Abstract
In patients with platinum-sensitive relapsed (PSR) ovarian cancer, olaparib maintenance monotherapy significantly improves progression-free survival (PFS) versus placebo. However, evidence in the Asian population is lacking. This is the first study to evaluate olaparib efficacy and tolerability exclusively in Asian patients with PSR ovarian cancer.
Considering the limited placebo effect and significant clinical benefit of olaparib in previous trials, and the rapid approval of olaparib in China, this phase III study was designed as an open-label, single-arm trial. Patients with high-grade epithelial PSR ovarian cancer were enrolled from country-wide clinical centers across China and Malaysia. Patients received oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity. Primary endpoint was median PFS (mPFS). Primary analysis of PFS using the Kaplan–Meier method was performed when data reached 60% maturity (clinicaltrials.gov NCT03534453).
Between 2018 and 2020, 225 patients were enrolled, and 224 received olaparib; 35.7% had received ≥3 lines of chemotherapy, 35.3% had achieved complete response to their last line of platinum-based chemotherapy, and 41.1% had a platinum-free interval ≤12 months. At primary data cut-off (December 25, 2020), overall mPFS was 16.1 months; mPFS was 21.2 and 11.0 months in BRCA-mutated and wild-type BRCA subgroups, respectively. Adverse events (AE) occurred in 99.1% of patients (grade ≥3, 48.7%); 9.4% discontinued therapy due to treatment-related AEs.
Olaparib maintenance therapy was highly effective and well tolerated in Asian patients with PSR ovarian cancer, regardless of BRCA status. This study highlights the promising efficacy of olaparib in this Asian population.
See related commentary by Nicum and Blagden, p. 2201
Olaparib, a PARP inhibitor, has shown encouraging efficacy in patients with platinum-sensitive relapsed (PSR) ovarian cancer in global phase III trials. However, evidence in the Asian population is lacking. In this phase III, open-label, single-arm trial, olaparib maintenance monotherapy was highly effective and well tolerated in Asian patients (>90% Chinese) with PSR ovarian cancer, regardless of their BRCA status. These results reinforce the current global evidence and strongly support use of olaparib in patients with PSR ovarian cancer in Asian clinical practice. This study also demonstrates good safety in the Asian population and shows that predictors of survival may include age at first dose, response to last chemotherapy, number of prior lines of therapy, and time to disease progression after second-to-last platinum-based chemotherapy; these prognostic factors require validation in subsequent clinical studies.
Introduction
Most patients (80%) with ovarian cancer of any stage respond to platinum-based chemotherapy (first-line therapy), although the majority will eventually relapse (1). For patients with platinum-sensitive relapsed (PSR) advanced disease, chemotherapy effectiveness is limited and prognosis is poor (2–4). An alternative approach to enable consolidation and prolongation of tumor responses is to use an effective and well-tolerated oral antitumor agent; PARP inhibitors (PARPi) are a class of antitumor therapy that target cells defective in homologous recombination repair (HRR), leading to cell death via apoptosis following suppression of the DNA repair pathway (5, 6). Olaparib is a potent, orally available PARPi that targets PARP-1, -2, and -3 to mediate this synthetic lethality in cells with homologous recombination deficiency (HRD), including those with BRCA1/2 mutations (7, 8). Previous PARPi clinical trials have demonstrated their efficacy in patients with PSR ovarian cancer (Supplementary Table S1; refs. 2, 9–13), and a meta-analysis of randomized controlled trials comprising patients with PSR ovarian cancer receiving PARPi maintenance treatment demonstrated a 74%, 76%, 66%, and 51% reduced risk of progression in patients with BRCA mutation (BRCAm), somatic BRCAm (sBRCAm), HRD, and wild-type status, respectively (14). Olaparib was the first PARPi approved by the European Medicines Agency (2014) for PSR disease due to the positive efficacy observed in the phase II Study19 trial, where patients receiving olaparib had a 65% reduction in risk of progression or death (2). Subsequent approval by the Food and Drug Administration (2017) was based on results from Study19, as well as the phase III SOLO2 trial (9), which corroborated the benefit of olaparib maintenance monotherapy in patients with BRCA1/2-mutated PSR ovarian cancer. In SOLO2, patients randomized to olaparib achieved a median progression-free survival (mPFS) of 19.1 months [95% confidence interval (CI), 16.3–25.7], compared with 5.5 months with placebo (95% CI, 5.2–5.8; ref. 9). In addition, treatment with olaparib was associated with a tolerable safety profile (2, 9).
