*PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.106659*

Preliminary studies indicated the olaparib exerted anti-cancer activity in BRCA-negative tumor having a defect in the HR pathway other than related to BRCA mutation (BRACAness phenotype) [22]. Upon these premises, the aim of phase II Study 19 was designed to assess efficacy and safety of olaparib monotherapy as maintenance treatment in patients with platinum-sensitive, relapsed, HGSOC who had a response to their most recent platinum-based chemotherapy [23]. No prospective BRCA testing was required for eligibility for this study, which enrolled 265 patients who had received two or more platinum-based regimens and had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib (400 mg twice daily) or placebo until the primary endpoint progression-free survival (PFS) defined as the time from randomization (on completion of chemotherapy) until the objective assessment of disease progression according to response evaluation criteria in solid tumors (RECIST) guidelines or death. In terms of efficacy results, median PFS in study 19 was significantly longer with olaparib than with placebo (8.4 months vs. 4.8 months; hazard ratio [HR] for progression or death, 0.35; 95%: confidence interval [CI], 0.25 to 0.49; P < 0.001) [23].

Furthermore, a prespecified exploratory analysis of all efficacy endpoints performed according to BRCA mutation status demonstrated that patients with a BRCA mutation had the greatest PFS benefit from treatment with olaparib maintenance therapy compared with placebo. For patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11.2 months [95% CI 8.3–not calculable] vs. 4.3 months [3.0–5.4]; HR 0.18 [95% CI 0.10–0.31]; p < 0.0001) [24]. In December 2014, olaparib was approved in the EU for the maintenance treatment of adults with platinum-sensitive, relapsed, HGSOC, FT, and PPC who are in complete or partial response to platinum-based chemotherapy and BRCA mutation-positive (germline and/or somatic).

To confirm olaparib benefits in the same setting using tablets as opposed to the previous capsule formulation, the double-blinded, randomized, and placebocontrolled phase III SOLO-2 trial was planned. This study enrolled 295 platinumsensitive relapsed patients with high-grade serous or endometrioid EOC, PT, or PPC, preselected for BRCA1/BRCA2 mutations who were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Participants were randomized 2:1 to maintenance olaparib (300 mg twice daily; tablet) or placebo. The primary endpoint for this study was investigator-assessed PFS. The trial met its primary endpoint with a median PFS of 19.1 months vs. 5.5 months (HR 0.30; 95% CI 0.22 to 0.41; P < 0.0001), substantially exceeding the efficacy results seen in Study 19 [25]. Despite SOLO-2 study enrolled only patients with BRCA mutations, based upon the combined results of both Study 19 and SOLO-2 US Food and Drug Administration (FDA) in 2017 and European Medicines Agency (EMA) in 2018 granted approval to olaparib for the maintenance treatment regardless of BRCA mutation status [26].

Zejula® (niraparib) is an oral, small molecule inhibitor of PARP enzymes, including PARP-1 and PARP-2 [27]. After niraparib 300 mg demonstrated preliminary antitumor activity in ovarian cancer patients in phase 1 dose-escalation study, phase III NOVA trial sought to establish the efficacy and safety of niraparib in patients with platinum-sensitive, recurrent, histologically confirmed ovarian cancer as maintenance treatment following complete or partial response to platinum-based chemotherapy [28]. Different from SOLO-2 trial, NOVA study enrolled two independent cohorts based on the presence or absence of a germline BRCA (gBRCA) mutation (gBRCAm) according to BRCA analysis testing (Myriad Genetics, Inc.) from tumor and blood

samples. In each cohort (n = 203 for gBRCAm cohort and n = 350 non-gBRCAm cohort), patients were randomly assigned to receive 300 mg of niraparib once daily or placebo in 28-day cycles until disease progression or unacceptable toxicity. Primary endpoint was PFS in intent-to-treat (ITT) analyses of the three predefined primary efficacy populations namely gBRCAm cohort, the HRD-positive subgroup of the nongBRCAmcohort, and the overall non-gBRCAm cohort. Patients in the niraparib group had a significantly longer median PFS than did those in the placebo group; 21.0 vs. 5.5 months in the gBRCAm cohort (HR, 0.27; 95% CI, 0.17–0.41) and 12.9 months vs. 3.8 months in the non-gBRCAm cohort for patients who had tumors with HRD (HR, 0.38; 95% CI, 0.24–0.59). Finally, the median PFS also favored the niraparib group in the overall non-gBRCAm cohort, 9.3 months vs. 3.9 months (HR ratio, 0.45; 95% CI, 0.34–0.61; P < 0.001 for all three comparisons) [28].

The overall results of this study indicated that, among patients with platinumsensitive, recurrent ovarian cancer, the median duration of PFS was significantly longer among those receiving niraparib compared to those receiving placebo. In March 2017, niraparib received its first FDA and EMA approval for the maintenance treatment of adult patients with recurrent EOC, FT, or PPC who are in a complete or partial response to platinum-based chemotherapy regardless of BRCA mutations or HRD status [27].

Rubraca® (rucaparib) is an oral, small molecule inhibitor of PARP enzymes, including PARP-1, 2, and 3 [29]. Like the other two PARPis, rucaparib was demonstrated to exert synthetic lethality in cells with HRD [29]. Data of efficacy as maintenance treatment of recurrent EOC was established in phase III ARIEL-3 study, where 564 patients with recurrent platinum-sensitive, high-grade serous or endometrioid ovarian carcinoma had completed at least two platinum-based chemotherapy regimens with response to the last regimen were included [30]. Patients were randomly assigned to receive rucaparib 600 mg twice daily or a placebo after stratification by HRD status, latest progression-free interval, and response to the latest platinum-based regimen. HRD combined tumor BRCA status as well as the percentage of genome-wide loss of heterozygosity (LOH) with the use of Foundation Medicine's T5 next-generation sequencing (NGS) assay.

For patients with BRCA mutations, median PFS in the rucaparib group was 16.6 months compared to 5.4 months in the placebo group (HR 0.23; 95% CI 0.16– 0.34; p < 0.0001). In patients with HRD tumors, patients receiving rucaparib also had improved PFS compared to placebo (13.6 months vs. 5.4 months; HR 0.32; 95% CI 0.24–0.42; p < 0.0001). In the ITT population, the median PFS was 10.8 months in the rucaparib group vs. 5.4 months in the placebo group (HR 0.36; 95% CI 0.30–0.45; p < 0.0001) [30]. Based on these data, in 2018, the FDA and EMA granted rucaparib a new indication concerning maintenance treatment for platinum-sensitive relapsed high-grade epithelial ovarian cancer in patients who are in response to platinum-based chemotherapy regardless of BRCA or HRD status [30].
