**2.2 Frontline maintenance treatment**

After the positive results achieved for relapsed disease, four Phase III studies investigated the role of PARP inhibitors as maintenance therapy following platinumbased chemotherapy in newly diagnosed advanced EOC (**Table 2**). The outcomes of these studies redesigned the treatment landscape of EOC offering several therapeutic options to patients in the frontline setting.

The evidence for the use of olaparib maintenance as a SOC for women with newly diagnosed advanced ovarian cancer and BRCA mutation is derived from the result of SOLO-1 trial [40]. In this double-blind, placebo-controlled, multicenter trial newly diagnosed stage III or IV, high-grade serous or endometrioid ovarian, FT, PPC, and germline BRCA mutations in complete response (CR) or partial response (PR) after platinumbased chemotherapy were randomized 2:1 to olaparib at 300 mg twice daily (n = 260) versus placebo (n = 131) for up to 2 years or until disease progression. At the primary analysis cutoff date of May 2018 the median PFS for patients treated with olaparib was not reached compared to 13.8 months for patients treated with placebo (HR, 0.30; 95% CI, 0.23–0.41; P < 0.001). Based on this data, in December 2018, olaparib received regulatory approval in the 1st-line maintenance setting for BRCAm advanced ovarian cancer in the US. The same indication has been granted in the EU in June 2019 [45].

Longer-term follow-up data from SOLO-1 revealed that the benefit of olaparib was sustained after treatment was stopped, with 48% of women treated with olaparib remaining progression-free for 5 years compared to 21% of placebo patients. Median PFS was 560 months (95% CI 419-not reached) for olaparib versus 138 months (111–182) for placebo (HR 0.33 [95% CI 0.25–0.43]) [46].

Shortly after, niraparib also demonstrated to improve PFS as first-line maintenance therapy vs. placebo in patients with newly diagnosed advanced ovarian cancer at high risk for relapse who responded to platinum-based chemotherapy irrespective of HRD status. The PRIMA trial was a randomized, double-blind, phase 3 trial in which participants after achieving a response to platinum-based chemotherapy were assigned in a 2:1 ratio to receive niraparib or placebo once daily [42]. At the onset of the trial, niraparib was administered at a fixed dose of 300 mg once daily. To improve safety and tolerability, following a protocol amendment, the dosage of niraparib was reduced to 200 mg once daily in patients with a body weight of <77 kg and/or a platelet count of <150,000/mcL at baseline. The primary end point was PFS in patients who had tumors with HRD and in the overall population, as determined by hierarchical testing. HRD was defined as the presence of a deleterious BRCA gene mutation and/or a myChoice test (Myriad Genetics, Inc.) score of ≥42 out of 100 (higher scores indicate higher levels of genomic abnormality). HR-proficient namely HRD-negative patients or patients who had an undetermined HRD status were included in the overall population. In the overall population, niraparib demonstrated a median PFS of 13.8 months compared with 8.2 months in patients who received placebo, leading to a 38% reduction in the risk of disease, progression, or death

(HR, 0.62; 95% CI, 0.50–0.76; P < 0.001). In a subgroup of patients whose tumors were positive for HRD, the median PFS with niraparib was 21.9 months compared with 10.4 months for placebo (HR, 0.43; 95% CI, 0.31–0.59; P < 0.001). In addition, in HRD-negative the median PFS with niraparib was 8.1 months compared with 5.4 months for placebo (HR 0.68, 95% CI 0.49–0.94) [42].

In April 2020, niraparib was approved by the FDA for frontline maintenance in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who experience complete or partial response to platinum-based chemotherapy [47]. A few months later also EMA granted the approval of niraparib for the same indication [48].

Two randomized phase 3 trials combining bevacizumab with a carboplatin–paclitaxel doublet for newly diagnosed EOC have demonstrated to improve PFS [49, 50]. Bevacizumab received regulatory approval for stage IIIB, IIIC, and IV as induction, in combination with chemotherapy, followed by maintenance monotherapy ovarian cancer in 2011 in the EU. On the contrary, FDA approved bevacizumab only in 2018 in this setting. Under the hypothesis that bevacizumab could cause hypoxia-induced HRD in the tumor and thereby increase sensitivity to PARPis, PAOLA-1 trial was designed to compare maintenance olaparib in combination with bevacizumab versus placebo plus bevacizumab [41]. Notably, PAOLA-1 was the only trial to include an active maintenance comparator in the first-line maintenance setting. The study enrolled 806 newly diagnosed advanced EOC patients who had no evidence of residual disease and were in clinical complete or partial response after receiving chemotherapy plus bevacizumab, regardless of surgical status and BRCAm status. Participants were randomized, to either bevacizumab (continued for 15 months) alone or olaparib (continued for up to 24 months) and bevacizumab.

In the overall population, a statistically significant improvement in median PFS (primary endpoint) for olaparib plus bevacizumab vs. bevacizumab alone (22.1 vs. 16.6 months, HR = 0.59; 95% CI = 0.49–0.72; P < 0.001) was observed. In the predefined subgroups, substantial PFS benefit was observed with the combination treatment vs. bevacizumab in the HRD population (including BRCA1/2 mutant; 37.2 vs. 17.7 months; HR = 0.33; 95% CI = 0.25–0.45). Further, for the patients that were HRD positive but did not have a BRCA mutation, the median PFS was 28.1 months in the combination arm versus 16.6 months in the bevacizumab arm (HR 0.43, 95% CI 0.28–0.66). Interestingly, the median PFS for the patients who tested negative for HRD was similar between the olaparib group and placebo; 16.6 months vs. 16.2 months (HR 1.00, 95% CI 0.75–1.35) [41].