In Study19, mPFS in the placebo arm was 4.8 months (2), while in the phase III NOVA trial of niraparib versus placebo in patients with/without gBRCAm, mPFS with placebo was 5.5 months in the gBRCAm cohort, and 3.9 months in the non-gBRCAm cohort (10). Together, these results demonstrated the poor outcomes achieved with placebo in patients with PSR ovarian cancer. Subsequent studies of niraparib and fuzuloparib in Chinese patients were consistent with observations from global studies (mPFS in placebo arm, 5.4–5.5 months; refs. 10, 12, 15). Due to the limited placebo effect and significant clinical benefit of olaparib in patients with PSR ovarian cancer, in addition to improved access to olaparib in China following express approval by the National Medical Products Administration, this phase III trial, L-MOCA, was designed as a single-arm study. The study aimed to evaluate the efficacy and tolerability of olaparib in Asian patients with PSR ovarian cancer, and as such was carried out exclusively in Asia. Here, we report the primary analysis of efficacy and safety from the L-MOCA study.
Patients and Methods
Patients and sites
Patients were recruited from 28 centers in China (n = 22) and Malaysia (n = 6), from which 267 patients were screened. Patients were eligible for inclusion if they were 18 years of age or older, had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–1, and had relapsed, high-grade serous or high-grade endometrioid epithelial ovarian cancer, including primary peritoneal and/or fallopian tube cancer. Patients had to have received at least two previous lines of platinum-based chemotherapy and achieved objective response [partial response (PR) or complete response (CR), according to modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1], with no evidence of rising cancer antigen 125 levels following the last platinum-based therapy prior to study enrollment. Patients were also required to have platinum-sensitive relapsed disease, defined as disease progression occurring at least 6 months after the last dose of platinum-based chemotherapy. For subgroup analysis of the primary endpoint, we grouped patients into partially platinum-sensitive (platinum-free interval of 6–12 months) and fully platinum-sensitive (platinum-free interval of more than 12 months; ref. 16). Patients gave consent to provide blood and/or tumor samples to confirm BRCA/HRR status as part of screening procedures. The limitation for detection of BRCA single-nucleotide variant or insertion/deletion was 5%, and HRR status was determined using next-generation sequencing on a panel of 72 genes (Supplementary Table S2). Samples were collected at any time following diagnosis, but prior to study entry. Normal organ and bone marrow function was required within 28 days prior to administration of study treatment. Patients were excluded if they had previously received PARPi treatment. Informed written consent was obtained from all study participants. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The trial protocol and any amendments were approved by the national regulatory authority and the respective ethics committees at each participating institution.
Design and treatment
In this open-label, single-arm, phase III study, eligible patients with high-grade epithelial PSR ovarian cancer received oral olaparib 300 mg (tablet formulation) twice daily. Olaparib treatment was initiated within 8 weeks after the last dose of chemotherapy until investigator-assessed disease progression or unacceptable toxicity. Patients could receive treatment beyond progression if the investigator deemed that the patient was experiencing benefit and did not meet other criteria for discontinuation. If required, toxicities could be managed by treatment interruptions and dose reductions. Repeat dose interruptions were permitted, as needed, for a maximum of 28 days on each occasion. Dose reduction [to 250 mg twice daily and then, if needed, to 200 mg twice daily (minimum dose)] was permitted, and permanent discontinuation of study treatment also allowed if the reduced dose was not tolerated. Dose escalation following a dose reduction was not permitted. After discontinuation of study treatment, patients were managed as per local clinical practice, and were followed until objective disease progression as defined by RECIST 1.1.
Study endpoints and assessments
The primary endpoint was investigator-assessed mPFS, defined as the time from date of first olaparib dose to date of disease progression or death. Clinical and objective radiologic tumor assessments were conducted according to RECIST 1.1 at baseline, every 12 weeks until Week 72, and every 24 weeks thereafter until objective disease progression. After disease progression, patients were followed every 12 weeks for additional disease progression and survival analyses.
The primary endpoint was further examined by type of BRCA mutation [BRCAm; somatic (sBRCAm), gBRCAm, or wild-type (BRCAwt)]; HRR mutation status (HRRwt vs. HRRm); age group at first dose (<65 vs. ≥65 years); time to progression following last platinum-based therapy (>12 vs. 6–12 months); previous line of anticancer therapy (second- vs. third-line); and response to most recent platinum-based chemotherapy (CR vs. PR). Secondary endpoints included overall survival (OS), time to study treatment discontinuation, time to first subsequent treatment, time to second progression, and time to second subsequent treatment. Safety endpoints were assessed in terms of adverse events (AE) and serious AEs, laboratory analyses, and vital signs. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Hematology and biochemistry parameters were assessed on Day 1, 8, 15, 22, and 29, every 4 weeks until Week 72, and every 12 weeks thereafter.
