Mansoor Isabelle Ray-Coquard
email: isabelle.ray-coquard@lyon.unicancer.fr

Mansoor Raza Mirza

Sandro Pignata
email: s.pignata@istitutotumori.na.it

Axel Walther
email: axel.walther@uhbw.nhs.uk

Ignacio Romero
email: iromero@fivo.org

Andreas Du Bois

Andreas Du Bois

Therapeutic options following second-line platinum-based chemotherapy in patients with recurrent ovarian cancer: Comparison of active surveillance and maintenance treatment

Keywords: Active surveillance, efficacy, maintenance treatment, postprogression, quality of life, safety neutrophil count decreased, granulocytopenia, or granulocyte count decreased. ¶ Thrombocytopenia or platelet count decreased. # Asthenia, fatigue, malaise, or lethargy. **Anemia or hemoglobin decreased

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Ovarian cancer is the eighth leading cause of death from cancer in women worldwide, with an estimated 185,000 deaths in 2018, representing 4% of all cancer deaths in women [START_REF] Ferlay | Global cancer observatory: cancer today[END_REF]. The relapsing nature of the disease has a profound impact on patients and their quality of life (QoL).

First-line therapy for patients with ovarian cancer consists of surgery and ≈6 cycles of carboplatin and paclitaxel chemotherapy with or without bevacizumab (Figure 1) [START_REF]Ovarian cancer including fallopian tube cancer and primary peritoneal cancer (version 1[END_REF][START_REF] Colombo | ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[END_REF]. Historically, patients would then be closely monitored (active surveillance) until disease recurrence. Although a more involved strategy than simply awaiting symptomatic relapse, active surveillance is a conservative management approach that does not include the proactive administration of pharmacologic treatment [START_REF]Ovarian cancer including fallopian tube cancer and primary peritoneal cancer (version 1[END_REF][START_REF] Colombo | ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[END_REF]; it does not delay disease progression or prolong patient survival [START_REF] Colombo | ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[END_REF][START_REF] Hanker | The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy[END_REF], and the majority of women with advanced ovarian cancer will experience disease recurrence requiring subsequent therapies [START_REF] Colombo | ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[END_REF][START_REF]Recurrence and treatment for ovarian cancer recurrence[END_REF].

Maintenance treatments have recently been developed to delay disease recurrence or progression for patients who have achieved a complete response (CR) or partial response (PR) to chemotherapy. Maintenance treatment comprises either the introduction of a new therapy immediately after a patient achieves a response to chemotherapy (switch maintenance), or the ongoing administration of a drug following initial treatment with that drug in combination with chemotherapy (continuation maintenance) [START_REF] Disilvestro | Maintenance treatment of recurrent ovarian cancer: Is it ready for prime time?[END_REF][START_REF] Markman | Maintenance chemotherapy in the management of epithelial ovarian cancer[END_REF]. Maintenance treatment may be given over extended durations of time and so should have a manageable tolerability profile and no detrimental impact on patient QoL [START_REF] Disilvestro | Maintenance treatment of recurrent ovarian cancer: Is it ready for prime time?[END_REF][START_REF] Markman | Maintenance chemotherapy in the management of epithelial ovarian cancer[END_REF].

Currently, the angiogenesis inhibitor bevacizumab (as continuation maintenance), the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and niraparib (as switch maintenance), and the combination of bevacizumab and olaparib are approved in Europe and/or the United States (US) as maintenance treatment following first-line chemotherapy (Figure 1) [START_REF] Disilvestro | Maintenance treatment of recurrent ovarian cancer: Is it ready for prime time?[END_REF][8][START_REF]Avastin (bevacizumab) injection, for intravenous use [summary of product characteristics[END_REF][START_REF]Lynparza (olaparib) tablets [prescribing information[END_REF][START_REF]Lynparza (olaparib)[END_REF][START_REF]Zejula (niraparib) capsules[END_REF]. However, ovarian cancer generally remains incurable, and many women will experience multiple relapses.

Because progression-free survival (PFS) time shortens following each recurrence and subsequent round of therapy [START_REF] Hanker | The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy[END_REF], maintenance treatment is also important for patients with recurrent ovarian cancer. Targeted maintenance treatments currently approved in Europe and the US for patients with recurrent ovarian cancer include bevacizumab (as continuation maintenance) and the PARP inhibitors olaparib, niraparib, and rucaparib (as switch maintenance) [8][START_REF]Avastin (bevacizumab) injection, for intravenous use [summary of product characteristics[END_REF][START_REF]Lynparza (olaparib) tablets [prescribing information[END_REF][START_REF]Lynparza (olaparib)[END_REF][START_REF]Zejula (niraparib) capsules[END_REF][START_REF]Zejula (niraparib) capsules [summary of product characteristics[END_REF][START_REF]Rubraca (rucaparib) tablets [prescribing information[END_REF][START_REF]Rubraca (rucaparib) tablets [summary of product characteristics[END_REF].

