Neoadjuvant carboplatin in triple-negative breast cancer: results from NACATRINE, a randomized phase II clinical trial

Abstract

Background Neoadjuvant chemotherapy (NACT) is the mainstay of treatment of stages II and III triple-negative breast cancer (TNBC). There is interest in the addition of carboplatin to NACT, especially in TNBC patients with germline BRCA mutations or other genomic alterations associated with DNA repair deficiency. This study aims to evaluate if the addition of carboplatin to NACT is associated with an increase in the pathological complete response (pCR) rates in TNBC. Methods We conducted an open-label phase II randomized clinical trial in a single center in Brazil. Patients with stage II and III TNBC were randomized in a 1:1 ratio to receive standard NACT with or without carboplatin. All the patients received doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) both intravenously (i.v.) q21 days for four cycles. Patients were then randomized for additional treatment with weekly (wk) paclitaxel (80 mg/m2 i.v., for 12 cycles) plus wk carboplatin AUC 1.5 (experimental arm) or without wk carboplatin (control arm). Randomization was stratified according to gBRCA status (deleterious mutation vs. no deleterious mutations), age (< 50 vs.≥ 50 years), or AJCC 8th edition clinical stage (II vs. III). The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints included recurrence-free survival, overall survival, and toxicity. Results Between 2017 and 2021, 146 patients were randomized; 73 on each arm. The median age was 45 years, and 69.8% were < 50 years. Most patients (66.4%) had locally advanced stage III disease, 67.1% had T3/T4 tumors, and 56.2% had clinically positive axillary lymph nodes. Germline BRCA status was available for all patients, and 19.9% had pathogenic BRCA1/2 variants. The pCR rate (ypT0ypN0) was numerically increased by 13.7%, being 43.8% (31 of 73 patients) in the experimental and 30.1% (22 of 73 patients) in the control arm, not meeting the prespecified goal of increasing the pCR in 15% (p value = 0.08). Survival outcomes are immature. The toxicity profile was consistent with routine clinical practice. There were more dose interruptions and hematological toxicity in the carboplatin arm. However, the incidence of serious adverse effects was low, and there was no difference in treatment discontinuation between the two arms. Conclusion The addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate of 13.7%, consistent with other similar clinical trials. Follow-up for survival outcomes and translational research initiatives are ongoing.