Statistical analyses
The target sample size was 220 patients. Based on the BRCAm rate of 21%, an estimated 46 patients with BRCAm ovarian cancer were expected to be enrolled (17). The primary analysis was performed when the data reached approximately 60% maturity (i.e., 132 events of disease progression or death). Assuming an mPFS of 8.4 months (2), 132 progression events provide a 95% CI of 7.1 to 10.0 months, and assuming an mPFS of 19.1 months in patients with BRCAm (9), 27 progression events (60% of 46 patients with BRCAm) provide a 95% CI of 13.1 to 27.9 months. Data were summarized by descriptive statistics, while time-to-event endpoints were analyzed using the Kaplan–Meier method. All statistical analyses were conducted using SAS (version 9.4).
Data availability
The data underlying this article will be shared on reasonable request.
Results
Patients
Between March 2018 and December 2020, 225 patients were enrolled. At primary analysis data cut-off (December 25, 2020), 224 patients had received oral olaparib twice daily (full analysis set); one enrolled patient chose not to receive olaparib treatment (Fig. 1). Demographic and baseline characteristics are shown in Table 1. Briefly, all patients were female, median age was 54.0 years [interquartile range (IQR), 50.0–61.5], and most patients were from China [91.5% (n = 205), Malaysia 8.5% (n = 19)]. There were 31 (13.8%) patients with stage IV, and 152 (67.9%) with stage III disease at diagnosis. More than one third (35.7%) of patients had received ≥3 lines of chemotherapy, and 15 (6.7%) patients had received prior treatment with bevacizumab. To their last line of chemotherapy, 145 (64.7%) and 79 (35.3%) patients achieved PR and CR, respectively. More than half (58.9%) the patients had a platinum-free interval >12 months, while 40.2% and 0.9% of patients had a platinum-free interval of 6 to 12 months and <6 months, respectively (Table 1). There were 60 (26.8%) patients who had undergone secondary cytoreductive surgery. Overall, 47.3% (n = 106) were positive for BRCAm [sBRCAm 6.3% (n = 14); gBRCAm 41.1% (n = 92)], while 52.2% (n = 117) were BRCAwt, and one patient's BRCA status was unknown. For HRRm status, there were 128 (57.1%) patients with HRRm, 95 (42.4%) patients with HRRwt, and one patient's HRR status was unknown.
Baseline characteristics and patient demographicsa.
. | Olaparib (n = 224) . |
---|---|
Age, years, median (IQR) | 54.0 (50.0–61.5) |
Female, n (%) | 224 (100.0) |
Country, n (%) | |
China | 205 (91.5) |
Malaysia | 19 (8.5) |
Body mass index (kg/m2), mean (SD) | 23.86 (3.7) |
Body mass index groups, n (%) | |
≤24 kg/m2 | 121 (54.0) |
>24 kg/m2 | 103 (46.0) |
ECOG performance status score, n (%) | |
0 | 154 (68.8) |
1 | 70 (31.3) |
Primary tumor location, n (%) | |
Ovary | 203 (90.6) |
Fallopian tube | 10 (4.5) |
Peritoneum | 5 (2.2) |
Other | 6 (2.7) |
FIGO stage at initial diagnosis, n (%) | |
Stage I | 9 (4.0) |
Stage II | 26 (11.6) |
Stage III | 152 (67.9) |
Stage IV | 31 (13.8) |
Unknown | 6 (2.7) |
Histology type, n (%) | |
Serous | 215 (96.0) |
Endometrioid | 7 (3.1) |
Other | 2 (0.9) |
BRCA mutation status, n (%) | |
wt | 117 (52.2) |
Germline | 92 (41.1) |
BRCA1 | 64 (28.6) |
BRCA2 | 28 (12.5) |
Somatic | 14 (6.3) |
BRCA1 | 9 (4.0) |
BRCA2 | 5 (2.2) |
Unknownb | 1 (0.4) |
HRR mutation status, n (%) | |
HRRm | 128 (57.1) |
HRRwt | 95 (42.4) |
Unknown | 1 (0.4) |
Age group at first dose, n (%) | |
<65 years | 187 (83.5) |
≥65 years | 37 (16.5) |
Last line of anticancer therapy, n (%) | |
2nd line | 144 (64.3) |
3rd line | 52 (23.2) |
4th line and beyond | 28 (12.5) |
Prior bevacizumab use, n (%) | 15 (6.7) |
Response to last line of platinum therapy, n (%) | |
CR | 79 (35.3) |
PR | 145 (64.7) |
Platinum-free interval, n (%) | |
<6 months | 2 (0.9) |
