*For medical professionals only
Numerous studies have confirmed that olaparib can bring significant benefits to the whole population of patients with ovarian cancer with PSR.
Key messages:
As a gynecological malignant tumor with the highest mortality rate, most patients are diagnosed at an advanced stage and are prone to recurrence. Olaparib has been exploring the field of PSR ovarian cancer for many years, and multiple clinical studies have confirmed that it can fully benefit patients with PSR ovarian cancer.
Study19 started the maintenance treatment journey of PSR patients, and olaparib significantly reduced the risk of disease progression or death in PSR patients by 65%;
The SOLO2 study confirmed that olaparib is the first and only PARPi with OS clinical benefit in the field of germline BRCA-mutated PSR;
The OPINION study further validated the efficacy of olaparib as maintenance therapy for ovarian cancer patients with non-gBRCAm-mutant PSR;
The L-MOCA study reinforces the evidence that olaparib in the Chinese population shows that olapar has a PFS benefit in patients with PSR, regardless of genetic status. Its mid-term OS data will be released at this year's ASCO Annual Meeting.
Ovarian cancer is a gynaecological malignancy with a high risk of death, with approximately 61,100 new cases and 32,600 deaths in China in 2022 [1]. With the increase of the number of recurrences and the number of chemotherapy lines, platinum resistance gradually progresses, and the 5-year survival rate is only 39%~46% [3]. For platinum-sensitive recurrent (PSR) ovarian cancer, maintenance therapy is an important means to reduce the risk of recurrence or delay recurrence.
Olaparib is the world's first polyadenosine diphosphate ribose polymerase inhibitor (PARPi) for PSR ovarian cancer, which traps PARP at DNA single-strand break sites, prevents repair and produces double-strand breaks with DNA replication, promoting apoptosis in tumor cells [3]. In this article, Professor Gao Qinglei from Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology will review the relevant research progress of olaparib in the field of PSR ovarian cancer based on the current diagnosis and treatment status of ovarian cancer, and lead readers to gain insights into how olaparib can consolidate its benefits in the whole population of PSR ovarian cancer through continuous exploration.
Groundbreaking work: Study19 opens the way to PARPi maintenance therapy
Before the 80~90s of the 20th century, chemotherapy was the main treatment method for advanced ovarian cancer, and the 5-year survival rate of patients was only 8.5%[4-5].
As early as 2012, the results of Study19, the first phase II clinical study of olaparib for the maintenance treatment of patients with PSR ovarian cancer, were published in the New England Journal of Medicine, a top medical journal [6], confirming that olaparib monotherapy maintenance therapy can significantly improve the PFS of PSR patients, regardless of whether there is a BRCA mutation or not, opening a new era of PARPi in the maintenance treatment of PSR ovarian cancer.
Study19 is a randomized, double-blind, placebo-controlled, global, multicenter Phase II clinical study to evaluate the efficacy and safety of oral olaparib as maintenance therapy for PSR ovarian cancer. The study included the entire population of patients with PSR (Figure 1). The results confirmed that olaparib significantly reduced the risk of disease progression or death in patients with PSR ovarian cancer by 65% (HR=0.35, P<0.001) and significantly extended median PFS by nearly 2-fold (8.4 versus 4.8 months) (Figure 2). Overall survival (OS) analysis [7] showed that patients with BRCA mutations were the dominant population, and olaparib showed an OS advantage over placebo in both the overall population and the BRCA-mutant subgroup (ITT population, 29.8 versus 27.8 months; BRCA mutant population, 34.9 versus 30.2 months). Study19 studies have shown that olaparib has made the research population closer to clinical practice through bold exploration and careful verification. Since then, olaparib has begun to explore further, and has carried out a number of studies such as SOLO2, OPINION, and L-MOCA.
Figure 1. Study 19 included baseline characteristics of the population
Figure 2. Study 19 studies PFS results
Excellence: SOLO2 research focuses on the most dominant populations for PSR
The Study19 study has confirmed that PARPi can benefit the whole population of PSR ovarian cancer, but BRCA mutant patients are the most dominant population of PARPi, and in order to verify the efficacy and safety of olaparib in BRCA mutant population, the SOLO2 study came into being. The SOLO2 study is a randomized, double-blind, placebo-controlled, global, multicenter, Phase III study of patients with germline BRCA-mutated PSR ovarian cancer with investigator-assessed PFS and secondary endpoints of investigator-assessed PFS2 (RECIST) and OS.
The results showed that olaparib maintenance therapy reduced the risk of disease progression or death by 70% (HR=0.30, P<0.0001) and significantly prolonged median PFS (19.1 versus 5.5 months) compared with placebo (Figure 3); Final OS results at five years of follow-up [9] showed that maintenance therapy with olaparib prolonged median OS by 12.9 months and reduced the risk of death by 26 percent, even though 38 percent of patients in the placebo group used PARPi in subsequent therapy (51.7 versus 38.8 months; HR=0.74) (Figure 4); Five-year OS rates were 9 percent higher with olaparib than with placebo (42.1 versus 33.2 percent). The SOLO2 study is the first and only PARPi with clinical OS benefit in patients with germline BRCA-mutated PSR ovarian cancer.