Given that a superior clinical benefit was not demonstrated with olaparib versus placebo in HR proficient patients, FDA and EMA approved olaparib in combination with bevacizumab for the maintenance treatment of adult patients with advanced EOC, FT, or PPC who are in CR or PR to front line platinum-based chemotherapy and whose cancer is associated with HRD status defined by either a deleterious or suspected deleterious BRCA mutation and/or genomic instability [21, 49].

During PARPis development, the attempts of combining these agents with cytotoxic chemotherapy have presented several challenges due to the overlapping toxicities such as myelosuppression, which made it difficult to establish appropriate dosages [52].

Among the similar same class of compounds, veliparib is considered to be less potent PARP catalytic inhibitor and a less potent DNA-PARP trapper [51]. Given this intrinsic pharmacological feature, veliparib is the only PARPi studied in combination with platinum-based chemotherapy in EOC in the first line setting. The aim of phase

III VELIA trial is to assess the safety and efficacy of veliparib in both the frontline induction (with carboplatin/paclitaxel chemotherapy) and maintenance phases in HGSOC, FT, or PPC [43].

A total of 1140 patients were enrolled and randomized into 3 arms. The first arm received carboplatin and paclitaxel plus placebo followed by placebo maintenance. Arm 2 received carboplatin and paclitaxel plus veliparib followed by placebo maintenance. The third arm was the most significant for improving PFS meeting the endpoint of the trial. Patients in this arm received carboplatin and paclitaxel plus veliparib followed by veliparib maintenance. Of note, after the 6 cycles of combination chemotherapy, patients received an additional 30 cycles of maintenance therapy with either placebo or veliparib 300 mg twice daily escalating to 400 mg twice daily if tolerated. In contrast with PRIMA, PAOLA-1, and SOLO1, the PFS (primary endpoint) of the VELIA study was calculated from the start of chemotherapy. In addition, due to the study design, patients with stable disease (not only subjects with CR or PR after carboplatin and paclitaxel) received singleagent veliparib maintenance [43].

In the primary analyses of the VELIA trial, the addition of veliparib to carboplatinpaclitaxel and continuation as maintenance therapy resulted in statistically significant improvements in PFS in the BRCAm, HRD, and ITT populations. Using myChoice assay (Myriad Genetics, Inc.), a score of ≥33 was considered to indicate HRD status. To increase the sensitivity of detecting a response to PARPi, threshold score was revised from 42 to 33. The overall study results showed a significant PFS benefit for the veliparib throughout arm versus the control arm. The median PFS for the induction and maintenance phases combined in the ITT population was 23.5 months compared with 17.3 months in the control arm (HR, 0.68; 95% CI, 0.56–0.83; P < 0.001). As expected, the magnitude of the clinical benefit was larger in subjects with BRCA mutations with a median PFS of 34.7 months compared with 22.0 months for veliparib and placebo, respectively (HR, 0.44; 95% CI, 0.28–0.68; P < 0.001). Lastly, the median PFS in the subgroup of patients with HRD was 31.9 months for the veliparib throughout arm versus 20.5 months for the chemotherapy-alone arm, with an HR of 0.57 (95% CI, 0.43–0.76; P < 0.001). Given that no benefit in terms of PFS was obtained in any stratified biomarker population looking at combination chemotherapy only arm vs. control arm these results suggest that the benefit from veliparib is gained with maintenance therapy extension [43]. Currently, no health regulatory agency has approved veliparib in any setting of advance EOC.

Finally, very recently, rucaparib monotherapy demonstrated a significant improvement in PFS when given as first-line maintenance in EOC following treatment of platinum-based chemotherapy. In the phase III ATHENA-MONO trial, 538 patients with high-grade ovarian, FT, or PPC were allocated in 4:1 fashion to either rucaparib or placebo. Rucaparib/placebo continued for a maximum of 24 months or until disease progression, unacceptable toxicity, or death [44]. The primary endpoint was investigator-assessed PFS, which was analyzed in the HRDpositive subgroup including BRCAm or BRCA wild type/LOH-high and the ITT population.

In the ITT population, the median PFS was 20.2 months with rucaparib compared to 9.2 months with placebo (HR, 0.52; 95% CI, 0.40–0.68; P < 0.0001). Further, the median PFS for the HRD-positive patient population treated with rucaparib was 28.7 months vs. 11.3 months among those who received placebo (p = 0.0004) with HR 0.47 (95% CI: 0.31–0.72). Finally, in the HRD-negative subgroup, the median PFS was 12.1 months in the rucaparib group and 9.1 months in the placebo group (HR, 0.65; 95% CI, 0.45–0.95) underscoring the benefit that rucaparib can provide to women with EOC irrespective of HRD status [44]. To date, rucaparib has not received approval in the first-line ovarian cancer maintenance setting.
