Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer

• Published in: Breast cancer research : BCR Vol. 15; no. 5; p. R88
• Main Authors: Dent, Rebecca A, Lindeman, Geoffrey J, Clemons, Mark, Wildiers, Hans, Chan, Arlene, McCarthy, Nicole J, Singer, Christian F, Lowe, Elizabeth S, Watkins, Claire L, Carmichael, James
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 01.01.2013; BioMed Central
• Subjects: Adult; African Americans; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast cancer; Cancer; Chemotherapy; Cohort Studies; Dosage and administration; Drug therapy; Drug therapy, Combination; Female; Health aspects; Humans; Middle Aged; Monosaccharides; Neoplasm Metastasis; Oncology, Experimental; Paclitaxel; Paclitaxel - administration & dosage; Pharmaceutical industry; Phthalazines - administration & dosage; Piperazines - administration & dosage; Poly(ADP-ribose) Polymerase Inhibitors; Sugars; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - mortality; Triple Negative Breast Neoplasms - pathology; Australia; United Kingdom
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/bcr3484

This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADPribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients who had received ≤1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade ≥2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade ≥3) and four in cohort 2 (two grade ≥3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707).