Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer

Author:

Lee, Jung-Min

Hays, John L

Chiou, Victoria L

Annunziata, Christina M

Swisher, Elizabeth M

Harrell, Maria I

Yu, Minshu

Gordon, Nicolas

Sissung, Tristan M

Ji, Jay

Figg, William D

Minasian, Lori

Lipkowitz, Stanley

Wood, Bradford J

Doroshow, James

Kohn, Elise C
Author Address

Women 39;s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Division of Medical Oncology, Department of Internal Medicine, The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA., Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., National Clinical Target Validation Laboratory, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, USA., Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute, NIH, Bethesda, MD, USA., Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA.,

Abstract:

To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores < 10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, = 8 cycles, with olaparib 400mg bid maintenance. Peripheral blood mononuclear cells were collected for polymorphisms and PAR levels, and paired tumor biopsies (pre-/post-cycle 1) for proteomics and apoptosis endpoints. 28 women were treated (median 5 prior regimens [0-12]). Dose-limiting toxicity was thrombocytopenia, and symptomatic hyponatremia with carboplatin AUC5. The maximum tolerated dose was olaparib 400mg bid+carboplatin AUC4. Grade 3 and 4 adverse events included neutropenia (36%), thrombocytopenia (11%), and anemia (11%). Responses included 1 complete response (CR; 69+months) and 5/27 partial responses (19%; median 4months [4-7]), for a response rate of 22%. Biomarker findings did not correlate with response. The long-term CR patient with prior negative BRCA testing was found to have deletion of BRCA1 exons1-2. The olaparib/carboplatin combination is tolerable and has modest activity in sporadic TNBC patients. Further evaluation of predictive biomarkers to identify those with BRCA wild type who had response is warranted.

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