Abstract 1527P
Background
The phase III POLO trial showed that in patients with metastatic pancreatic cancer (mPC) and a germline BRCA mutation (gBRCAm) who had not progressed on platinum-based chemotherapy (PBC), progression-free survival (PFS) was significantly longer with maintenance olaparib than with placebo (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.35, 0.82; median 7.4 months vs 3.8 months), with pre-specified subgroup analyses showing consistency (Golan et al. NEJM 2019). Additional pre-specified and post hoc subgroup, sensitivity and multivariate analyses further assessed consistency with primary PFS.
Methods
Participants had received first-line PBC for ≥ 16 weeks and were randomized 3:2 to maintenance olaparib 300 mg bid or placebo. The primary endpoint was PFS by blinded independent central review. Subgroup analyses assessed treatment effect consistency with the primary endpoint of PFS; multivariate analyses assessed impact of baseline factors; sensitivity analyses assessed evaluation time (scan frequency) and deviation (protocol deviation) biases.
Results
All pre-specified and post hoc subgroup analyses showed PFS benefits with olaparib versus placebo were consistent with primary PFS, including for patients stratified by Eastern Cooperative Oncology Group (ECOG) status, dose interruptions, previous primary malignancies, liver metastasis and location (table). Multivariate analyses demonstrated a PFS improvement with olaparib versus placebo when adjusted for baseline factors, while sensitivity analyses showed no indication of bias (table). Table: 1527P
| PFS analysis | Olaparib, N | Placebo, N | HR | 95% CI |
| Primary/pre-specified/full analysis set | ||||
| Primary | 92 | 62 | 0.53 | 0.35, 0.82 |
| Post hoc/exploratory subgroup | ||||
| ECOG status at baseline | ||||
| Normal | 65 | 38 | 0.61 | 0.38, 1.01 |
| Restricted | 25 | 23 | 0.46 | 0.23, 0.91 |
| Dose interruption | 38 | 10 | 0.61 | 0.28, 1.53 |
| No dose interruption | 52 | 51 | 0.57 | 0.35, 0.93 |
| Previous primary malignancy | 29 | 12 | 0.61 | 0.28, 1.49 |
| No previous primary malignancy | 63 | 50 | 0.55 | 0.35, 0.87 |
| Liver metastasis | 61 | 48 | 0.61 | 0.39, 0.97 |
| Europe | 49 | 39 | 0.59 | 0.35, 1.00 |
| Multivariate | ||||
| Adjusted for 13 baseline factors | 83 | 56 | 0.54 | 0.36, 0.82 |
| Sensitivity | ||||
| Evaluation time bias | 92 | 62 | 0.55 | 0.36, 0.85 |
| Deviation bias | 71 | 49 | 0.47 | 0.29, 0.76 |
Conclusions
Maintenance olaparib provided a consistent, significant PFS benefit versus placebo in patients with mPC and a gBRCAm who had not progressed on PBC, irrespective of clinical factors, geographical location or other baseline factors.
Clinical trial identification
NCT02184195.
Editorial acknowledgement
Oxford PharmaGenesis, Oxford, UK.
Legal entity responsible for the study
AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
D. Hochhauser: Research grant/Funding (self), research collaboration: Merck Serono. H. Kindler: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Astellas; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: BMS; Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Advisory/Consultancy: Five Prime; Advisory/Consultancy, Research grant/Funding (institution): INHIBRx; Advisory/Consultancy: Inventiva; Advisory/Consultancy: Kyowa; Advisory/Consultancy: Merck; Advisory/Consultancy: Paredox; Research grant/Funding (institution): Aduro; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Fibrogen; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Merck; Honoraria (institution): Polaris; Research grant/Funding (institution): Verastem. P. Hammel: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Erytech; Honoraria (self): BMS; Honoraria (self): Servier. M. Reni: Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy: Shire; Advisory/Consultancy: Baxter; Advisory/Consultancy: Novocure; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Baxalta; Advisory/Consultancy: Novartis; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Servier; Travel/Accommodation/Expenses: AstraZeneca. E. Van Cutsem: Honoraria (self): Array; Honoraria (self): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self): Biocartis; Honoraria (self): Bristol Myers Squibb; Honoraria (self), Research grant/Funding (institution): Celgene; Honoraria (self): Daiichi; Honoraria (self): Halozyme; Honoraria (self): GSK; Honoraria (self): Incyte; Honoraria (self), Research grant/Funding (institution): Ipsen; Honoraria (self), Research grant/Funding (institution): Lilly; Honoraria (self), Research grant/Funding (institution): Merck Sharp & Dohme; Honoraria (self), Research grant/Funding (institution): Merck KGaA; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self): Pierre-Fabre; Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Servier; Honoraria (self): Sirtex and Taiho; Research grant/Funding (institution): Boehringer-Ingelheim. T. Macarulla: Advisory/Consultancy, Travel/Accommodation/Expenses: