Real‐world clinical outcomes of olaparib therapy in Chinese patients with advanced serous ovarian cancer treated in Macau

Abstract Background Olaparib has been approved as an active and maintenance therapy for patients with platinum‐sensitive, BRCA‐mutated high‐grade serous ovarian cancer (SOC). However, the efficacy and safety data is lack among Chinese ovarian cancer patients. Aim This real‐world study aimed to evaluate the effectiveness and safety profile of olaparib in patients from mainland China, where olaparib is currently unavailable. Methods and results This single‐center, observational study included 65 patients with pathologically confirmed advanced serous ovarian cancer from Kiang Wu Hospital in Macau between December 2015 and September 2017. Progression‐free survival (PFS) and other endpoints (treatment response, disease progression, and adverse events) were evaluated. PFS was estimated using the Kaplan‐Meier method. The median treatment duration was 4 months (range, 1‐15). The median PFS for the overall population was 4.2 months (95% CI 2.7‐5.2), while those for patients with wild‐type BRCA1/2 and BRCA1/2 mutations were 3.1 months (95% CI 1.3‐4.6) and 5.3 months (95% CI 2.8‐7.1), respectively. The median PFS tended to be longer for patients on maintenance therapy (between 9.0 months [95% CI 1.4‐17.5] and 10.0 months [95% CI 2.5‐18.1]) than for those on active therapy (between 3.1 months [95% CI 2.1‐3.8] and 3.0 months [95% CI 1.4‐4.5]). Most patients (87.0%) experienced low‐grade adverse events; the most common of which were fatigue (49.0%) and nausea (35.0%). Conclusion Our findings demonstrate clinical benefit of olaparib to mainland Chinese patients with high‐grade SOC, particularly for patients with BRCA mutations and who require maintenance therapy.


| INTRODUCTION
Ovarian cancer is one of the most common malignancies of the female reproductive system and the leading cause of death from gynecological tumors. 1 In China, it was estimated that 52 100 new cases and 22 500 deaths from ovarian cancer would occur in 2015. 2 High-grade serous ovarian cancer is the most common type of ovarian cancer. It is associated with aggressive disease progression and poor prognosis, accounting for up to 80% of ovarian cancer deaths. 3 Although survival rates of ovarian cancer have improved significantly in the last decade due to advancements in surgical techniques and the induction of new chemotherapeutic drugs, 4,5 disease recurrence and treatment resistance often occur.
When either BRCA1 or BRCA2 is defective, double-strand breaks are repaired through alternative mechanisms such as single-strand repair, which are mediated by poly (ADP-ribose) polymerase (PARPs). [10][11][12][13] In BRCA-mutated cells, inhibition of PARP activity leads to cell death as DNA damages cannot be repaired. 14 PARP-inhibitors exploit the concept of "synthetic lethality" between BRCA and PARP to cause tumor cell death. 15,16 One such example is olaparib, a potent PARP inhibitor that has been shown to have a selective cytotoxic effect on BRCA-mutant tumor cells in in vitro, 15,16 in vivo, 17 and clinical studies. 18 Olaparib was approved in 2014 for the treatment of patients with deleterious germline BRCA-mutated advanced ovarian cancer who have received three or more lines of chemotherapy in the United States, 19 and for maintenance treatment of patients with platinumsensitive, BRCA-mutated (germline and/or somatic), high-grade serous ovarian cancer who are in complete or partial response to platinum-based chemotherapy in Europe. 20,21 More recently, in 2018, olaparib was approved as maintenance treatment for women with platinum-sensitive relapsed ovarian cancer regardless of BRCA mutation status in Japan 22 and Europe. 23

| Study population
Inclusion criteria included aged ≥18 years, pathological diagnosis of serous ovarian cancer, undergone surgery and received platinumcontaining chemotherapy, undergone BRCA gene testing, received at least one course of olaparib treatment, and at least one measurable or evaluable lesion or elevated cancer antigen 125 (CA 125) levels, defined as levels above the upper limit of normal (ie, 35 U/mL). Key exclusion criteria included diagnosis of nonepithelial ovarian cancer.

| Treatment and follow-up
Patients received oral olaparib capsules 300 to 400 mg twice daily until disease progression, with each course of treatment lasting 28 days. Patients were treated with a standard dose of 400 mg; 300 mg was prescribed for patients who were unable to tolerate the standard dose. In the event of toxicity, the dose may be adjusted to 250 to 400 mg twice daily, based on patient's tolerability, or discontinued at the investigator's discretion. Patients were followed up monthly until disease progression via regular check-up by physicians and CT/MRI scans in mainland China, and via telephone as most patients were nonresident in Macau. The last follow-up date was on 30 May 2018.