6–12 months | 90 (40.2) |
>12 months | 132 (58.9) |
Cytoreductive surgery (prior to enrollment), n (%) | 60 (26.8) |
. | Olaparib (n = 224) . |
---|---|
Age, years, median (IQR) | 54.0 (50.0–61.5) |
Female, n (%) | 224 (100.0) |
Country, n (%) | |
China | 205 (91.5) |
Malaysia | 19 (8.5) |
Body mass index (kg/m2), mean (SD) | 23.86 (3.7) |
Body mass index groups, n (%) | |
≤24 kg/m2 | 121 (54.0) |
>24 kg/m2 | 103 (46.0) |
ECOG performance status score, n (%) | |
0 | 154 (68.8) |
1 | 70 (31.3) |
Primary tumor location, n (%) | |
Ovary | 203 (90.6) |
Fallopian tube | 10 (4.5) |
Peritoneum | 5 (2.2) |
Other | 6 (2.7) |
FIGO stage at initial diagnosis, n (%) | |
Stage I | 9 (4.0) |
Stage II | 26 (11.6) |
Stage III | 152 (67.9) |
Stage IV | 31 (13.8) |
Unknown | 6 (2.7) |
Histology type, n (%) | |
Serous | 215 (96.0) |
Endometrioid | 7 (3.1) |
Other | 2 (0.9) |
BRCA mutation status, n (%) | |
wt | 117 (52.2) |
Germline | 92 (41.1) |
BRCA1 | 64 (28.6) |
BRCA2 | 28 (12.5) |
Somatic | 14 (6.3) |
BRCA1 | 9 (4.0) |
BRCA2 | 5 (2.2) |
Unknownb | 1 (0.4) |
HRR mutation status, n (%) | |
HRRm | 128 (57.1) |
HRRwt | 95 (42.4) |
Unknown | 1 (0.4) |
Age group at first dose, n (%) | |
<65 years | 187 (83.5) |
≥65 years | 37 (16.5) |
Last line of anticancer therapy, n (%) | |
2nd line | 144 (64.3) |
3rd line | 52 (23.2) |
4th line and beyond | 28 (12.5) |
Prior bevacizumab use, n (%) | 15 (6.7) |
Response to last line of platinum therapy, n (%) | |
CR | 79 (35.3) |
PR | 145 (64.7) |
Platinum-free interval, n (%) | |
<6 months | 2 (0.9) |
6–12 months | 90 (40.2) |
>12 months | 132 (58.9) |
Cytoreductive surgery (prior to enrollment), n (%) | 60 (26.8) |
Abbreviations: CR, complete response; ECOG, Eastern Cooperative Oncology Group; FIGO, The International Federation of Gynecology and Obstetrics; HRR, homologous recombination repair; IQR, interquartile range; m, mutation; PR, partial response; SD, standard deviation; wt, wild type.
aData presented for patients in full analysis set.
bStatus unknown due to test failure in both blood and tumor samples.
Efficacy
After a median follow-up of 15.5 months, we performed the primary efficacy analysis upon 139 (62.1%) investigator-assessed events of disease progression or death [n = 136 (60.7%) patients had disease progression, n = 3 (1.3%) died prior to disease progression). Overall mPFS was 16.1 months (95% CI, 13.3–18.3; Fig. 2A), and the estimated 6-month and 12-month PFS rates were 76.0% (95% CI, 69.8–81.2) and 57.1% (95% CI, 50.2–63.5), respectively. Subgroup analysis showed that mPFS was 21.2 months (95% CI, 16.4–24.9) and 11.0 months (95% CI, 8.3–15.8) in patients with BRCAm and BRCAwt, respectively. Analysis by BRCAm subgroup (Table 2) revealed that mPFS was 16.1 months (95% CI, 5.9–not evaluable) and 21.4 months (95% CI, 16.5–24.9) in patients with sBRCAm and gBRCAm, respectively (Fig. 2B). Patients with HRRm versus those with HRRwt status had an mPFS of 18.3 (95% CI, 14.5–24.1) versus 13.3 months (95% CI, 8.3–16.5; Table 2).
Kaplan–Meier estimates of PFS (full analysis set). A, Overall analysis and B, subgroup analysis of BRCA mutation type. Primary efficacy analysis was performed after 139 investigator-assessed events of disease progression or death (60.7% of patients had disease progression, n = 136; 1.3% died prior to disease progression, n = 3). CI, confidence interval; NE, not evaluable.
Kaplan–Meier estimates of PFS (full analysis set). A, Overall analysis and B, subgroup analysis of BRCA mutation type. Primary efficacy analysis was performed after 139 investigator-assessed events of disease progression or death (60.7% of patients had disease progression, n = 136; 1.3% died prior to disease progression, n = 3). CI, confidence interval; NE, not evaluable.
Subgroup analysis of mPFS.
