Abstract
Although poly(adenosine diphosphate‐ribose) polymerase inhibitors (PARPis) and bevacizumab were approved as first‐line maintenance for advanced ovarian cancer (OC), evidence comparing this combination with PARPi monotherapy, especially in BRCA‐mutated/homologous recombination‐deficient (HRD) patients, is lacking. This study compared combined fuzuloparib (a PARPi) plus apatinib (a vascular endothelial growth factor receptor‐2 inhibitor) with either fuzuloparib or placebo as first‐line maintenance in patients with advanced OC. Patients who had newly diagnosed, advanced OC and responded to first‐line, platinum‐based chemotherapy were randomized 2:2:1 to receive combined fuzuloparib (100 mg twice daily) plus apatinib (375 mg daily), fuzuloparib (150 mg twice daily) plus placebo, or double‐placebo treatment. The primary end point was blinded independent review committee (BIRC)‐assessed progression‐free survival (PFS). Six hundred seventy‐four patients were randomized to receive fuzuloparib plus apatinib (n = 269), fuzuloparib (n = 269), or placebo (n = 136). At the final analysis (November 1, 2024; 385 BIRC‐assessed PFS events; median follow‐up, 40 months), the median BIRC‐assessed PFS was 26.9 months with the combination versus placebo (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.44–0.75; one‐sided p < .0001) and 29.9 months with fuzuloparib monotherapy versus placebo (HR, 0.58; 95% CI, 0.44–0.75; one‐sided p < .0001) compared with 11.1 months with placebo. A PFS benefit was observed regardless of germline BRCA1/2 mutation status. In homologous recombination‐deficient patients (including those with BRCA1/2 mutations), combined fuzuloparib and apatinib produced a PFS similar to that of fuzuloparib (34.1 vs. 35.8 months, respectively); in homologous recombination‐proficient patients, PFS had a trend favoring the combination (16.6 vs. 11.0 months; HR, 0.73; 95% CI, 0.45–1.19). Both treatments were well tolerated. Overall survival was immature. Both fuzuloparib and combination therapy improved PFS compared with placebo as maintenance therapy for patients who had newly diagnosed, advanced OC. Adding apatinib to fuzuloparib did not prolong PFS among homologous recombination‐deficient patients. There was a PFS benefit trend among homologous recombination‐proficient patients who received combination therapy compared with those who received monotherapy.
Keywords: clinical trials, gynecologic oncology, ovarian neoplasms, progression‐free survival
INTRODUCTION
Ovarian cancer (OC) is the most fatal gynecologic malignancy, accounting for 4.7% of cancer deaths worldwide in 2020. 1 Approximately 70% of patients with epithelial OC are diagnosed at an advanced stage. 2 , 3 Standard treatment for patients with advanced OC involves a combination of platinum‐based chemotherapy (PBC) and cytoreductive surgery. Maintenance therapy is available for patients who achieve a complete response (CR) or a partial response (PR) after first‐line treatment, with the objective of prolonging progression‐free survival (PFS) and, potentially, overall survival (OS). 4
Maintenance options typically include poly(adenosine diphosphate‐ribose) polymerase (PARP) inhibitors, bevacizumab (if bevacizumab was used in addition to PBC), or a combination of both. 4 , 5 The selection of maintenance therapy takes into consideration the patient's breast cancer gene (BRCA1/2) mutation status and homologous recombination deficiency (HRD) status. Patients with BRCA1/2 mutations or HRD may adopt single‐agent PARP inhibitor or a PARP inhibitor in combination with bevacizumab as first‐line maintenance. 4 , 5 The use of combination therapy was based on positive results from the PAOLA‐1 trial (ClinicalTrials.gov identifier NCT02477644), which compared the PARP inhibitor olaparib plus bevacizumab versus bevacizumab alone, as well as results from the single‐arm OVARIO trial (ClinicalTrials.gov identifier NCT03326193), which assessed the combination of the PARP inhibitor niraparib plus bevacizumab. 6 , 7 However, to date, there are no prospective data comparing the efficacy of a PARP inhibitor plus bevacizumab or other antiangiogenic drugs with a PARP inhibitor alone. FZOCUS‐1 (ClinicalTrials.gov identifier NCT05206890) is a randomized, double‐blind, placebo‐controlled phase 3 trial aiming to compare the efficacy and safety of fuzuloparib, a PARP inhibitor, plus apatinib, a vascular epithelial growth factor receptor‐2 inhibitor, versus fuzuloparib monotherapy or placebo as first‐line maintenance for patients with newly diagnosed, advanced OC.
Fuzuloparib is a novel, potent, and orally available PARP inhibitor that has been approved in China as treatment for platinum‐sensitive, germline BRCA1/2‐mutated, recurrent OC (objective response rate, 69.9%; median PFS, 12.0 months) and as maintenance therapy for platinum‐sensitive, recurrent OC progressing after second‐line or later PBC. 8 , 9 In the FZOCUS‐2 trial (ClinicalTrials.gov identifier NCT03863860), fuzuloparib as maintenance therapy for platinum‐sensitive, recurrent OC demonstrated a significant improvement in median PFS compared with placebo (12.9 vs. 5.5 months), regardless of germline BRCA1/2 mutation status, with an overall hazard ratio (HR) of 0.25 (95% confidence interval [CI], 0.17–0.36). 9
Apatinib is an oral vascular endothelial growth factor receptor‐2 inhibitor that has been approved in China as treatment for multiple advanced cancers. 10 , 11 , 12 , 13 In an early phase clinical trial, promising antitumor activity was observed with the combination of fuzuloparib plus apatinib in platinum‐sensitive OC, producing an objective response rate of 80% and a median PFS of 12.1 months. 14 The study also revealed a drug‐drug interaction between fuzuloparib and apatinib, which led to a dose reduction of fuzuloparib in the combination therapy group in the FZOCUS‐1 trial (150 mg in monotherapy vs. 100 mg in combination therapy). Apatinib, when combined with pegylated liposomal doxorubicin or oral etoposide, also demonstrated encouraging efficacy in OC. 15 , 16
In the current study, apatinib was selected for the combination therapy over bevacizumab. One reason is that both fuzuloparib and apatinib are given orally, thus double oral administration is more convenient than the intravenously administered bevacizumab. Moreover, although no study to date has directly compared the efficacy of apatinib versus bevacizumab, apatinib‐containing treatment studies demonstrated comparable efficacy between apatinib and bevacizumab in several clinical settings. The median PFS of the combination of apatinib plus pegylated liposomal doxorubicin in the APPROVE study (ClinicalTrials.gov identifier NCT04348032) and the combination of oral etoposide in the AEROC study (ClinicalTrials.gov identifier NCT02867956) conducted in patients with platinum‐resistant recurrent OC was 5.8 months and 8.1 months, respectively, which is similar to results from the AURELIA study (median PFS, 6.7 months; ClinicalTrials.gov identifier NCT00976911). 15 , 16 , 17 In the CARE‐310 study (ClinicalTrials.gov identifier NCT03764293) of first‐line treatment for unresectable hepatocellular carcinoma, the efficacy of apatinib combined with camrelizumab, an immune checkpoint inhibitor, was comparable to the results from the IMbrave150 study (ClinicalTrials.gov identifier NCT03434379). 12 , 18
At the interim analysis of FZOCUS‐1 (data cutoff, March 31, 2023), the primary objectives were met, demonstrating significantly prolonged PFS by a blinded independent review committee (BIRC) with fuzuloparib plus apatinib or fuzuloparib alone versus placebo. 19 Based on this interim analysis, fuzuloparib was approved in China as first‐line maintenance therapy for advanced OC. Here, we present results from the final analysis of FZOCUS‐1 after a median follow‐up of 40 months.
