Original Research| Volume 109, P84-91, March 2019

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A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes

Published:January 28, 2019DOI:


      • Olaparib combined with eribulin showed efficacy in patients previously treated with anthracycline and taxanes.
      • In pharmacokinetics, no drug interaction between eribulin and olaparib was observed.
      • Poly(ADP-ribose) polymerase inhibition was observed from the lowest dose of olaparib.



      We conducted a multicenter phase I/II trial of olaparib plus eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer (TNBC) to determine the recommended phase II dose (RP2D) (phase I) and to examine the efficacy and safety (phase II) (UMIN00009498) of the combined therapy.

      Patients and methods

      In phase I, olaparib tablet was orally administered twice daily from level 1:25 mg BID to level 7:300 mg BID, with 1.4 mg/m2 of eribulin on days 1 and 8. In phase II, patients were treated with RP2D to assess the response rate (independent review). The planned sample size was 24 with a threshold of 10%.


      One of the 24 patients enrolled in phase I experienced dose-limiting toxicity. The RP2D was established as 300 mg twice daily for olaparib and 1.4 mg/m2 for eribulin. Among the 24 patients in phase II, the median number of administered courses was 5.5 (range: 1–28). Grade ≥III adverse events included neutropenia (83.3%), leucopenia (83.3%), anaemia (41.7%), febrile neutropenia (33.3%) and thrombosis (8.3%). The response rate was 29.2% (independent; N = 7/24; 90% confidence interval [CI]; 14.6–47.9). Median progression-free survival and overall survival were 4.2 (95% CI, 3.0–7.4) and 14.5 (95% CI, 4.8–22.0) months, respectively. Germline BRCA1/2 mutation status was observed in three patients in phase I and 2 patients in phase II, respectively. The Cmax and area under the curve for olaparib increased in a dose-dependent manner, and these parameters for eribulin and olaparib were not influenced by each other.


      Combination therapy of olaparib with eribulin shows antitumour activity against advanced or metastatic TNBC, but caution must be exercised in the presence of febrile neutropenia.