. | Patients with event, n (%) . | mPFS (95% CI) . |
---|---|---|
BRCA mutation status | ||
BRCAm | 56 (25.0) | 21.2 (16.4–24.9) |
Germline BRCAm | 48 (21.4) | 21.4 (16.5–24.9) |
Somatic BRCAm | 8 (3.6) | 16.1 (5.9–NE) |
BRCAwt | 82 (36.6) | 11.0 (8.3–15.8) |
HRR mutation status | ||
HRRm | 69 (30.8) | 18.3 (14.5–24.1) |
HRRwt | 69 (30.8) | 13.3 (8.3–16.5) |
Age group at first dose | ||
<65 years | 117 (52.2) | 15.8 (11.0–18.2) |
| 22 (9.8) | 19.7 (11.1–22.2) |
Last line of previous anticancer therapy | ||
2nd line | 82 (36.6) | 18.0 (15.8–22.1) |
3rd line | 38 (17.0) | 8.8 (6.8–13.9) |
4th line and beyond | 19 (8.5) | 13.3 (5.5–20.1) |
Time to disease progression on second to last platinum-based chemotherapy | ||
>12 months | 70 (31.3) | 20.9 (16.2–24.1) |
6–12 months | 67 (29.9) | 9.3 (8.3–14.1) |
Best response | ||
CR | 43 (19.2) | 19.7 (15.8–22.2) |
PR | 96 (42.9) | 13.9 (11.0–16.6) |
. | Patients with event, n (%) . | mPFS (95% CI) . |
---|---|---|
BRCA mutation status | ||
BRCAm | 56 (25.0) | 21.2 (16.4–24.9) |
Germline BRCAm | 48 (21.4) | 21.4 (16.5–24.9) |
Somatic BRCAm | 8 (3.6) | 16.1 (5.9–NE) |
BRCAwt | 82 (36.6) | 11.0 (8.3–15.8) |
HRR mutation status | ||
HRRm | 69 (30.8) | 18.3 (14.5–24.1) |
HRRwt | 69 (30.8) | 13.3 (8.3–16.5) |
Age group at first dose | ||
<65 years | 117 (52.2) | 15.8 (11.0–18.2) |
| 22 (9.8) | 19.7 (11.1–22.2) |
Last line of previous anticancer therapy | ||
2nd line | 82 (36.6) | 18.0 (15.8–22.1) |
3rd line | 38 (17.0) | 8.8 (6.8–13.9) |
4th line and beyond | 19 (8.5) | 13.3 (5.5–20.1) |
Time to disease progression on second to last platinum-based chemotherapy | ||
>12 months | 70 (31.3) | 20.9 (16.2–24.1) |
6–12 months | 67 (29.9) | 9.3 (8.3–14.1) |
Best response | ||
CR | 43 (19.2) | 19.7 (15.8–22.2) |
PR | 96 (42.9) | 13.9 (11.0–16.6) |
Abbreviations: CI, confidence interval; m, mutation; CR, complete response; HRR, homologous recombination repair; NE, not evaluable; PR, partial response; wt, wild type.
Subgroup analysis of the primary endpoint by other baseline clinical characteristics (Table 2) showed that patients who were aged <65 years at first dose had an mPFS of 15.8 months (95% CI, 11.0–18.2), and those who were ≥65 years of age had an mPFS of 19.7 months (95% CI, 11.1–22.2). Patients who achieved CR to last chemotherapy prior to study enrollment had an mPFS of 19.7 months (95% CI, 15.8–22.2), compared with 13.9 months (95% CI, 11.0–16.6) in patients who achieved PR. In patients who were previously treated with second- and third-line anticancer treatment, mPFS was 18.0 months (95% CI, 15.8–22.1) and 8.8 months (95% CI, 6.8–13.9), respectively. Patients who progressed after 12 months versus 6–12 months after second-to-last platinum-based chemotherapy had an mPFS of 20.9 months (95% CI, 16.2–24.1) versus 9.3 months (95% CI, 8.3–14.1).
Secondary endpoint analyses (N = 224) showed that median time to first subsequent treatment or death was 19.0 months (95% CI, 16.7–21.8); at 12 months, 89.1% (95% CI, 84.2–92.6) of patients were free from subsequent treatment or death. Median time from first dose to second progression was 26.2 months (95% CI, 23.6–not reached), and the 12-month second progression-free rate was 87.1% (95% CI, 81.8–91.0). Median time to study treatment discontinuation was 13.8 months (95% CI, 9.8–16.2). The percentage of patients remaining on treatment at 12 months was 50.8% (95% CI, 44.1–57.1). At primary data cut-off, median time to second subsequent treatment or death and median OS had not been reached.