METHODS
Study population
Women aged 18–75 years with newly diagnosed OC, fallopian cancer, or primary peritoneal cancer were recruited. Patients were eligible if they had International Federation of Gynecology and Obstetrics stage III or IV disease, had received primary debulking surgery or neoadjuvant therapy with interval debulking surgery, had received from six to nine cycles of PBC and achieved a CR or PR, and had an Eastern Cooperative Oncology Group performance status of 0 to 1 with adequate organ function. Bevacizumab was allowed during first‐line PBC but not as maintenance therapy. Key exclusion criteria included other malignant tumors within 5 years; prior treatment with PARP inhibitors, including, but not limited to, olaparib, niraparib, and rucaparib; prior treatment with apatinib; untreated central nervous system metastases; uncontrolled heart disease or hypertension; or grade 2 or higher hemorrhage according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, within 4 weeks before randomization. The full eligibility criteria are listed in the protocol.
The protocol and all amendments were approved by the ethics committees of the study centers. The study was conducted in accordance with the Declaration of Helsinki, Guidelines for Good Clinical Practice, and local laws and regulations. All patients provided written informed consent.
Study design and interventions
This multicenter, two‐stage, phase 3 trial was conducted at 57 sites in China (ClinicalTrials.gov identifier NCT04229615). Stage 1 of the study was a safety run‐in to assess the safety of fuzuloparib in combination with apatinib (see Figure S1). Stage 2 was a randomized, double‐blind, placebo‐controlled study to assess the efficacy and safety of fuzuloparib plus apatinib or fuzuloparib alone as first‐line maintenance therapy for advanced OC. In stage 1 of the study, 16 patients were enrolled and received fuzuloparib in combination with apatinib. The combination therapy demonstrated acceptable tolerability, with 44% of patients reporting adverse events (AEs) related to the study treatment, leading to the initiation of stage 2. This report presents findings from stage 2 of the study.
No later than 12 weeks after completing the last dose of PBC, patients were randomly assigned at a 2:2:1 ratio to receive oral fuzuloparib (100 mg twice daily) plus oral apatinib (375 mg daily), oral fuzuloparib (150 mg twice daily), or matching placebo. Randomization was conducted using a centralized, interactive web response system with a block size of five and stratified by germline BRCA1/2 mutation status (presence vs. absence) and response to primary treatment (complete resection [R0] and CR vs. R1 resection and CR vs. PR regardless of surgical outcome). Patients were treated in 28‐day cycles until radiographic disease progression, intolerable toxicity, or up to 2 years of follow‐up after randomization and treatment with no evidence of disease on imaging, and a cancer antigen 125 (CA‐125) level below the upper limit of normal. Crossover was not allowed.
End points
The primary end point was PFS assessed by BIRC in the overall population and the germline BRCA1/2‐mutated subpopulation. PFS was defined as the time from randomization to disease progression according to Response Evaluation Criteria in Solid Tumors version 1.1 or death from any cause.
The secondary endpoints included PFS assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1, OS, best overall response, time to progression, time to study treatment discontinuation or death, time to first subsequent therapy or death, time to second progression (PFS‐2), and chemotherapy‐free interval as well as safety, tolerability, and patient‐reported outcomes (PROs). The association between PFS and patient's HRD status was also explored.
Assessments
Tumor response was assessed with computed tomography or magnetic resonance imaging performed every 12 weeks for the first 30 cycles after randomization and every 24 weeks thereafter until confirmed disease progression, death, consent withdrawal, initiation of new anticancer therapy, or study completion. A CR or PR was confirmed during the next planned assessment or from 4 to 6 weeks after the first response. CA‐125 levels were tested every three cycles during the treatment period. Upon treatment discontinuation, patients who did not progress underwent radiographic assessment and a CA‐125 test once every 3 months until radiologic disease progression or initiation of other anticancer therapy. Survival follow‐up was conducted every 2 months until death, loss to follow‐up, or study completion.
Peripheral whole blood and tumor tissue samples were collected at screening for biomarker testing, including germline BRCA1/2 mutation testing, at the central laboratory. HRD status was assessed using the Precision Human HRD Assay panel (Precision Scientific). Positive HRD status was defined as an HRD score ≥42 or the presence of germline or somatic BRCA1/2 mutation.
PRO were assessed using the Functional Ovarian Symptom Index (FOSI) and the European Quality of Life Scale 5‐Dimensions, 5‐Level (EQ‐5D‐5L) questionnaires every 12 weeks for the first 30 cycles and every 24 weeks thereafter. Safety was assessed by AEs, laboratory tests, physical examinations, vital signs, 12‐lead electrocardiogram, and echocardiogram. AEs were monitored throughout the study and were graded according to CTCAE version 5.0.
Statistical analysis
A sample size of 660 patients (with an expected germline BRCA1/2 mutation rate of 35%) targeting 446 PFS events was required to detect superiority of fuzuloparib with or without apatinib over placebo using a log‐rank test with adequate power at an overall one‐sided α of .025. Specifically, in the BRCA1/2‐mutated subpopulation, the median PFS was assumed to be 12 months among placebo‐treated patients, and the HR was assumed to be 0.45 for fuzuloparib versus placebo and 0.4 for fuzuloparib plus apatinib versus placebo. In the overall population, it was assumed that the median PFS was 12 months among placebo‐treated patients, and the HR was 0.50 between fuzuloparib plus apatinib and placebo, 0.67 between fuzuloparib and placebo, and 0.75 between the combination therapy and fuzuloparib monotherapy. In the BRCA1/2 wild‐type subpopulation, the HR between the combination therapy and monotherapy groups was simulated to be 0.685. The efficacy boundaries were calculated using the Lan–DeMets (O'Brien–Fleming) α spending function. In total, 446 PFS events in the overall population and 138 PFS events in the BRCA1/2‐mutated subpopulation were required to detect: (1) superiority of fuzuloparib over placebo in the BRCA1/2‐mutated subpopulation at a one‐sided α of .005 with 83% power; (2) superiority of fuzuloparib over placebo in the overall population at a one‐sided α of .02 with 87% power; and (3) other hypotheses (see Figure S2). Assuming an enrollment period of 14 months, a study duration of 45 months, and an estimated dropout rate of 10%, at least 660 patients were required.