Shire Pharmaceuticals; Advisory/Consultancy: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Servier; Advisory/Consultancy: Baxter; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy: QED Therapeutics; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Amgen; Advisory/Consultancy, Travel/Accommodation/Expenses: Incyte and H3 Biomedicine; Travel/Accommodation/Expenses: Sanofi. M.J. Hall: Non-remunerated activity/ies: Myriad Genetic Laboratories; Travel/Accommodation/Expenses, Non-remunerated activity/ies: Caris Life Science; Non-remunerated activity/ies: Foundation Medicine; Non-remunerated activity/ies: Invitae; Non-remunerated activity/ies: Ambr; Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): Merck. J.O. Park: Honoraria (self), Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Servier; Research grant/Funding (institution): MedPacto; Honoraria (self): AstraZeneca; Honoraria (self): Sanofi ; Honoraria (self): Merck Sereno. D. Arnold: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Non-remunerated activity/ies: Bayer; Advisory/Consultancy, Non-remunerated activity/ies: BMS; Advisory/Consultancy: Biocompatibles; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Non-remunerated activity/ies: MSD; Advisory/Consultancy, Non-remunerated activity/ies: Servier; Advisory/Consultancy, Non-remunerated activity/ies: Sanofi; Advisory/Consultancy, Non-remunerated activity/ies: Roche; Advisory/Consultancy, Non-remunerated activity/ies: Sirtex; Advisory/Consultancy: Terumo. D-Y. Oh: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Bayer; Advisory/Consultancy: Taiho; Advisory/Consultancy: ASLAN; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Zymeworks ; Advisory/Consultancy: Celgene; Research grant/Funding (self): Array; Research grant/Funding (self): Eli Lilly. A. Reinacher-Schick: Research grant/Funding (institution): Alexion; Research grant/Funding (institution), Travel/Accommodation/Expenses: Amgen; Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Research grant/Funding (institution), Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Mologen Berlin; Research grant/Funding (institution): AIO Studien GmbH; Research grant/Funding (institution): Pharma Consulting Group AB Schweden; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Servier ; Research grant/Funding (institution): Syneed medidata GmbH; Honoraria (self), Travel/Accommodation/Expenses: Merck-Serono; Travel/Accommodation/Expenses: onkowissen.de; Travel/Accommodation/Expenses: Pierre Fabre; Honoraria (self): Amgen, AstraZeneca, Baxalta; Honoraria (self): BMS; Honoraria (self), Travel/Accommodation/Expenses: MSD; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Sanofi Aventis ,Servier; Honoraria (self): Shire. G. Tortora: Honoraria (self): Celgene; Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): Pfizer; Honoraria (self): Merck Serono ; Honoraria (self): Servier. H. Algül: Advisory/Consultancy: Servier, ; Advisory/Consultancy: Celgene; Advisory/Consultancy: Astra Zeneca; Advisory/Consultancy: MSD,; Research grant/Funding (self): Chugai; Non-remunerated activity/ies: Lilly ; Non-remunerated activity/ies: Revolution Medicine. E.M. O'Reilly: Advisory/Consultancy: Inovio, Jazz, OncoQuest; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca, Agios, Array; Research grant/Funding (self): BMS, Polaris Puma; Advisory/Consultancy: Janssen, Kyowa Kirin; Advisory/Consultancy, Research grant/Funding (self): Casi,Celgene, Beigene,; Advisory/Consultancy: LAM, Merck ; Advisory/Consultancy: Loxo, Mina; Advisory/Consultancy, Research grant/Funding (self): Exelixis, Halozyme,Incyte; Advisory/Consultancy: Novella,Onxeo, OncoQuest; Advisory/Consultancy: 3DMed, PCI Biotech; Advisory/Consultancy: AlignMed, Pfizer; Advisory/Consultancy: Amgen, Pieris; Advisory/Consultancy: Antengene, RedHill; Advisory/Consultancy: Aptus,Sanofi; Advisory/Consultancy: Aslan, Servier; Advisory/Consultancy: Astellas, Silsenseed; Advisory/Consultancy: Bioline, SillaJen; Advisory/Consultancy: Boston Scientific, Sobi; Advisory/Consultancy: BridgeBio, Targovax; Advisory/Consultancy: CARsgen, Tekmira; Advisory/Consultancy: Cipla, TwoXAR; Advisory/Consultancy: CytomX, Vicus; Advisory/Consultancy: Daiichi,Yakult and Yiviva; Advisory/Consultancy: Debiopharm, Delcarth,Hengrul,; Advisory/Consultancy: Eisai, Genoscience,Ipsen; Research grant/Funding (self): QED, Roch; Advisory/Consultancy, Research grant/Funding (self): Bayer,Lilly; Research grant/Funding (self): Genetech; Research grant/Funding (self): MabVax; Research grant/Funding (self): Novartis. D. McGuinness: Full/Part-time employment, contractor: AstraZeneca. K. Cui, G. Locker: Full/Part-time employment: AstraZeneca. K. Schlienger: Full/Part-time employment: Merk. T. Golan: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Teva; Advisory/Consultancy: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Merck/MSD; Speaker Bureau/Expert testimony: Bioline; Speaker Bureau/Expert testimony: Roche.