The objective of this study was to evaluate the real-world application, efficacy, and safety data of olaparib for maintenance therapy and active treatment in patients with ovarian cancer in China. Patients with ovarian cancer from 17 institutions in China treated with olaparib as maintenance or active therapy from January 2018 to March 2020 were included in this study. The medical records were reviewed, and follow-up information was collected for analysis of the patients' clinicopathologic characteristics as well as the effectiveness and safety of olaparib. A total of 251 patients receiving olaparib were included, with 84 as maintenance therapy after first-line chemotherapy (FL-M), 97 as maintenance therapy after platinum-sensitive recurrence (PSR-M), and 70 as active treatment (AT). The probability of progression-free survival (PFS) at 12 months was 87.6% in the FL-M group and 63.8% in the PSR-M group. According to the multivariate analysis, complete response (CR) to chemotherapy for the PSR-M patients was the only factor affecting the PFS (HR = 0.414, P = 0.014), and platinum sensitivity was the only factor affecting PFS improvement in the AT group (HR = 0.317, P = 0.009). In the AT group, the objective response rate was 37.1%, the CR rate was 7.1%, and 30% of the patients had stable disease. Eight (3.2%) patients discontinued olaparib due to toxicity. Anemia was the most common adverse event. In conclusion, olaparib is effective and well tolerated in the real-world setting of ovarian cancer treatment. Platinum sensitivity is positively correlated to the effectiveness of olaparib in both maintenance and active treatment.

Ovarian cancer is the leading cause of death among gynecologic malignancies, and over 70% of cases are diagnosed at the advanced stage (1, 2). Although standard treatment of optimal debulking surgery and platinum-based chemotherapy results in a response rate of approximately 80%, 70%–80% of patients still relapse within 2 years (3). In addition, recurrent ovarian cancer can rarely be cured, and patients usually die from toxicity due to chemotherapy or acquired drug resistance (4, 5). In recent years, researchers have continued to explore innovative treatment approaches targeting different anticancer mechanisms.

One of the novel drug classes is PARP inhibitors, which target DNA repair. PARP is a nuclear enzyme involved in single-strand break repair through the base excision repair pathway (6). In the absence of PARP activity, the lesions are converted into double-strand breaks, which can be repaired by homologous recombination (6). Mutations in homologous recombination repair genes, such as breast cancer gene (BRCA)1/2, lead to homologous recombination deficiency (7). PARP inhibitors induce the persistence of DNA lesions and subsequent apoptosis in BRCA1/2-deficient tumor cells; thus, PARP is a therapeutic target for patients with BRCA1/2 mutations (8).

Olaparib was the first PARP inhibitor to be developed and approved for the treatment of ovarian cancer (9). In 2017, the FDA extended the maintenance indication of olaparib to BRCA-mutated (BRCAm) and nonmutated patients with ovarian cancer. In 2018, it approved olaparib as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer with a BRCA mutation following platinum-based chemotherapy. This approval was based on the results of the SOLO1 trial, which demonstrated a significantly prolonged progression-free survival (PFS) in the olaparib group than in the placebo group [HR = 0.30, 95% confidence interval (CI) = 0.23–0.41; P < 0.001]. Besides, olaparib was also approved by the FDA for recurrent ovarian cancer treatment of BRCAm patients who had previously received three or more lines of chemotherapy. In August 2018, olaparib was approved by the National Medical Products Administration in China for the maintenance treatment of patients with platinum-sensitive recurrent ovarian cancer, regardless of the BRCA status. However, reimbursement of drug costs from medical insurance claims was not initiated until January 2020.

Clinical trials have strict inclusion and exclusion criteria, which do not reflect exact real-world outcomes (10). Therefore, although the efficacy and safety data of olaparib for ovarian cancer have been confirmed by high-quality clinical trials (11–14), real-world evidence is still essential for general clinical practice. The aim of this study was to retrospectively evaluate the real-world clinical data of olaparib for ovarian cancer in China to explore the extent of its off-label use, compliance, effectiveness, and safety profile.

Study design and population

The current study was a retrospective study conducted in 17 centers in China. The study protocol was approved by the Peking University Cancer Hospital & Institute Review Board (2020YJZ01). The study was conducted in compliance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Because of its retrospective design and anonymous characteristics, the requirement of informed consent from the patients was waived.

We screened consecutive patients who were treated with olaparib between January 1, 2018, and March 31, 2020, in the 17 centers. The search terms for potentially eligible patients were “olaparib” in the medical records and “ovarian cancer” in the pathologic records. As olaparib is expensive, the number of patients who had used this drug was limited. The inclusion criteria of the patients in this study were as follows: (i) at least 18 years old; (ii) having pathologically confirmed epithelial ovarian cancer, fallopian tube cancer, or peritoneal cancer; (iii) received olaparib for at least 1 month, unless it was discontinued because of toxicity. Patients were excluded from this study if they had borderline epithelial tumors or concurrent chemotherapy.

Outcomes

The efficacy of olaparib treatment was measured by the PFS and the objective response rate (ORR). PFS was defined as the interval between the day olaparib was started and the progression of disease or the last follow-up. The response to olaparib was described as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), based on the RECIST 1.1 (15). The ORR was defined as CR + PR. The safety of olaparib treatment was evaluated by adverse events (AE), which were graded according to the Common Terminology Criteria for Adverse Events, version 5.0 (16).

Data collection

Data were extracted from the patients' medical records. The baseline clinical characteristics of all included patients were collected. The information regarding the indication for olaparib treatment, including maintenance treatment of patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who were in CR or PR to first-line platinum-based chemotherapy (FL-M), maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were in CR or PR to platinum-based chemotherapy (PSR-M), and active treatment (AT) of patients with recurrent advanced ovarian cancer, was also compiled. In AT group, both platinum-sensitive and platinum-resistant recurrence were included. Platinum-sensitive recurrence was defined as relapse over 6 months from CR or PR to the last platinum-based chemotherapy. In addition, the reasons for dose reduction or drug interruption, other than toxicity, were noted.

