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01-11-2019 | Breast Cancer | Original Article

Exposure–response analysis to inform the optimal dose of veliparib in combination with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer patients

Authors: Silpa Nuthalapati, Sven Stodtmann, Stacie Peacock Shepherd, Christine K. Ratajczak, Sven Mensing, Rajeev Menon, Hao Xiong

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2019

Abstract

Purpose

Veliparib, a poly(ADP-ribose)-polymerase (PARP) 1 and 2 enzyme inhibitor, was administered at 120 mg twice daily (BID) for 7 days in a 21-day cycle with carboplatin/paclitaxel in the Phase 2 BROCADE study in patients with BRCA-deficient recurrent or metastatic breast cancer, a dose based on Phase 1 results. Population pharmacokinetic (PK) and exposure–response analyses were undertaken to retrospectively evaluate whether an optimal dose was used in BROCADE.

Methods

A population PK analysis was performed using data from 168 patients in BROCADE along with data from 288 subjects in another 5 studies. The relationship between veliparib exposure and efficacy variables (including progression-free survival [PFS] and objective response rate [ORR]) and safety variables (selected grade 3 or greater hematological adverse events) were analyzed.

Results

Veliparib PK parameters in BROCADE were comparable to the previous studies. Creatinine clearance on veliparib apparent clearance and lean body weight on veliparib apparent volume of distribution were identified as covariates. A trend of better efficacy (PFS and ORR) in the veliparib arm compared to placebo was observed. However, veliparib exposure-efficacy response was relatively flat with higher veliparib exposures not showing better efficacy. No exposure–response relationship was observed in grade 3 or greater hematological toxicities (anemia, neutropenia, leukopenia, and thrombocytopenia).

Conclusions

The exposure–response analysis suggested that intermittent 7-day veliparib 120 mg BID dosing in a 21-day cycle provided additional efficacy without meaningfully impacting the safety and tolerability when co-administered with carboplatin and paclitaxel in patients with BRCA-deficient breast cancer. A higher dose of veliparib is unlikely to provide greater benefit in this combination in patients with BRCA-deficient recurrent or metastatic breast cancer.

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Title: Exposure–response analysis to inform the optimal dose of veliparib in combination with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer patients
Authors: Silpa Nuthalapati
Sven Stodtmann
Stacie Peacock Shepherd
Christine K. Ratajczak
Sven Mensing
Rajeev Menon
Hao Xiong
Publication date: 01-11-2019
Publisher: Springer Berlin Heidelberg
Keywords: Breast Cancer
Breast Cancer
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03930-2

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