Efficacy was analyzed in the intention‐to‐treat population, safety was analyzed in the as‐treated population, and PROs were analyzed in those who had baseline and postbaseline data from the FOSI or EQ‐5D‐5L questionnaire. BIRC‐assessed PFS was estimated using the Kaplan–Meier method, with 95% CIs estimated using the Brookmeyer–Crowley method. Comparisons of PFS between groups in the overall population, the BRCA1/2‐mutated subpopulation, and the BRCA1/2 wild‐type subpopulation were done using a stratified log‐rank test. The HRs for BIRC‐assessed PFS were estimated with a Cox proportional hazards model stratified by randomization strata. BIRC‐assessed PFS was further analyzed among subgroups in which HRs and 95% CIs were estimated using an unstratified Cox model. Investigator‐assessed PFS, OS, time to progression, time to first subsequent therapy or death, time to study treatment discontinuation or death, time to second progression, and chemotherapy‐free interval were analyzed using similar methods. Safety outcomes were descriptively summarized. Changes in FOSI and EQ‐5D‐5L scores from baseline were analyzed using mixed‐effects model repeated measures, providing the least squares mean in each treatment group and the between‐group differences.
The protocol specified conducting a final analysis when the targeted PFS events were collected or when the last enrolled patient had completed 31 months of follow‐up, whichever occurred first. As of November 1, 2024, 385 BIRC‐assessed PFS events had occurred, and the last patient had completed 31 months of follow‐up, which met the criteria for a final analysis. Data analyses were performed using SAS software version 9.4 (SAS Institute, Inc.).
RESULTS
Patients
Between August 27, 2020, and April 1, 2022, 674 patients were enrolled and randomized to the fuzuloparib plus apatinib group (n = 269), the fuzuloparib group (n = 269), or the placebo group (n = 136). All patients had received at least one dose of the study treatment as assigned. As of the data cutoff date (November 1, 2024) for the final analysis, the median follow‐up from randomization to data cutoff date was 40.1 months (range, 31.1–50.0 months), 40.1 months (range, 31.1–50.2 months), and 39.9 months (range, 31.1–49.4 months) in the three groups, respectively. In total, 657 patients (97.5%) had discontinued study treatment, mainly because of radiographic progression and completion of up to 2 years of follow‐up (see Figure S3).
Demographics and baseline characteristics were generally balanced among treatment groups (Table 1). The median age was 54 years (range, 29–75 years). Among all patients, 212 (31.5%) had germline BRCA1/2 mutations, 486 (72.1%) were HRD‐positive (including those with germline or somatic BRCA1/2 mutations), and 118 (17.5%) were HRD‐negative or homologous recombination proficient (HRP); 385 patients (57.1%) had undergone primary debulking surgery, and 375 (55.6%) had achieved R0 resection after cytoreduction.
TABLE 1.
Demographics and baseline characteristics.
| Fuzuloparib + apatinib, N = 269 | Fuzuloparib, N = 269 | Placebo, N = 136 | |
|---|---|---|---|
| Age: Median [range], years | 54 [31–73] | 54 [29–73] | 54 [32–75] |
| Age, years | |||
| ≤65 | 237 (88.1) | 247 (91.8) | 120 (88.2) |
| >65 | 32 (11.9) | 22 (8.2) | 16 (11.8) |
| FIGO stage | |||
| III | 218 (81.0) | 212 (78.8) | 112 (82.4) |
| IV | 51 (19.0) | 57 (21.2) | 24 (17.6) |
| ECOG performance status | |||
| 0 | 151 (56.1) | 151 (56.1) | 79 (58.1) |
| 1 | 118 (43.9) | 118 (43.9) | 56 (41.2) |
| gBRCA1/2 mutation | |||
| Present | 85 (31.6) | 84 (31.2) | 43 (31.6) |
| Absent | 184 (68.4) | 185 (68.8) | 93 (68.4) |
| Tumor HRD status | |||
| Positive, including gBRCA1/2 or tBRCA1/2 mutations | 194 (72.1) | 201 (74.7) | 91 (66.9) |
| Negative | 47 (17.5) | 41 (15.2) | 30 (22.1) |
| Unknown | 28 (10.4) | 27 (10.0) | 15 (11.0) |
| Neoadjuvant therapy | |||
| Yes | 120 (44.6) | 112 (41.6) | 57 (41.9) |
| No | 149 (55.4) | 157 (58.4) | 79 (58.1) |
| Cytoreductive surgery type | |||
| Primary | 149 (55.4) | 157 (58.4) | 79 (58.1) |
| Interval | 120 (44.6) | 112 (41.6) | 57 (41.9) |
| Cytoreductive surgery outcome | |||
| R1/R2 | 119 (44.2) | 118 (43.9) | 62 (45.6) |
| R0 | 150 (55.8) | 151 (56.1) | 74 (54.4) |
| No. of cycles of first‐line PBC | |||
| 6 | 145 (53.9) | 140 (52.0) | 79 (58.1) |
| 7–9 | 123 (45.7) | 127 (47.2) | 57 (41.9) |
| Bevacizumab during chemotherapy | |||
| Yes | 18 (6.7) | 21 (7.8) | 6 (4.4) |
| No | 251 (93.3) | 248 (92.2) | 130 (95.6) |
| Time from last chemotherapy to randomization | |||
| 4–8 weeks | 134 (49.8) | 130 (48.3) | 70 (51.5) |
| From >8 to ≤12 weeks | 135 (50.2) | 139 (51.7) | 64 (47.1) |
| Response to surgery and first‐line PBC | |||
| No evidence of disease a | 74 (27.5) | 74 (27.5) | 37 (27.2) |
| CR | 145 (53.9) | 143 (53.2) | 73 (53.7) |
| PR | 50 (18.6) | 52 (19.3) | 26 (19.1) |
Note: Data are shown as the number (%) unless otherwise specified.
Abbreviations: CR, complete response; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; gBRCA1/2, germline breast cancer susceptibility gene 1 or 2; HRD, homologous recombination deficiency; PBC, platinum‐based chemotherapy; PR, partial response; R0, absence of gross residual disease; R1, residual disease <1 cm; R2, residual disease ≥1 cm; tBRCA1/2, tumor breast cancer susceptibility gene 1 or 2.
No evidence of disease refers to achieving R0 resection after cytoreduction and a CR after PBC.
