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Chinese Trial Suggests PARP, VEGF Inhibitor Combo Benefits Advanced BRCA1/2-Mutant Breast Cancer

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NEW YORK – The PARP inhibitor fuzuloparib, either given alone or with the VEGFR2 inhibitor apatinib, improved progression-free survival in patients with HER2-negative metastatic breast cancer whose tumors harbor germline BRCA1 or BRCA2 mutations, according to data presented Thursday. 

In China, fuzuloparib is marketed by Jiangsu Hengrui Pharmaceuticals under the brand name AiRuiYi. Apatinib is also marketed by Jiangsu Hengrui in China under the brand name Aitan, but in the US, the same drug is called rivoceranib and is being developed by Elevar Therapeutics. 

Huiping Li, a researcher and breast oncologist at Peking University Cancer Hospital and Institute in Beijing, presented the results of a Phase III study of fuzuloparib and apatinib during a plenary presentation hosted and webcast by the European Society for Medical Oncology (ESMO) on Thursday afternoon. 

The study included previously treated patients with HER2-negative breast cancer with confirmed deleterious or suspected deleterious germline BRCA1/2 mutations, though Li noted that the majority, about 60 percent, had BRCA2 mutations. To be eligible for the trial, patients had to have up to two prior lines of chemotherapy, and if their tumors were hormone-receptor positive, they had to have at least one prior endocrine therapy. 

By the data cutoff of Dec. 15, 2023, the PARP inhibitor-VEGF inhibitor combination appeared to outperform both standard chemo and single-agent VEGF inhibition. 

Of the 203 patients in the efficacy-evaluable population, median progression-free survival among 70 patients who received fuzuloparib plus apatinib was 11 months. Meanwhile, 66 patients who received standard chemo lived for a median of just three months without their cancers progressing, and 67 patients who received fuzuloparib monotherapy lived for a median of 6.7 months without their cancers progressing. 

Of note, patients on the chemo arm were allowed to cross over to receive the single-agent PARP inhibitor if their cancers progressed. Even though the crossover design could complicate the overall survival comparison between the treatment arms — and indeed, 39.4 percent of patients crossed over from chemo to the PARP inhibitor — fuzuloparib, both alone and combined with apatinib, still extended patients' overall survival versus standard chemo. Among the patients who received the combination, the median overall survival was 29.2 months, versus 21.5 months for patients on chemo and 31.5 months for patients who received fuzuloparib monotherapy. 

As for tumor responses, Li shared that the overall response rate in the combined fuzuloparib-apatinib arm was 67.3 percent, versus 43.6 percent in the fuzuloparib monotherapy arm, and 23.3 percent in the chemo arm. The median duration of response in these arms were 9.8 months, 7.6 months, and 3.9 months, respectively. 

Li said that the toxicity profiles of the individual drugs and combination regimens were all similar to what's been previously shown, though the side effects she presented were not insignificant. The most common adverse grade 3 or higher adverse event across all three arms was decreased white blood cell count and decreased neutrophil count. The rates of serious treatment-related adverse events in the combination, monotherapy, and chemo arms were 12.9 percent, 17.9 percent, and 13.6 percent, respectively. Among patients who received the fuzuloparib-apatinib doublet, 7.1 percent had to discontinue treatment due to side effects, and the same was true for 3.4 percent of patients who received chemo. Although none of the patients on fuzuloparib monotherapy discontinued the drug due to side effects, one patient died due to septic shock caused by the PARP inhibitor.

Weighing the risk of adverse events against the benefits seen in the study, however, Li still concluded that the findings support the use of fuzuloparib plus apatinib or fuzuloparib alone for this patient population.

Although the notion of combining a PARP inhibitor with a VEGF inhibitor is not novel, most studies testing this combination approach to date have involved patients with platinum-sensitive ovarian cancer, Evandro de Azambuja, a researcher and breast cancer oncologist at the Jules Bordet Institute in Brussels, said during a discussion of the data. 

De Azambuja also recognized that other single-agent PARP inhibitors have been evaluated, and some have even been approved, for previously treated, BRCA-mutated breast cancer patients. For instance, Merck and AstraZeneca's PARP inhibitor Lynparza (olaparib) was evaluated in the OlympiAD study in this setting, and Pfizer's PARP inhibitor Talzenna (talazoparib) was evaluated in the EMBRACA study. Both PARP inhibitors are now approved for germline BRCA1/2-mutated, HER2-negative metastatic breast cancer patients. 

In the OlympiAD and EMBRACA studies, Lynparza improved patients' progression-free survival versus chemotherapy comparators, but not overall survival, de Azambuja noted. In the latest study, fuzuloparib alone and in combination with apatinib numerically improved overall survival compared to chemo, but de Azambuja pointed out that the PARP inhibitor didn't statistically significantly improve overall survival. 

While Lynparza and Talzenna are approved as monotherapies in BRCA1/2-mutated breast cancer patients, the fuzuloparib trial raises the intriguing possibility of a PARP inhibitor-VEGF combination, de Azambuja noted. 

"Is this a rebirth for VEGF combinations?" he asked hypothetically during his discussion. About 15 years ago, Genentech's VEGF inhibitor Avastin (bevacizumab) with chemo had been an option for advanced breast cancer patients based on data showing that the combination extended median progression-free survival by 5.5 months compared to just chemo. But when the combination didn't provide an overall survival advantage, the US Food and Drug Administration in 2011 controversially withdrew the breast cancer indication from the market. 

After a contentious public hearing and reviewing "thousands of pages" of data and public comments, FDA officials were not swayed that the Avastin-chemo regimen would benefit breast cancer patients more than it would harm them. 

The latest fuzuloparib-apatinib data presents the possibility of reviving the use of VEGF inhibitors in breast cancer by combining them with PARP inhibitors. Additionally, de Azambuja wondered whether this drug combination could work in patients with mutations in genes involved in homologous recombination repair other than BRCA1 and BRCA2. 

"Patients with PALB2 mutations do benefit from [Lynparza] and other PARP inhibitors, … so we should include those patients in these clinical trials," he said. 

Finally, he noted that the fuzuloparib study had a relatively small patient population, and the inclusion of only Asian patients raises questions about the generalizability of the results. 

"But we have to acknowledge that neither [Lynparza] or [Talzenna] are available in the [Asian] region, so this represents an important step forward," he said, adding that he would especially like to see the PARP inhibitor-VEGF inhibitor combination approach tested in Western populations, where only single-agent PARP inhibitors are available at the moment.