SABCS 2013 - CARE Breast Cancer Faculty Update - High-Risk Breast Cancer

SABCS 2013 S5-02: Veliparib/Carboplatin Plus Standard Neoadjuvant Therapy for High-Risk Breast Cancer: First Efficacy Results From the I-SPY 2 Trial. HS. Rugo et al.

Background: I-SPY 2 is a multicenter, phase 2 screening trial using adaptive randomization within biomarker subtypes to evaluate a series of novel agents/combinations when added to standard neoadjuvant therapy (paclitaxel q wk x 12, doxorubicin & cyclophosphamide q 2-3 wk x 4, T/AC) vs. T/AC (control arm) for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR in breast and axilla) at surgery. The goal is to identify/graduate regimens that have ≥ 85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked phase 3 neoadjuvant trial. Experimental regimens can "graduate" in at least 1 of 10 possible signatures defined by hormone-receptor (HR) & HER2 status and MammaPrint (MP) classification, with a maximum number of 120 total patients enrolled per arm. This is the first report from 1-SPY 2, which is the efficacy results of the oral PARP inhibitor veliparib (V, ABT-888) at 50 mg PO BID in combination with carboplatin (Cb) AUC 6 q 3 weekly x 4 with weekly paclitaxel.

Conclusions: 72 patients were randomized to receive veliparib/Cb and standard chemotherapy while 62 patients were randomized to the standard chemotherapy (control) arm. In the HER2-negative population, the estimated pCR rate was 33% (V + Cb) vs. 22% (control). Adaptive randomization successfully identified a biomarker signature for V + Cb. The estimated pCR rate for V + Cb was 52% (95% CI: 35%–69%) versus 26% (95% vCI: 11%–40%) for the control arm in the triple-negative breast cancer signature. and is the subset recommended for this regimen's subsequent development. The estimated probability of success for this combination in a phase 3 trial is 90%.Greater hematological toxicity was seen in the V + Cb arm, with subsequent dose reductions required in the 49% of cases with carboplatin and in 27% with the paclitaxel dose. A slight delay (17 days median) from treatment to surgery was also seen in the combination arm.

The I-SPY 2 standing trial mechanism efficiently evaluates agents/combinations in biomarker-defined patient subsets as a means to accelerate drug development in early stage breast cancer.

The combination of a PARP inhibitor (veliparib) and carboplatin on a backbone of a standard taxane/anthracycline regimen shows promising activity in TNBC.

A phase 3 trial will need to be performed to dissect out the differential activity of the PARP inhibitor from that of carboplatin in TNBC.

Future translation work from the collected biospecimens and serial MRIs may further refine a subset within TNBC to enrich for in the confirmatory phase 3 trial.
— CARE Breast Cancer Faculty