The patients received oral olaparib tablets (300 mg, twice daily) and were followed up monthly with AE evaluation until disease progression. Imaging exams, including ultrasound, CT, or MRI, were conducted every 3 months or at the physician's discretion. The last follow-up was on March 31, 2020.

Statistical analysis

The categorical variables were described as a percentage, and the continuous variables were described as a median and range. The PFS was analyzed using the Kaplan–Meier method. Univariate and multivariate Cox regression models were established to determine factors that could affect the PFS for patients receiving olaparib treatment. If the P value was less than 0.1 according to the univariate analysis, this factor would be taken into multivariate analysis. Statistical analyses were performed using SPSS software, version 22.0.

Data availability

All data and materials generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Patient characteristics

The details of the clinical characteristics of the included patients are listed in Table 1. A total of 253 potentially eligible patients were screened, and 251 patients were ultimately included in the current study. Two cases were excluded because of the pathologic diagnosis of borderline tumors. The median age of the included patients was 55 (range: 33–86) years old. Among the included patients receiving olaparib, 84 patients (33.5%, 84/251) were in the FL-M group, 97 patients (38.6%, 97/251) were in the PSR-M group, and 70 patients (27.9%, 70/251) were in the AT group. The percentages of high-grade serous carcinomas in the FL-M, PSR-M, and AT groups were 89.3%, 82.5%, and 78.6%, respectively. Seven patients in the FL-M group, 3 patients in the PSR-M group, and 1 patient in the AT group discontinued treatment due to economic reasons.

Table 1.

Patient characteristics of all 251 included patients.

FL-M groupPSR-M groupAT groupTotal
Characteristics(N = 84)(N = 97)(N = 70)(N = 251)
Age (years), median (range) 56 (33–86) 55 (37–83) 55 (37–83) 55 (33–86) 
Tumor location, n (%) 
 Ovary 80 (95.2) 91 (93.8) 68 (97.1) 239 (95.2) 
 Fallopian tube 2 (2.4) 5 (5.2) 2 (2.9) 9 (3.6) 
 Primary peritoneum 2 (2.4) 1 (1.0) 3 (1.2) 
Histology, n (%) 
 Serous 81 (96.4) 89 (91.8) 64 (91.4) 234 (93.2) 
 Endometrioid 1 (1.0) 1 (1.4) 2 (0.8) 
 Clear cell 1 (1.2) 5 (5.2) 2 (2.9) 8 (3.2) 
 Others 2 (2.4) 2 (2.0) 3 (4.3) 7 (2.8) 
Tumor grade, n (%) 
 High 78 (92.9) 87 (89.7) 58 (82.9) 223 (88.8) 
 Low 5 (6.0) 6 (6.2) 9 (12.9) 20 (8.0) 
 Unknown 1 (1.1) 4 (4.1) 3 (4.2) 8 (3.2) 
Initial FIGO stage, n (%) 
 I 8 (9.5) 9 (6.3) 17 (6.8) 
 II 7 (8.3) 9 (6.3) 5 (7.1) 21 (8.4) 
 III 50 (59.5) 55 (56.7) 42 (60.0) 147 (58.5) 
 IV 14 (16.7) 16 (16.5) 18 (25.7) 48 (19.1) 
 Unknown 5 (6.0) 8 (8.2) 5 (7.1) 18 (7.2) 
Germline BRCA status, n (%) 
 BRCA1 mutation 37 (44.0) 24 (24.7) 21 (30.0) 82 (32.7) 
 BRCA2 mutation 9 (10.7) 10 (10.3) 5 (7.1) 24 (9.6) 
 BRCA wild-type 25 (29.8) 34 (35.1) 26 (37.1) 85 (33.8) 
 Unknown 13 (15.5) 29 (29.9) 18 (25.7) 60 (23.9) 
Number of previous lines of chemotherapy, n (%) 
 1 84 (100) 16 (22.9) 100 (39.8) 
 2 66 (68.0) 29 (41.4) 95 (37.8) 
 3 21 (21.6) 12 (17.1) 33 (13.1) 
 ≥4 10 (10.3) 13 (18.6) 23 (9.2) 
Sensitivity to platinum-based chemotherapy, n (%) 
 Platinum-sensitive n/a n/a 28 (40.0)  
 Platinum-resistant   42 (60.0) n/a 
Response to platinum-based chemotherapy, n (%)    (N = 181) 
 CR 60 (71.4) 56 (57.7) n/a 116 (64.1) 
 PR 24 (28.6) 41 (42.3)  65 (35.9) 
Number of cycles of recent chemotherapy, n (%)    (N = 181) 
 <4 1 (1.2) 15 (15.4) n/a 16 (8.8) 
 4–8 78 (92.80) 79 (81.5)  157 (86.7) 
 >8 5 (6.0) 3 (3.1)  8 (4.4) 
Time between last course of chemotherapy and initiation of olaparib (months), n (%)    (N = 181) 
 ≤2 67 (79.8) 80 (82.5) n/a 147 (81.2) 
 >2 17 (20.2) 17 (17.5)  34 (18.8) 
FL-M groupPSR-M groupAT groupTotal
Characteristics(N = 84)(N = 97)(N = 70)(N = 251)
Age (years), median (range) 56 (33–86) 55 (37–83) 55 (37–83) 55 (33–86) 
Tumor location, n (%) 
 Ovary 80 (95.2) 91 (93.8) 68 (97.1) 239 (95.2) 
 Fallopian tube 2 (2.4) 5 (5.2) 2 (2.9) 9 (3.6) 
 Primary peritoneum 2 (2.4) 1 (1.0) 3 (1.2) 
Histology, n (%) 
 Serous 81 (96.4) 89 (91.8) 64 (91.4) 234 (93.2) 
 Endometrioid 1 (1.0) 1 (1.4) 2 (0.8) 
 Clear cell 1 (1.2) 5 (5.2) 2 (2.9) 8 (3.2) 
 Others 2 (2.4) 2 (2.0) 3 (4.3) 7 (2.8) 
Tumor grade, n (%) 
 High 78 (92.9) 87 (89.7) 58 (82.9) 223 (88.8) 
 Low 5 (6.0) 6 (6.2) 9 (12.9) 20 (8.0) 
 Unknown 1 (1.1) 4 (4.1) 3 (4.2) 8 (3.2) 
Initial FIGO stage, n (%) 
 I 8 (9.5) 9 (6.3) 17 (6.8) 
 II 7 (8.3) 9 (6.3) 5 (7.1) 21 (8.4) 
 III 50 (59.5) 55 (56.7) 42 (60.0) 147 (58.5) 
 IV 14 (16.7) 16 (16.5) 18 (25.7) 48 (19.1) 
 Unknown 5 (6.0) 8 (8.2) 5 (7.1) 18 (7.2) 
Germline BRCA status, n (%) 
 BRCA1 mutation 37 (44.0) 24 (24.7) 21 (30.0) 82 (32.7) 
 BRCA2 mutation 9 (10.7) 10 (10.3) 5 (7.1) 24 (9.6) 
 BRCA wild-type 25 (29.8) 34 (35.1) 26 (37.1) 85 (33.8) 
 Unknown 13 (15.5) 29 (29.9) 18 (25.7) 60 (23.9) 
Number of previous lines of chemotherapy, n (%) 
 1 84 (100) 16 (22.9) 100 (39.8) 
 2 66 (68.0) 29 (41.4) 95 (37.8) 
 3 21 (21.6) 12 (17.1) 33 (13.1) 
 ≥4 10 (10.3) 13 (18.6) 23 (9.2) 
Sensitivity to platinum-based chemotherapy, n (%) 
 Platinum-sensitive n/a n/a 28 (40.0)  
 Platinum-resistant   42 (60.0) n/a 
Response to platinum-based chemotherapy, n (%)    (N = 181) 
 CR 60 (71.4) 56 (57.7) n/a 116 (64.1) 
 PR 24 (28.6) 41 (42.3)  65 (35.9) 
Number of cycles of recent chemotherapy, n (%)    (N = 181) 
 <4 1 (1.2) 15 (15.4) n/a 16 (8.8) 
 4–8 78 (92.80) 79 (81.5)  157 (86.7) 
 >8 5 (6.0) 3 (3.1)  8 (4.4) 
Time between last course of chemotherapy and initiation of olaparib (months), n (%)    (N = 181) 
 ≤2 67 (79.8) 80 (82.5) n/a 147 (81.2) 
 >2 17 (20.2) 17 (17.5)  34 (18.8) 

