [0.44-1.28]; lower DS, HR = 1.04 [0.68-1.59]).

Conclusions

High DS identifies synchronous M1 PC pts who benefit from Doce. DS is the 1st molecular classifier independent of metastatic volume to show a statistically significant interaction with Doce in directly randomised M1 PC pts.

Clinical trial identification

NCT00268476, ISRCTN78818544.

Editorial acknowledgement

Legal entity responsible for the study

UCL.

Funding

Cancer Research UK, Medical Research Council, Prostate Cancer UK, The John Black Charitable Foundation, Prostate Cancer Foundation, National Institute of Health, UK NIHR, Orchid, Department of Defense, Sanofi, Novartis, Veracyte.

Disclosure

E. Grist: Financial Interests, Personal, Full or part-time Employment: UCL; Non-Financial Interests, Principal Investigator: Janssen; Non-Financial Interests, Project Lead: Veracyte. J. Proudfoot: Financial Interests, Personal, Full or part-time Employment: Veracyte. A.A. Hamid: Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, Astellas; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Institutional, Local PI: Astellas. W. Cross: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Bayer, Janssen, Astellas, Ipsen, Myriad Genetics, Allied Healthcare. S. Gillessen: Financial Interests, Institutional, Advisory Board, 2022: Amgen, AstraZeneca, Bayer, MSD Merck Sharp & Dohme, Myriad Genetic, Orion; Financial Interests, Institutional, Advisory Board, 2023: BMS, Daiichi Sankyo, Innomedica, Ipsen, Boehringer Ingelheim, Innomedica, Bayer; Financial Interests, Institutional, Invited Speaker, 2022: ESMO, Silvio Grasso Consulting; Financial Interests, Institutional, Other, Interview 2022: PeerVoice; Financial Interests, Institutional, Invited Speaker, 2023: SAKK, Meister ConCept GmbH, ASCO GU, EPG Health, S. Grasso Consulting, AdMeTech Foundation; Financial Interests, Institutional, Other, Faculty activity 2022: WebMD-Medscape; Financial Interests, Personal, Other, Travel support 2022: AstraZeneca; Financial Interests, Personal, Invited Speaker, 2022: DESO, SAKK; Financial Interests, Personal, Other, Travel support 2023: Bayer; Financial Interests, Institutional, Invited Speaker, 2024: Intellisphere LLC; Financial Interests, Personal, Other, Travel support 2024: Gilead; Financial Interests, Personal, Invited Speaker, Speaker OncoSummit 02.2024: Meister ConCept GmbH; Financial Interests, Personal, Other, Travel Support 2024: Intellisphere LLC; Financial Interests, Institutional, Other, Scientific Committee Pfizer Forschungspreis 2022/2023: Pfizer; Financial Interests, Institutional, Other, Consulting Agreement: TOLREMO; Financial Interests, Personal, Invited Speaker, 2023/2024: ESMO; Financial Interests, Institutional, Advisory Board, 2024: Ipsen, Macrogenics; Financial Interests, Personal, Other, Part of a patent for a biomarker, but (for the moment) no income, but I could not write none in the dropdown menu: Proteomedix/Onconetix; Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator: Astellas; Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. 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, Personal, Other, Educational lecture not associated with any products: Eisai; 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. 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, Personal and Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Baxter, GSK; Financial Interests, Institutional, Research Grant: Clovis, Abcodia Pvt Ltd., Akagera, Amgen, Aspirin Foundation, Bayer, BMS US, Bri-BioCepheid, Cipla, CSL Behring, Eli Lilly, Emergent Biosolutions, Gilead Sciences, Grifols, Johnson & Johnson, Pfizer, Sanofi, ViiVHealthcare, Micronoma, Modus Theraputics, Mylan, Serum Institute of India, Shionogi, SyntenyBiotechnology, Takeda, Tibotec, Transgene, Virco and Xenothera; 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; Non-Financial Interests, Advisory Role, ROSSINI Trial Platform: University of Birmingham. F. Feng: Financial Interests, Personal, Advisory Board: Janssen, Bayer, Tempus; Financial Interests, Personal, Advisory Board, No longer an active relationship; termed 2020.: Myovant Sciences, Roivant Sciences; Financial Interests, Personal, Advisory Board, One-time: Astellas Pharma; Financial Interests, Personal, Advisory Board, Scientific advisory board. I receive stock options from SerImmune in return