Figure 3. PFS data from the SOLO2 study
Figure 4. OS data from the SOLO2 study
Overall benefit: The OPINION study explores more people who benefit
The SOLO2 study has demonstrated a clinically meaningful OS benefit for patients with germline BRCA-mutated PSR ovarian cancer, where BRCA1/2 mutations account for only 20 percent of patients [10]. In order to further improve the survival prognosis of patients with PSR ovarian cancer, it is urgent to explore a wider range of beneficiary groups. To validate the efficacy of olaparib in the non-germic BRCA mutant (non-gBRCAm) population, the OPINION study was conducted.
The OPINION study is a single-arm, open-label, global, multicenter, Phase III.b study of olaparib monotherapy maintenance therapy in patients with ovarian cancer with non-gBRCAm PSR who have received prior second-line or higher platinum-based regimens [11]. The results showed that the median PFS of olaparib in the non-gBRCAm PSR population was 9.2 months (Fig. 5), and olaparib was effective in all subgroups, regardless of HRD/sBRCA mutation status (Fig. 6); The final OS results presented at ESMO 2022 [12] showed that the median OS was 32.7 months in the olaparib group, and the Kaplan-Meier OS rates at 24 and 30 months were 65.8% and 54.9%, respectively (Figure 7). The study further validates the effectiveness of olaparib as maintenance therapy in patients with non-gBRCAm PSR ovarian cancer.
Figure 5. PFS data from the OPINION study
Figure 6. OPINION examined PFS data from each subgroup
Figure 7. OS data from the OPINION study
Adding Evidence: The L-MOCA Study Consolidates the Evidence for Olaparib in the Chinese Population
A number of foreign studies (Study19, SOLO2 and OPINION study) have confirmed that olaparib can prolong PFS in patients with PSR ovarian cancer, and in order to further consolidate the data of olaparib maintenance therapy in the Chinese population, the L-MOCA study came into being. The L-MOCA study is a single-arm, multicenter, Phase III clinical study of patients with PSR ovarian cancer in an Asian population, with 91.5 percent of Chinese patients with PSR ovarian cancer and a small number of Malaysian patients (8.5 percent) [13].
The results show that The median PFS of olaparib monotherapy in the ITT population was 16.1 months, and the benefit of olapar in patients with PSR ovarian cancer was beneficial regardless of gene status (BRCA mutant subgroup, 21.2 months; germline BRCA-mutant subgroup, 21.4 months; BRCA wild-type subgroup, 11.0 months) (Figure 8), and the benefit of patients with PSR ovarian cancer who received 2nd line chemotherapy was better than that of patients with ≥ 3rd line of chemotherapy, suggesting that the benefit of good drugs was better when used early, and the subgroup data showed that the median PFS of patients in the 2nd line BRCA wild-type subgroup was 14.1 months (Figure 9) 。 The interim OS data of the L-MOCA study will be presented at this year's ASCO Annual Meeting (Abstract No. 5559), and the safety data are consistent with the safety data of previous global multicenter studies dominated by European and American populations, and no new safety signals have been found. The L-MOCA study further strengthens the effect that olaparib can achieve significant efficacy in the whole population of ovarian cancer with PSR in China.
Figure 8. L-MOCA studies PFS data from patients with different gene states
Figure 9. L-MOCA was used to study PFS data in subgroups of previous treatment lines under different gene mutation states
brief summary
There is an unmet clinical need in the diagnosis and treatment of ovarian cancer in mainland China, and the advent of PARPi has changed the treatment model of ovarian cancer, which is a milestone. Current clinical evidence suggests that olaparib shows a significant survival advantage in the maintenance treatment of PSR ovarian cancer. With the publication of the interim OS data of the L-MOCA study (abstract number: 5559), we believe that the position of PARPi represented by olaparib in the treatment of ovarian cancer will be further consolidated, and we also expect that the emergence of new treatment options will better serve clinical practice, thereby further improving the survival rate of ovarian cancer patients.
Expert Profile
Prof. Qinglei Gao
Chief Physician and Ph.D. Supervisor
- Director of the Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Selected into the national "Ten Thousand Talents Program"
- Ministry of Science and Technology "Young and Middle-aged Leading Talents in Science and Technology Innovation"
- Member and secretary of the Ovarian Cancer Quality Control Committee of the National Cancer Center
- Vice Chairman of the Tumor Microenvironment Committee of the Chinese Anti-Cancer Association
- Chairman of the Obstetrics and Gynecology Branch of Hubei Medical Association
- He is good at the surgery and comprehensive treatment of gynecological malignant tumors, and his research direction is "precise diagnosis and treatment of ovarian cancer and clinical transformation", and he won 1 first prize of Chinese Medical Science and Technology Award as the first person to complete it
- He led 1 key R&D plan of the 14th Five-Year Plan and presided over 6 projects of the National Natural Science Foundation of China
- 以第一/通讯作者在 the Lancet Digital Health、J Exp Med、Nature Commun 等杂志发表SCI论文 100篇，IF>10分 25篇
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