Here, we discuss the benefits and limitations of active surveillance versus approved targeted maintenance treatment options for patients with recurrent ovarian cancer following a response to second-line platinum-based chemotherapy (Figure 1).

We also consider which patients may be eligible to receive maintenance treatment in the second-line setting, taking into consideration clinical characteristics of individual patients and results of recent studies of first-line maintenance treatments.

Active surveillance

Active surveillance involves close monitoring of patients in remission from ovarian cancer who are not receiving any treatment. Close monitoring may include: regular physical examinations; evaluation of cancer antigen 125 (CA-125) levels; and radiographic imaging when clinically indicated (including significant CA-125 elevation) [START_REF]Ovarian cancer including fallopian tube cancer and primary peritoneal cancer (version 1[END_REF][START_REF] Colombo | ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[END_REF]. When planning follow-up after chemotherapy for recurrent disease, European Society for Medical Oncology (ESMO)-European Society for Gynecological Oncology (ESGO) consensus guidelines and National Comprehensive Cancer Network (NCCN) guidelines recommend that patients are assessed every 2-4 months for the first 2 years and every 3-6 months for the next 3 years [START_REF]Ovarian cancer including fallopian tube cancer and primary peritoneal cancer (version 1[END_REF][START_REF] Colombo | ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[END_REF]; however, local practices vary considerably. Indeed, the optimum follow-up and method for detection of disease recurrence have not been established [START_REF] Colombo | ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[END_REF][START_REF] Le | Follow-up of patients who are clinically diseasefree after primary treatment for fallopian tube, primary peritoneal, or epithelial ovarian cancer: a Program in Evidence-Based Care guideline adaptation[END_REF][START_REF] Salani | An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations[END_REF]. Assessments should be individualized according to prognostic factors and treatment modalities.

Active surveillance awaits the natural history of the disease, rather than trying to prolong the time to next chemotherapy or overall survival (OS). For patients with recurrent ovarian cancer, active surveillance is associated with a short time to disease progression after second-line chemotherapy. In clinical trials of maintenance treatment with PARP inhibitors in the setting of recurrent disease, patients randomized to placebo (equivalent to active surveillance) consistently experienced disease progression 4-6 months after completing second-or later-line chemotherapy [START_REF] Coleman | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF][START_REF] Ledermann | Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial[END_REF][START_REF] Mirza | Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[END_REF][START_REF] Pujade-Lauraine | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial[END_REF]. Furthermore, in a population-based study of patients with BRCA1 or BRCA2 (BRCA) wild-type ovarian cancer who received ≥2 lines of platinum-based chemotherapy who were on active surveillance, 56% were treated for disease recurrence or died within 6 months of their last platinum-based treatment [START_REF] Louie-Gao | Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence[END_REF].

Maintenance treatment for recurrent ovarian cancer

Maintenance treatment for recurrent ovarian cancer is the extended pharmacologic treatment of a patient who has had a CR or PR to their most recent therapy. Maintenance treatments may delay disease progression by eliminating residual cancerous entities, slowing cell turnover, preventing tumor neo-angiogenesis, and/or manipulating the antitumor immune response [START_REF] Disilvestro | Maintenance treatment of recurrent ovarian cancer: Is it ready for prime time?[END_REF][START_REF] Khalique | Maintenance therapy in ovarian cancer[END_REF]. The main goals of maintenance treatment are to extend clinically meaningful survival and prolong the period between chemotherapy treatment lines, allowing patients to avoid the toxicities associated with chemotherapy that can affect their QoL. Prolonging PFS and extending the time to subsequent chemotherapy may be particularly beneficial in the context of the current COVID-19 pandemic since hospital admissions and recurrent hospital visits are risk factors for infection [START_REF] Yu | SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan, China[END_REF][START_REF]ESMO management and treatment adapted recommendations in the COVID-19 era: epithelial ovarian cancer[END_REF][START_REF] Monk | COVID-19 and ovarian cancer: Exploring alternatives to intravenous (IV) therapies[END_REF]. An ideal maintenance treatment should also have manageable toxicity and should not have a negative impact on the efficacy of subsequent therapies or a detrimental impact on patient QoL. Initial attempts at maintenance treatment for ovarian cancer using chemotherapy were of limited success. A meta-analysis of 1644 patients with ovarian cancer found no significant improvement in OS or PFS in patients who received first-line maintenance chemotherapy versus observation alone, and maintenance chemotherapy was associated with an increased risk of toxicity [START_REF] Chen | Maintenance chemotherapy for ovarian cancer[END_REF].

