Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer

Abstract

VP1-2022: Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer

Published: March 16, 2022
A.N.J. Tutt, J. Garber, R.D. Gelber, K-A. Phillips, A. Eisen, O.T. Johannsson...
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Background

OlympiA is the first phase III randomised clinical trial (RCT) testing a PARP inhibitor as adjuvant therapy. At the first event driven interim analysis [Data CutOff 1 (DCO1), 27/03/20; median follow up (MFU) 2.5 years] OL significantly improved the primary endpoint of invasive disease-free survival (IDFS) and secondary endpoint of distant DFS (DDFS) compared with placebo (PL) [both p<0.001]. OS did not cross the pre-specified boundary (p<0.01) (Tutt et al NEJM 2021). The second pre-specified analysis of OS and updated IDFS, DDFS and safety descriptive analyses was planned after 330 IDFS events [DCO2 12/07/21; MFU 3.5 years].

Methods

From 6/14-5/19 this double-blind RCT coordinated by BIG and sponsored by AstraZeneca/NRG randomised 1836 patients (pts) with gBRCAm HER2-negative high-risk EBC after (neo)adjuvant chemotherapy ([N]ACT) 1:1 to one year of continuous oral OL (300 mg BID) or PL. The boundary for a 2-sided significance test of the OS hazard ratio (HR) was p< 0.015. Baseline pt and tumour characteristics were balanced as previously reported.

Results

OL significantly improved OS vs PL with HR 0.68; (98.5.% CI 0.47, 0.97; P = 0.009) crossing the significance boundary with additional events at DCO2. Total deaths 75/921 and 109/915 in pts assigned to OL and PL, respectively; 4-yr OS% 89.8% vs 86.4% (diff. 3.4%; 95% CI -0.1%, 6.8%). Improvements in IDFS and DDFS were sustained with similar effect size: IDFS HR 0.63 (95% CI 0.50, 0.78), 4-yr IDFS 82.7% vs 75.4% (diff. 7.3%; 95% CI 3.0%, 11.5%). DDFS HR 0.61; 95% CI 0.48, 0.77); 4-yr DDFS 86.5% vs 79.1% (diff. 7.4%; 95% CI 3.6%, 11.3%). OL benefit was consistent across all subgroups, including hormone-receptor+ (all HR <1.0). AEs remained consistent with OL’s safety profile. G3+ AEs in >1% of OL pts were anaemia (8.7%), neutropaenia (4.9%), leukopaenia (3.0%), fatigue (1.8%) and lymphocytopaenia (1.3%). SAEs and previously specified AESI were not increased by OL. No new cases or excess of MDS or AML were reported for OL.

Conclusions

In pts with gBRCAm and high-risk HER2-negative EBC after [N]ACT, at 3.5 years MFU, adjuvant olaparib significantly improved OS, as well as IDFS and DDFS, with acceptable toxicity and no evidence of excess MDS or AML.

Clinical trial identification

BIG 6-13, NSABP B-55.

Authors and Affiliations:

A.N.J. Tutt1, J. Garber2, R.D. Gelber2, K-A. Phillips3, A. Eisen4, O.T. Johannsson5, P. Rastogi6, K.Y. Cui7, S-A. Im8, R. Yerushalmi9, A.M. Brufsky10, M. Taboada11, G. Rossi12, G. Yothers13, C. Singer14, L.E. Fein15, N. Loman16, D. Cameron17, C. Campbell18, C.E. Geyer191Breast Cancer Now Research Unit, ICR - Institute of Cancer Research, London, UK, 2Dana Farber Cancer Institute, Boston, MA, USA, 3Medical Oncology, Peter MacCallum Cancer Center, Melbourne, VIC, Australia, 4Medical Oncology, Sunnybrook Health Sciences Centre - Odette Cancer Centre, Toronto, ON, Canada, 5Medical Oncology, The National University Hospital of Iceland - Landspitali, Reykjavik, Iceland, 6Oncology, NSABP Foundation, Pittsburgh, PA, USA, 7Global Medicine Development, AstraZeneca US, Gaithersburg, MD, USA, 8Internal Medicine, SNUH - Seoul National University Hospital, Seoul, Republic of Korea, 9Oncology, Clalit Health Services, Petah Tikva, Israel, 10Oncology, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA, 11AstraZeneca, Royston, UK, 12R&D Department, Breast International Group (BIG) - AISBL, Brussels, Belgium, 13Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA, 14Center for Breast Health, MedUni Wien - Medical University of Vienna, Vienna, Austria, 15Oncology Department, Instituto de Oncología de Rosario, Rosario, Argentina, 16Medical Oncology, Skane University Hospital, Lund, Sweden, 17Oncology Department, ECC - Edinburgh Cancer Centre - SCAN, Edinburgh, UK, 18Frontier Science (Scotland) Ltd, Kincraig, UK, 19Clinical Research Department Undo, Houston Methodist Cancer Center, Houston, TX, USA

