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Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer

Mené sur 27 patientes atteintes d'un cancer du sein de stade métastatique présentant une mutation constitutionnelle BRCA1 ou BRCA2, cet essai de phase I évalue la dose maximale tolérée, l'efficacité, du point de vue du taux de réponse, et la toxicité du véliparib, un inhibiteur de PARP, seul ou en combinaison avec du carboplatine

Purpose: We aimed to establish the maximum tolerated dose (MTD) of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2-(BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment post-progression, and to correlate PAR levels with clinical outcome. Experimental Design:Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID) and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results:Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia (MTD: veliparib 150 mg po BID and carboplatin [AUC of 5]). Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 phase II trial patients, with a 14% RR in BRCA1 (n=22) and 36% in BRCA2 (n=22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions:Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted

Clinical Cancer Research

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