Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCA-wt) breast cancer patients in a phase I study of single-agent veliparib (V).

Abstract

135 Background: Veliparib (V) (ABT-888) is an oral, potent inhibitor of PARP 1/2. PARP inhibitors have preclinical and clinical efficacy in BRCA+ malignancies. There are genotypic and phenotypic similarities between BRCA+ cancers, serous ovarian cancer and basal-like breast cancer and we postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose -limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed V in 2 cohorts of patients, BRCA+ and BRCA-wt (consisting of serous ovarian cancer and triple-negative breast cancer (TNBC). Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28 day cycle. BRCA+ and BRCA-wt patients were enrolled in 2 separate cohorts with 2 separate escalations. Results: 98 (70 BRCA+ and 28 BRCA-wt) pts have been enrolled. The maximum administered dose (MAD) was 500mg BID and the MTD/RP2D is 400mg BID for both cohorts. 59 BRCA+ pts and 24 BRCA-wt pts (21 TNBC and 3 ovary) were evaluable for response. ORR was defined as CR+PR and clinical benefit rate (CBR) as CR+PR+SD > 6 months. Results are summarized in the table. Conclusions: There is evidence of anti-tumor activity with V comparable to that of other PARP inhibitors in the BRCA+ population. There was indication of dose responsiveness with greater activity in this population at higher doses. There is less activity in the mostly TNBC, BRCA-wt population, although there was evidence of benefit in a small number of patients. Ongoing tissue correlative studies will help to identify potential mechanisms of sensitivity and resistance. Clinical trial information: NCT00892736. [Table: see text]

Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/orBRCAMutation–Associated Breast Cancer

“…These results are consistent with other veliparib studies in which patients with BRCA wild-type TNBC experienced objective tumor response (13, 47). Patients whose carcinomas had a basal phenotype by IHC did not have better responses than patients with non-basal-like TNBCs.…”

“…This is significant because there is evidence for a dose response relationship with veliparib, and single agent activity is observed beginning at 300 mg BID (13). In germline BRCA mutation-associated cancer, a recently completed phase I study evaluated 9 dose levels of veliparib monotherapy and demonstrated a 29% overall response rate (at all dose levels combined) and a higher response rate of 60% at the RP2D (47). The finding of higher clinical response rates with higher doses of veliparib, despite achieving 90% PARP inhibition at lower doses by PAR assay (12, 13) suggests that combinations which allow for higher PARP inhibitor dosing may be preferred in order to achieve the best therapeutic response.…”

Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083

“…Preclinical evidence demonstrate that PARPis potentiate the effects of platinum in vivo (13–17) and emerging data suggest synergism between PARPis and platinum compounds in BRCA -associated BCs (18–20). Consequently, the California Cancer Consortium conducted companion clinical trials in patients with BRCA -associated MBC.…”

Elucidating the Genomic Landscape of Breast Cancer: How will this Affect Treatment?

“…Responses to PARP-inhibitors have also been reported in patients with sporadic high grade serous ovarian carcinoma [27] and triple negative breast cancer [24]. Tumor responses to PARP-inhibitors in the BRCA1 and BRCA2 wild-type population may be related to other types of HRD.…”

“…In breast cancer patients with germline BRCA1/ BRCA2 mutations, the reported response rate with PARP-inhibitors (olaparib, veliparib, niraparib and BMN-673) ranges from 13-55%, with greater clinical benefit in the triple negative subgroup [22][23][24][25][26][27]. Based on these promising results, Phase III clinical trials in advanced breast cancers in patients with germline BRCA1/2 mutations have started with the four PARP-inhibitors: olaparib (OLYMPIA trial, NCT02000622), veliparib (NCT02163694), niraparib (BRAVO trial, NCT01905592) and BMN 673 (EMBRACA trial, NCT01945775).…”