Safety
The incidence of AEs of any CTCAE grade was 99.1%; the most common AEs of any grade were anemia (76.4%), nausea (54.0%), and leukopenia (24.1%; Table 3). AEs of grade 3 or higher were reported in 48.7% of patients; among these, anemia (25.0%), decreased neutrophil count (14.3%), and decreased platelet count (4.9%) were most common. Serious AEs occurred in 57 (25.4%) patients, of which 39 (17.4%) cases were treatment-related. There were three cases (1.3%) of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), two of which occurred during the treatment period (Supplementary Table S3).
Summary of AEs.
n (%)a . | Olaparib (n = 224) . | |
---|---|---|
Any AE | 222 (99.1) | |
Grade ≥3 | 109 (48.7) | |
Treatment-related AE | 220 (98.2) | |
Grade ≥3 | 96 (42.9) | |
Any serious AE | 57 (25.4) | |
Treatment-related serious AE | 39 (17.4) | |
Any AE leading to treatment discontinuation | 22 (9.8) | |
Treatment-related AE leading to treatment discontinuation | 21 (9.4) | |
Any AE occurring in >10% of patients | Grade 1 or 2 | Grade 3 or 4 |
Anemia | 115 (51.4) | 56 (25.0) |
Nausea | 120 (53.6) | 1 (0.4) |
Leukopenia | 46 (20.5) | 8 (3.6) |
Vomiting | 52 (23.2) | 5 (2.2) |
Neutropenia | 30 (13.4) | 12 (5.4) |
Decreased appetite | 41 (18.3) | 0 (0.0) |
Cough | 26 (11.6) | 0 (0.0) |
Nasopharyngitis | 26 (11.6) | 0 (0.0) |
Thrombocytopenia | 18 (8.1) | 6 (2.7) |
n (%)a . | Olaparib (n = 224) . | |
---|---|---|
Any AE | 222 (99.1) | |
Grade ≥3 | 109 (48.7) | |
Treatment-related AE | 220 (98.2) | |
Grade ≥3 | 96 (42.9) | |
Any serious AE | 57 (25.4) | |
Treatment-related serious AE | 39 (17.4) | |
Any AE leading to treatment discontinuation | 22 (9.8) | |
Treatment-related AE leading to treatment discontinuation | 21 (9.4) | |
Any AE occurring in >10% of patients | Grade 1 or 2 | Grade 3 or 4 |
Anemia | 115 (51.4) | 56 (25.0) |
Nausea | 120 (53.6) | 1 (0.4) |
Leukopenia | 46 (20.5) | 8 (3.6) |
Vomiting | 52 (23.2) | 5 (2.2) |
Neutropenia | 30 (13.4) | 12 (5.4) |
Decreased appetite | 41 (18.3) | 0 (0.0) |
Cough | 26 (11.6) | 0 (0.0) |
Nasopharyngitis | 26 (11.6) | 0 (0.0) |
Thrombocytopenia | 18 (8.1) | 6 (2.7) |
Abbreviation: AE, adverse event.
aPercentages are based on the number of subjects in the full analysis set.
Median duration of olaparib exposure was 300.5 days (IQR, 169.0–552.0), and median daily dose of olaparib was 589.5 mg (IQR, 508.1–596.5). Treatment-related AEs led to dose reduction in 100 (44.6%) patients, and to treatment discontinuation in 21 (9.4%) patients.
Discussion
In this open-label, single-arm, phase III study, oral olaparib monotherapy in Asian patients (91.5% Chinese) with PSR ovarian cancer led to a promising duration of PFS per investigator assessment of the primary endpoint (overall mPFS 16.1 months; 95% CI, 13.3–18.3). Furthermore, oral olaparib monotherapy was well tolerated in this patient population. In Study19, overall mPFS in patients with PSR ovarian cancer (with/without gBRCAm) randomized to olaparib was 8.4 months (2). It is worth noting that an olaparib capsule was used in Study19, and we speculate that this discrepancy may explain some of the differences observed between these two studies, but data directly comparing olaparib treatment formulations are not currently available. Future studies should investigate the role olaparib formulation plays in patient outcomes, allowing better interpretation of these clinical data. We also note the higher proportion of patients with germline BRCA2 mutations in L-MOCA compared with Study19 (12.5% vs. 4.4%, respectively). While evidence in the PSR ovarian cancer population is lacking, a sub-analysis of the SOLO1 trial (olaparib maintenance in newly diagnosed ovarian cancer) demonstrated increased PARPi sensitivity among BRCA2 compared with BRCA1 patients (18). The reason for the higher proportion of patients with BRCA2 in L-MOCA compared with Study19 may be due to a higher rate of BRCA2 among Asian patients (19); however, the rate of germline BRCA2 mutation in L-MOCA did not exceed that reported for the international NOVA (37.0%) and SOLO2 (29.6%) trials (9, 10). In the NORA trial (Chinese patients with PSR, 2 prior lines, with/without gBRCAm), overall investigator-assessed mPFS was 18.3 months in the niraparib arm (12), and in an interim analysis of the phase III FZOCUS-2 trial, Chinese patients with PSR ovarian cancer (with/without gBRCAm) randomized to fuzuloparib achieved an mPFS of 12.9 months (Supplementary Table S1; ref. 15). Head-to-head studies are needed in order to draw direct comparisons between the efficacy of different PARPis overall, and in patient subpopulations.
