New Engl J Med
375
:
23-34
2016
.

Adaptive randomization of veliparib-carboplatin treatment in breast cancer

Rugo HS, Olopade OI, DeMichele A, Yau C, van t Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ for the I-SPY Investigators

BACKGROUND

The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match ex- perimental regimens with responding cancer subtypes. We report results for veli- parib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin.

METHODS

In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of bio- marker subtypes).

Veliparib–carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by mag- netic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well.

RESULTS

With regard to triple-negative breast cancer, veliparib–carboplatin had an 88% pre- dicted probability of success in a phase 3 trial. A total of 72 patients were random- ly assigned to receive veliparib–carboplatin, and 44 patients were concurrently as- signed to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib–carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib– carboplatin was greater than that of the control.

CONCLUSIONS

The process used in our trial showed that veliparib–carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Health- care Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.)

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