Ovarian cancer is the second most common cause of death related to gynecologic malignancy and the eighth leading cause of death from cancer in women worldwide [1
]. The progression-free survival (PFS) of patients with advanced ovarian cancer after first-line chemotherapy is 4–12 months [2
]. For ovarian cancer patients who respond to platinum-based chemotherapy at recurrence, a median PFS of 5–6 months from end of treatment has been reported [3
]. Next-line chemotherapy can be offered to patients, but the treatment-free interval usually shortens each time recurrence is treated. Toxicity due to chemotherapy and acquired drug resistance are barriers to further treatment in patients with recurrent ovarian cancer, and tolerable treatment options for long-term disease control are needed.
Olaparib (Lynparza™) is a poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor that induces synthetic lethality in BRCA1/2
-deficient tumor cells [5
]. Previous studies have shown the effectiveness of olaparib in platinum-sensitive high-grade serous recurrent ovarian cancer (HSROC). Data from a Phase II trial to assess the efficacy and safety of olaparib maintenance monotherapy in platinum-sensitive HSROC patients, Study 19 (NCT00753545), showed a significant improvement in PFS in the olaparib-treated group relative to the placebo group (hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.25–0.49; p
< 0.0001) [3
]. The Phase III SOLO2 (Study of OLaparib in Ovarian cancer) trial (NCT01874353) of olaparib tablets as maintenance monotherapy in patients with platinum-sensitive HSROC and a BRCA1/2
m) revealed significantly improved PFS in the olaparib-treated group compared to the placebo group (HR 0.30, 95% CI 0.22–0.41; p
< 0.0001) [4
In Korea, olaparib is approved for the maintenance treatment of patients with platinum-sensitive HSROC with BRCAm. The Korean Food and Drug Administration (KFDA) has permitted the use of olaparib in a maintenance setting based on the results of Study 19 since August 2015, and olaparib has been widely used clinically since January 2016—the date from which reimbursement for this treatment was initiated by the National Health Insurance Service of Korea.
Safety data from previous trials indicate that olaparib monotherapy is generally well tolerated by recurrent ovarian cancer patients [7
]. This suggests that the long-term use of olaparib as maintenance monotherapy is a feasible option in recurrent ovarian cancer patients. However, the real-world effectiveness of olaparib could be different from its effectiveness in clinical trials because the patient population in the real world is an unselected, general clinical practice population that includes patients with less favorable prognostic factors than patients selected for clinical trials. Here, we present our real-world experience with olaparib in patients with HSROC with BRCA
m treated at four major tertiary institutions in Korea.
Our real-world experience of the safety and effectiveness of olaparib maintenance treatment in HSROC patients with BRCA1/2
mutation is consistent with that reported in previous studies [3
] with tolerable toxicity profiles. Our results can be compared to those of Study 19, a phase II trial of olaparib capsules as maintenance monotherapy in patients with platinum-sensitive HSROC, as we used the same indications and regimen (capsule 400 mg bid). The use of olaparib in Korea was permitted based on the results of Study 19, and it is mandatory for physicians in Korea to follow the recommendations and guidelines of the Korea Health Insurance Review and Assessment Service (KHIRA).
There were some differences between olaparib-treated patients with BRCA
= 74) in Study 19 and patients in our study [10
]. Median patient age was greater in Study 19 (57.5 years vs. 54.0 years) and we only included patients with ovarian cancer, while Study 19 included patients with fallopian tube and primary peritoneal cancer (12%). Furthermore, our study included dominantly Asian patients in contrast to Study 19. BRCA
mutation status was similar between Study 19 (BRCA1
2%) and our study (BRCA1
3%). In Study 19, 18 of 136 patients with BRCA
m (13.2%) had definite somatic BRCA
], while we had only six patients (6.0%) with somatic BRCA
mutation. Platinum-free interval and objective response to the most recent chemotherapy were similar in the two studies [3
]. Despite an insufficient follow-up period in our study, median PFS was similar (14.6 months compared to 11.2 months in patients with BRCA
m in Study 19). There were also differences in observed numbers of AEs between our study and Study 19. Among patients with BRCA
m in Study 19, 97% had AEs. The most common non-hematologic AE was nausea (73%), while the most common hematologic AE was anemia (26%). In our study, 64 total episodes (64.0%) of AEs were observed, with 13 cases (13.0%) of nausea/vomiting and 24 cases (24.0%) of anemia. The percentage of anemia was similar in the two studies (26% vs. 24%), but grade ≥ 3 anemia was observed in only 5% of patients in Study 19 compared to 14% of our patients.