In L-MOCA, investigator-assessed mPFS in patients with BRCAm was 21.2 months. In SOLO2, mPFS among patients with BRCAm randomized to olaparib was 19.1 months (9). Among patients in the gBRCAm subgroup of L-MOCA, mPFS was 21.4 months, while in the phase II and III fuzuloparib studies, mPFS in patients with gBRCAm randomized to fuzuloparib was 10.3 and 12.9 months, respectively (15, 20). mPFS in sBRCAm and BRCAwt subgroups of the current study (i.e., non-gBRCAm) were 16.1 and 11.0 months, respectively. In the phase IIIb, single-arm OPINION study, in which patients with non-gBRCAm PSR ovarian cancer received olaparib maintenance therapy, mPFS was 9.2 months (21). The NORA study reported mPFS of 11.1 months following niraparib treatment in a non-gBRCAm (including sBRCAm) population (12); however, this was assessed by a blinded and independent central review (22). Overall, patients with BRCAm in the L-MOCA study achieved a greater PFS benefit compared with patients with BRCAwt (21.2 months vs. 11.0 months, respectively). While our study was designed as a single-arm study in part due to the proven efficacy of olaparib compared with placebo (2, 6, 9), previous randomized controlled trials in patients with PSR ovarian cancer have shown superior outcomes in patients receiving PARPi treatment compared with placebo, regardless of BRCA status (2, 10, 12, 15). The clinical benefit of olaparib seen in this study reinforces that observed in global studies, and supports its use in patients with PSR ovarian cancer, including Asian patients, regardless of BRCA status. Another subgroup analysis revealed that patients with HRRm had a numerically longer mPFS (18.3 months) than patients with HRRwt (13.3 months). There is limited evidence supporting the accuracy of HRR as a biomarker for response to olaparib treatment, and so an exploratory analysis of the association between HRD status and olaparib efficacy will be performed to investigate HRD biomarker status in PSR ovarian cancer.
The baseline demographics and clinical characteristics reported here show that this study population is largely representative of the PSR ovarian cancer population seen in clinical practice. We performed subgroup analyses of mPFS according to certain baseline characteristics to better understand predictors of survival in this population, particularly in those with poor prognosis. Patients who achieved CR following previous platinum-based chemotherapy had a longer mPFS than those whose best response was PR. In Study19, CR was found to be a significant prognostic factor for longer PFS (HR, 0.46; P < 0.001; ref. 2). This trend was also observed in the NORA trial (Chinese patients), where those who achieved CR and PR to last platinum-based therapy had a 74% and 66% reduction in risk of progression from niraparib (versus placebo), respectively (12). We also found that patients who received second-line treatment prior to study enrollment appeared to have a longer mPFS than those who had received three previous lines of therapy (18.0 vs. 8.8 months). All patients in NORA had previously received second-line therapy (12), thus, together, showing that this patient subgroup may derive substantial PFS benefit from PARPi therapy. Finally, we showed that platinum-free interval may be an important factor in patient selection and for determining prognosis. A previous study demonstrated that a platinum-free interval >12 months was associated with improved treatment outcomes (23). In our study, patients who had a platinum-free interval >12 months versus 6 to 12 months had a longer mPFS. While a substantial proportion of patients enrolled in L-MOCA had potentially negative prognostic factors, the promising overall mPFS achieved in this study suggests that patients with PSR ovarian cancer treated in real-world clinical practice (24, 25) can gain substantial PFS benefit with olaparib.