for serving on their Scientific Advisory Board. The stock options are awarded on a yearly basis. I have not exercised any stock options yet and therefore have made no income: SerImmune; Financial Interests, Personal, Advisory Board, One-time advisory board meeting in 2021. This relationship has since termed/is no longer active: Foundation Medicine; Financial Interests, Personal, Other, Consultant for the Global Translational Sciences Research Program at Varian. This relationship termed 3/31/2022.: Varian; Financial Interests, Personal, Advisory Board, Served on BMS' 2022 Scientific Advisory board for their tumor microenvironment group: Bristol Myers Squibb (BMS); Financial Interests, Personal, Other, Consultant: Exact Sciences, Novartis; Financial Interests, Personal, Advisory Board, I serve on the scientific advisory board for this company when it was Bluestar Genomics, and have received stock options from them.: ClearNote Health, formerly known as; Financial Interests, Personal, Other, I am a medical advisor with stock options: Artera; Financial Interests, Personal, Advisory Board, I served on the one-time ESMO Advisory Board: POINT Biopharma; Financial Interests, Personal, Full or part-time Employment, Professor of Radiation Oncology, Urology and Medicine. Full time employee (FTE): University of California, San Francisco; Financial Interests, Personal, Stocks/Shares, I am an advisor with stock options.: Artera; Non-Financial Interests, Leadership Role, NRG Oncology is a large clinical trials group funded by the NCI, a branch of the National Institutes of Health. As Chair of the Genitourinary Cancer Committee for NRG, my role is to help investigators design proposals for clinical trials, that are then evaluated by the NCI for funding. All funding decisions are made by the NCI -- not by NRG or by myself.: NRG Oncology. N. Clarke: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca; Financial Interests, Personal, Invited Speaker: Ipsen, Bayer, Pfizer, Janssen; Non-Financial Interests, Leadership Role, Principal Investigator The Propel Trial: AstraZeneca. E. Davicioni: Financial Interests, Personal, Full or part-time Employment: Veracyte. C. Sweeney: Financial Interests, Personal, Advisory Board, Consultancy: Genentech_Roche, Bayer, Astellas, Pfizer, Pfizer, Sanofi, Lilly; Financial Interests, Personal, Other, Consultancy: Janssen, MSD; Financial Interests, Personal, Advisory Board: Point, Cellcentric; Financial Interests, Personal, Advisory Board, Consultant: Advancell; Financial Interests, Personal, Advisory Board, Advisory Boards: BMS; Financial Interests, Personal, Advisory Board, Consutlant: Amphista; Financial Interests, Personal, Stocks/Shares: Leuchemix; Financial Interests, Personal, Stocks/Shares, Consultant: Advancell; Financial Interests, Institutional, Advisory Board, Abiraterone plus cabozantinib: Exelixis; Financial Interests, Institutional, Research Grant: Bayer, Janssen, Astellas, Pfizer, Dendreon, Sanofi. 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, Advisory Board, Assisted with submissions regarding licencing for abiraterone: Janssen; Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi; Financial Interests, Institutional, Advisory Board, 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, Coordinating PI, Funding for STAMPEDE trial: Janssen, Astellas; Financial Interests, Institutional, Coordinating PI, Funding for RADIO trial bladder cancer: AstraZeneca. 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; Financial Interests, Institutional, Funding, Grant funding to my institution for the STAMPEDE2 trial.: Novartis AAA; 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. G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion, Novartis, Blue Earth Therapeutics; Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research; Financial Interests, Institutional, Advisory Board: Artera, Veracyte; Financial Interests, Institutional, Research Grant: Janssen, Astellas, Novartis; Financial Interests, Institutional, Coordinating PI: Janssen; Financial Interests, Institutional, Local PI: Novartis, Pfizer; Non-Financial Interests, Principal Investigator: Janssen, Astellas; Non-Financial Interests, Advisory Role: Janssen, AstraZeneca; Non-Financial Interests, Project Lead: Artera, Veracyte. All other authors have declared no conflicts of interest.