Abbreviations: AT group, patients receiving active treatment; CR, complete response; FIGO, the International Federation of Gynecology and Obstetrics; FL-M group, patients receiving olaparib as maintenance therapy after first-line chemotherapy; n/a, not applicable; PR partial response; PSR-M group, patients receiving maintenance therapy after platinum-sensitive recurrence.

Among the 84 patients in the FL-M group, 15 patients had International Federation of Gynecology and Obstetrics (FIGO) stage I or II cancer, including 11 patients with a BRCA mutation, 3 patients with wild-type BRCA (BRCAwt; including 2 patients with a germline RAD51c mutation), and 1 patient without genetic testing. Of all patients in the FL-M group, 54.7% had a BRCA mutation, 29.8% had BRCAwt, and 15.5% had an unknown BRCA status. Among the 97 patients in the PSR-M group, 34 patients (35.0%) had a BRCA mutation, 34 patients (35.0%) had BRCAwt, and the remaining 39 (29.9%) patients had an unknown BRCA status. The proportion of patients who had received second-line chemotherapy, that is, maintenance therapy for their first relapse, was 68% (66/97). The percentage of patients who achieved a CR before the maintenance treatment was 71.4% in the FL-M group and 57.7% in the PSR-M group. About 80% of patients in both the FL-M and PSR-M groups began olaparib maintenance therapy within 2 months of finishing chemotherapy.

Of the 70 patients in the AT group, 15 were treated with other targeted drugs in combination, including 11 with bevacizumab and 4 with tyrosine kinase inhibitors such as apatinib or anlotinib. Among the 15 patients receiving combined drug therapy, 5 had a BRCA mutation, 9 had BRCAwt, and 1 had an unknown BRCA status. Among them, there were only 3 patients with platinum-sensitive recurrence and 12 patients with platinum-resistant recurrence. Of the 70 patients in the AT group, 18 were not tested for BRCA, 26 had BRCAwt, and 26 had a BRCA mutation. There were 25 patients (35.7%) who had received three lines of chemotherapy previously, while most of the patients (64.3%) had only received one to two lines of chemotherapy previously.

The follow-up times [median (range)] for the FL-M group, PSR-M group, AT group, and all included patients were 9 (1–24) months, 13 (2–26) months, 7.5 (1–25) months, and 9 (1–26) months, respectively.

Treatment response and PFS for the included patients after olaparib treatment

As only patients in the AT group had solid lesions to be measured, the ORR was evaluated in those 70 AT patients. The ORR of the AT group was 37.1% (26/70). Patients with platinum-sensitive recurrence, BRCAm, or fewer than three previous lines of chemotherapy achieved a better ORR. The olaparib treatment response of the AT patients is shown in Table 2.

Table 2.

The treatment response of 70 patients receiving olaparib as active treatment.

