Adaptive treatment using veliparib-carboplatin shows benefit in breast cancer

1. The addition of veliparib-carboplatin to standard therapy in treating triple-negative breast cancer patients showed higher rates of pathological complete response compared to standard therapy alone.

2. The toxicity associated with adding veliparib-carboplatin was greater than standard therapy alone, namely neutropenia, anemia and thrombocytopenia.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Breast cancer is a heterogeneous disease presenting challenges for diagnosis and subsequent management. Using the unique biologic properties of tumours, genetic testing can aid in identifying breast cancer subtypes and, in turn, direct targeted therapies. Veliparib is an inhibitor of poly (ADP-ribose) polymerase (PARP), a class of medications shown to potentiate the effects of carboplatin.

This study aimed to rapidly identify these subtypes, and then randomize patients to have veliparib-carboplatin in addition to paclitaxel, versus paclitaxel alone. The primary endpoint was pathological complete response. The results showed adding veliparib-carboplatin had higher rates of pathological complete response compared to standard therapy alone for triple-negative breast cancer patients. However, there was greater toxicity associated with adding veliparib-carboplatin, most commonly pancytopenia. The strengths of this study was the randomization of patients, and having data supporting adaptive therapy which allows patients to have a more personalized approach to their care and streamlines future randomized controlled trials.  The limitations of this study were the small numbers of patients involved in the randomization, and uneven distribution of study arms.

Click to read the study, published today in NEJM

Relevant Reading:  The brave new world of clinical cancer research: adaptive biomarker-driven trials integrating clinical practice with clinical research.

In-Depth [randomized controlled trial]: This study was an adaptive randomized controlled trial aimed to match experimental therapies with breast cancer subtypes.  The study subdivided stage II and III breast cancer patients having tumours 2.5 cm or greater, according to 8 biomarkers with respect to HER-2, hormone receptors and a 70-gene assay. Patients underwent randomization according to subtype and experimental therapy that would accordingly be best suited.  Veliparib-carboplatin in addition to standard therapy versus standard therapy along was aimed at HER-2 negative tumours and their 3 subtypes (HER-2 negative, hormone-receptor positive and HER-2 negative, and triple negative).  The primary endpoint was complete pathological response.  MRI was used to assess degree of response, and Bayesian predictive probabilities were used to estimate success in subsequent phase 3 study.

Patients were eligible for study inclusion between May 2010 to July 2012. Within the group of HER-2 negative tumours, the estimated response rate was 33% (95% Bayesian probability interval (PI) 23-43%) among the veliparib-carboplatin group, versus 22% (95%PI 10-35%) in the control group. In the triple negative breast cancer group, the probability of veliparib-carboplatin being superior to control was 99%, and was estimated to have an 88% predicted probability of success with veliparib-carboplatin in a phase 3 trial. A total of 72 patients were randomized to receive veliparib-carboplatin plus paclitaxel, and 44 patient received paclitaxel alone.  The estimated rate of pathological complete response was 51% (95%PI 36-66%) in the veliparib-carboplatin group versus 26% (95%PI 9-43%) in the control group. In terms of toxicity, there was grade 3 or 4 hematologic side effects in the veliparib-carboplatin versus control. The results were as follows: 71% versus 2% of patients had neutropenia, 1% versus 0% had febrile neutropenia, 21% versus 0% had thrombocytopenia and 28% versus 0% had anemia. Dose reductions in paclitaxel occurred in 23 patients (32%) in the veliparib-carboplatin group and none in the control group.

Image: PD

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