The toxicity profile of olaparib in this study was largely consistent with previous international studies (2, 9). The majority of patients (99.1%) in L-MOCA had ≥1 AEs (Study19, 95.6%; SOLO2, 98.0%; refs. 2, 9). In the current study, the most common AEs of any grade were anemia, nausea, and leukopenia; in Study19 and SOLO2 these were nausea, fatigue, and vomiting (2, 9). Consistent with previous global olaparib trials (2, 9), the majority of AEs in L-MOCA were grade 1 or 2. Comparison of PARPi trials (not head-to-head) suggests grade 3/4 hematologic AEs, in particular thrombocytopenia, are more likely to occur with niraparib or rucaparib than with olaparib (26). Headache, dizziness, and insomnia were infrequently reported in our study (8.5%, 10.3%, and 6.3%, respectively). In contrast, these neurologic toxicities were more common with niraparib (up to 25.9%, 16.6%, and 28.8%, respectively; refs. 10, 12) and rucaparib (18%, 15%, and 14%, respectively; ref. 11). The incidence of MDS and AML in this study (1.3%) was lower than in SOLO2 (2%; ref. 9), and consistent with other PARPi trials (NOVA, 1.4%; ARIAL3, 1.0%; refs. 10, 11). Notably, in L-MOCA, MDS was regularly monitored after treatment discontinuation. In addition, dose reduction was required for 44.6% of patients; this was higher than in Study19 and SOLO2, where 22.8% and 25% of patients treated with olaparib, respectively, required a dose reduction (2, 9). However, these data were lower than those reported in the NORA trial, in which 93.8% of patients had individualized niraparib dosing, and 60% of patients required a dose reduction due to treatment-emergent AEs (12). Moreover, 67% of patients in the NOVA trial required a dose reduction (10).
In SOLO2, median OS in olaparib-treated patients was 51.7 months (95% CI, 41.5–59.1), suggesting there may be potential long-term survival benefits associated with olaparib in PSR ovarian cancer (27). We are looking forward to reporting the long-term survival benefit of olaparib in Asian patients with PSR ovarian cancer in L-MOCA, as well as reporting results of an exploratory mPFS analysis in HRD subgroups in this Asian PSR ovarian cancer population.
The study had two key limitations. First, the single-arm study design prevented comparison of the primary endpoint to a control. Second, the data may not be fully representative of the Asian population, because the study only enrolled patients in China and Malaysia.
Conclusion
The findings from this open-label, phase III study demonstrate that olaparib maintenance monotherapy is associated with promising efficacy and is well tolerated in an Asian population with advanced PSR ovarian cancer, independent of BRCA status. These data reinforce global evidence that strongly support the use of olaparib in the treatment of PSR ovarian cancer in Asian clinical practice.
Authors' Disclosures
A.M. Rozita reports grants from Novartis, Zeria Pharmaceutical Co. Ltd, and AstraZeneca outside the submitted work. No disclosures were reported by the other authors.
Authors' Contributions
Q. Gao: Conceptualization, resources, writing–original draft, project administration, writing–review and editing. J. Zhu: Resources, data curation, writing–original draft, writing–review and editing. W. Zhao: Resources, data curation, writing–original draft, writing–review and editing. Y. Huang: Resources, data curation, writing–original draft, writing–review and editing. R. An: Resources, data curation, writing–original draft, writing–review and editing. H. Zheng: Resources, data curation, writing–original draft, writing–review and editing. P. Qu: Resources, data curation, writing–original draft, writing–review and editing. L. Wang: Resources, data curation, writing–original draft, writing–review and editing. Q. Zhou: Resources, data curation, writing–original draft, writing–review and editing. D. Wang: Resources, data curation, writing–original draft, writing–review and editing. G. Lou: Resources, data curation, writing–original draft, writing–review and editing. J. Wang: Resources, data curation, writing–original draft, writing–review and editing. K. Wang: Resources, data curation, writing–original draft, writing–review and editing. J. Low: Resources, data curation, writing–original draft, writing–review and editing. B. Kong: Resources, data curation, writing–original draft, writing–review and editing. A.M. Rozita: Resources, data curation, writing–original draft, writing–review and editing. L.C. Sen: Resources, data curation, writing–original draft, writing–review and editing. R. Yin: Resources, data curation, writing–original draft, writing–review and editing. X. Xie: Resources, data curation, writing–original draft, writing–review and editing. J. Liu: Resources, data curation, writing–original draft, writing–review and editing. W. Sun: Resources, data curation, writing–original draft, writing–review and editing. J. Su: Methodology, writing–original draft, project administration, writing–review and editing. C. Zhang: Formal analysis, methodology, writing–original draft, writing–review and editing. R. Zang: Resources, methodology, writing–original draft, project administration, writing–review and editing. D. Ma: Conceptualization, resources, investigation, methodology, writing–original draft, project administration, writing–review and editing.
Acknowledgments
This work was supported by AstraZeneca China, who provided funding for study design, data collection, analysis, interpretation, medical writing, and decision to submit the manuscript. The authors would like to thank the participants, the collaborating general practitioners, and other clinical staff. Editorial assistance in manuscript preparation was provided by Tim Stentiford, BSc (Hons), PGDip SciComm, CMPP; Anita Abeygoonesekera, BSc (Hons), BPharm (Hons); and Alice Carruthers BSc (Hons), PhD, of Nucleus Global, Shanghai, China, funded by AstraZeneca in accordance with Good Publication Practice 3 guidelines.
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Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).