No. of patientsCR, n (%)PR, n (%)ORR, n (%)SD, n (%)PD, n (%)
AT group705 (7.1)21 (30)26 (37.1)21 (30)23 (32.9)
Platinum sensitivity 
 Sensitive 28 4 (14.3) 16 (57.1) 20 (71.4) 5 (17.9) 3 (10.7) 
 Resistant 42 1 (2.4) 5 (11.9) 6 (14.3) 16 (38.1) 20 (47.6) 
Germline BRCA status 
 Mutated BRCA 26 1 (3.8) 9 (34.6) 10 (38.4) 8 (30.8) 8 (30.8) 
 Wild-type BRCA 26 0 (0) 2 (7.7) 2 (7.7) 10 (38.5) 14 (53.8) 
Number of previous lines of chemotherapy 
 <3 45 5 (11.1) 16 (35.6) 21 (46.7) 13 (28.9) 11 (24.4) 
 ≥3 25 0 (0) 5 (20.0) 5 (20.0) 8 (32.0) 12 (48.0) 
No. of patientsCR, n (%)PR, n (%)ORR, n (%)SD, n (%)PD, n (%)
AT group705 (7.1)21 (30)26 (37.1)21 (30)23 (32.9)
Platinum sensitivity 
 Sensitive 28 4 (14.3) 16 (57.1) 20 (71.4) 5 (17.9) 3 (10.7) 
 Resistant 42 1 (2.4) 5 (11.9) 6 (14.3) 16 (38.1) 20 (47.6) 
Germline BRCA status 
 Mutated BRCA 26 1 (3.8) 9 (34.6) 10 (38.4) 8 (30.8) 8 (30.8) 
 Wild-type BRCA 26 0 (0) 2 (7.7) 2 (7.7) 10 (38.5) 14 (53.8) 
Number of previous lines of chemotherapy 
 <3 45 5 (11.1) 16 (35.6) 21 (46.7) 13 (28.9) 11 (24.4) 
 ≥3 25 0 (0) 5 (20.0) 5 (20.0) 8 (32.0) 12 (48.0) 

Abbreviations: AT group, patients receiving active treatment; CR, complete response; FL-M group, patients receiving olaparib as maintenance therapy after first-line chemotherapy; PD, progressive disease; PR partial response; PSR-M group, patients receiving maintenance therapy after platinum-sensitive recurrence; SD, stable disease.

Figure 1 illustrates the Kaplan–Meier curves for the PFS of the three subgroups of patients. Progression events were observed in 62 patients (24.7%, 62/251), including 7 (8.3%, 7/84) in the FL-M group, 32 (33.0%, 32/97) in the PSR-M group, and 23 (32.9%, 23/70) in the AT group. The 12-month PFS of the FL-M group was 87.6% (95% CI: 72.3–94.8). One patient died because of disease progression during follow-up. Among the PSR-M patients, the 12-month PFS was 63.8% (95% CI: 51.9–73.6). Nine patients died because of disease progression during follow-up. The patients in the AT group had a median PFS of 6 (95% CI: 3.418–8.582) months, and the 12-month PFS was 31.1% (95% CI: 17.9–45.3). Sixteen patients died of disease progression during follow-up.

Figure 1.

Kaplan–Meier curves for PFS in the FL-M group, patients receiving olaparib as maintenance therapy after first-line treatment (A); the PSR-M group, patients receiving olaparib as maintenance therapy after platinum-sensitive recurrence (B); and the AT group, patients receiving olaparib as active treatment (C).

Figure 1.

Kaplan–Meier curves for PFS in the FL-M group, patients receiving olaparib as maintenance therapy after first-line treatment (A); the PSR-M group, patients receiving olaparib as maintenance therapy after platinum-sensitive recurrence (B); and the AT group, patients receiving olaparib as active treatment (C).

Close modal

Influencing factors for PFS

No factor was found to influence the PFS of the patients in the FL-M group. According to multivariate analysis, the type of response (CR vs. PR) to the last course of chemotherapy was an independent predictor for the PFS in the PSR-M group (Fig. 2A), and the platinum sensitivity of the patients had a significant impact on the PFS in the AT group (Fig. 2B). The details of the regression results are shown in Table 3.

Figure 2.

Kaplan–Meier curves for PFS. A, Patients in the PSR-M group reaching a CR after chemotherapy had a better PFS than those reaching a PR after chemotherapy (log-rank test: HR = 0.414, 95% CI: 0.205–0.836, P = 0.014). B, Patients in the AT group who were sensitive to the last course of platinum chemotherapy had a better PFS than those who were not sensitive to the last course of platinum chemotherapy (log-rank test: HR = 0.317, 95% CI: 0.134–0.747, P = 0.009).

Figure 2.

Kaplan–Meier curves for PFS. A, Patients in the PSR-M group reaching a CR after chemotherapy had a better PFS than those reaching a PR after chemotherapy (log-rank test: HR = 0.414, 95% CI: 0.205–0.836, P = 0.014). B, Patients in the AT group who were sensitive to the last course of platinum chemotherapy had a better PFS than those who were not sensitive to the last course of platinum chemotherapy (log-rank test: HR = 0.317, 95% CI: 0.134–0.747, P = 0.009).

Close modal
Table 3.

Cox regression analysis of factors associated with PFS in the three groups.