Efficacy
As of November 1, 2024, 385 (57.1%) BIRC‐assessed PFS events were observed in the overall population, including 150 (55.8%) in the fuzuloparib plus apatinib group, 144 (53.5%) in the fuzuloparib group, and 91 (66.9%) in the placebo group. The median PFS was 26.9 months (95% CI, 20.3–36.6 months) with fuzuloparib plus apatinib, 29.9 months (95% CI, 22.1–36.1 months) with fuzuloparib, and 11.1 months (95% CI, 8.3–16.6 months) with placebo (Figure 1). The HR versus placebo was 0.57 (95% CI, 0.44–0.75; one‐sided p < .0001) for combination therapy recipients and 0.58 (95% CI, 0.44–0.75; one‐sided p < .0001) for monotherapy recipients.
FIGURE 1.
Progression‐free survival assessed by a blinded independent review committee in the overall population. Tick marks indicate the time points at which data were censored. CI indicates confidence interval; HR, hazard ratio; PFS, progression‐free survival.
BIRC‐assessed PFS with fuzuloparib plus apatinib or fuzuloparib alone was noted regardless of germline BRCA1/2 mutation status. Among germline BRCA1/2‐mutated patients, the HR was 0.50 (95% CI, 0.30–0.84; one‐sided p = .0039) for fuzuloparib plus apatinib versus placebo and 0.51 (95% CI, 0.30–0.86; one‐side p = .0050) for fuzuloparib versus placebo (Figure 2A). Among germline BRCA1/2 wild‐type patients, the HR was 0.61 (95% CI, 0.45–0.83; one‐sided p = 0.0009) for fuzuloparib plus apatinib versus placebo and 0.60 (95% CI, 0.44–0.82; one‐sided p = .0006) for fuzuloparib versus placebo (Figure 2B). The PFS benefits over placebo were generally consistent across clinically relevant subgroups (see Figure S4). The investigator‐assessed PFS, as well as other efficacy end points, indicated similar trends in favor of fuzuloparib plus apatinib or fuzuloparib over placebo (see Table S1).
FIGURE 2.
Progression‐free survival assessed by a blinded independent review committee in (A) the germline BRCA1/2‐mutated subpopulation and (B) the germline BRCA1/2 wild‐type subpopulation. Tick marks indicate the time points at which data were censored. CI indicates confidence interval; HR, hazard ratio; NR, not reached; PFS, progression‐free survival.
Compared with fuzuloparib monotherapy, combination therapy did not result in additional PFS benefits in the overall population (HR, 1.04; 95% CI, 0.83–1.32; one‐sided p = .6393) or the germline BRCA1/2‐mutated subpopulation (HR, 1.11; 95% CI, 0.69–1.79; one‐sided p = .6667). Similar findings were noted in the patients with HRD disease (including those with germline or somatic BRCA1/2 mutations), among whom the median PFS was 34.1 months (95% CI, 22.4–41.2 months) in the fuzuloparib plus apatinib group compared with 35.8 months (95% CI, 27.3 to not reached) in the fuzuloparib group (HR, 1.09; 95% CI, 0.83–1.44; Figure 3A). In those with HRP disease, the median PFS was 16.6 months (95% CI, 10.2–22.1 months) with fuzuloparib plus apatinib and 11.0 months (95% CI, 6.5–16.6 months) with fuzuloparib alone. The HR between fuzuloparib plus apatinib versus fuzuloparib was 0.73 (95% CI, 0.45–1.19), suggesting a PFS trend in favor of combination therapy among patients with HRP disease (Figure 3B).
FIGURE 3.
Progression‐free survival assessed by a blinded independent review committee in (A) the HRD subgroup and (B) the HRP subgroup. Tick marks indicate the time points at which data were censored. CI indicates confidence interval; HR, hazard ratio; HRD, homologous recombination deficiency; HRP, homologous recombination proficient; NR, not reached; PFS, progression‐free survival.
In total, 168 deaths (24.9%) were observed, including 68 (25.3%), 68 (25.3%), and 32 (23.5%) in the fuzuloparib plus apatinib, fuzuloparib, and placebo groups, respectively. The median OS was not reached in all three groups. The 36‐month survival rate was 78.9% (95% CI, 73.3%–83.4%) with combination therapy, 77.0% (95% CI, 71.3%–81.7%) with fuzuloparib, and 76.6% (95% CI, 68.2%–83.0%) with placebo (Table 2). PRO results indicated increasing trends in FOSI and EQ‐5D‐5L scores over time with fuzuloparib plus apatinib and fuzuloparib treatment, although the overall changes from baseline were not significant (see Figure S5).
TABLE 2.
Overall survival.
| Fuzuloparib + apatinib, N = 269 | Fuzuloparib, N = 269 | Placebo, N = 136 | |
|---|---|---|---|
| Events, no. (%) | 68 (25.3) | 68 (25.3) | 32 (23.5) |
| 12‐month survival rate [95% CI], % | 98.5 [96.1–99.4] | 98.5 [96.1–99.4] | 97.8 [93.2–99.3] |
| 24‐month survival rate [95% CI], % | 89.3 [84.9–92.5] | 89.9 [85.6–92.9] | 87.9 [81.1–92.4] |
| 36‐month survival rate [95% CI], % | 78.9 [73.3–83.4] | 77.0 [71.3–81.7) | 76.6 [68.2–83.0] |
| Median OS, months | NR | NR | NR |
Abbreviations: CI, confidence interval; NR, not reached; OS, overall survival.
Safety
The median treatment duration was 23.9 months (range, 0.1–49.7 months) in the fuzuloparib group and 14.6 months (range, 0.03–39.6 months) in the placebo group. In the combination group, the median treatment duration with fuzuloparib was 23.7 months (range, 0.2–50.0 months), and with apatinib, it was 18.3 months (range, 0.2–50.0 months). The median relative dose intensity of fuzuloparib was 95.8% in the combination group and 95.1% in the fuzuloparib group. The median relative dose intensity of apatinib was 96.1% in the combination group.
There were 263 (97.8%), 266 (98.9%), and 128 (94.1%) patients in the fuzuloparib plus apatinib, fuzuloparib, and placebo groups who experienced AEs related to any of the study treatment (treatment‐related AEs [TRAEs]), among whom 131 (48.7%), 123 (45.7%), and 10 (7.4%) patients, respectively, had TRAEs of CTCAE grade 3 or higher (Table 3). Most grade 3 or higher TRAEs were hematologic toxicities. The most common (≥10%) grade 3 or higher TRAEs in the fuzuloparib plus apatinib group were anemia and hypertension, whereas those in the fuzuloparib group were anemia, decreased platelet count, and decreased neutrophil count (Table 4). The incidence of hypertension was higher among patients who received combination therapy than among those who received fuzuloparib alone (10.4% vs. 0.4%).
TABLE 3.