Legal entity responsible for the study: Breast International Group.

Funding: AstraZeneca and Merck and Co., Inc.

Collaborators: Robin McConnel, FS, UK; Martine Piccart, BIG, Belgium; Simon Hollingsworth, AstraZeneca, UK; Anitra Fielding, AstraZeneca, USA; Larissa Korde, NCI, USA; Giuseppe Viale, IEO, Italy; Sunil Lakhani, ANZBCTG, Australia; Peter Lucas, NRG Oncology, USA; Liesbet De Vos, BIG HQ, Belgium; Amal Arahmani, BIG HQ, Belgium; Evandro de Azambuja, IJB, Belgium; Elmar Stickeler, AGO-B, Germany; Agnes Jager, BOOG, Netherlands; Elzbieta Senkus-Konefka, CEEOG, Poland; Monica Arnedos, EORTC, France; Eduardo-M De Dueñas, GEICAM, Spain; Frederik Marmé, GBG, Germany; Gabriele Zoppoli, GOIRC, Italy; Lorenzo Gianni, IBCSG, Italy; Judith Bliss, ICR-CTSU, UK; Masakazu Toi, JBCRG, Japan; Anne Armstrong, NCRI-BCSG, UK; Judith Balmaña, SOLTI, Spain; Wolfgang Janni, SUCCESS St G, Germany; Jonas Bergh, SweBCG, Sweden; Tsang-Wu Liu, TCOG, Taiwan; Suzette Delaloge, UCBG, France; James Ford, ECOG, USA; Priyanka Sharma, SWOG, USA; Tiffany Traina, Alliance, USA; Sue Friedman, Patient Advocate, USA; Tanja Spanic, Patient Advocate, Slovenia; Susan Domchek, USA; Rita Schmutzler, Germany; Karen Gelmon, Canada; Michael Gnant, Austria; Barbro Linderholm, Sweden; Sibylle Loibl, Germany; Shao Zhmin, China; Fatiha Elsafy, AstraZeneca, USA; Olga Andriienko, AstraZeneca, USA; Gursel Aktan, Merck, USA; Vasiliki Karantza Merck, USA; Konstantinos Tryfonidis, Merck, USA.

