An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer

Ovarian cancer is one of the leading causes of gynecologic cancer-related death worldwide (1). In China, approximately 52,100 new ovarian cancer cases and 22,500 ovarian cancer-related deaths were recorded in 2015 (2). Among Chinese patients with ovarian cancer, about 28.5% have a germline BRCA1 or BRCA2 mutation (3). In addition, more than 70% of patients with ovarian cancer present with advanced stage at diagnosis, which has a 5-year overall survival rate of only 29% (4, 5).

Surgery and platinum-based adjuvant chemotherapy as the first-line treatment for advanced ovarian cancer yields poor outcomes, with approximately 80% of patients developing relapse and requiring multiple lines of subsequent chemotherapy (6). Consecutive treatment gradually reduces tumor sensitivity to chemotherapy, shortens the time to progression, and increases treatment toxicity. After the third disease recurrence, the benefit from chemotherapy diminishes, and patients commonly have little platinum-free interval (PFI; ref. 7). Therefore, novel therapies that are not only well tolerated, but also effective for improving progression-free survival in patients with recurrent ovarian cancer are needed.

Tumors with the BRCA1/2 mutation are characterized by a deficiency in the homologous recombination repair pathway. Inhibition of the PARP could destroy DNA replication forks and break double-strand DNA, block the alternative DNA repair pathway of BRCA1/2-mutated tumor cells, and ultimately lead to synthetic lethality (8). Several studies showed that PARP inhibitors (PARPis) have potential antitumor activity and low toxicity in ovarian cancers with germline BRCA1/2 mutants (9–13). PARPis are commonly used for maintenance therapy of ovarian cancer, and accumulated evidences have shown that they can also be used in the treatment of recurrent ovarian cancers with BRCA mutation (14–16). Two PARPis (olaparib and rucaparib) have been approved by the FDA for the late-line treatment of BRCA-mutated recurrent ovarian cancer. Another PARPi (niraparib) was also approved for homologous recombination deficiency–positive advanced ovarian cancer (9, 10, 17). However, in some countries or regions of the world, including China, no efficacious PARPi is available for use as a treatment option in BRCA-mutated advanced ovarian cancers who relapsed to prior chemotherapy. Thus, developing new therapies for effective management of recurrent ovarian cancer is an important unmet medical need.

A phase I trial of fluzoparib, a potent orally administered PARPi (18), showed that it has acceptable safety profile and promising preliminary antitumor activity in advanced ovarian cancer, particularly in platinum-sensitive disease (19, 20). This study aimed to investigate the efficacy and safety of fluzoparib in patients with germline BRCA1/2 mutations and platinum-sensitive relapsed ovarian cancer who had received two or more lines of prior chemotherapy.

This open-label, multicenter, single-arm phase II study was approved by the Institutional Review Board of each site and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. This study was registered in ClinicalTrials.gov (number NCT03509636). All patients provided written informed consent before participation in the study.

This study was conducted at 26 sites in China (Supplementary Table S1). The subjects were patients with platinum-sensitive recurrent ovarian cancer (disease progression or relapse ≥6 months after the last dose of platinum-based therapy) and BRCA1/2 mutation who had previously received two to four lines of platinum-based chemotherapy. The inclusion criteria were age ≥18 years; with histologically confirmed high-grade serous or grade 2 to 3 endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma; with at least one measurable lesion according to the RECIST v1.1; with a pathogenic germline BRCA1/2 mutation based on confirmatory testing by a central laboratory (21); an Eastern Cooperative Oncology Group performance status of 0 or 1; adequate organ function; and a life expectancy of more than 12 weeks. The exclusion criteria were another malignancy within 5 years; untreated central nervous system metastases; previous treatment with a PARPi; immunocompromise or active hepatitis; previous antitumor treatment (radiotherapy, chemotherapy, hormone therapy, surgery, or targeted therapy) within 4 weeks of receiving study treatment; and grade ≥2 adverse events (excluding alopecia) per the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 caused by prior treatment.