status, the number of previous chemotherapy regimens, and platinum-free intervals in our study were similar to those reported by the SOLO2 study [4
]. Median age was also similar, but our age range was wider (56 years (range 51–63) vs. 53 years (29–79)). In SOLO2, the 24 month PFS was 43%, while ours was 42.4%. Higher numbers of AEs were reported in the SOLO2 study than in our study. In SOLO2, ninety-eight percent of total patients had AEs with nausea (76%), most common for non-hematologic AE, and anemia (43%) for hematologic AE. Anemia and nausea were the two most common AEs in our study as well, but fewer patients in our study than in the SOLO2 study experienced these AEs. Differences between our findings and those of Study 19 and SOLO2 might be due to differences in tablet and capsule compositions. In Study 19, which administered olaparib in capsule form, 68.4% of patients experienced nausea and 16.9% experienced anemia [3
] compared to 76% with nausea and 43% with anemia in the SOLO2 study that administered olaparib in tablet form. Currently, there are no established guidelines for transitioning patients from capsules to tablets for olaparib [11
]. However, there should be further studies of capsules and tablets to determine their relative efficacy and safety.
Differences in AEs between our study and Study 19 might have been caused by different treatment patterns in a real-world setting and biases caused by the retrospective nature of the study. Randomized controlled trials (RCTs) should adhere strictly to the study protocol, but in the real world, treatment can vary depending on the physician [12
]. In Study 19, treatment was interrupted for any grade 3 or 4 AE that was considered related to treatment; if the toxicity resolved or decreased in severity to grade 1, treatment was restarted with a reduction in dose to 200 or 100 mg twice daily. In our study, physicians usually reduced the dose without interruption, with 25% DR in 49% of patients with AEs rather than an immediate 50% DR. In Study 19, dose interruption occurred in 36% of patients overall, including 42% of patients in the olaparib-treated group. In our data, the dose was reduced in 36% patients, with no drug interruptions. Eight patients had dose re-escalation after dose reduction compared to 28 patients who maintained their reduced dose. There is the possibility that maintenance on a reduced dose may account for the lower rate of AEs in our study. Additionally, in a real-world setting, it is difficult for physicians to record all symptoms unless informed by the patient, which could also have contributed to our lower rate of AEs. Our study is based on retrospectively collected data, and there is the possibility of bias caused by incomplete data collection.
Real-world data are important as they involve circumstances and conditions outside the scope of highly controlled clinical trial settings [13
]. RCTs focus on the efficacy of a drug, whereas real-world data can provide information about feasibility, effectiveness, safety, epidemiology, and/or the costs of treatment related to the drug [14
]. Although data from RCTs have the highest reliability, follow-up observations from completed RCT research are important as they reflect actual clinical aspects, and RCT and real-world data can complement one another.
To the best of our knowledge, this study is the first to describe a real-world experience with olaparib maintenance in HSROC patients with BRCAm. Inclusion criteria, treatment, and follow-up protocols were relatively consistent among institutions and physicians because medical practices in Korea are performed under the guidelines and recommendations of the KHIRA. Olaparib has to be prescribed every month based on laboratory tests by physician appointment, and image evaluations (mostly CT scans) are required every 3 months.
There are several potential limitations to the current study. First, it was based on retrospectively collected data. Therefore, our study may have had biases, especially due to incomplete data collection, and the lack of specific protocols and safety profiles in a real-world setting may have interfered with the accurate interpretation of data. The use of multi-institutional study data could also be considered a limitation of our study because, in a retrospective setting, multiple physicians from different institutions may not have used identical management protocols for each clinical situation. Also, the patient number was not large enough for more specific subgroup analysis, and observation time was not long enough to determine survival outcomes.