The TOPACIO trial tested the PARP inhibitor niraparib plus pembrolizumab in women with triple-negative breast cancer.
Combination therapy with niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and pembrolizumab had clinical activity in triple-negative breast cancer (TNBC), according to the results of the TOPACIO trial. However, that activity appeared limited to patients with BRCA-mutated tumors, a finding that aligns with PARP inhibitor activity seen to date. The two PARP inhibitors olaparib and talazoparib are currently approved for TNBC patients with BRCA mutations. Results of this study were published in JAMA Oncology.
TOPACIO is an open-label, single-arm, multicenter, phase II clinical trial that included 55 women with advanced or metastatic TNBC from 34 sites across the United States, all of whom received niraparib in combination with pembrolizumab on day 1 of each 21-day cycle. Patients were eligible for the trial regardless of BRCA mutation status or programmed death ligand 1 (PD-L1) expression.
In terms of the safety profile, 32 patients (58%) had a grade 3 or higher treatment-related adverse event. The most common grade 3 or higher events were anemia (18%), thrombocytopenia (15%), and fatigue (7%). “These are typical class effects from PARP inhibitors,” said Yuan Yuan, MD, PhD, a medical oncologist specializing in breast cancer at City of Hope, during an interview with Cancer Network, who was not involved in the current study. “Totally not surprising,” she added.
As for immune-related adverse events, the most frequent any-grade events were adrenal insufficiency (2%), hyperglycemia (2%), hyperthyroidism (2%), hypothyroidism (7%), pneumonitis (2%), and polymyalgia rheumatica (2%). There were only 2 grade 3 immune-related adverse events, one of which was adrenal insufficiency and the other polymyalgia rheumatica. Yuan said the immune toxicities were “very consistent” with what’s been seen for pembrolizumab.
For the entire study population, the overall response rate (ORR) was 21% (10 of 47 evaluable patients), which included 5 confirmed complete responses and 5 confirmed partial responses. In addition, 13 patients had stable disease, yielding a disease control rate (DCR) of 49% (23 of 47 evaluable patients). Seven patients were still on treatment.
“I definitely think there is a signal for the combination,” said Yuan. That said, she cautioned, the study is a single-arm trial without a control. “There would need to be a confirmatory study comparing the PARP inhibitor plus immune checkpoint inhibitor vs single agent,” she said. She added that the response rate “appears” to be higher in the single-arm trial than the historical data using the PARP inhibitor alone.
For patients with BRCA mutations, the clinical activity was even more pronounced, with an ORR of 47% (7 of 15 evaluable patients), a DCR of 80% (12 of 15 evaluable patients), and a median progression-free survival (PFS) of 8.3 months (95% CI, 2.1 months–not estimable).
However, the opposite was true for patients without a BRCA mutation; the ORR dropped to 11% (3 of 27 evaluable patients), DCR to 33% (9 of 27 evaluable patients), and the median PFS to 2.1 months (95% CI, 1.4–2.5 months).
“There is a good scientific rationale to do this combination,” said Yuan. “But when you look at the patients without BRCA tumors, the overall response rate is a little bit disappointing.” She said the ORR for these patients-that is, 11%-is “almost comparable” with a single-agent immune checkpoint inhibitor.