*2.1.2 Treatment of recurrent epithelial ovarian cancer*

In the US, the first indication for the clinical use of PARP inhibitors in EOC was given for the treatment setting (non-maintenance) of recurrent disease. In 2014, under FDA's accelerated approval pathway, olaparib received its first indication for the treatment of women with recurrent ovarian cancer with gBRCAm who received three or more prior lines of chemotherapy [31]. This approval was based on the analysis of 137 patients from Study 42 which included subjects with measurable

BRCA-deficient recurrent disease treated with a median of 3.4 prior lines of chemotherapy [32]. The objective response rate (ORR) for patients in this cohort with measurable disease was 34% (95% CI, 26–42%) and the median duration of response was 7.9 months (95% CI, 5.6–9.6 months). Of note, this accelerated approval was not restricted to either the platinum-sensitive or platinum-resistant disease setting. The justification is the assumption that olaparib would have a better response rate and favorable safety profile as compared with available single-agent chemotherapeutic options given usually in this setting [31]. Along with the drug, the FDA also approved a molecular companion diagnostic test, BRACAnalysis CDx (Myriad Genetics, Inc.) to detect the presence of gBRCA mutations in blood samples [31].

Accelerated approvals were contingent on the results of phase III confirmatory trial SOLO-3. This open-label study was conducted to compare olaparib with non-platinum chemotherapy in patients with gBRCAm platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy [33]. Approximately 266 patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician's choice (PC) single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was ORR in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was PFS assessed by BICR in the ITT population. The BICR-assessed ORR was 72.2% with olaparib versus 51.4% with PC, for an odds ratio of 2.53 (95% CI 1.40–4.58; P = 0.002). Median PFS was 13.4 months with olaparib versus 9.2 months with chemotherapy (HR 0.62, 95% CI 0.43–0.91; P = 0.013) [33]. As of August 2022, the manufacturer of olaparib, AstraZeneca (AZ) has released a Dear HCP Letter informing HCPs that a recent subgroup analysis indicated a potential detrimental effect on OS for olaparib compared to the chemotherapy control arm in SOLO3. AZ is having active discussions with FDA about revisions to the olaparib US prescribing information label and are planning to voluntarily withdraw the late line treatment indication. At the time of publishing, olaparib still holds an active indication for late line treatment [34].

Additionally, rucaparib received FDA accelerated approval in 2016 for treatment of recurrent BRCA-associated EOC based on combined data from two single-arm trials Study 10 and ARIEL2 [35]. The combined analyses included 106 patients with BRCA mutations (germline or somatic) and advanced EOC who had received at least two prior platinum-based chemotherapy regimens. The ORR for treatment with rucaparib 600 mg orally twice a day was 54%, with a median duration of response (DOR) of 9.2 months. As expected, ORR was greatest for those with platinumsensitive disease (66%; 95% CI: 54–76%) and lowest in platinum-refractory patients (0%; 95% CI: 0–41%). Rucaparib received accelerated approval based on ORR and DOR seen in phase II trials. At the same time, approval of a companion diagnostic test, FoundationFocus CDx BRCA (Foundation Medicine, Inc.) to detect tumor BRCA1 and BRCA2 mutations (germline and/or somatic) was granted [36].

Continued approval of rucaparib in this indication was contingent upon of demonstration of clinical benefit in confirmatory phase 3 trial, ARIEL4 conducted in germline or somatic BRCA mutated patients with relapsed, HGSOC, FT, or PPC that had received at least 2 prior chemotherapy regimens, with at least 1 of which being platinum-based. Treatment with rucaparib was administered at 600 mg twice daily in the investigational arm (n = 233), and in the control arm (n = 116), weekly paclitaxel was given for those who were platinum-resistant or partially sensitive, and platinum-based chemotherapy monotherapy or doublet regimen was given to those who were fully sensitive to platinum. The investigator-assessed median PFS in the efficacy population was 7.4 months (95% CI, 7.3–9.1) with rucaparib in comparison with 5.7 months (95% CI, 5.5–7.3) with chemotherapy (HR, 0.64; 95% CI, 0.49–0.84; P = 0.001). In the ITT population, the median PFS was the same at 7.4 months (95% CI, 6.7–7.9) and 5.7 months (95% CI, 5.5–6.7) in the rucaparib and chemotherapy arms, respectively, but showed a hazard ratio of 0.67 (95% CI, 0.52–0.86; P = 0.0017) [37]. As of June 2022, the manufacturer of rucaparib, Clovis has released a Dear HCP Letter informing HCPs that they have voluntarily withdrawn rucaparib's late line treatment indication in consultation with FDA after a detrimental effect of OS was observed for rucaparib compared to the chemotherapy control arm in the ARIEL-4 trial. Clovis has confirmed they have voluntarily requested the withdrawal of the same BRCAm OC treatment indication in EU. At the time of publishing, Rubraca's indication in later line treatment is still active in EU [38].

Lastly, the role of niraparib in later lines of treatment of patients with relapsed EOC was assessed in a single-arm study [39]. QUADRA was a multicenter, open-label, single-arm study that evaluated the safety and efficacy of niraparib in 463 patients with metastatic, relapsed, HGSOC, FT, or PPC, who were treated previously with at least 3 lines of chemotherapy. QUADRA met its primary endpoint: ORR was 24% (95% CI 16–34%) with the median DOR being 8.3 months. Of note, niraparib demonstrated efficacy beyond patients with BRCA mutation; within the cohort of 35 patients


**Table 2.** *Results of Phase III Trials for PARPi maintenance in front-line setting.* with non-BRCA-mutated tumors who were HRD-positive and platinum-sensitive, the ORR was 20%. As a result, in October 2019, niraparib received FDA approval as a monotherapy treatment for recurrent EOC who had received three or more prior chemotherapy regimens in the context of HRD-positive tumors. HRD positive status is defined by either a deleterious, suspected deleterious BRCA mutation, or genomic instability, and who has progressed more than six months after responding to the last platinum-based chemotherapy [27].
