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

According to the Cancer Genome Atlas, aggressive tumors such as high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) exhibit genomic characteristics associated with deficiencies in the homologous recombination (HR) repair pathway (e.g. BRCA deficiency) [1, 2]. Poly (ADP-ribose) polymerase (PARP) inhibitors cause the accumulation of double-strand breaks that cannot be effectively repaired, leading to synthetic lethality in HR-deficient cells [3, 4]. PARP inhibitors are currently indicated as treatment for BRCA-mutated (BRCA^mut) OC and HER2- BC, as well as maintenance treatment for OC after response to platinum-based chemotherapy, regardless of BRCA^mut [5‐7]. Therefore, BRCA detection becomes particularly important. To further expand the scope of potential patients who could benefit from PARP inhibitors (e.g. those with platinum-resistant, non-BRCA^mut disease) and to spare the toxicities from repeated platinum therapy, there is a need for exploration of effective chemo-free combination regimens.

Anti-angiogenic therapy could induce hypoxia in the tumor microenvironment, cause genetic instability and downregulation of BRCA1/2 and lead to HR deficiency, thereby potentiating response to PARP inhibitors [8‐10]. The combination of anti-angiogenic therapy and a PARP inhibitor has been evaluated in several clinical trials. In phase 2 trials of platinum-sensitive recurrent OC, the addition of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab to niraparib, or the VEGF receptor (VEGFR) inhibitor cediranib to olaparib, improved progression-free survival (PFS) [11‐13]. Promising anti-tumor activity was also observed with the olaparib-cediranib combination in patients with platinum-resistant OC, regardless of BRCA mutation status [14‐16]. However, the administration of bevacizumab requires intravenous infusion, which may decrease the convenience of treatment. In addition, although cediranib is an oral tyrosine kinase inhibitor (TKI), the olaparib-cediranib combination has been associated with tolerability issues, leading to dose reduction in over 70% of OC patients [13].

Fuzuloparib (formerly known as fluzoparib) is a novel PARP inhibitor. It has been approved in China as treatment for germline BRCA1/2-mutated (gBRCA1/2^mut), platinum-sensitive recurrent OC, and as maintenance therapy for platinum-sensitive recurrent OC, regardless of BRCA1/2 mutation status [17‐19]. In phase 2 and 3 trials, fuzuloparib was well tolerated in OC patients, with a low treatment discontinuation rate due to adverse events (AEs) [17, 18]. Compared with other approved PARP inhibitors, fuzuloparib has a lower risk of gastrointestinal toxicities, which might be related to its postprandial administration and high oral bioavailability [20]. Apatinib is a highly selective VEGFR2-targeted TKI. It has demonstrated efficacy and safety across a wide variety of solid tumors, including OC and BC [21‐24]. In a murine xenograft model, the combination of fuzuloparib and apatinib showed enhanced antitumor efficacy compared with apatinib alone, without apparent incremental toxicity [20]. Currently, the oral combination of fuzuloparib and apatinib is undergoing clinical development, aiming to improve treatment convenience and spare patients from the toxicities associated with conventional chemotherapy. In this phase 1 trial, we assessed the safety, clinical activity, and pharmacokinetics (PK) of fuzuloparib plus apatinib in the treatment of patients with advanced OC or TNBC. Furthermore, we conducted biomarker analysis according to gBRCA1/2 mutation.

This multi-center, open-label, dose-escalation and PK-expansion phase 1 study (ClinicalTrials.gov, number NCT03075462) was conducted in 10 centers in China. Patients enrolled were women aged 18–70 years, had confirmed advanced high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer (with or without gBRCA^mut), or TNBC. Patients with OC were required to have received 2–4 prior lines of platinum-based chemotherapy. Both platinum-sensitive (disease progression or relapse ≥ 6 months after the last platinum-based chemotherapy) or resistant (disease progression or relapse within 1–6 months after the last platinum-based therapy) disease were allowed. Patients with TNBC were required to receive ≤ 2 prior lines of chemotherapy for advanced disease, and had disease progression or recurrence during or after the last anti-cancer treatment. Other inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, a life expectancy of ≥ 3 months, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and adequate organ functions. Key exclusion criteria were prior use of PARP inhibitors or anti-angiogenic agents, central nervous system metastases, uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg), a history of congestive heart failure, bowel obstruction or gastrointestinal bleeding (grade 3 or 4 per Common Terminology Criteria for Adverse Events [CTCAE] v4.03) within 4 weeks.