Disclosure: A.N.J. Tutt: Financial Interests: Advisory Board, Personal, Related to targeted therapies in DNA repair deficient: Pfizer, Vertex, Artios, Prime Oncology; Advisory Board, Personal, Breast Cancer Moonshot SAB: MD Anderson; Advisory Board, Personal: Inbiomotion; Advisory Board, Personal, Trodelvy: Gilead; Advisory Board, Personal, Targeting ATR kinase: Merck KGaA; Advisory Board, Institutional: Gilead; AstraZeneca; Invited Speaker, Personal, BRCA1/2 Mutagenesis, PARP inhibitors in early breast cancer: SABCS 2020 & 2021; Expert Testimony, Institutional, CRUK expert panel Chairman: CRUK; Expert Testimony, Institutional, Paid into research institute account: GE Healthcare; Expert Testimony, Personal: EM Partners; Expert Testimony, Personal, Taking part in an educational video: Medscape Education; Invited Speaker, Institutional, Paid into research account at the Institute of Cancer Research: AZ Symposium ESMO 2021; Invited Speaker, Institutional, Speaker at round table: VJ Oncology, Invited Speaker, Institutional: Innovation in Breast Cancer Symposium 2022; Stocks/Shares, Personal: Inbiomotion; Royalties, Personal, ICR rewards to inventor's payments paid to Andrew Tutt's research accounts at The Institute of Cancer Research and to personal accounts: AstraZeneca. These are associated with royalties paid to The Institute of Cancer Research (ICR) for the use of PARP inhibitors in DNA deficient cancers, licensee - AstraZeneca; Research Grant, No financial interest, Institutional, Research support for sample preparation Myriad analysis of HR deficiency for TNT trial: Myriad genetics; Coordinating PI, Financial interest, Personal and Institutional, Financial support to my academic and hospital institutions for costs associated with global academic study chair and local site costs for OlympiA trial / travel expenses related to any trial related travel: AstraZeneca. Payments through Breast International Group for trial conduct in OlympiA trial and through CRO's for commercial PARP inhibitor trial: AstraZeneca; Research Grant, No financial interest, Institutional, Local site for a trial associated with DNA repair deficient TNBC: Merck KGaA; Research Grant, No financial interest, Institutional, Support for analysis of LAR subtype outcome in TNT trial: Medivation; Non-Financial Interests: Other, Member of Strategy Group: NCRI Strategy Group; Other, Member of the Committee: ESMO Guidelines Committee; Officer, Committee Member: ESMO 2023 Scientific Committee; Product Samples, Institutional, Responsible for care of patients receiving Olaparib on named patient programme in Breast Cancer @ Guy's London: Guy's Hospital; Other: Other, Grant funded to study homologous recombination deficient breast and other cancers, BCN receive payments through AstraZeneca related to PARP inhibitor patents: Breast Cancer Now; Other, Grant funded to study homologous recombination deficient breast and other cancers, CRUK receive payments through AstraZeneca related to PARP inhibitor patents: CRUK.J. Garber: Financial Interests, Personal, Advisory Board, no funds x 2 yrs: Helix Genetics; Financial Interests, Invited Speaker, provides genetic analysis for institutional germline samples at no cost: Invitae Genetics; Financial Interests, Institutional, Other, Coinvestigator on collaborative research using Ambry data at no cost to Dana Farber PIs: Ambry Genetics; Non-Financial Interests, Leadership Role, Scientific Director: Breast Cancer Research Foundation; Non-Financial Interests, Invited Speaker: Foundation Board, American Association for Cancer Research; Non-Financial Interests, Invited Speaker, Non-Profit: Facing Our Risk of Cancer Empowered.R.D. Gelber: Financial Interests, Institutional, Invited Speaker, Salary support to institution: AstraZeneca, Novartis, Roche, Merck.K-A. Phillips: Non-Financial Interests, Advisory Role, Scientific Advisory Committee member: Breast Cancer Trials; Non-Financial Interests, Project Lead, Project lead in Australia for the OlympiA study: Breast Cancer Trials; Non-Financial Interests, Project Lead, Project lead in Australia for the DECRESCENDO study: Breast Cancer Trials; Non-Financial Interests, Advisory Role, Member Expert Advisory Group on Cancer Clusters: Victorian Department of Health and Human Services; Non-Financial Interests, Advisory Role, Strategic Advisory Committee Member: Breast Cancer Network Australia; Non-Financial Interests, Advisory Role, Cancer Genetics Reference Committee Member: NSW Cancer Institute; Non-Financial Interests, Advisory Role, Register of experts for breast and hereditary cancer: Medical Oncology Group of Australia; Non-Financial Interests, Advisory Role, Breast Cancer Optimal Care Pathway Committee Member: Cancer Council Victoria; Other, Leadership Fellow: National Health and Medical Research Council (Australia); Other, Practitioner Fellow: National