Univariate analysisMultivariate analysis
HR (95% CI)PHR (95% CI)P
FL-M group (N = 84) 
Age 1.029 (0.961–1.100) 0.410   
Response to last course of chemotherapy 0.520 (0.115–2.339) 0.394   
(CR vs. PR)     
Cycles of last course of chemotherapy 0.295 (0.066–1.326) 0.111   
(≥6 vs. <6)     
Dose reduction 1.451 (0.281–7.500) 0.657   
(No vs. yes)     
Stage 0.036 (0–307.584) 0.472   
I/II vs. III/IV     
Germline BRCA status 0.341 (0.061–1.899) 0.219   
(Mutated vs. wild type)     
Time between last course of chemotherapy and initiation of olaparib 0.657 (0.078–5.511) 0.698   
(≤2 months vs. >2 months)     
PSR-M group (N = 97) 
Response to last course of chemotherapy 0.414 (0.205–0.836) 0.014 0.414 (0.205–0.836) 0.014 
(CR vs. PR)     
Age 1.036 (1.001–1.073) 0.046 1.023 (0.987–1.06) 0.214 
Cycles of last course of chemotherapy 2.084 (0.931–4.666) 0.074 1.502 (0.641–3.525) 0.349 
(<4 vs. ≥4)     
Dose reduction 0.522 (0.251–1.084) 0.081 0.555 (0.266–1.156) 0.116 
(No vs. yes)     
Germline BRCA status   — — 
(Mutated vs. wild type) 0.888 (0.39–2.025) 0.778   
Previous lines of chemotherapy 0.746 (0.261–2.132) 0.585 — — 
(≤3 vs. >3)     
Time between last course of chemotherapy and initiation of olaparib 0.812 (0.349–1.888) 0.629 — — 
(≤2 months vs. >2 months)     
AT group (N = 70) 
Platinum sensitivity 0.216 (0.097–0.477) <0.001 0.255 (0.103–0.633) 0.003 
(sensitive vs. resistant)     
Previous lines of chemotherapy 0.457 (0.243–0.86) 0.015 0.881 (0443–1.756) 0.72 
(≤3 vs. >3)     
Germline BRCA status     
(Mutated vs. wild type) 0.497 (0.247–0.998) 0.049 0.971 (0.451–2.089) 0.94 
Dose reduction 0.477 (0.197–1.155) 0.101 — — 
(No vs. yes)     
Age 0.976 (0.946–1.007) 0.128 — — 
Combined with other targeted therapy 0.894 (0.424–1.883) 0.767 — — 
(No vs. yes)     
Univariate analysisMultivariate analysis
HR (95% CI)PHR (95% CI)P
FL-M group (N = 84) 
Age 1.029 (0.961–1.100) 0.410   
Response to last course of chemotherapy 0.520 (0.115–2.339) 0.394   
(CR vs. PR)     
Cycles of last course of chemotherapy 0.295 (0.066–1.326) 0.111   
(≥6 vs. <6)     
Dose reduction 1.451 (0.281–7.500) 0.657   
(No vs. yes)     
Stage 0.036 (0–307.584) 0.472   
I/II vs. III/IV     
Germline BRCA status 0.341 (0.061–1.899) 0.219   
(Mutated vs. wild type)     
Time between last course of chemotherapy and initiation of olaparib 0.657 (0.078–5.511) 0.698   
(≤2 months vs. >2 months)     
PSR-M group (N = 97) 
Response to last course of chemotherapy 0.414 (0.205–0.836) 0.014 0.414 (0.205–0.836) 0.014 
(CR vs. PR)     
Age 1.036 (1.001–1.073) 0.046 1.023 (0.987–1.06) 0.214 
Cycles of last course of chemotherapy 2.084 (0.931–4.666) 0.074 1.502 (0.641–3.525) 0.349 
(<4 vs. ≥4)     
Dose reduction 0.522 (0.251–1.084) 0.081 0.555 (0.266–1.156) 0.116 
(No vs. yes)     
Germline BRCA status   — — 
(Mutated vs. wild type) 0.888 (0.39–2.025) 0.778   
Previous lines of chemotherapy 0.746 (0.261–2.132) 0.585 — — 
(≤3 vs. >3)     
Time between last course of chemotherapy and initiation of olaparib 0.812 (0.349–1.888) 0.629 — — 
(≤2 months vs. >2 months)     
AT group (N = 70) 
Platinum sensitivity 0.216 (0.097–0.477) <0.001 0.255 (0.103–0.633) 0.003 
(sensitive vs. resistant)     
Previous lines of chemotherapy 0.457 (0.243–0.86) 0.015 0.881 (0443–1.756) 0.72 
(≤3 vs. >3)     
Germline BRCA status     
(Mutated vs. wild type) 0.497 (0.247–0.998) 0.049 0.971 (0.451–2.089) 0.94 
Dose reduction 0.477 (0.197–1.155) 0.101 — — 
(No vs. yes)     
Age 0.976 (0.946–1.007) 0.128 — — 
Combined with other targeted therapy 0.894 (0.424–1.883) 0.767 — — 
(No vs. yes)     

AEs

The details of AEs for the included patients are listed in Table 4. Anemia was the most common AE resulting in dose interruption, reduction, or discontinuation. Meanwhile, nausea/vomiting was the most common nonhematologic AE. Eight patients discontinued olaparib due to AEs, including four cases of anemia, two cases of nausea/vomiting, one case of neutropenia, and one case of rash. The median time from the initiation of olaparib to the first dose reduction was 2 months (range: 1–11 months), while most cases of dose reduction (76.9%, 50/65) happened within the first 3 months of treatment (Fig. 3).

Table 4.

AEs for 251 patients treated with olaparib.

