Approximately 5% of all breast cancers are associated with germline mutations in BRCA1 or BRCA2, and these patients are more likely to be diagnosed at a young age and to have triple-negative breast cancer, for which few treatment options are available in the metastatic setting.1, 2, 3 The reported 5-year survival for patients with metastatic breast cancer is 27%, and is only 11% for patients with metastatic triple-negative breast cancer.4 Thus, new treatments that provide durable benefit for patients with germline BRCA mutation-associated advanced breast cancer are needed.
Research in context
Evidence before this study
We searched PubMed in November, 2019, using the search terms “BRCA1”, “BRCA2”, and “breast cancer” for primary publications published between June 1, 2015, and November, 2019 . We selected phase 2 or phase 3 studies of platinum chemotherapy, poly(ADP-ribose) polymerase (PARP) inhibitors, or both, in patients with advanced breast cancer and germline BRCA mutations.
The phase 3 TNT trial showed a higher proportion of objective responses and improved progression-free survival when patients with advanced BRCA1 or BRCA2 mutation-positive triple-negative breast cancer were treated with carboplatin compared with docetaxel. The phase 2 TBCRC009 trial evaluated cisplatin or carboplatin in patients with metastatic triple-negative breast cancer, showing more objective responses in the subgroup of patients with germline BRCA mutations. These trials indicate that platinum chemotherapy might be particularly effective in treating patients with BRCA mutation-positive advanced triple-negative breast cancer, which has led to updates to both National Comprehensive Cancer Network and European School of Oncology–European Society of Medical Oncology breast cancer guidelines where platinum chemotherapy is now included as a preferred regimen for these patients.
The phase 3 OlympiAD and EMBRACA trials showed improved progression-free survival with olaparib or talazoparib monotherapy, respectively, when compared with physicians' choice of non-platinum chemotherapy in patients with advanced, HER2-negative breast cancer and a germline BRCA mutation. The phase 2 BROCADE trial showed numerically longer (although not significant) progression-free survival and overall survival with the addition of veliparib to carboplatin and paclitaxel in patients with advanced germline BRCA mutation-positive breast cancer, without substantial additional toxicity. These results warranted further study in a larger phase 3 trial.
Added value of this study
To our knowledge, BROCADE3 is the first phase 3 trial to evaluate a PARP inhibitor with platinum doublet chemotherapy for BRCA mutation-associated breast cancer, showing a significant improvement in progression-free survival with the addition of veliparib to carboplatin and paclitaxel. In subgroup analyses, the progression-free survival benefit was similar in patients with triple-negative breast cancer and those with hormone receptor-positive breast cancer.
Implications of all the available evidence
BROCADE3 has shown, we believe for the first time, that the combination of a PARP inhibitor, veliparib, with platinum chemotherapy significantly improves progression-free survival with little additional toxicity in patients with advanced HER2-negative breast cancer and a BRCA mutation. These data suggest that veliparib, in combination with carboplatin and paclitaxel, should be considered as a new treatment option for patients with BRCA-associated advanced breast cancer who are candidates for chemotherapy.
BRCA1 and BRCA2-mutated breast cancers have a deficiency in homologous recombination repair, impairing the ability of cancer cells to repair DNA damage, and are known to be sensitive to both poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents.5, 6, 7, 8 Clinical evidence has shown that this vulnerability can be exploited for the treatment of advanced, HER2-negative breast cancer, and has led to the inclusion of both classes of agents in treatment guidelines. However, reports of the emergence of reversion mutations that restore BRCA function in patients treated with either platinum chemotherapy or PARP inhibitors have led to concerns about cross-resistance and, for this reason, patients who are resistant or refractory to platinum chemotherapy are often excluded from PARP inhibitor clinical trials. Given this concern, a strong scientific rationale exists to combine PARP inhibitors with platinum chemotherapy on the basis of common mechanisms of sensitivity and acquired resistance,9 and observed potentiation of platinum activity by PARP inhibitors preclinically, to maximise the therapeutic benefit derived from exploiting pathogenic BRCA mutations.10 However clinical application of these combinations has been challenging,11, 12 largely owing to haematological toxicity.13, 14
Veliparib (ABT-888) is a potent, orally bioavailable, selective PARP1 and PARP2 inhibitor10 that has shown antitumour activity and acceptable toxicity as a single agent and in combination with carboplatin and paclitaxel in patients with BRCA mutation-associated breast cancer.15, 16 Veliparib selectively inhibits the polymerase activity of PARP without substantial trapping of PARP protein onto DNA damage repair intermediates.17, 18 This mechanism of action makes veliparib more suitable than other PARP inhibitors to be administered in combination with platinum-based chemotherapy, since PARP trapping has been shown to be associated with myelosuppression.19 In a randomised, placebo-controlled, phase 2 study (BROCADE),20 numerical (although not significant) increases in median progression-free survival and overall survival were observed with the addition of veliparib to carboplatin and paclitaxel versus carboplatin and paclitaxel alone in patients with BRCA-mutated advanced breast cancer. The safety profile was similar between the two treatment groups, with common adverse events generally being haematological and gastrointestinal.20 Haematological events were generally manageable with dose reductions and standard supportive measures and gastrointestinal events were typically low grade. Here, we report results from BROCADE3, a randomised, controlled, phase 3 trial comparing veliparib with placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel are discontinued before progression, in patients with HER2-negative, inoperable, locally advanced or metastatic breast cancer with germline BRCA1 or BRCA2 mutations.