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        • Yonemori K.
        • Tamura K.
        • Kodaira M.
        • Fujikawa K.
        • Sagawa T.
        • Esaki T.
        • et al.
        Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours.
        Cancer Chemother Pharmacol. 2016; 78: 525-531
        • Lee J.M.
        • Hays J.L.
        • Chiou V.L.
        • Annunziata C.M.
        • Swisher E.M.
        • Harrell M.I.
        • et al.
        Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer.
        Oncotarget. 2017; 8: 79175-79187
        • Lee J.M.
        • Cimino-Mathews A.
        • Peer C.J.
        • Zimmer A.
        • Lipkowitz S.
        • Annunziata C.M.
        • et al.
        Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly(ADP-ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women's cancers: a dose-escalation, phase I study.
        J Clin Oncol. 2017; 35: 2193-2202
        • Bang Y.J.
        • Xu R.H.
        • Chin K.
        • Lee K.W.
        • Park S.H.
        • Rha S.Y.
        • et al.
        Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 1637-1651
        • Robson M.
        Are BRCA1- and BRCA2-associated breast cancers different? Prognosis of BRCA1-associated breast cancer.
        J Clin Oncol. 2000; 18: 113S-118S
        • Turner N.C.
        • Reis-Filho J.S.
        Basal-like breast cancer and the BRCA1 phenotype.
        Oncogene. 2006; 25: 5846-5853
        • Atchley D.P.
        • Albarracin C.T.
        • Lopez A.
        • Valero V.
        • Amos C.I.
        • Gonzalez-Angulo A.M.
        • et al.
        Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer.
        J Clin Oncol. 2008; 26: 4282-4288
        • Turner N.C.
        • Reis-Filho J.S.
        • Russell A.M.
        • Springall R.J.
        • Ryder K.
        • Steele D.
        • et al.
        BRCA1 dysfunction in sporadic basal-like breast cancer.
        Oncogene. 2007; 26: 2126-2132
        • Turner N.
        • Tutt A.
        • Ashworth A.
        Hallmarks of 'BRCAness' in sporadic cancers.
        Nat Rev Canc. 2004; 4: 814-819
        • Miyoshi Y.
        • Murase K.
        • Oh K.
        Basal-like subtype and BRCA1 dysfunction in breast cancers.
        Int J Clin Oncol. 2008; 13: 395-400
        • Abd El-Rehim D.M.
        • Ball G.
        • Pinder S.E.
        • Rakha E.
        • Paish C.
        • Robertson J.F.
        • et al.
        High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses.
        Int J Canc. 2005; 116: 340-350
        • Hashimto J.
        • Fujimori H.
        • Masutani M.
        • Hasimoto T.
        • Hamada A.
        • Yamamoto H.
        • et al.
        Phamacodynamic assay by ELISA for assessing PARP activity inhibition in a phase 1 study of eribulin plus olaparib.
        The 74th Japanese Cancer Society, Nagoya, Japan2015
        • Kaufman P.A.
        • Awada A.
        • Twelves C.
        • Yelle L.
        • Perez E.A.
        • Velikova G.
        • et al.
        Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
        J Clin Oncol. 2015; 33: 594-601
        • Cortes J.
        • O'Shaughnessy J.
        • Loesch D.
        • Blum J.L.
        • Vahdat L.T.
        • Petrakova K.
        • et al.
        Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
        Lancet. 2011; 377: 914-923
        • Pivot X.
        • Marme F.
        • Koenigsberg R.
        • Guo M.
        • Berrak E.
        • Wolfer A.
        Pooled analyses of eribulin in metastatic breast cancer patients with at least one prior chemotherapy.
        Ann Oncol. 2016; 27: 1525-1531
        • Mateo J.
        • Moreno V.
        • Gupta A.
        • Kaye S.B.
        • Dean E.
        • Middleton M.R.
        • et al.
        An adaptive study to determine the optimal dose of the tablet formulation of the PARP inhibitor olaparib.
        Targeted Oncol. 2016; 11: 401-415
        • Rajan A.
        • Carter C.A.
        • Kelly R.J.
        • Gutierrez M.
        • Kummar S.
        • Szabo E.
        • et al.
        A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors.
        Clin Cancer Res. 2012; 18: 2344-23451
        • Liu J.F.
        • Tolaney S.M.
        • Birrer M.
        • Fleming G.F.
        • Buss M.K.
        • Dahlberg S.E.
        • et al.
        A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer.
        Eur J Cancer. 2013; 49: 2972-2978
        • Khan O.A.
        • Gore M.
        • Lorigan P.
        • Stone J.
        • Greystoke A.
        • Burke W.
        • et al.
        A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours.
        Br J Cancer. 2011; 104: 750-755
        • Del Conte G.
        • Sessa C.
        • von Moos R.
        • Viganò L.
        • Digena T.
        • Locatelli A.
        • et al.
        Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.
        Br J Cancer. 2014; 111: 651-659
        • Dean E.
        • Middleton M.R.
        • Pwint T.
        • Swaisland H.
        • Carmichael J.
        • Goodege-Kunwar P.
        • et al.
        Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours.
        Br J Cancer. 2012; 106: 468-474
        • Balmana J.
        • Tung N.M.
        • Isakoff S.J.
        • Graña B.
        • Ryan R.D.
        • Saura C.
        • et al.
        Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors.
        Ann Oncol. 2014; 25: 1656-1663
        • Samol J.
        • Ranson M.
        • Scott E.
        • Macpherson E.
        • Carmichael J.
        • Thomas A.
        • et al.
        Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study.
        Invest N Drugs. 2012; 30: 1493-1500
        • Aogi K.
        • Iwata H.
        • Masuda N.
        • Mukai H.
        • Yoshida M.
        • Rai Y.
        • et al.
        A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer.
        Ann Oncol. 2012; 23: 1441-1448
        • Kaufman B.
        • Shapira-Frommer R.
        • Schmutzler R.K.
        • Audeh M.W.
        • Friedlander M.
        • Balmaña J.
        • et al.
        Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
        J Clin Oncol. 2015; 33: 244-250
        • Gelmon K.A.
        • Tischkowitz M.
        • Mackay H.
        • Swenerton K.
        • Robidoux A.
        • Tonkin K.
        • et al.
        Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
        Lancet Oncol. 2011; 12: 852-861
        • Robson M.
        • Im S.A.
        • Senkus E.
        • Xu B.
        • Domchek S.M.
        • Masuda N.
        • et al.
        Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.
        N Engl J Med. 2017; 377: 523-533
        • Tolaney S.M.
        • Kalinsky K.
        • Kaklamani V.
        • Savulsky C.
        • Olivo M.
        • Aktan G.
        • et al.
        AbstPD6-13Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer.
        San Antonio Breast Cancer Symposium, 2017
        • Domchek S.M.
        • Postel-Vinay S.
        • Bang Y.-J.
        • Park Y.H.
        • Alexandre J.
        • Delord J.-P.
        • et al.
        Abst:PD6-11An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC).
        San Antonio Breast Cancer Symposium, 2017
        • Yau C.
        • Wolf D.
        • Brown-Swigart L.
        • Hirst G.
        • Sanil A.
        • Singhrao R.
        • et al.
        Abst:PD6-14Analysis of DNA repair deficiency biomarkers as predictors of response to the PD1 inhibitor pembrolizumab: Results from the neoadjuvant I-SPY 2 trial for stage II-III high-risk breast cancer.
        SABCS, 2017
        • Prasanna T.
        • Wu F.
        • Khanna K.K.
        • Yip D.
        • Malik L.
        • Dahlstorm J.E.
        • et al.
        Optimizing poly (ADP-ribose) polymerase inhibition through combined epigenetic and immunotherapy.
        Cancer Sci. 2018; 109: 3383-3392