Fuzuloparib With or Without Apatinib Improves PFS in BRCA+ HER2– Breast Cancer


Treatment with fuzuloparib, either with or without apatinib, provided superior progression-free survival benefit compared with chemotherapy in HER2– metastatic breast cancer with germline BRCA1/2 mutations.

Fuzuloparib With or Without Apatinib Improves PFS in BRCA+ HER2– Breast Cancer

Fuzuloparib With or Without Apatinib Improves PFS in BRCA+ HER2– Breast Cancer

Patients with HER2-negative metastatic breast cancer harboring germline BRCA1/2 mutations treated with fuzuloparib with or without apatinib derived a superior progression-free survival (PFS) benefit compared with standard chemotherapy, according to data from a phase 3 study (NCT04296370) presented during the ESMO Virtual Plenary: May 2024.1

The median blinded independent central review (BICR)–assessed PFS with fuzuloparib plus apatinib (n = 70) was 11.0 months (95% CI, 8.4-13.1) vs 3.0 months (95% CI, 1.6-5.3) with standard chemotherapy (n = 66), translating to a 73% reduction in the risk of disease progression and death (HR, 0.27; 95% CI, 0.17-0.43; P < .0001). Single-agent fuzuloparib (n = 67) led to a median BICR-assessed PFS of 6.7 months (95% CI, 4.2-7.6) vs 3.0 months (95% CI, 1.6-5.3) with chemotherapy, equating to a 51% reduction in the risk of disease progression or death (HR, 0.49; 95% CI, 0.32-0.75; P = .0004). As such, the study met its primary objectives, according to Huiping Li, of the Key Laboratory of Carcinogenesis and Translational Research in the Department of Breast Oncology at Peking University Cancer Hospital and Institute, in Beijing, China.

Moreover, a key secondary objective was met in that fuzuloparib monotherapy also significantly improved BICR-assessed PFS vs chemotherapy, at a median of 6.7 months (95% CI, 4.2-7.6) and 3.0 months (95% CI, 1.6-5.3), respectively (HR, 0.49; 95% CI, 0.32-0.75; P = .0004).

“Taken together, our findings support the use of fuzuloparib plus apatinib or fuzuloparib alone for [patients with] HER2-negative metastatic breast cancer [and] a germline BRCA mutation,” Li said in a presentation of the data.

The randomized, open-label, multicenter, 2-part study enrolled patients with pathologically confirmed HER2-negative breast cancer and a confirmed deleterious or suspected deleterious germline BRCA1/2 mutation. They needed to have prior exposure to an anthracycline and/or a taxane but had not received more than 2 lines of prior chemotherapy regimens for recurrent or metastatic disease; they also must have received at least 1 line of endocrine therapy for hormone receptor–positive disease in the recurrent or metastatic setting. Patients were between the ages of 18 and 75 years and had an ECOG performance status of 0 or 1.

Study participants were randomly assigned 1:1:1 to fuzuloparib at 100 mg twice daily plus apatinib at 500 mg once daily or fuzuloparib at 150 mg twice daily or physician’s choice of chemotherapy in the form of capecitabine or vinorelbine in continuous 21-day cycles. Notably, patients in the chemotherapy arm were able to crossover to single-agent fuzuloparib following disease progression by BICR assessment.

Stratification factors included number of prior chemotherapy regimens for metastatic disease (0 vs ≥1), hormone receptor status (hormone receptor positive vs triple negative), and prior use of platinum-based therapy (yes vs no).

BICR-assessed PFS served as the primary end point, and secondary end points included investigator-assessed PFS, PFS-2, objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.

Data from the first part of the study indicated that fuzuloparib paired with apatinib had acceptable safety and tolerability, according to Li. During the plenary, she shared findings from the randomized second portion of the research.

The overall type I error for the study was at a 1-sided alpha of .025. “One-hundred and ninety-eight PFS events per BICR could provide 98% power to show an HR of 0.50 for the comparison between fuzuloparib plus apatinib and chemotherapy, and 85% power to show an HR of 0.60 for the comparison between fuzuloparib and chemotherapy,” Li explained. “For the comparison between fuzuloparib plus apatinib and fuzuloparib, 125 PFS events per BICR were expected, and the minimum detectable difference corresponded to a HR of 0.70.”

The interim analysis would occur when approximately 139 PFS events by BICR assessment occurred. By the data cutoff date of December 15, 2023, a total of 141 PFS events occurred and so the analysis was conducted, Li said.