The enrolled patients were given 150-mg fluzoparib orally twice daily (28 days per cycle) until disease progression per RECIST v1.1, intolerable toxicity, or withdrawal of consent, whichever occurred first. Dose interruption at a maximum of 4 weeks and dose reduction to 100 mg twice daily and subsequently to 50 mg twice daily were permitted owing to treatment toxicity. Fluzoparib treatment beyond RECIST v1.1 progression was allowed on the basis of investigator’s judgement in this trial.

Tumor response was assessed via CT and MRI per RECIST v1.1 at 8-week (2-cycle) intervals for 40 weeks and then every 12 weeks thereafter. Complete or partial response must be confirmed 4 weeks (±7 days) later after it was first noted. Imaging data were reviewed by both an independent review committee (IRC) and the investigator. After treatment was completed or discontinued because of adverse events, patients were followed-up every 2 months to assess survival. Adverse events were evaluated from the day of signing the informed consent form to 30 days after the last dose of study treatment. Treatment-related adverse events were evaluated up to 30 days after the last administration of fluzoparib or until the start of a new antitumor therapy, whichever occurred earlier. All adverse events were graded according to the CTCAE v4.03. The serum cancer antigen 125 (CA-125) level was assessed according to the Gynecologic Cancer InterGroup (GCIG) criteria. The BRCA status was tested in an ISO15189-certified and National Center for Clinical Laboratories (NCCL)-assessed clinical molecular diagnostic laboratory (BGI) using next-generation sequencing.

The primary endpoint was the objective response rate assessed by IRC, which was defined as the percentage of patients whose best overall response was complete or partial response per RECIST v1.1. The secondary endpoints were the objective response rate per RECIST v1.1 and GCIG CA-125 criteria, duration of response (i.e., the period between the onset of complete or partial response until objective evidence of progressive disease or death), progression-free survival (i.e., the time from treatment initiation until disease progression or death of any cause, whichever occurred first), overall survival (i.e., the time from the date of treatment until any cause of death or the last follow-up), and safety.

On the basis of an exact binomial method, with the assumption of an objective response rate of 55% for fluzoparib, 90 patients were required under a two-sided significance level of 5% and a power of 80%. Allowing a drop-out rate of 20%, a total of 112 patients were required to be enrolled.

Patients who received at least one dose of the study drug were included in the full analysis set. Patients administered with at least one dose and had safety data recorded after the dose constituted the safety set. Efficacy was assessed in the full analysis set, and safety was assessed in the safety set. The objective response rate and disease control rate were presented with accompanying 95% confidence intervals (CI) calculated using the Clopper–Pearson method. The medians of time-to-event endpoints (progression-free survival, overall survival, and duration of response) were calculated using the Kaplan–Meier methods, with the 95% CI estimated on the basis of the Brookmeyer–Crowley method. All statistical analyses were conducted using SAS software, version 9.2 or higher.

Of the 159 patients assessed for eligibility between April 4, 2018 and March 21, 2019, 113 patients were enrolled and received at least one dose of fluzoparib (Fig. 1). The median age was 52 years (range, 35–79 years). There were 77 (68.1%) patients who had received two lines of prior platinum-based chemotherapy; 29 (25.7%) patients, three previous lines; and seven (6.2%) patients who received four previous lines. In total, 82 (72.6%) patients had partially platinum-sensitive disease (≥6–<12 months from completion of last platinum therapy to progression). The baseline patient and disease characteristics are summarized in Table 1.

As of data cutoff on March 21, 2020, the median follow-up period was 15.9 months [interquartile range (IQR), 13.5–18.5]. There were 28 (24.8%) patients who were still under fluzoparib treatment at the data cut-off date. The main reasons for treatment discontinuation was disease progression (N = 67, 78.8%). Seventy-three patients received postdiscontinuation treatment; the most common was platinum-based chemotherapy (N = 61, 54.0%; Supplementary Table S2). The median time to first subsequent therapy was 13.5 months (95% CI, 11.3–15.8).