| Efficacy and safety assessments
The primary efficacy endpoint was PFS. Other efficacy endpoints included treatment response (complete or partial response) and disease progression (stable or progressive disease). Treatment response and disease progression were based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). 28,29 Complete response was defined as the disappearance of all target lesions and reduction of any pathological lymph nodes to <10 mm in short axis; partial response was defined as a minimum of 30% reduction in the sum of diameters of target lesions, relative to the baseline sum diameters.
Progressive disease was defined as a minimum of 20% increase in the sum of diameters of target lesions, relative to the smallest sum on study; the sum must also have had an absolute increase of at least 5 mm. 28 Stable disease was defined as neither sufficient shrinkage (relative to baseline) to qualify for partial or complete response, nor sufficient increase in the sum of diameters (relative to the smallest sum at baseline or on study, whichever is smallest) to qualify for progressive disease. 29 Treatment response and disease progression were evaluated based on CT/MRI imaging, and the serum marker CA 125 (Gynecologic Cancer InterGroup criteria 30

| Statistical analysis
Demographic variables, baseline disease characteristics, and adverse events were summarized by descriptive statistics. PFS of the overall patient population, according to BRCA1/2 mutation status and according to treatment purpose, were evaluated. The Kaplan-Meier method was used to estimate PFS, and the log-rank test was used for differential analysis. Statistical analyses were performed using SPSS version 20.0 software package (SPSS Inc., Chicago, IL, USA).
For all analyses, P < 0.05 was considered to be statistically significant.

| Patient characteristics
A total of 65 patients were enrolled into the study. Baseline characteristics of these patients are shown in Table 1. Over half of the patients (58.5%) were diagnosed with high-grade serous ovarian cancer, and 80.0% of patients expressed germline or somatic BRCA mutant gene.
The median duration of treatment was 4 months (range, 1-15), while the median time to follow-up was 21 months (range, 1-24). The majority of patients (78.5%) received olaparib as an active therapy for tumor recurrence after at least three lines of chemotherapy.

| Efficacy
The results for PFS are presented in Figure 1. The median PFS for the overall patient population was 4.2 months (95% CI 2.7-5.2; Figure 1A).  Figure 1B). Figure 1C shows

| Safety
A summary of adverse events is provided in Table 3. Of the 65 patients, two-thirds (66%) experienced adverse events, and 13% experienced grade III to IV adverse events. The most common adverse events were fatigue (49%), gastrointestinal disturbances (nausea: 35%; vomiting: 14%), and leukopenia (20%). Three patients (5%) had dose reductions due to adverse events. Three patients (5%) discontinued olaparib treatment due to pain and/or disease progression.

| DISCUSSION
The present study sought to investigate the real-world effectiveness and safety of olaparib in Chinese patients with advanced serous ovarian cancer previously treated in mainland China, where olaparib is unavailable. Our findings showed that the median PFS for patients who received olaparib for maintenance therapy tended to be longer than that for patients who received olaparib for active therapy.
Patients with BRCA1/2 mutations also tended to have longer median PFS than those with BRCA1/2wild-type. Although adverse events occurred in two-thirds (66%) of patients, the majority of patients (87%) experienced low grade adverse events (grades I-II). The most common adverse events were fatigue and gastrointestinal disturbances (49% for both).
The median PFS with olaparib as a maintenance therapy after at least two lines of chemotherapy in the present study (9.0 months) is consistent with published data from studies of maintenance treatment   in a similar patient population (8.4 months). 24 Median PFS for patients who received olaparib for active therapy after at least three lines of chemotherapy tended to be shorter than that for maintenance therapy, as expected. However, the median PFS of olaparib active therapy in our study (approximately 3 months) was less than half of those reported in previous clinical trials (6.5 to 8.5 months 25,31  Further studies are required to confirm the optimal dosing regimen for olaparib in the patients who experience treatment-related adverse events, and who have comorbidities and poor performance status.
More importantly, physicians need to recognize that responses to treatment vary between individuals, and that personalized dosing regimens may be necessary for optimal treatment outcomes.
Interpretations made here may be limited due to the short median duration of treatment in our study (4 months In conclusion, our analysis of real-world treatment outcomes of olaparib treatment in mainland Chinese patients with high-grade serous ovarian cancer demonstrated clinical benefit, especially for BRCAmutated patients and patients requiring maintenance therapy. Greater access to olaparib may help to improve treatment prospects and outcomes for patients with serous ovarian cancer in mainland China.