Breast Cancer Foundation (Australia).A. Eisen: Financial Interests, Institutional, Invited Speaker, Local PI for Brevity Study: RNA Diagnostics; Financial Interests, Institutional, Invited Speaker, Local PI for LUCY study: AstraZeneca.K.Y. Cui: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca.S-A. Im: Financial Interests, Personal, Advisory Board, no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pfizer, Lilly, MSD, GSK, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Pfizer, Roche, Eisai, Dae Woong; Financial Interests, Institutional, Invited Speaker, Clinical Trial Budget: AstraZeneca; Eisai, Hanmi, Novartis, Roche, Pfizer, Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm.R. Yerushalmi: Financial Interests, Personal, Invited Speaker: Roche, Teva, Medison, MSD, AstraZeneca; Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis, AstraZeneca, Gilead.A.M. Brufsky: Financial Interests, Personal, Advisory Board: Gilead, AstraZeneca, Novartis, Lilly, Pfizer, Daiichi Sankyo, Roche/Genentech, Puma, Eisai, Merck; Financial Interests, Personal, Other, Consultant: Sanofi, General Electric; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, Gilead, Puma, Roche/Genetech.M. Taboada: Financial Interests, Personal, Full or part-time Employment, Statistician: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca.G. Rossi: Financial Interests, Institutional, Royalties, My institution receives royalties from Agendia for MammaPrint, due to the collaboration on the conduct of the MINDACT trial: Agendia; Financial Interests, Institutional, Funding, My Institution receives funding for the conduct of clinical trials from: AstraZeneca, Roche/Genentech, Novartis; Sanofi/Aventis. Financial Interests, Institutional, Funding, Research funding: Tesaro; Pfizer, Servier, Biovica, GlaxoSmithKline; G. Yothers: Financial Interests, Personal, Other, Data monitoring Committee member for the agent Elflornithine: Orbus Theraputics, Inc.; Financial Interests, Institutional, Other, Deputy Group Statistician: NRG Oncology Foundation; Financial Interests, Personal, Other, Group Statistician: NSABP Foundation; Non-Financial Interests, Other, Executive Committee Member: Olympia Trial; Non-Financial Interests, Other, GI Cancer Steering Committee Member: NCI Cancer Therapy Evaluation Program (CTEP); Non-Financial Interests, Member: ASCO.C. Singer: Financial Interests, Personal, Other, Consultancy: Amgen; Financial Interests, Personal, Advisory Board, Advisory Function: Novartis; Financial Interests, Personal, Advisory Board, Advisory Role: Roche; Financial Interests, Personal, Other, Study Support: Pfizer; Financial Interests, Personal, Advisory Board, Advisory, Speaker Honoraria, Study Support: AstraZeneca; Financial Interests, Personal, Invited Speaker, Study Coordinator: Amgen; Non-Financial Interests, Principal Investigator, Study: Amgen, AstraZeneca; Non-Financial Interests, Project Lead, Register: Pfizer.L.E. Fein: Financial Interests, Personal and Institutional, Invited Speaker, Advisory Role and PI in several clinical trials: Pfizer; Financial Interests, Personal and Institutional, Invited Speaker, PI of several clinical trials: Merck Sharp & Dohme (MSD); Financial Interests, Institutional, Invited Speaker, My Institution received funds for several clinical trials and I have advisory role: Sanofi; Financial Interests, Personal and Institutional, Invited Speaker, OlympiA Study Steering Committee Member and local PI: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, APHINITY Steering Committee Member and local PI: Roche; Financial Interests, Personal and Institutional, Invited Speaker, Local PI for several clinical trials: Lilly.D. Cameron: Financial Interests, Institutional, Advisory Board: Roche, Pfizer, AstraZeneca, Daiichi Sankyo, SeaGen, Synthon, Zymeworks; Financial Interests, Institutional, Invited Speaker, funding and drug for UK participation in a French-led Novartis funded study. Institutional funding received for consultancy work: Novartis.C.E. Geyer: Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Other, Consulting: Athenex; Financial Interests, Personal, Invited Speaker, Co-Chair of SC for KATHERINE: Genentech/Roche; Financial Interests, Personal, Invited Speaker, Co-Chair of SC for lidERA: Genentech/Roche; Financial Interests, Personal, Invited Speaker, NSABP B-59/GeparDouze: Genentech/Roche; Financial Interests, Personal, Invited Speaker, Co-Chair of SC for DESTINY-Breast05: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Co-Chair of SC for BrighTNess: AbbVie; Non-Financial Interests, Advisory Role, Uncompensated Advisory Boards: Genentech/Roche; Non-Financial Interests, Advisory Role, Uncompensated Advisory Board: Daiichi Sankyo, Seagen, AstraZeneca; Non-Financial Interests, Other, Co-Chair of OlympiA EC and SC: AstraZeneca.All other authors have declared no conflicts of interest.