A total of 113 patients constituted the efficacy analysis population. As of data cutoff, there were five (4.4%) complete responses and 74 (65.5%) partial responses recorded by the IRC, and 14 (12.4%) complete responses and 66 (58.4%) partial responses recorded by the investigator, achieving objective response rates of 69.9% (95% CI, 60.6–78.2) by IRC assessment and 70.8% (95% CI, 61.5–79.0) by investigator assessment (Table 2). In the 109 patients with platinum-sensitive disease, the IRC-assessed objective response rate was 70.6% (95% CI, 61.2–79.0; N = 77), and the investigator-assessed objective response rate was also 70.6% (95% CI, 61.2–79.0; N = 77). In the overall cohort, the IRC-assessed disease control rate 94.7% (95% CI, 88.8–98.0), while the investigator-assessed disease control rate was 92.9% (95% CI, 86.5–96.9). The best change in the size of target lesions per patient is shown in Fig. 2A and Supplementary Fig. S1A. In patients with complete or partial response, the response was durable, with a median duration of 10.2 months (95% CI, 8.3–12.0) and 8.5 months (95% CI, 7.4–10.2) on IRC and investigator assessment, respectively (Supplementary Fig. S2). The objective response rates were consistent across all the prespecified subgroups (BRCA mutation status, time from last platinum-based chemotherapy to progression/relapse, lines of previous chemotherapy, lines of previous platinum-based chemotherapy, and age), although the 2 patients harboring both BRCA1 and BRCA2 mutations had a lower objective response rate than did the entire population (Fig. 2B; Supplementary Fig. S1B).

A total of 77 patients had a CA-125 level exceeded twice the upper limit of the normal range on two consecutive measurements in the screening period. After fluzoparib treatment, 70 (90.9%) patients had a reduction of ≥50% in CA-125 level than baseline. The objective response was also evaluated according to RECIST v1.1 and the GCIG CA-125 criteria. Among them, 68 of the 77 patients (88.3%; 95% CI, 79.0–94.5) achieved objective response on investigator assessment.

At the date of data cutoff, the IRC-assessed disease progression/mortality rate was 60.2% (68/113), whereas the investigator-assessed rate was 69.0% (78/113; Fig. 3A; Supplementary Fig. S3). The IRC-assessed median progression-free survival was 12.0 months (95% CI, 9.3–13.9), whereas the investigator-assessed median progression-free survival was 10.3 months (95% CI, 9.2–12.0). Of the 77 patients with investigator-assessed disease progression, 34 patients continued to receive fluzoparib treatment after progression. The progression-free survival assessed by both IRC and investigator were consistent across all the prespecified subgroups (Supplementary Fig. S4).

As of data cutoff, 14 (12.4%) of the 113 patients died. The median overall survival is currently not reached (95% CI, 21.0–not estimable; Fig. 3B). The probability of 12-month survival was 93.7% (95% CI, 87.2–96.9) and that of 18-month survival was 89.2% (95% CI, 81.2–93.9).

The median exposure period to fluzoparib was 10.8 months (IQR, 7.4–14.6). A total of 113 patients were included in the safety analysis, and all of them experienced any-cause adverse events (Table 3; Supplementary Table S3). Meanwhile, grade ≥3 adverse events occurred in 72 (63.7%) patients, and the most common were anemia/decreased hemoglobin (N = 37, 32.7%), decreased white blood cell count (N = 14, 12.4%), decreased platelet count (N = 14, 12.4%), decreased lymphocyte count (N = 12, 10.6%), and decreased neutrophil count (N = 12, 10.6%). Treatment was interrupted and the dose was reduced in 45 (39.8%) and 39 (34.5%) patients, respectively (Supplementary Tables S4 and S5). One patient discontinued treatment due to adverse events.

