Veliparib–Chemotherapy ‘A Compelling Option’ For BRCA-Mutated Breast Cancer

Author: By Shreeya Nanda, Senior medwireNews Reporter 

medwireNews: Patients with advanced HER2-negative breast cancer and germline BRCA1/2 mutations derive a significant progression-free survival (PFS) benefit from the addition of veliparib to carboplatin plus paclitaxel, indicates the BROCADE3 trial. 

Combining the PARP inhibitor with chemotherapy led to “little additional toxicity”, say the researchers, who therefore believe that the combination is “a compelling treatment option” for this patient population. 

In the double-blind, phase III study, 509 patients with locally advanced or metastatic disease and deleterious or suspected deleterious BRCA1/2 mutations were randomly assigned to receive carboplatin AUC 6 mg/mL per min on day 1 plus paclitaxel 80 mg/m2 on days 1, 8 and 15 of each 21-day cycle either alongside veliparib 120 mg twice daily or placebo on days –2 to 5. Participants who discontinued chemotherapy prior to progression could continue in a blinded manner to receive monotherapy with veliparib 300–400 mg twice daily or placebo. 

The veliparib and control groups were followed up for a median of 35.7 and 35.5 months, respectively, and the corresponding median investigator-assessed PFS times were 14.5 and 12.6 months. This equated to a significant 29% reduction in the risk for progression or death with the addition of veliparib, report the researchers in The Lancet Oncology. 

Véronique Diéras, from Centre Eugène Marquis in Rennes, France, and co-investigators highlight the delayed separation of the Kaplan–Meier curves (at around 13 months) indicating the presence of non-proportional hazards, which they speculate could be due to the transition of a subset of patients to monotherapy before disease progression or the presence of a subgroup that does not benefit from veliparib addition. 

The authors point out, however, that “subgroup analyses of progression-free survival did not identify such a subgroup defined by clinical characteristics”, but they urge caution in interpreting these results owing to the small patient numbers. 

Writing in a related commentary, Melinda Telli, from Stanford University in California, USA, says: “Although one can question the clinical relevance of a 1·9 month difference in median progression-free survival on the surface, a deeper look at the Kaplan-Meier curves provides many interesting insights. 

“The shapes of the progression-free survival curves are quite distinct from the PARP inhibitor monotherapy studies in that the curves begin to separate late and there is a long tail on the curves.” 

Specifically, the PFS rates at the 2- and 3-year timepoints were higher with the combination than chemotherapy alone, at 33.6% versus 19.8% and 25.7% versus 10.7%, respectively. 

Overall survival data were not mature at the time of analysis, but a prespecified interim analysis did not show a significant difference between the study arms. 

Serious adverse events (AEs) were more common in the veliparib than the control arm, at rates of 34% and 29%, respectively, and the incidence of AE-related dose reductions (17 vs 8%) and discontinuations (16 vs 11%) was also higher with veliparib. 

But Véronique Diéras and colleagues note that “[p]atient-reported outcomes showed no clinically meaningful differences between treatment groups, indicating that the addition of veliparib to carboplatin–paclitaxel does not increase treatment-related symptom burden.” 

They continue: “Moreover, these analyses revealed no systematic, clinically meaningful deterioration in global health status or quality of life scores with time, suggesting that the regimen was generally well tolerated.” 

The commentator says that the trial findings “challenge the existing dogma of sequential single-agent therapy in this genetically distinct group of patients with advanced breast cancer”, and “force us to consider whether a strategy of platinum-based induction combination chemotherapy followed by PARP inhibitor maintenance, as is standardly used in ovarian cancer, might ultimately lead to superior outcomes”. 

And she concludes: “Questions regarding the optimal duration of chemotherapy and whether or not a PARP inhibitor is required in the chemotherapy phase remain unanswered.” 

References 

Diéras V, Han HS, Kaufman B, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol; Advance online publication 27 August 2020. doi: 10.1016/S1470-2045(20)30447-2

Telli ML. BROCADE3: a challenge to the treatment paradigm in BRCA breast cancer? Lancet Oncol; Advance online publication 27 August 2020. doi: 10.1016/ S1470-2045(20)30431-9