The trial protocol was approved by the institutional review board or ethnic review committee of each participating center. All procedures were conducted in accordance with the guidelines of Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent before enrollment.

In this phase 1 trial, the chemo-free combination of fuzuloparib and apatinib demonstrated good tolerability and therapeutic efficacy in biomarker-unselected patients with recurrent gynecological cancers. No MTD was established, and no saturation of plasma drug exposure was observed up to fuzuloparib 100 mg bid plus apatinib 500 mg qd.This highest tested dose combination was determined to be the RP2D. The safety profile of the fuzuloparib-apatinib combination was consistent with the individual agents, with no new safety signals identified. The most frequently reported grade 3 or worse TRAEs were hypertension (the most common TRAE associated with apatinib monotherapy [21, 22, 25]) and hematologic toxicities (the most common TRAEs associated with fuzuloparib monotherapy [17‐19]). These events were generally manageable with standard supportive care and dose modification, without leading to treatment discontinuation.

In this study, obvious anti-tumor activity was seen for fuzuloparib plus apatinib, with a confirmed ORR of 36.5% and DCR of 65.4% across all dose levels. Specifically, the ORR was 80% for patients with platinum-sensitive recurrent OC, which was much higher than the 35.3% for patients with platinum-resistant recurrent OC. The cross-sensitivity between platinum-based chemotherapy and fuzuloparib-apatinib combination could be partly explained by the overlap between resistance mechanisms of platinum and PARP inhibitor, which involves the reactivation of the HR repair pathway [26]. Notably, the gBRCA1/2 mutation rate of 26.7% for HGSOC patients in our study was slightly higher than the reported rates of 19–23.8% for BRCA-unselected OC patients (> 90% serous histology) in phase 3 trials of other PARP inhibitors [27‐29]. This difference could be attributed to the relatively small sample size of this study. Consistent with previous reports [12, 13, 29], BRCA1/2^mut was predictive of favorable efficacy outcome in OC and the ORR ranged from 30.8% in gBRCA^wt, platinum-resistant disease to 100% in gBRCA^mut, platinum-sensitive disease in this study. In a previous phase 2 trial, fuzuloparib monotherapy achieved an ORR of 69.9% and a median PFS of 12.0 months in patients with gBRCA^mut, platinum-sensitive OC (~ 70% received 2 prior lines of chemotherapy and none received PARP inhibitor) [17]. In this study, our subjects represented a heavily pretreated patient population with recurrent OC, similar to that in the phase 2 trial of fuzuloparib monotherapy. Although the sample size was limited, the ORR and PFS achieved with the combination therapy in patients with platinum-sensitive OC with or without gBRCA^mut, appeared to be comparable to those achieved with fuzuloparib monotherapy in patients with platinum-sensitive OC with gBRCA^mut. Given the established superior efficacy of PARP inhibitors in treating patients with gBRCA^mut OC [13, 29], our preliminary data support the potential clinical benefits with the addition of apatinib.