Treatment-related adverse events of any grade were reported 110 (97.3%) of the 113 patients (Supplementary Table S6), with the most common being nausea (N = 72, 63.7%), decreased white blood cell count (N = 66, 58.4%), asthenia (N = 64, 56.6%), and anemia/decreased hemoglobin (N = 71, 62.8%). There were 67 (59.3%) patients who had grade ≥3 treatment-related adverse events, and the most common were anemia/decreased hemoglobin (N = 37, 32.7%), decreased platelet count (N = 14, 12.4%), decreased white blood cell count (N = 14, 12.4%), decreased neutrophil count (N = 11, 9.7%), and decreased lymphocyte count (N = 10, 8.8%). Serious treatment-related adverse events were reported in 24 (21.2%) patients, with the most common one being anemia (N = 13, 11.5%; Supplementary Table S7). One (0.9%, death from unknown cause) treatment-related death was reported.

Overall, 44 (38.9%) patients had adverse events of special interest, including 37 (32.7%) patients with anemia/decreased hemoglobin, 7 (6.2%) with bone marrow failure, 3 (2.7%) with pneumonitis, and 2 (1.8%) with febrile neutropenia.

This study met its primary endpoint, achieving a higher-than-expected IRC-assessed and investigator-assessed objective response rate of 69.9% (95% CI, 60.6–78.2) and 70.8% (95% CI, 61.5–79.0), respectively. The response was durable (10.2 months; 95% CI, 8.3–12.0). Although overall survival data are currently immature, the probability of 12-month survival reached 93.7% (95% CI, 87.2–96.9). No new safety signals were identified. To our best knowledge, this single-arm phase II trial is the largest study in China to date to show the promising antitumor activity and safety profile of fluzoparib in patients with heavily pretreated platinum-sensitive relapsed ovarian cancer and with BRCA1 or BRCA2 mutations.

Olaparib had an objective response rate of 72.2% (109/151) per IRC and 46% (18/39) per investigator, while rucaparib had an objective response rate of 65.8% (52/79) per investigator in relapsed patients with platinum-sensitive disease and BRCA 1 or BRCA2 mutation (22–24). In our study, fluzoparib achieved an objective response rate of 70.6% (77/109) both per IRC and investigator in patients with germline BRCA1/2 mutation and PFI≥6 months recurrent ovarian cancer. Although cross-trial comparisons should be interpreted with caution due to the different patient populations included, this study demonstrated the promising efficacy of fluzoparib in ovarian cancer. On the other hand, maintaining clinically meaningful disease response is an important descriptor of treatment efficacy. The durable response of 10.2 months further supported fluzoparib to be a potential treatment option for patients with pretreated recurrent ovarian cancer with platinum-sensitive disease and BRCA1 or BRCA2 mutation.

Findings from subgroup analysis of objective response and progression-free survival were generally consistent across all the prespecified subgroups. Both the objective response rate and progression-free survival in patients with PFI ≥6–<12 months were comparable with those in patients with PFI ≥12 months (objective response rate, 73.2% vs. 63.0%; progression-free survival, 12.0 vs. 9.3 months), suggested the efficacy of fluzoparib in the partially platinum-sensitive (PFI ≥6–<12 months) subpopulation. In the four patients with PFI <6 months, two patients responded to fluzoparib per IRC and three responded to fluzoparib per investigator. Similar observations were also been found with olaparib or rucaparib, which led to a response rate of 30% (24/81) and 25% (5/20) assessed by investigator in platinum-resistant patients, respectively (22, 24). Further validations in larger cohorts are warranted because of the small sample size of platinum-resistant patients in this study.

With respect to safety, the results showed that fluzoparib had acceptable safety profile. The most commonly observed adverse events were similar with the known toxicities of PARPis, including nonhematologic (nausea, asthenia, and vomiting) and hematologic toxicities (decreased white blood cell count, anemia/decreased hemoglobin, decreased platelet count, and decreased neutrophil count; 22–24). All grade ≥3 adverse events that occurred in more than 3% of the patients were hematologic toxicities, and the incidence rates of all nonhematologic toxicities were less than 3%. Only one treatment discontinuation due to toxicity was reported. Myelodysplastic syndrome and acute myeloid leukemia are adverse events of special interest commonly associated with olaparib or rucaparib, but none of them were currently reported with fluzoparib. Gastrointestinal events are regarded as common toxicities of PARPis. In this study, only three patients treated with fluzoparib developed vomiting of grade ≥3. The less incidence of gastrointestinal events may be related to the pattern of postprandial administration and better bioavailability of fluzoparib (18).

