**4. General recommendations for patient selection for front-line maintenance PARPi treatment**

For decades the initial therapeutic approach for patients with EOC relied on surgery followed by platinum-based chemotherapy [68]. Surgery allows confirmation of the diagnosis, as well as staging of the disease. The main goal of the primary debulking surgery (PDS), which plays a cardinal role in the overall management of advanced EOC (stages III and IV), is to obtain an optimal cytoreduction defined as complete resection of all visible tumors [69]. When complete cytoreduction is not attainable, either due to an extensive disease burden or to poor performance status, the patients are treated first with neoadjuvant platinum-based chemotherapy [70, 71]. This strategy usually encompasses the administration of three cycles of chemotherapy and upon response to the systemic treatment, the interval debulking surgery (IDS) is performed. After surgery, chemotherapy is continued for up to six cycles. When PDS is considered appropriate, intravenous platinum and taxane regimen every 21 days for six cycles represent the adjuvant treatment [72]. However, the timing of surgical intervention in relation to systemic treatment (neoadjuvant vs. adjuvant) is still an unsettled matter.

Since 2011, in the first line setting, the addition of the vascular endothelial growth factor inhibitor (VEGFi), bevacizumab to chemotherapy following debulking surgery has become SOC given the positive results relative to PFS benefit demonstrated in two randomized phase III trials, GOG-0218 and ICON7 [49, 50]. However, the addition of bevacizumab is currently recommended in a subgroup of patients with poor prognosis, namely patients with stage III and residual disease after surgery or stage IV based on a post hoc overall survival analysis.

With the advent of PARPis in the clinic, the paradigm for the treatment of EOC has undergone remarkable changes. To assist health care providers, clinical practice guidelines have been updated to support the decision-making process and to ensure consistency of treatment is aligned with current best evidence-based medicine. In addition to this practice, we also strongly advocate as a primary principle, that sound clinical judgment (e.g., concern relative to treatment-associated toxicity, performance status, and other comorbidities) and patient preference should be also considered. This mindset is extremely important especially when the risk-benefit profile of treatment in a subset of patients has not been clearly established and, therefore, other management options are available.

For newly diagnosed patients, testing for BRCA mutation (germline/somatic) is strongly recommended, given that systemic therapeutic options are available in frontline setting. Maintenance use of olaparib for 2 years as first-line management approach should be the SOC for all patients with BRCA1/2 mutation in newly diagnosed advanced EOC after a response to chemotherapy based on SOLO-1 trial results. As mentioned in the 5-year follow-up analysis of SOLO-1, olaparib recipients had doubled the median PFS compared to those treated with placebo [46].

If BRCA mutation (germline/somatic) results are negative, HRD test should be considered to identify a subgroup of women who are BRCA wild type but derive greater clinical benefit from a PARPi. In the presence of positive HRD score after CR or PR to front-line platinum-based chemotherapy, maintenance use of niraparib for 3 years or olaparib in combination with bevacizumab are available options based on PRIMA and PAOLA-1 study, respectively. Both studies enrolled newly diagnosed EOC patients, regardless of their BRCA status.

PRIMA trial enrolled high-risk patients, that is, 35% of patients had stage IV [42] and 45% of patients had visible disease after PDS or IDS [73]. Among patients with HRD and BRCA wild type, the median PFS was 19.6 months in the niraparib group vs. 8.2 months in the placebo group (HR = 0.50; 95% CI 0.31–0.83) [42].

In PAOLA-1 trial, the median PFS was 28.1 months vs. 16.6 months, respectively, for HRD-positive BRCA wild-type. Due to that fact that PAOLA-1 study design did not have olaparib maintenance only arm, the value of adding bevacizumab remains uncertain [41].

Patients with HRR-proficient tumors have poorer prognosis. Nonetheless, for woman whose tumor is found to be HRR proficient (HRD negative), PARPi monotherapy can still be offered, despite the diminished clinical benefit seen among this cohort of women based on PRIMA trial results. [74] In HRD-negative patients, niraparib demonstrated a modest yet statistically significant improvement in median PFS 8.1 months vs. 5.4 months, with niraparib versus placebo (HR 0.68, CI 95% 0.49– 0.94). Conversely, in PAOLA-1 study, olaparib plus bevacizumab did not show a significant improvement in PFS in HRD-negative patients [41].

Therefore, bevacizumab monotherapy regimen upfront after induction with chemotherapy may be considered a valid strategy in patients with HRD negative tumors considering specific clinical characteristics (e.g., pleural effusions or ascites) with the option to administer a PARPi in later lines upon recurrence. It has been noted, however, that this approach will need to demonstrate a subsequent response to platinum to guarantee PARPis sensitivity. Indeed, the American Society of Clinical Oncology (ASCO) guideline supports the use of PARPis in all patients with advanced EOC in the front-line maintenance setting regardless of HRD status. Based on the current label, only niraparib is approved in the first-line maintenance treatment setting regardless of biomarker status. In this scenario, bevacizumab could be postponed to later line for the treatment of women with both platinum-sensitive and platinumresistant diseases [75].

Lastly, given that patients enrolled in these studies excluded women who previously received PARPi, no data are currently available on the efficacy of retreatment with PARPi after progression. Hence, up to this point, the recommendation advises against PARP inhibitor retreatment in advance EOC [75]. Needless to say, this area of research is becoming the highest unmet need in ovarian cancer due to the increasing patient population receiving first-line PARPis.