A handful of clinical trials have assessed the combination of an anti-angiogenic agent and a PARP inhibitor as treatment for recurrent OC, and the ORR ranged from 60%-79.6% in platinum-sensitive disease [11‐13, 29] and 11.1%-15.4% in platinum-resistant disease [14‐16]. Direct comparison between studies was difficult considering the differences in patients characteristics (e.g. proportion of patients with BRCA mutation/HR deficiency) and study design (e.g. no. of lines of prior treatment [chemotherapy, PARP inhibitor, and anti-angiogenic agent] allowed); nevertheless, the ORR of 30.8% with fuzuloparib-apatinib in patients with gBRCA^wt, platinum-resistant OC was encouraging for a difficult-to-treat population. Importantly, tumor response with fuzuloparib plus apatinib in OC was durable regardless of platinum sensitivity or BRCA mutation status, which highlights the necessity for developing new biomarker to better identify potential responders in the gBRCA^wt, platinum-resistant OC population. Notably, in a recent phase 3 trial, cediranib plus olaparib failed to significantly extend PFS versus standard chemotherapy (median, 10.4 vs 10.3 months) in patients with platinum-sensitive OC (64.6% with 1 line of prior therapy). This was speculated to be attributed to the decreased dosing intensity (71.6% of participants required dose modification) and increased rate of treatment discontinuation (21.2% withdrew treatment) due to AEs with the combination [29]. In this study, treatment with fuzuloparib plus apatinib resulted in a median PFS of 12.1 months in patients with platinum-sensitive OC progressing after ≥ 2 lines of platinum-based chemotherapy. The combination was well tolerated, with only 21.2% requiring dose modification and none requiring dose discontinuation due to TRAE. The overall favorable safety profile of fuzuloparib-apatinib supports long-term and sustained use of these drugs, which potentially distinguishing this combination from others under development.

Although the PARP inhibitors olaparib and talazoparib have shown robust efficacy in gBRCA^mut TNBC, the prevalence of this mutation is low, ranging from 10–20% in TNBC [30‐32]. A phase 1 trial has evaluated the combination of olaparib with cediranib in pretreated TNBC patients with or without BRCA1/2 mutation; however, the trial observed limited anti-tumor activity (no objective response and 2 SD in 8 patients), likely due to the small sample size. In the present study, fuzuloparib plus apatinib resulted in an ORR of 22.7% and DoR of 4.5 months in patients with TNBC who had received up to 2 prior lines of chemotherapy. While the clinical activity was modest, the fuzuloparib-apatinib combination as a later-line therapy showed similar effectiveness to conventional chemotherapy and had fewer toxicities in treating a general TNBC population [32, 33], suggesting that it might be considered as chemo-free option under specific conditions. Alternatively, an encouraging ORR of 66.6% and DCR of 100% was obtained with the combination in the subgroup of gBRCA1/2^mut TNBC. Based on the consistent efficacy of PARP inhibitors shown in gBRCA1/2^mut, HER2- BC, and the promising results observed in phase 1 trials for fuzuloparib with or without apatinib in gBRCA1/2^mut BC [19], we have initiated a phase 1/3 trial (NCT04296370) to assess fuzuloparib with or without apatinib, compared to investigator's choice of chemotherapy, in the treatment of gBRCA^mut, HER2- BC. This ongoing study includes a run-in phase 1 part, followed by a 3-arm, randomized, phase 3 part. The trial will provide definitive evidence regarding the impact of including apatinib in the treatment regimen for HER2- BC.

When used as combination therapy, the PK profile of fuzuloparib (40–100 mg bid) was similar to that of fuzuloparib monotherapy; however, the exposure of apatinib (250–500 mg qd) at steady state was reduced by 47.7%-65.0% across dose levels when compared to apatinib used as monotherapy. This observation indicates the presence of drug-drug interaction. As the PK profiles of two drugs in multiple doses for combination therapy have been investigated, the data imply that higher dose level of apatinib may be tolerable when combined with fuzuloparib. Besides, the decreased exposure of apatinib suggests potential lower related toxicity of apatinib when used in combination with fuzuloparib. Based on the PK data, it’s recommended that the dose of apatinib be adjusted first in the combination, in the management of intolerable AEs that were potentially related to either agent.

In summary, the combination of fuzuloparib and apatinib showed hematologic DLTs and acceptable safety in patients with recurrent OC and TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was determined to be the RP2D. With the activity observed in OC and TNBC, further investigation of the combination therapy is warranted as a potential alternative to cytotoxic treatment.