The major limitation of this study was its open-label, single-arm design. First, no control arm was included. Second, the subgroup analysis suggested that the objective response to fluzoparib was less affected by the prespecified subgroup parameters, and potential biomarkers that can accurately predict the treatment effect of fluzoparib need further exploration.

In conclusion, this phase II study demonstrated that fluzoparib has promising antitumor activity in patients with platinum-sensitive recurrent ovarian cancer and BRCA1 or BRCA2 mutations who had previously received two to four lines of chemotherapy. Fluzoparib had an acceptable safety profile. Collectively, these findings support that fluzoparib as a novel PARPi, could be an additional treatment option for this patient population.

B. Zhang, Y. Wang, and Q. Wang are employees of Jiangsu Hengrui Medicine Co., Ltd. No disclosures were reported by the other authors.

N. Li: Conceptualization, data curation, supervision, investigation, methodology, project administration, writing–review and editing. H. Bu: Conceptualization, data curation, supervision, investigation, methodology, project administration, writing–review and editing. J. Liu: Data curation, supervision, investigation, methodology, writing–review and editing. J. Zhu: Data curation, supervision, investigation, methodology, writing–review and editing. Q. Zhou: Data curation, supervision, investigation, methodology, writing–review and editing. L. Wang: Data curation, supervision, investigation, methodology, writing–review and editing. R. Yin: Data curation, supervision, investigation, methodology, writing–review and editing. X. Wu: Data curation, supervision, investigation, methodology, writing–review and editing. S. Yao: Data curation, supervision, investigation, methodology, writing–review and editing. K. Gu: Data curation, supervision, investigation, methodology, writing–review and editing. H. Zhang: Data curation, supervision, investigation, methodology, writing–review and editing. G. Li: Data curation, supervision, investigation, methodology, writing–review and editing. H. Pan: Data curation, supervision, investigation, methodology, writing–review and editing. Q. Wu: Data curation, supervision, investigation, methodology, writing–review and editing. R. An: Data curation, supervision, investigation, methodology, writing–review and editing. X. Yang: Data curation, supervision, investigation, methodology, writing–review and editing. Y. Zhu: Data curation, supervision, investigation, methodology, writing–review and editing. X. Wan: Data curation, supervision, investigation, methodology, writing–review and editing. W. Duan: Data curation, supervision, investigation, methodology, writing–review and editing. J. Xiong: Data curation, supervision, investigation, methodology, writing–review and editing. H. Guo: Data curation, supervision, investigation, methodology, writing–review and editing. G. Lou: Data curation, supervision, investigation, methodology, writing–review and editing. J. Wang: Data curation, supervision, investigation, methodology, writing–review and editing. W. Hu: Data curation, supervision, investigation, methodology, writing–review and editing. X. Zhang: Data curation, supervision, investigation, methodology, writing–review and editing. Y. Meng: Data curation, supervision, investigation, methodology, writing–review and editing. B. Zhang: Software, formal analysis, methodology, writing–review and editing. Y. Wang: Data curation, supervision, methodology, project administration, writing–review and editing. Q. Wang: Conceptualization, data curation, supervision, methodology, project administration, writing–review and editing. L. Wu: Conceptualization, resources, data curation, supervision, funding acquisition, investigation, methodology, project administration, writing–review and editing.

We are grateful to all the patients and their families and all members of the collaborative group in this trial. We thank Ning Hao (Knowlands Medpharm) for his input in statistical analyses. Medical writing support was provided by Tengfei Zhang (Medical Writer at Hengrui) according to Good Publication Practice Guidelines.

This work was supported by Jiangsu Hengrui Medicine Co., Ltd.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.