Elsevier

The Lancet Oncology

Volume 21, Issue 10, October 2020, Pages 1269-1282
The Lancet Oncology

Articles
Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(20)30447-2Get rights and content

Summary

Background

BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.

Methods

BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m2 intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days −2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694.

Findings

Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin–paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin–paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9–43·6) in the veliparib group and 35·5 months (23·1–45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5–17·7) in the veliparib group versus 12·6 months (10·6–14·4) in the control group (hazard ratio 0·71 [95% CI 0·57–0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths.

Interpretation

The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.

Funding

AbbVie.

Introduction

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.

Section snippets

Study design and participants

BROCADE3 is a phase 3, double-blind, randomised, placebo-controlled study done at 147 centres (eg, hospitals) in 36 countries worldwide (appendix pp 1–6).

Patients (aged ≥18 years) with histologically or cytologically confirmed metastatic or locally advanced, unresectable, HER2-negative breast cancer and suspected deleterious or deleterious germline BRCA1 or BRCA2 mutations and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled. Patients could have measurable or

Results

Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were randomly assigned (figure 1). A total of 509 patients (n=337 in the veliparib group; n=172 in the control group) had a germline BRCA1 or BRCA2 mutation confirmed by the core laboratory; these patients comprised the intention-to-treat population. Among all randomly assigned patients, 507 received at least one dose of veliparib or placebo and were included in the safety analyses (336 in the

Discussion

The results of this phase 3 trial show that when added to carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before disease progression, veliparib resulted in a durable improvement in progression-free survival, with benefit evident at 2 years and 3 years after randomisation, in patients with advanced HER2-negative breast cancer and a germline BRCA1 or BRCA2 mutation. These results are noteworthy given the high activity of the carboplatin and

Data sharing

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymised individual and trial-level data (analysis datasets), as well as other information (eg, protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who

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