Safety summary.
| Fuzuloparib + apatinib, N = 269 | Fuzuloparib, N = 269 | Placebo, N = 136 | |
|---|---|---|---|
| Any TRAE a | 263 (97.8) | 266 (98.9) | 128 (94.1) |
| Related to fuzuloparib/placebo | 262 (97.4) | 265 (98.5) | 128 (94.1) |
| Related to apatinib/placebo | 263 (97.8) | 266 (98.9) | 128 (94.1) |
| Grade ≥3 TRAE | 131 (48.7) | 123 (45.7) | 10 (7.4) |
| Related to fuzuloparib/placebo | 123 (45.7) | 122 (45.4) | 9 (6.6) |
| Related to apatinib/placebo | 129 (48.0) | 123 (45.7) | 10 (7.4) |
| Serious TRAE | 39 (14.5) | 37 (13.8) | 0 (0.0) |
| Related to fuzuloparib/placebo | 37 (13.8) | 35 (13.0) | 0 (0.0) |
| Related to apatinib/placebo | 39 (14.5) | 34 (12.6) | 0 (0.0) |
| TRAE leading to any dose reduction or treatment interruption | 155 (57.6) | 154 (57.2) | 20 (14.7) |
| Related to fuzuloparib/placebo | 146 (54.3) | 151 (56.1) | 18 (13.2) |
| Related to apatinib/placebo | 154 (57.2) | 153 (56.9) | 20 (14.7) |
| TRAE leading to any treatment discontinuation | 39 (14.5) | 24 (8.9) | 0 (0.0) |
| Leading to fuzuloparib/placebo discontinuation | 6 (2.2) | 3 (1.1) | 0 (0.0) |
| Leading to apatinib/placebo discontinuation | 39 (14.5) | 24 (8.9) | 0 (0.0) |
| TRAE leading to death | 0 (0.0) | 1 (0.4) | 0 (0.0) |
| Related to fuzuloparib/placebo | 0 (0.0) | 1 (0.4) | 0 (0.0) |
| Related to apatinib/placebo | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Note: Data are shown as the number (%).
Abbreviation: TRAE, treatment‐related adverse event.
TRAE refers to adverse event related to any of the treatments with fuzuloparib, apatinib, or matching placebo.
TABLE 4.
Common treatment‐related adverse events. a
| Fuzuloparib + apatinib, N = 269 | Fuzuloparib, N = 269 | Placebo, N = 136 | ||||
|---|---|---|---|---|---|---|
| Any grade | Grade ≥3 | Any grade | Grade ≥3 | Any grade | Grade ≥3 | |
| Decreased white blood cell count | 158 (58.7) | 13 (4.8) | 185 (68.8) | 25 (9.3) | 37 (27.2) | 1 (0.7) |
| Anemia | 125 (46.5) | 29 (10.8) | 159 (59.1) | 64 (23.8) | 24 (17.6) | 1 (0.7) |
| Decreased neutrophil count | 137 (50.9) | 26 (9.7) | 151 (56.1) | 31 (11.5) | 36 (26.5) | 2 (1.5) |
| Decreased platelet count | 134 (49.8) | 22 (8.2) | 139 (51.7) | 34 (12.6) | 20 (14.7) | 0 (0.0) |
| Nausea | 88 (32.7) | 0 (0.0) | 100 (37.2) | 0 (0.0) | 11 (8.1) | 0 (0.0) |
| Decreased lymphocyte count | 65 (24.2) | 8 (3.0) | 86 (32.0) | 20 (7.4) | 14 (10.3) | 0 (0.0) |
| Increased blood creatinine | 63 (23.4) | 1 (0.4) | 81 (30.1) | 0 (0.0) | 10 (7.4) | 0 (0.0) |
| Increased alanine aminotransferase | 79 (29.4) | 7 (2.6) | 74 (27.5) | 4 (1.5) | 37 (27.2) | 0 (0.0) |
| Increased aspartate aminotransferase | 90 (33.5) | 5 (1.9) | 67 (24.9) | 2 (0.7) | 28 (20.6) | 0 (0.0) |
| Hypertriglyceridemia | 95 (35.3) | 21 (7.8) | 64 (23.8) | 7 (2.6) | 23 (16.9) | 2 (1.5) |
| Urinary tract infection | 44 (16.4) | 1 (0.4) | 54 (20.1) | 1 (0.4) | 20 (14.7) | 0 (0.0) |
| Hypercholesterolemia | 72 (26.8) | 1 (0.4) | 53 (19.7) | 0 (0.0) | 18 (13.2) | 0 (0.0) |
| Hyperglycemia | 63 (23.4) | 1 (0.4) | 43 (16.0) | 0 (0.0) | 11 (8.1) | 0 (0.0) |
| Asthenia | 55 (20.4) | 1 (0.4) | 40 (14.9) | 0 (0.0) | 12 (8.8) | 0 (0.0) |
| Hypertension | 92 (34.2) | 28 (10.4) | 17 (6.3) | 1 (0.4) | 8 (5.9) | 1 (0.7) |
| Hypothyroidism | 0 (0.0) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Autoimmune thyroiditis | 0 (0.0) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Hyperparathyroidism | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Hyperthyroidism | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.7) | 0 (0.0) |
Note: Data are shown as the number (%).
Treatment‐related adverse events of any grade occurring in ≥20% of patients are listed.
Serious TRAEs were reported by 39 (14.5%), 37 (13.8%), and zero (0%) patients in the three groups, respectively. In the combination group, 39 patients (14.5%) discontinued fuzuloparib and/or apatinib because of TRAEs. In the fuzuloparib group, 24 patients (8.9%) discontinued study treatment, of whom three (1.1%) discontinued fuzuloparib and 24 (8.9%) discontinued apatinib placebo.
DISCUSSION
PARP inhibitors and antiangiogenic agents play crucial roles in first‐line maintenance therapy for patients with advanced OC. However, it remains to be determined which patients benefit most from combination therapy based on differential biomarker status. In the FZOCUS‐1 trial, 674 patients were enrolled and randomized at a 2:2:1 ratio to receive fuzuloparib plus apatinib, fuzuloparib monotherapy, or matching placebo, with germline BRCA1/2 mutation and HRD status assessed. In the current study, we evaluated the efficacy and safety of fuzuloparib, with or without apatinib, as maintenance therapy in patients with newly diagnosed, advanced OC who achieved a CR or PR to first‐line chemotherapy.