Result in dose interruption, n (%)Result in dose reduction, n (%)Result in drug discontinuation, n (%)
Adverse eventsTotalG1/2, n (%)G3/4, n (%)TotalG1/2, n (%)G3/4, n (%)TotalG1/2, n (%)G3/4, n (%)
Total 56 (22.3) 32 (12.7) 24 (9.6) 65 (25.9) 41 (16.3) 24 (9.6) 8 (3.2) 1 (0.4) 7 (2.8) 
Anemia 30 (11.9) 13 (5.2) 17 (6.8) 36 (14.3) 20 (8) 16 (6.3) 4 (1.6) 1 (0.4) 3 (1.2) 
Nausea/vomiting 8 (3.2) 7 (2.8) 1 (0.4) 11 (4.4) 9 (3.6) 2 (0.8) 2 (0.8) 2 (0.8) 
Neutropenia 4 (1.6)  4 (1.6) 5 (2) 1 (0.4) 4 (1.6) 1 (0.4) 1 (0.4) 
Thrombocytopenia 4 (1.6) 3 (1.2) 1 (0.4) 4 (1.6) 3 (1.2) 1 (0.4) 
Rash 2 (0.8) 1 (0.4) 1 (0.4) 2 (0.8) 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 
Fatigue 2 (0.8) 2 (0.8) 2 (0.8) 2 (0.8) 
Oral mucositis 2 (0.8) 2 (0.8) 2 (0.8) 2 (0.8) 
Constipation 1 (0.4) 1 (0.4) 1 (0.4) 
Palpitation 1 (0.4) 1 (0.4) 1 (0.4) 
Arthralgia 1 (0.4) 1 (0.4) 
Elevated ALT/AST 1 (0.4) 1 (0.4) 
Elevated creatinine 1 (0.4) 1 (0.4) 
Result in dose interruption, n (%)Result in dose reduction, n (%)Result in drug discontinuation, n (%)
Adverse eventsTotalG1/2, n (%)G3/4, n (%)TotalG1/2, n (%)G3/4, n (%)TotalG1/2, n (%)G3/4, n (%)
Total 56 (22.3) 32 (12.7) 24 (9.6) 65 (25.9) 41 (16.3) 24 (9.6) 8 (3.2) 1 (0.4) 7 (2.8) 
Anemia 30 (11.9) 13 (5.2) 17 (6.8) 36 (14.3) 20 (8) 16 (6.3) 4 (1.6) 1 (0.4) 3 (1.2) 
Nausea/vomiting 8 (3.2) 7 (2.8) 1 (0.4) 11 (4.4) 9 (3.6) 2 (0.8) 2 (0.8) 2 (0.8) 
Neutropenia 4 (1.6)  4 (1.6) 5 (2) 1 (0.4) 4 (1.6) 1 (0.4) 1 (0.4) 
Thrombocytopenia 4 (1.6) 3 (1.2) 1 (0.4) 4 (1.6) 3 (1.2) 1 (0.4) 
Rash 2 (0.8) 1 (0.4) 1 (0.4) 2 (0.8) 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 
Fatigue 2 (0.8) 2 (0.8) 2 (0.8) 2 (0.8) 
Oral mucositis 2 (0.8) 2 (0.8) 2 (0.8) 2 (0.8) 
Constipation 1 (0.4) 1 (0.4) 1 (0.4) 
Palpitation 1 (0.4) 1 (0.4) 1 (0.4) 
Arthralgia 1 (0.4) 1 (0.4) 
Elevated ALT/AST 1 (0.4) 1 (0.4) 
Elevated creatinine 1 (0.4) 1 (0.4) 

Abbreviations: ALT, alanine aminotransferase; AST, raised aspartate aminotransferase; G, grade.

Figure 3.

The bar chart showing the proportion of patients who had their olaparib dose reduced with time. The time of the olaparib dose reduction was mainly in the first 3 months (76.9%). With the extension of the duration of medication use, the proportion of patients with an olaparib dose reduction gradually decreased.

Figure 3.

The bar chart showing the proportion of patients who had their olaparib dose reduced with time. The time of the olaparib dose reduction was mainly in the first 3 months (76.9%). With the extension of the duration of medication use, the proportion of patients with an olaparib dose reduction gradually decreased.

Close modal

Because of the high recurrence rate of ovarian cancer, the low survival rate, and the limited availability of drugs other than chemotherapy in the past, the emergence of PARP inhibitors has brought hope for the treatment of ovarian cancer (17). The current multicenter study aimed to explore the real-world clinical application of olaparib in China. Of the 251 included patients, 84 patients were in the FL-M group, 97 patients were in the PSR-M group, and 70 patients were in the AT group. The ORR of patients in the AT group was 37.1%. Patients achieving a CR after their last course of chemotherapy and platinum sensitivity were factors having a significant effect on the PFS in the PSR-M group and AT group, respectively, indicating that platinum sensitivity is essential for the efficacy of olaparib for both maintenance and active treatment.

In the PSR-M group, the 12-month PFS rate was 63.8%, which is similar to that of the SOLO2 study (65%; ref. 12). However, the patients enrolled in the SOLO2 study all had a BRCA mutation. In this study, the proportion of patients with a BRCA mutation was only 35%. It has been reported that a BRCA mutation may cause olaparib maintenance therapy to be more effective (11). However, the percentage of CR after platinum-containing chemotherapy was 57.7% (56/97) in the current study, which was higher than that in SOLO2 (46%). This may be the reason that the 12-month PFS rate in this study is close to that in SOLO2.

In the current study, we found that the only factor affecting the PFS in the PSR-M group was the response to platinum-based chemotherapy before olaparib maintenance therapy. The patients achieving a CR had a significantly better PFS than those with a PR (P = 0.014). This result is consistent with several previous clinical trials and multiple real-world studies (11, 18–20). Therefore, patients with platinum-sensitive recurrence who achieve a CR after platinum-based chemotherapy are those who benefit the most from PARP inhibitor maintenance treatment. Besides platinum sensitivity, the number of cycles of chemotherapy may affect the efficacy of the chemotherapy treatment. Patients in Study 19 and SOLO-2 were required to receive at least four cycles of platinum-based chemotherapy before olaparib maintenance therapy. In this study, 15 patients (15.4%) received fewer than four cycles of chemotherapy before olaparib maintenance therapy, and 40% of those patients reached a CR. On the other hand, the proportion of CR patients who received at least four cycles of chemotherapy was 61%, and there was no significant difference in the CR between the two groups (P = 0.13). Besides, according to the univariate analysis, there was no significant correlation between the PFS and the number of chemotherapy courses. Thus, whether the number of chemotherapy courses reached four before maintenance treatment may have little influence on the prognosis. More importantly, it is platinum sensitivity that has the most influence on whether a CR can be achieved.

Olaparib was approved by the FDA as a treatment for patients with BRCAm advanced ovarian cancer who were treated with three or more lines of chemotherapy (21). It has been reported that patients with BRCAm are more likely to respond to olaparib than those with BRCAwt (22). In the AT group of the current study, the ORR of patients with BRCAm (38.4%) was significantly greater than that of patients with BRCAwt (7.7%; P < 0.05). However, we did not find that the mutation status affected the PFS of the patients. This result may be due to the low overall number of cases and the low rate of BRCA testing (74.3%). Nevertheless, BRCA testing should be encouraged before the clinical application of olaparib to better predict the drug efficacy.

