A multicentered randomized phase II comparison of single-agent carboplatin versus the combination of carboplatin and everolimus for the treatment of advanced triple-negative breast cancer.

TPS1109 Background: Triple negative breast cancer (TNBC) is an aggressive disease with unmet clinical needs. Women with TNBC tend to be younger and demonstrate early recurrence, higher histological grade, higher rate of visceral metastasis and increased mortality rates when compared to hormone positive breast cancer. Prognosis for metastatic TNBC is especially poor. Due to lack of targeted therapies, there is no standard treatment of choice for triple negative breast cancer and chemotherapy remains the accepted standard. Many chemotherapeutic agents have been reported to have clinical activity either as single agent or in combination. Seventy percent of breast cancers with BRCA-1 germline mutations are triple negative, which suggests a shared carcinogenic pathway between them. In preoperative and metastatic settings, both TNBC and BRCA-1 associated breast cancers are particularly sensitive to DNA cross-linking agents such as platinum compounds due to defective DNA repair by homologous recombination. The recent TNT trial showed in patients with triple negative metastatic or recurrent locally advanced breast cancer with BRCA1/2 mutations, carboplatin resulted in a significantly higher overall response rate versus docetaxel (68% versus 33.3%; p=0.03). Triple negative breast cancers are associated with a high frequency of PTEN loss, which leads to mTOR activation. Moreover, it has been reported that mTOR activation may confer resistance to platinum agents such as cisplatin, a phenomenon that may be reversible by the addition of an mTOR inhibitor such as everolimus. There are reports of synergy between mTOR inhibitors and platinum compounds in pre-clinical and clinical data. Methods: We have opened a multi-centered randomized phase II trial comparing carboplatin AUC 4 q 3 weeks vs carboplatin AUC 4 q 3 weeks combined with daily 5 mg everolimus. 41 of planned 72 patients from the Mount Sinai Health System have been enrolled and are randomized in a 2:1 allocation. The primary objective is to compare progression-free survival in patients treated with carboplatin+everolimus to patients treated with carboplatin alone. Patients may have had up to 3 prior regimens for metastatic disease. Exploratory biomarker assessment is being done to identify markers of response. Clinical trial information: NCT02531932.