Compared with placebo, fuzuloparib monotherapy prolonged PFS in the BRCA1/2‐mutated subgroup (HR, 0.51; 95% CI, 0.30–0.86) and the BRCA1/2 wild‐type subgroup (HR, 0.60; 95% CI, 0.44–0.82). These findings are consistent with those reported for other PARP inhibitors, such as olaparib, niraparib, rucaparib, and senaparib, as first‐line maintenance monotherapy, which produced HRs ranging from 0.33 to 0.46 in the BRCA‐mutated population and from 0.43 to 0.65 in the BRCA1/2 wild‐type population. 20 , 21 , 22 , 23 , 24 Fuzuloparib was approved in China as first‐line maintenance therapy for advanced ovarian cancer regardless of BRCA mutation status in May 2024. In the HRP subgroup, the median PFS was 11.0 months with fuzuloparib monotherapy versus 5.5 months with placebo (HR, 0.68; 95% CI, 0.40–1.15). Results from the PRIMA, PRIME, ATHENA‐MONO, and FLAMES trials (ClinicalTrials.gov identifiers NCT02655016, NCT03709316, NCT03522246, and NCT04169997, respectively) consistently demonstrated HRs ranging from 0.41 to 0.74 with the aforementioned PARP inhibitors compared with placebo in HRP populations. 21 , 22 , 23 , 24 HRs in the PRIMA, PRIME, and ATHENA‐MONO trials had 95% CIs below 1.0, whereas the FLAMES and FZOCUS‐1 trials had 95% CIs overlapping 1.0. Notably, the two latter studies both enrolled limited proportions of patients with HRP disease (27.5% in FLAMES and 17.5% in FZOCUS‐1, excluding unknown homologous recombination status), highlighting the need to further evaluate the efficacy of PARP inhibitors as first‐line maintenance therapy in those with HRP, advanced OC.
The use of combination therapy was based on evidence from the PAOLA‐1 trial, which compared olaparib plus bevacizumab versus bevacizumab alone, and from the single‐arm OVARIO study. 6 , 7 To our knowledge, FZOCUS‐1 was the first study to compare the efficacy of a PARP inhibitor plus an antiangiogenic agent with the efficacy of a PARP inhibitor as first‐line maintenance treatment for advanced OC. In the FZOCUS‐1 trial, the combination of fuzuloparib plus apatinib resulted in a median PFS of 26.9 months in the overall population, which is comparable to the 22.1 months observed with olaparib plus bevacizumab in PAOLA‐1 and the 19.6 months with niraparib plus bevacizumab in OVARIO. 6 , 7 A direct comparison between fuzuloparib plus apatinib and fuzuloparib monotherapy revealed no additional PFS benefit from the combination therapy in the HRD subgroup (including germline or somatic BRCA1/2‐mutated patients), with median PFS of 34.1 versus 35.8 months (HR 1.09; 95% CI, 0.83–1.44). These results suggest that combining an antiangiogenic agent (in this case, apatinib) with the PARP inhibitor fuzuloparib does not improve efficacy in patients with HRD OC, including those with germline or somatic BRCA1/2 mutations. Further data are anticipated from the AGO‐OVAR 28, NIRVANA‐1, and NRG‐GY036 trials (ClinicalTrials.gov identifiers NCT05009082, NCT‐05183984, and NCT06580314, respectively), which are directly comparing niraparib or olaparib plus bevacizumab versus niraparib or olaparib monotherapy. 25 , 26 , 27
For patients with HRP OC, bevacizumab remains a first‐line maintenance option, as evidenced by the PAOLA‐1 trial, which demonstrated no significant difference in PFS between a PARP inhibitor plus bevacizumab and bevacizumab alone within an HRP subpopulation. 6 In contrast, FZOCUS‐1 suggested a numerical trend toward improved PFS with the combination therapy of fuzuloparib plus apatinib over fuzuloparib monotherapy in patients with HRP OC, extending the median PFS by 5.6 months (16.6 vs. 11.0 months), with an HR of 0.73 (95% CI, 0.45–1.19). Although the 95% CI overlaps 1.0, it is worth noting that the FZOCUS‐1 study enrolled a rather small HRP subgroup (17.5%), which largely limited our ability to detect a statistically significant difference in the HRP population and resulted in a wide 95% CI.
This potential benefit trend in HRP patients aligns with the mechanisms of PARP inhibitors and antiangiogenic agents. PARP inhibitor monotherapy, by exploiting deficient DNA repair through synthetic lethality, works best in HRD tumors. HRP tumors, conversely, are inherently resistant to PARP inhibitor monotherapy because of intact DNA repair. Antiangiogenic agents disrupt tumor angiogenesis by inducing hypoxia and affecting homologous recombination repair. Thus the addition of an antiangiogenic agent may restore sensitivity of HRP tumors to PARP inhibitors, leading to enhanced antitumor activity with combination therapy compared with monotherapy. Because the HRP subpopulation is associated with a poorer prognosis compared with the HRD subpopulation, further exploration of novel maintenance strategies in the HRP population remains warranted. It should be pointed out that patients in our combination group did not receive apatinib during chemotherapy. Whether the combination of apatinib during chemotherapy and continued use during the maintenance phase can provide greater benefits to patients with HRP OC remains to be studied.
There were two main reasons for using apatinib instead of bevacizumab in the current study. First, the efficacy of apatinib combined with chemotherapy in OC is comparable to that of bevacizumab, as mentioned in the beginning of this article. Second, both apatinib and fuzuloparib are administered orally, which is convenient and suitable for maintenance therapy. Another reason for not using bevacizumab during maintenance therapy was to evaluate whether patients, especially those with HRD OC who received bevacizumab during chemotherapy, could still benefit from maintenance with only a PARP inhibitor. Only 45 patients (6.7%) received bevacizumab during chemotherapy in the intention‐to‐treat population.
The OS data from the FZOCUS‐1 trial were not mature at the time of the current analysis, with only 24.9% of events having occurred. The available data demonstrated comparable 3‐year OS rates between the combination and fuzuloparib monotherapy arms (78.9% vs. 77.0%, respectively) in the intention‐to‐treat population. The reported results are still based on early data. With PARP inhibitors developed over time, leading to approvals and withdrawals, longer term data are necessary to more definitively address these issues. The FZOCUS‐1 trial is ongoing, and the updated OS data will be reported when available.
It is worth noting that the dosage of fuzuloparib was reduced in the combination regimen (100 mg) compared with the single‐agent regimen (150 mg) because an early phase study had indicated a drug‐drug interaction between fuzuloparib and apatinib. Specifically, when used as combination therapy, the exposure of apatinib at steady state was reduced by 48% to 65% compared with apatinib used as monotherapy, whereas the pharmacokinetics profile of fuzuloparib was generally unaffected by apatinib dosing. 14 Consequently, the dosage of fuzuloparib was adjusted to ensure an effective and meaningful level of apatinib plasma concentration in the combination regimen. Regarding safety, the incidence of grade 3 or higher fuzuloparib‐related AEs was comparable between the two intervention groups. Apatinib‐related AEs, such as hypertension and proteinuria, were more frequent in the combination group.
The AE profile of fuzuloparib monotherapy was in line with the safety data reported in previous fuzuloparib trials. 8 , 9 TRAEs of grade 3 or higher were mainly hematological toxicities. Anemia, neutropenia, and thrombocytopenia were common AEs associated with PARP inhibitors. 28 , 29 The incidence of hypertension and proteinuria was higher in the fuzuloparib plus apatnib group than the fuzuloparib group, which can be attributed to the addition of apatinib. 11 , 30
TRAEs led to fuzuloparib and/or apatinib discontinuation in 14.5% of patients in the combination group and led to fuzuloparib discontinuation in 1.1% of patients in the monotherapy group. The higher incidence of treatment discontinuation with fuzuloparib plus apatinib could be one reason why the combination therapy resulted in similar PFS as the monotherapy. There was no grade 3 or higher nausea or vomiting reported during the study because of the pattern of postprandial administration and the high bioavailability of fuzuloparib.
