Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer

Christian Deaton, Mercer University College of Pharmacy

Carboplatin is an alkylating agent that is used for the treatment of ovarian cancer, as well as lung, head, and neck cancer.  This agent works by interacting with deoxyribonucleic acid (DNA) and interfering with DNA repair.  [1]

Veliparib is an anti-cancer drug that targets cancer cells by blocking poly-adenosine-diphosphate-ribose polymerase (PARP), thereby preventing the repair of DNA in cancer cells.   It is suggested that veliparib can possibly make cancer cells more susceptible to anticancer treatments. [2]

Triple-negative breast cancer is characterized by an offending tumor that is human epidermal growth factor receptor 2 (HER2)-negative, estrogen-receptor–negative, and progesterone-receptor–negative.  This type of breast cancer is defined by the lack of targeted therapy available for women who are affected by it.  Due to its triple-negative status, triple-negative tumors are considered to not respond well to receptor-targeted treatments. [3]

Adaptive Randomization of Veliparib– Carboplatin Treatment in Breast Cancer  [4]
Design Multi-center, randomized, open-label; N= 272
Objective Determine safety and efficacy of multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer
Study Groups Patients receiving paclitaxel; n= 46

Patients receiving paclitaxel, trastuzumab; n= 18

Patients receiving paclitaxel, veliparib, carboplatin; n= 75

Methods Experimental regimens are compared against a common control regimen consisting of standard neoadjuvant therapy.  Participants received weekly paclitaxel intravenously for 12 doses, alone or in combination with an experimental regimen.
After receiving paclitaxel with or without veliparib–carboplatin, all patients received doxorubicin and cyclophosphamide every two to three weeks for four doses, with myeloid growth factor support as appropriate, after which they underwent surgery.
To assess efficacy, biomarkers used were based upon triple negative status (HER2-negative, estrogen-receptor–negative, and progesterone-receptor–negative).
Duration May 2010 – July 2012
Primary Outcome Measure The absence of residual cancer in the breast or lymph nodes at the time of surgery (pathological complete response)
Baseline Characteristics
  Veliparib-Carboplatin; n=72 Control; n= 44
Age, average 48.5 47.5
Caucasian, n 54 34
Hormone receptor-positive, n 33 23
Average tumor size, cm 5 5
Palpable node, n 31 22
Results Estimated rates of pathological complete response in the triple-negative population were 51% in the veliparib–carboplatin group versus 26% in the control group
Adverse Events Common Adverse Events: nausea (90%)
Serious Adverse Events: urinary tract infection (7%)
Percentage that Discontinued due to Adverse Events: 9%
Study Author Conclusions Veliparib–carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer.

The study revealed that veliparib and carboplatin benefited patients with triple-negative breast cancer when compared to a regimen of paclitaxel alone.  In the veliparib–carboplatin group, there were high rates of adverse toxic effects. It was unclear whether the carboplatin or veliparib attributed to the adverse toxic events, or whether it was associated with the doxorubicin–cyclophosphamide treatment part of the study.

Breast cancer gene (BRCA) mutations were found among patients in the trial.  By design, adaptive randomization increased the number of patients with triple-negative breast cancer who were assigned to receive veliparib–carboplatin, as compared with other experimental regimens. Therefore, the group that underwent adaptive randomization and were assigned to receive veliparib–carboplatin, may have been enriched for BRCA mutations.  Limitations of the study include population size, short duration of study, and diversity among subjects.

 

 

References

  1. Product Information: PARAPLATIN(R) IV injection, carboplatin IV injection. Bristol-Myers Squibb Company, Princeton, NJ, 2010
  2. Wagner LM. Profile of veliparib and its potential in the treatment of solid tumors. Onco Targets Ther. 2015;8:1931-9
  3. Roepman P, Horlings HM, Krijgsman O, et al. Microarray-based determination of estrogen receptor, progesterone receptor, and HER2 receptor status in breast cancer. Clin Cancer Res 2009;15:7003-11
  4. Rugo, Hope S., Olopade, Olufunmilayo I., DeMichele, Angela, Yau, Christina, et al. Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer.  N Engl J Med. 2016; 375; 23-34
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