A total of 203 patients underwent randomization and were included in the efficacy analyses; 70 were assigned to receive fuzuloparib plus apatinib, 67 were assigned to receive single-agent fuzuloparib, and 66 were assigned to receive standard chemotherapy. In these groups, 70, 67, and 59 of patients, respectively, received treatment and were included in the safety analyses; at the time of data cutoff, 15, 13, and 5 patients, respectively, were still receiving treatment.

The demographics and baseline characteristics were well balanced across the doublet, monotherapy, and chemotherapy arms, according to Li. The median age ranged from 47.5 years to 49.0 years. In the respective arms, 48.6%, 53.7%, and 57.6% of patients, respectively, had an ECOG performance status of 1. More than half of patients had hormone receptor–positive status (58.6%; 62.1%; 62.1%) and germline BRCA2 mutations (62.9%; 61.2%; 53.0%). Most patients across the arms previously received 1 or more lines of chemotherapy (70.0%; 74.6%; 72.7%) and had measurable disease at baseline (74.3%; 82.1%; 65.2%).

Additional data showed that the HR for PFS with fuzuloparib plus apatinib vs fuzuloparib alone was 0.60 (95% CI, 0.40-0.91; P - .0079).

Moreover, fuzuloparib with or without apatinib also demonstrated a trend toward improved OS vs standard chemotherapy, despite a crossover rate of 39.4% from chemotherapy to single-agent fuzuloparib, Li noted. The median OS was 29.2 months (95% CI, 24.6-not reached [NR]) with the doublet vs 21.5 months (95% CI, 15.6-31.9) with chemotherapy (HR, 0.58; 95% CI, 0.33-1.02). The median OS was 31.5 months (95% CI, 17.8-NR) with the monotherapy and the HR for OS with the monotherapy vs chemotherapy was 0.61 (95% CI, 0.35-1.08).

“The ORR, DCR, and median DOR were numerically improved with fuzuloparib plus apatinib or alone compared with standard chemotherapy,” Li said.

The ORRs in the doublet, monotherapy, and chemotherapy arms were 67.3% (95% CI, 52.9%-79.7%), 43.6% (95% CI, 30.3%-57.7%), and 23.3% (95% CI, 11.8%-38.6%), respectively. The respective DCRs were 87.1% (95% CI, 77.0%-93.9%), 80.6% (95% CI, 69.1%-89.2%), and 47.0% (95% CI, 34.6%-59.7%), respectively. The median DOR was 9.8 months (95% CI, 7.0-11.8) with the doublet, 7.6 months (95% CI, 5.5-14.0) with the monotherapy, and 3.9 months (95% CI, 2.6-12.5) with chemotherapy.

“The profile and severity of toxicity were consistent with previous reports of fuzuloparib and apatinib,” Li said.

Any-grade treatment-related adverse effects (TRAEs) were reported in 98.6% of those given the doublet, 92.5% of those who received the monotherapy, and 93.2% of those given chemotherapy; grade 3 or higher TRAEs occurred in 51.4%, 49.3%, and 40.7% of patients, respectively. Moreover, serious TRAEs were reported in 12.9%, 17.9%, and 13.6% of patients, respectively.

In the doublet arm, TRAEs led to dose interruption or reduction for 50.0% and 21.4% of patients, respectively, and 7.1% of patients experienced TRAEs that led to discontinuation. In the monotherapy arm, these respective rates were 37.3%, 34.3%, and 0%; in the chemotherapy arm, these rates were 37.3%, 10.2%, and 3.4%. One patient who received single-agent fuzuloparib experienced a TRAE that led to death.

The most common grade 3 or higher TRAEs reported in the fuzuloparib/apatinib, fuzuloparib, and chemotherapy arms were decreased white blood cell count (8.6%; 19.4%; 18.6%), decreased neutrophil count (12.9%; 20.9%; 23.7%), nausea (1.4%; 1.5%; 0%), anemia (11.4%; 37.3%; 8.5%), hypertension (12.9%; 0%; 0%), increased aspartate aminotransferase (4.3%; 1.5%; 5.1%), increased alanine aminotransferase (4.3%; 1.5%; 3.4%), decreased platelet count (10.0%; 11.9%; 0%), vomiting (1.4%; 1.5%; 0%), asthenia (2.9%; 0%; 0%), hypertriglyceridemia (8.6%; 1.5%; 1.7%), and Palmar-plantar erythrodysesthesia syndrome (0%; 0%; 1.7%).

Disclosures: Dr Li did not report any conflicts of interest.


Li H, Liu J, Liu Y, et al. Fuzuloparib with or without apatinib in HER2- metastatic breast cancer (mBC) patients (pts) with germline BRCA1/2 mutations (gBRCA1/2m): a randomized phase III trial. Presented at the 2024 ESMO Virtual Plenary Session; May 9, 2024. Accessed May 9, 2024.

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