Ovarian cancer has the poorest prognosis and the highest mortality among gynecological cancers [1]. Cytoreductive surgery and platinum-based chemotherapy are traditional standard treatment methods [2], and additional studies have reported that the use of the angiogenesis inhibitor bevacizumab increases progression-free survival (PFS) in high-risk groups [3]. Aggressive surgery, chemotherapy, and targeted therapy are applied to ovarian cancer treatment, but 70–75% of ovarian cancer patients still experience recurrence, and the 5-year survival rate is only 23%. There are still needs for additional treatment for ovarian cancer patients.

Poly-ADP-ribose polymerase (PARP) inhibitors are anti-cancer drugs, and the effectiveness of first-line maintenance therapy in the treatment of ovarian cancer patients has recently been proven through several studies ^[4][5][6][7][4,5,6,7]. Among ovarian cancer patients with BRCA mutation or homologous recombination deficiency (HRD), the efficacy of PARP inhibitors has been proven, and BRCA mutation and HRD are currently indicated for PARP inhibitor maintenance treatment. Approximately 11–15% of ovarian cancer patients have BRCA1/2 germline mutations, 7% have BRCA1/2 somatic mutations, and it has been reported that HRD is found in about 50% of patients with epithelial ovarian cancer ^[8][9][8,9].

Recently, HRD status has been proven as an important biomarker in ovarian cancer treatment with predictive and prognostic value. Approximately 50% of high-grade serous ovarian cancer is HRD according to the Cancer Genome Atlas (TCGA) project [10]. HRD is a complicated genomic signature that appears when cells cannot repair damaged double-stranded DNA via homologous recombination repair (HRR) pathway [11]. For maintaining genomic stability and cell function, cells must repair DNA damages. The compromised HRR pathway may lead to genomic instability in the form of genomic scarring, resulting in malignant transformation [12]. BRCA1 and BRCA2 as well as ATM, BARD1, BRIP1, H2AX, MRE11, PALB2, RAD51, RAD51C/D, RPA and Fanconi Anemia Complementation Group genes are representative genes that have important roles in the HRR pathway as important causative factors of HRD [13]. HRD-related genomic markers, known as “scars”, can be explained as abnormalities that cause structural modifications in chromosomes. The most substantial genomic scars are loss of heterozygosity (LOH) [14], telomeric–allelic imbalance (TAI) [15], and large-scale state transitions (LSTs) [16], which are components for assessment of the genomic instability score (GIS) to inform the status of HRD.

Actions of PARP inhibitors are based on synthetic lethality in HRD-positive tumor cells. PARP1 is an enzyme associated with the recovery of single-strand DNA breaks via the base excision pathway [17]. PARP inhibitor binds to PARP1 at single-strand DNA breaks to avoid effective repair and to cause DNA-protein crosslinks processing into double-strand breaks (DSB), which leads to increased genomic instability and cell death in BRCA1/2-mutated or other HRD-related cells that are defective in their DSB repair functions. Based on these findings, HRD has been identified as a prognostic biomarker for PARP inhibitor therapy in ovarian cancer, and other malignancies such as breast, pancreatic, and prostate cancer ^[18][19][20][18,19,20].

3. First-Line Maintenance PARP Inhibitor Treatment RCTs in Ovarian Cancer

The efficacy of PARP inhibitor as first-line maintenance therapy was shown in a number of clinical trials. In a phase 3 trial SOLO-1/GOG-3004/ENGOT [4], a total of 391 ovarian cancer patients with BRCA mutation (germline or somatic) were enrolled for efficacy of olaparib maintenance therapy. The median PFS for the olaparib group was 49.9 months, compared to 13.8 months in the placebo group with 70% reduced risk (hazard ratio [HR] 0.3; 95% confidence interval [CI] 0.23–0.41; p < 0.001). The SOLO-1 [4] was a representative study that marked the beginning of PARP inhibitor first-line maintenance in ovarian cancer patients, but it was conducted only for ovarian cancer patients with BRCA mutation. Information for HRD and BRCA wildtype ovarian cancer patients could not be provided. In the other trials using PARP inhibitor maintenance in ovarian cancer patients, the analysis was conducted for all patients and HRD was used as a criterion for stratification. In a phase 3 trial of PRIMA/ENGOT-OV26/GOG-3012 [5], niraparib was investigated as a first-line maintenance therapy in patients with advanced-stage ovarian cancer patients regardless of BRCA status. A total of 733 ovarian cancer patients underwent randomization to receive niraparib or a placebo up to a 36-month period. In 373 patients with HRD, the median PFS was 21.9 months in the niraparib maintenance group compared to 10.4 months in the placebo group (HR 0.43; 95% CI 0.31–0.59; p < 0.001). In the overall population, the niraparib maintenance group had a median PFS of 13.8 months, compared to 8.2 months for the placebo group (HR 0.62; 95% CI 0.50–0.76; p < 0.001). In the phase 3 VELIA/GOG-3005 [6] trial, veliparib as a maintenance treatment and alongside chemotherapy was evaluated. In this study, 1140 patients who had newly diagnosed advanced ovarian cancer were randomized in a 1:1:1 ratio. They were assigned to one of three treatment groups: chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). The results showed that the median PFS in the veliparib throughout group was 23.5 months, which was significantly longer than the median PFS of 17.3 months in the placebo throughout group (HR 0.68; 95% CI 0.56–0.83; p < 0.001). In the BRCA-mutation cohort and HRD cohort, the veliparib throughout group showed a prominent reduced risk (HR 0.44; 95% CI 0.28–0.68; p < 0.001, and HR 0.57; 95% CI 0.43–0.76; p < 0.001, respectively). In the PAOLA-1/ENGOT-OV25 trial [21], olaparib combined with bevacizumab as first-line maintenance in ovarian cancer patients was investigated. A study investigated 806 patients with newly diagnosed, advanced, high-grade ovarian cancer who had responded to platinum-taxane and bevacizumab. All participants received maintenance bevacizumab every 3 weeks for 15 months, and were randomized in a 2:1 ratio to receive either olaparib or placebo. The results showed that the median PFS for the olaparib/bevacizumab group was 22.1 months, which was significantly longer than the median PFS of 16.6 months in the placebo/bevacizumab group (HR 0.59; 95% CI 0.49–0.72; p < 0.001). In the subgroup of patients with HRD (n = 387), the PFS for the olaparib/bevacizumab group was even longer, with a median of 37.2 months, compared to 17.7 months in the placebo/bevacizumab group (HR 0.33; 95% CI 0.25–0.45). The absence of the olaparib-only maintenance group was limitation of this trial. In an ATHENA (GOG-3020/ENGOT-ov45 trial [7], rucaparib as first-line maintenance in ovarian cancer patients was evaluated. A total of 538 patients with newly diagnosed, histologically confirmed, advanced (stage III–IV), high-grade epithelial ovarian cancer who had completed cytoreductive surgery (R0/complete resection was permitted) before chemotherapy or following neoadjuvant were enrolled for investigation. Patients were randomized 4:1 to receive rucaparib or a placebo as maintenance therapy. Median PFS was 28.7 months with rucaparib versus 11.3 months with placebo in the HRD population (HR 0.47; 95% CI, 0.31 to 0.72, p = 0.0004); 20.2 months versus 9.2 months in the intent-to-treat population (HR 0.52; 95% CI, 0.40 to 0.68; p < 0.0001) and 12.1 months versus 9.1 months in the HRD-negative population (HR 0.65; 95% CI 0.45 to 0.95).