PARP INHIBITOR INTERACTS WITH WEEKLY PACLITAXEL

Breast Cancer Res. 2013 Sep 25;15(5):R88. [Epub ahead of print]

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.

Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A, McCarthy NJ, Singer CF, Lowe ES, Watkins CL, Carmichael J.

Abstract

INTRODUCTION:

This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral PARP inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC).

METHODS:

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 3 weeks per 4-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).

RESULTS:

19 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--100%) in cohort 1 and 73% (29--100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression.

CONCLUSIONS:

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).