Previous studies also have shown that the therapeutic effect of olaparib deteriorates with an increase in the number of previous chemotherapy lines (23, 24). The first version of the 2020 National Comprehensive Cancer Network Guidelines for Ovarian Cancer (2020 Version 1) changed the recommendation of olaparib as the treatment of choice from after recurrence and third-line treatment or more to its use after two lines of chemotherapy to achieve a better treatment effect for patients. In this study, most of the patients (64.3%, 45/70) in the AT group received only one or two lines of chemotherapy. We found that the ORR of olaparib for patients receiving fewer than three lines of previous chemotherapy (46.7%) was much better than that for patients receiving at least three lines of chemotherapy (20%). The univariate analysis also indicated that the number of previous lines of chemotherapy had an impact on the PFS (P = 0.015). However, according to the multivariate regression analysis, we did not find that this factor was an independent factor that could influence the PFS (P = 0.72). This result may be due to the strong correlation between the number of previous lines of chemotherapy and platinum sensitivity. According to our multivariate regression analysis, platinum sensitivity is an independent factor influencing the PFS in the AT group. Meanwhile, only 8% (2/25) of the patients with three or more lines of previous chemotherapy were still platinum sensitive, compared with a platinum-sensitivity rate of 58% (26/45) for patients with fewer than three lines of previous chemotherapy, suggesting that with the increase of recurrence times, the proportion of platinum-sensitive patients significantly decreased, and the significant increase of platinum-resistant patients significantly affected the therapeutic effect of olaparib.

Previous studies have demonstrated that adding cediranib to olaparib or adding bevacizumab to niraparib can improve the ORR and PFS, compared with single-agent olaparib or niraparib in platinum-sensitive recurrent patients (25, 26). Among the patients with platinum-resistant recurrence, no randomized controlled study has been published to date. However, it has been reported that the ORR for both olaparib alone and olaparib combined with cediranib for platinum-resistant patients is fairly low at around 18% (27, 28). In this study, olaparib combined with antiangiogenic agents was not found to prolong the PFS of patients, which may be related to the small number of cases in this study and the fact that 12/15 (80%) of the patients using combination treatment had a platinum-resistant recurrence. Thus, further research is needed to improve the efficacy of PARP inhibitors in patients with platinum-resistant recurrence.

No new AEs were found in this study. The proportion of patients requiring a dose reduction was slightly higher than that of patients with a suspended dose. In a clinical trial, patients who experience an AE, especially those at level 3 or above, need to suspend the drug first and then continue to take the drug after returning to grade 1. In this real-world study, doctors sometimes directly reduce the dose of the drug but do not suspend the drug. At the same time, patients may be reluctant to suspend the drug due to a fear of its negative impact on the efficacy of treatment. Anemia is the leading cause of drug reduction and termination. Prevention, close follow-up, and aggressive treatment of anemia will improve drug safety and patient compliance. In this study, 4.4% of the patients (11/251) terminated their medication due to economic factors. This rate was even higher than the rate of 3.2% of patients who terminated their medication due to adverse drug reactions. It is hoped that this phenomenon can be significantly improved after the emergence of reimbursement after filing medical insurance claims.

In this study, 15 patients on first-line maintenance therapy had stage I or II cancer, and 46.3% had BRCAwt or an unknown BRCA status. The application of olaparib in this group of patients should be driven by a strong desire on the part of the patients and clinicians to delay recurrence through maintenance therapy. Because of the limited follow-up time, there were only seven progression events in the FL-M group, making it difficult to find possible factors affecting the PFS and the efficacy of olaparib for this group of patients.

This multicenter study is currently the largest cohort of real-world clinical application data of olaparib treatment in China, which included real-world data of olaparib in first-line maintenance treatment, maintenance treatment for platinum-sensitive recurrence, and active treatment for recurrence. However, the number of cases for each treatment group was still limited, especially for subgroup analysis. Because of the short time of entry into the Chinese market, the follow-up time of the patients was not long enough to obtain more survival data and analysis.

In summary, this multi-institutional, retrospective study focusing on olaparib for the treatment of ovarian cancer in real-world clinical practice includes the largest cohort of patients in China. Our results indicate that olaparib is effective and safe both for maintenance therapy and active treatment. Platinum sensitivity is the most important factor affecting the effectiveness of olaparib. Clinical trials investigating olaparib in different clinical settings are desperately needed to guide real-world clinical practice.

No disclosures were reported.

H. Zheng: Conceptualization, data curation, software, formal analysis, validation, investigation, visualization, writing–original draft, writing–review and editing. Y. Gao: Conceptualization, data curation, supervision, validation, investigation, visualization, project administration, writing–review and editing. H. Guo: Resources, data curation, investigation. L. Li: Data curation, formal analysis, investigation, visualization. Q. Li: Resources, data curation, validation, visualization. H. Cui: Data curation, formal analysis, validation, visualization. A. Lin: Data curation, validation, visualization. L. Sun: Data curation, validation, visualization. Y. Hu: Data curation, validation, visualization. S. Kang: Data curation, validation, visualization. W. Duan: Data curation, validation, visualization. L. Pan: Data curation, validation, visualization. S. Wang: Data curation, validation, visualization. Y. Yang: Data curation, validation, visualization. Y. Li: Data curation, validation, visualization. W. Kong: Data curation, validation, visualization. Y. Xiang: Data curation, validation, visualization. X. Tian: Data curation, validation, visualization. B. Ling: Data curation, validation, visualization. C. Ha: Data curation, validation, visualization. W. Bai: Data curation, validation, visualization.

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.