The FZOCUS‐1 trial compared fuzuloparib plus apatinib with fuzuloparib as first‐line maintenance therapy for advanced OC. At the time of protocol development (September 2019), neither PARP inhibitors nor bevacizumab were approved in China as first‐line maintenance therapy for advanced OC. Nevertheless, the study adopted a 2:2:1 randomization ratio to ensure that fewer patients (approximately 20%) received placebo treatment. The dual oral administration of fuzuloparib and apatinib was more convenient in clinical practice. The limitation of this study was the relatively short follow‐up duration, such that OS data are currently immature. Furthermore, this study only enrolled Chinese patients, which may limit generalizability of the findings.
CONCLUSION
In conclusion, at this final PFS analysis, fuzuloparib improved PFS compared with placebo as maintenance therapy for patients with newly diagnosed, advanced OC after a response to first‐line PBC. To our knowledge, this study is the first to indicate that the addition of an antiangiogenic agent (in this case, apatinib) to a PARP inhibitor (in this case, fuzuloparib) does not improve PFS among patients who have BRCA‐mutated or HRD OC.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Supporting information
Supporting Information S1
AUTHOR CONTRIBUTIONS
Lingying Wu: Conceptualization; methodology; data acquisition, recruitment, analysis, and interpretation; writing. Jing Wang: Methodology; data acquisition, recruitment, and interpretation. Qingshui Li: Methodology; data acquisition and recruitment; interpretation. Danbo Wang: Data acquisition and recruitment. Cuiying Zhang: Data acquisition and recruitment. Junying Tang: Data acquisition and recruitment. Guonan Zhang: Data acquisition and recruitment. Min Hao: Data acquisition and recruitment. Desheng Yao: Data acquisition and recruitment. Qinglei Gao: Data acquisition and recruitment. Youzhong Zhang: Data acquisition and recruitment. Ruifang An: Data acquisition and recruitment. Rutie Yin: Data acquisition and recruitment. Li Wang: Data acquisition and recruitment. Bairong Xia: Data acquisition and recruitment. Qi Zhou: Data acquisition and recruitment. Hongying Yang: Data acquisition and recruitment. Jianqing Zhu: Data acquisition and recruitment. Kui Jiang: Data acquisition and recruitment. Zhengzheng Chen: Data acquisition and recruitment. Qiang Wu: Data acquisition and recruitment. Wei Duan: Data acquisition and recruitment. Yi Huang: Data acquisition and recruitment. Hui Zhang: Data acquisition and recruitment. Shuqing Wei: Data acquisition and recruitment. Guiling Li: Data acquisition and recruitment. Yuanguang Meng: Data acquisition and recruitment. Ke Wang: Data acquisition and recruitment. Xinfeng Yang (Jiangxi Cancer Hospital): Data acquisition and recruitment. Xianghua Huang: Data acquisition and recruitment. Lingya Pan: Data acquisition and recruitment. Jinjin Yu: Data acquisition and recruitment. Ge Lou: Data acquisition and recruitment. Yu Zhang: Data acquisition and recruitment. Huaijun Zhou: Data acquisition and recruitment. Xiaoqing Guo: Data acquisition and recruitment. Hong Yang: Data acquisition and recruitment. Xiaodong Cheng: Data acquisition and recruitment. Xiumin Li: Data acquisition and recruitment. Wuliang Wang: Data acquisition and recruitment. Hongqin Zhao: Data acquisition and recruitment. Yunxia Li: Data acquisition and recruitment. Yingjie Yang: Data acquisition and recruitment. An Lin: Data acquisition and recruitment. Wenjun Cheng: Data acquisition and recruitment. Lihong Chen: Data acquisition and recruitment. Xiaoying Xie: Data acquisition and recruitment. Wen Di: Data acquisition and recruitment. Yuanjing Hu: Data acquisition and recruitment. Mo Chen: Data acquisition and recruitment. Hongwu Wen: Data acquisition and recruitment. Liping Cai: Data acquisition and recruitment. Xiaohua Wu: Data acquisition and recruitment. Zhongqiu Lin: Data acquisition and recruitment. Quanren Wang: Methodology. Xinfeng Yang (Jiangsu Hengrui Pharmaceuticals): Data Analysis. Ning Li: Conceptualization; methodology; data acquisition, recruitment, analysis, and interpretation; writing. All authors participated in reviewing and editing the final writing.
ACKNOWLEDGMENTS
We are grateful to all participants and their families, the investigators, and the site staff.
Wu L, Wang J, Li Q, et al. Fuzuloparib with or without apatinib as maintenance therapy in newly diagnosed, advanced ovarian cancer (FZOCUS‐1): A multicenter, randomized, double‐blind, placebo‐controlled phase 3 trial. CA Cancer J Clin. 2026;e70042. doi: 10.3322/caac.70042
The first three authors contributed equally to this article.
Contributor Information
Lingying Wu, Email: wulingying@csco.org.cn.
Ning Li, Email: liningnci@126.com.