1.
Siegel
RL
,
Miller
KD
,
Jemal
A
. 
Cancer statistics, 2017
.
CA Cancer J Clin
2017
;
67
:
7
30
.
2.
Dochez
V
,
Caillon
H
,
Vaucel
E
,
Dimet
J
,
Winer
N
,
Ducarme
G
. 
Biomarkers and algorithms for diagnosis of ovarian cancer: CA125, HE4, RMI and ROMA, a review
.
J Ovarian Res
2019
;
12
:
28
.
3.
Pignata
S
,
C Cecere
S
,
Du Bois
A
,
Harter
P
,
Heitz
F
. 
Treatment of recurrent ovarian cancer
.
Ann Oncol
2017
;
28
:
viii51
viii6
.
4.
Borley
J
,
Brown
R
. 
Epigenetic mechanisms and therapeutic targets of chemotherapy resistance in epithelial ovarian cancer
.
Ann Med
2015
;
47
:
359
69
.
5.
Colombo
PE
,
Fabbro
M
,
Theillet
C
,
Bibeau
F
,
Rouanet
P
,
Ray-Coquard
I
. 
Sensitivity and resistance to treatment in the primary management of epithelial ovarian cancer
.
Crit Rev Oncol Hematol
2014
;
89
:
207
16
.
6.
Lord
CJ
,
Ashworth
A
. 
PARP inhibitors: synthetic lethality in the clinic
.
Science
2017
;
355
:
1152
8
.
7.
Ledermann
JA
,
Drew
Y
,
Kristeleit
RS
. 
Homologous recombination deficiency and ovarian cancer
.
Eur J Cancer
2016
;
60
:
49
58
.
8.
Farmer
H
,
McCabe
N
,
Lord
CJ
,
Tutt
AN
,
Johnson
DA
,
Richardson
TB
, et al
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
.
Nature
2005
;
434
:
917
21
.
9.
Lorusso
D
,
Tripodi
E
,
Maltese
G
,
Lepori
S
,
Sabatucci
I
,
Bogani
G
, et al
Spotlight on olaparib in the treatment of BRCA-mutated ovarian cancer: design, development and place in therapy
.
Drug Des Devel Ther
2018
;
12
:
1501
9
.
10.
Blonde
L
,
Khunti
K
,
Harris
SB
,
Meizinger
C
,
Skolnik
NS
. 
Interpretation and impact of real-world clinical data for the practicing clinician
.
Adv Ther
2018
;
35
:
1763
74
.
11.
Ledermann
J
,
Harter
P
,
Gourley
C
,
Friedlander
M
,
Vergote
I
,
Rustin
G
, et al
Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer
.
N Engl J Med
2012
;
366
:
1382
92
.
12.
Pujade-Lauraine
E
,
Ledermann
JA
,
Selle
F
,
Gebski
V
,
Penson
RT
,
Oza
AM
, et al
Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial
.
Lancet Oncol
2017
;
18
:
1274
84
.
13.
Moore
K
,
Colombo
N
,
Scambia
G
,
Kim
BG
,
Oaknin
A
,
Friedlander
M
, et al
Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer
.
N Engl J Med
2018
;
379
:
2495
505
.
14.
Kaufman
B
,
Shapira-Frommer
R
,
Schmutzler
RK
,
Audeh
MW
,
Friedlander
M
,
Balmana
J
, et al
Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation
.
J Clin Oncol
2015
;
33
:
244
50
.
15.
Eisenhauer
EA
,
Therasse
P
,
Bogaerts
J
,
Schwartz
LH
,
Sargent
D
,
Ford
R
, et al
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
.
Eur J Cancer
2009
;
45
:
228
47
.
16.
US Department of Health Human Services
. 
Common terminology criteria for adverse events (CTCAE) Version 5.0
; 
2017
.
17.
Tsibulak
I
,
Zeimet
AG
,
Marth
C
. 
Hopes and failures in front-line ovarian cancer therapy
.
Crit Rev Oncol Hematol
2019
;
143
:
14
9
.
18.
Coleman
RL
,
Oza
AM
,
Lorusso
D
,
Aghajanian
C
,
Oaknin
A
,
Dean
A
, et al
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial
.
Lancet
2017
;
390
:
1949
61
.
19.
Labidi-Galy
SI
,
de La Motte Rouge
T
,
Derbel
O
,
Wolfer
A
,
Kalbacher
E
,
Olivier
T
, et al
Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers
.
Gynecol Oncol
2019
;
155
:
262
9
.
20.
Cecere
SC
,
Giannone
G
,
Salutari
V
,
Arenare
L
,
Lorusso
D
,
Ronzino
G
, et al
Olaparib as maintenance therapy in patients with BRCA 1–2 mutated recurrent platinum sensitive ovarian cancer: real world data and post progression outcome
.
Gynecol Oncol
2020
;
156
:
38
44
.
21.
Kim
G
,
Ison
G
,
McKee
AE
,
Zhang
H
,
Tang
S
,
Gwise
T
, et al
FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy
.
Clin Cancer Res
2015
;
21
:
4257
61
.
22.
Gelmon
KA
,
Tischkowitz
M
,
Mackay
H
,
Swenerton
K
,
Robidoux
A
,
Tonkin
K
, et al
Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study
.
Lancet Oncol
2011
;
12
:
852
61
.
23.
Matulonis
UA
,
Penson
RT
,
Domchek
SM
,
Kaufman
B
,
Shapira-Frommer
R
,
Audeh
MW
, et al
Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety
.
Ann Oncol
2016
;
27
:
1013
9
.
24.
Penson
RT
,
Valencia
RV
,
Cibula
D
,
Colombo
N
,
Leath
CA
 3rd
,
Bidziński
M
, et al
Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial
.
J Clin Oncol
2020
;
38
:
1164
74
.
25.
Liu
JF
,
Barry
WT
,
Birrer
M
,
Lee
J-M
,
Buckanovich
RJ
,
Fleming
GF
, et al
Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study
.
Lancet Oncol
2014
;
15
:
1207
14
.
26.
Mirza
MR
,
Åvall Lundqvist
E
,
Birrer
MJ
,
dePont Christensen
R
,
Nyvang
GB
,
Malander
S
, et al
Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial
.
Lancet Oncol
2019
;
20
:
1409
19
.
27.
Colombo
N
,
Nicoletto
MO
,
Benedetti Panici
P
,
Tognon
G
,
Bologna
A
,
Lissoni
AA
, et al
BAROCCO: A randomized phase II study of weekly paclitaxel vs cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)
.
Ann Oncol
2019
;
30
:
v851
934
.
28.
Vanderstichele
A
,
Nieuwenhuysen
EV
,
Han
S
,
Concin
N
,
Gorp
TV
,
Berteloot
P
. 
Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer
.
J Clin Oncol
37
:
15s
, 
2019
(
suppl; abstr 5507
).