REFERENCES
- 1. Webb PM, Jordan SJ. Global epidemiology of epithelial ovarian cancer. Nat Rev Clin Oncol. 2024;21(5):389‐400. doi: 10.1038/s41571-024-00881-3 [DOI] [PubMed] [Google Scholar]
- 2. Cannistra SA. Cancer of the ovary. N Engl J Med. 2004;351(24):2519‐2529. doi: 10.1056/nejmra041842 [DOI] [PubMed] [Google Scholar]
- 3. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393(10177):1240‐1253. doi: 10.1016/s0140-6736(18)32552-2 [DOI] [PubMed] [Google Scholar]
- 4. Gaillard S, Lacchetti C, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: ASCO guideline update. J Clin Oncol. 2025;43(7):868‐891. doi: 10.1200/jco-24-02589 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. González‐Martín A, Harter P, Leary A, et al. Newly diagnosed and relapsed epithelial ovarian cancer: ESMO clinical practice guideline for diagnosis, treatment and follow‐up. Ann Oncol. 2023;34(10):833‐848. doi: 10.1016/j.annonc.2023.07.011 [DOI] [PubMed] [Google Scholar]
- 6. Ray‐Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first‐line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416‐2428. doi: 10.1056/nejmoa1911361 [DOI] [PubMed] [Google Scholar]
- 7. Hardesty MM, Krivak TC, Wright GS, et al. OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first‐line platinum‐based chemotherapy with bevacizumab. Gynecol Oncol. 2022;166(2):219‐229. doi: 10.1016/j.ygyno.2022.05.020 [DOI] [PubMed] [Google Scholar]
- 8. Li N, Bu H, Liu J, et al. An open‐label, multicenter, single‐arm, phase II study of fluzoparib in patients with germline BRCA1/2 mutation and platinum‐sensitive recurrent ovarian cancer. Clin Cancer Res. 2021;27(9):2452‐2458. doi: 10.1158/1078-0432.ccr-20-3546 [DOI] [PubMed] [Google Scholar]
- 9. Li N, Zhang Y, Wang J, et al. Fuzuloparib maintenance therapy in patients with platinum‐sensitive, recurrent ovarian carcinoma (FZOCUS‐2): a multicenter, randomized, double‐blind, placebo‐controlled, phase III trial. J Clin Oncol. 2022;40(22):2436‐2446. doi: 10.1200/jco.21.01511 [DOI] [PubMed] [Google Scholar]
- 10. Li J, Qin S, Xu J, et al. Apatinib for chemotherapy‐refractory advanced metastatic gastric cancer: results from a randomized, placebo‐controlled, parallel‐arm, phase II trial. J Clin Oncol. 2013;31(26):3219‐3225. doi: 10.1200/jco.2013.48.8585 [DOI] [PubMed] [Google Scholar]
- 11. Li J, Qin S, Xu J, et al. Randomized, double‐blind, placebo‐controlled phase III trial of apatinib in patients with chemotherapy‐refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016;34(13):1448‐1454. doi: 10.1200/jco.2015.63.5995 [DOI] [PubMed] [Google Scholar]
- 12. Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first‐line therapy for unresectable hepatocellular carcinoma (CARES‐310): a randomised, open‐label, international phase 3 study. Lancet. 2023;402(10408):1133‐1146. doi: 10.1016/s0140-6736(23)00961-3 [DOI] [PubMed] [Google Scholar]
- 13. Li H, Liu J, Liu Y, et al. VP2‐2024: 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 [abstract]. Ann Oncol. 2024;35(6):574‐575. doi: 10.1016/j.annonc.2024.04.003 [DOI] [Google Scholar]
- 14. Liu Y, Wang W, Yin R, et al. A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple‐negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis. BMC Med. 2023;21:376. doi: 10.1186/s12916-023-03046-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Wang T, Tang J, Yang H, et al. Effect of apatinib plus pegylated liposomal doxorubicin vs pegylated liposomal doxorubicin alone on platinum‐resistant recurrent ovarian cancer: the APPROVE randomized clinical trial. JAMA Oncol, 2022;8(8):1169‐1176. doi: 10.1001/jamaoncol.2022.2253 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Lan CY, Wang Y, Xiong Y, et al. Apatinib combined with oral etoposide in patients with platinum‐resistant or platinum‐refractory ovarian cancer (AEROC): a phase 2, single‐arm, prospective study. Lancet Oncol, 2018, 19(9): 1239‐1246, doi: 10.1016/s1470-2045(18)30349-8 [DOI] [PubMed] [Google Scholar]
- 17. Pujade‐Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum‐resistant recurrent ovarian cancer: the AURELIA open‐label randomized phase III trial. J Clin Oncol. 2014;32(13):1302‐1308. doi: 10.1200/jco.2013.51.4489 [DOI] [PubMed] [Google Scholar]
- 18. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894‐1905. doi: 10.1056/nejmoa1915745 [DOI] [PubMed] [Google Scholar]
- 19. Wu L, Li N, Wang J, et al. Fuzuloparib as maintenance therapy among patients with advanced ovarian cancer after a response to first‐line platinum‐based chemotherapy: results from a randomized, placebo‐controlled, phase III trial. Gynecol Oncol. 2024;190(suppl 1):S74‐S75. doi: 10.1016/j.ygyno.2024.07.110 [DOI] [Google Scholar]
- 20. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495‐2505. doi: 10.1056/nejmoa1810858 [DOI] [PubMed] [Google Scholar]
- 21. González‐Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391‐2402. doi: 10.1056/nejmoa1910962 [DOI] [PubMed] [Google Scholar]
- 22. Li N, Zhu J, Yin R, et al. Treatment with niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2023;9:1230‐1237. doi: 10.1001/jamaoncol.2023.2283 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA–MONO/GOG‐3020/ENGOT‐ov45). J Clin Oncol. 2022;40(34):3952‐3964. doi: 10.1200/jco.22.01003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Wu X, Liu J, Wang J, et al. Senaparib as first‐line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial. Nat Med. 2024;30(6):1612‐1621. doi: 10.1038/s41591-024-03003-9 [DOI] [PubMed] [Google Scholar]
- 25. Heitz F, Marth C, Henry S, et al. AGO‐OVAR 28/ENGOT‐ov57: Niraparib versus niraparib in combination with bevacizumab in patients with carboplatin‐taxane based chemotherapy in advanced ovarian cancer—a multicenter, randomized, phase III trial [abstract]. J Clin Oncol. 2022;40(suppl 16):TPS5612. doi: 10.1200/jco.2022.40.16_suppl.tps5612 [DOI] [PubMed] [Google Scholar]
- 26. Sghaier S, Corbaux P, Ray‐Coquard I, et al. NIRVANA‐1: maintenance therapy with niraparib versus niraparib‐bevacizumab in patients with advanced ovarian cancer. Future Oncol. 2023;19(25):1715‐1727. doi: 10.2217/fon-2023-0167 [DOI] [PubMed] [Google Scholar]
- 27. Freyer G, Gonzalez Martin AJ, Raspagliesi F, et al. 615TiP NIRVANA‐1: a multicentre randomized study comparing carboplatin‐paclitaxel (CP) followed by niraparib (nira) to CP–bevacizumab (bev) followed by nira‐bev in patients with FIGO stage III ovarian high‐grade epithelial cancer and no residual disease after upfront surgery [abstract]. Ann Oncol. 2022;33(suppl 7):S826. doi: 10.1016/j.annonc.2022.07.1871 [DOI] [Google Scholar]
- 28. Essam‐Eldin S, Salah E, Ahmed H, Elhalawani H, Abdel‐Rahman O. Hematological toxicities following treatment of cancer patients with PARP inhibitors. Ann Oncol. 2017;28:x177. doi: 10.1093/annonc/mdx668.001 [DOI] [Google Scholar]
- 29. Maiorano BA, Catalano M, Maiorano MFP, et al. Hematological toxicity of parp inhibitors in solid tumors: a systematic review and safety meta‐analysis. Cancer Metastasis Rev. 2025;44(3):65. doi: 10.1007/s10555-025-10283-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Qin S, Li Q, Gu S, et al. Apatinib as second‐line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double‐blind, randomised, placebo‐controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2021;6(7):559‐568. doi: 10.1016/s2468-1253(21)00109-6 [DOI] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Supporting Information S1