Recently, maintenance treatment with a targeted agent, such as bevacizumab, olaparib, niraparib, or rucaparib, has become standard of care for patients with recurrent ovarian cancer who have responded to second-line or later chemotherapy [START_REF] Matulonis | Management of newly diagnosed or recurrent ovarian cancer[END_REF].

Bevacizumab, an anti-vascular endothelial growth factor monoclonal IgG1 antibody administered intravenously, inhibits the growth of tumor blood vessels and restricts blood supply to tumor tissues [START_REF] Burger | Incorporation of bevacizumab in the primary treatment of ovarian cancer[END_REF]. PARP inhibitors are orally bioavailable drugs that bind to the catalytic domain of PARP enzymes preventing the repair of single-strand breaks in DNA [START_REF] Wahlberg | Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors[END_REF].

Despite the availability of these effective and generally well-tolerated therapies and clinical guidelines recommending their use [START_REF]Ovarian cancer including fallopian tube cancer and primary peritoneal cancer (version 1[END_REF][START_REF] Colombo | ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease[END_REF], real-world evidence suggests that ≈51% of eligible patients do not receive targeted maintenance treatment in the secondline maintenance setting [START_REF] Garofalo | Realworld data analysis of ovarian cancer (OC) maintenance utilization among maintenance eligible patients[END_REF].

Efficacy benefits of maintenance therapy for recurrent ovarian cancer

Extension of PFS. The principal goal of maintenance treatment is to delay disease progression and prolong the period between chemotherapy courses. Pivotal clinical trials of molecularly targeted agents as maintenance treatments for patients with recurrent ovarian cancer have shown that they are all associated with significantly longer PFS than control across predefined and exploratory patient subgroups (Figure

2).

In two clinical studies, patients with platinum-sensitive recurrent ovarian cancer receiving bevacizumab maintenance treatment following second-line chemotherapy plus bevacizumab showed a reduced risk of disease progression or death versus control (OCEANS: 52% reduction [START_REF] Aghajanian | OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer[END_REF]; GOG-0213: 37% reduction [START_REF] Coleman | Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial[END_REF]). Bevacizumab maintenance treatment following second-line treatment with carboplatin and pegylated liposomal doxorubicin plus bevacizumab was also shown to be effective for women with platinum-sensitive recurrent ovarian cancer (19% reduction in the risk of disease progression or death vs carboplatin and gemcitabine plus bevacizumab) [START_REF] Pfisterer | Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, openlabel, phase 3 trial[END_REF]; however, this combination is not currently approved in the US or Europe for platinum-sensitive patients [8,[START_REF]Avastin (bevacizumab) injection, for intravenous use [summary of product characteristics[END_REF].

Two clinical studies of maintenance treatment with olaparib in women with platinum-sensitive recurrent ovarian cancer demonstrated a significantly reduced risk of investigator-assessed disease progression or death with olaparib versus placebo both in a BRCA-mutant cohort (SOLO2/ENGOT-OV21: 70% reduction) and an unrestricted, all-comer population (Study 19: 65% reduction) [START_REF] Pujade-Lauraine | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial[END_REF][START_REF] Ledermann | Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer[END_REF]. Subgroup analyses of Study 19 showed an 82% reduction in the risk of disease progression or death in patients who had BRCA-mutant ovarian cancer and a 46% decrease in patients who had BRCA wildtype ovarian cancer [START_REF] Ledermann | Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial[END_REF][START_REF] Ledermann | Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer[END_REF]. Olaparib was also associated with a significant increase in blinded, independent, central radiology review (BICR)-assessed PFS versus placebo in both studies [START_REF] Ledermann | Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial[END_REF][START_REF] Pujade-Lauraine | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial[END_REF][START_REF] Ledermann | Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer[END_REF].

In the NOVA/ENGOT-OV16 study of patients with platinum-sensitive recurrent ovarian cancer, niraparib maintenance treatment significantly improved median BICRassessed PFS versus placebo regardless of the presence or absence of a germline BRCA (gBRCA) mutation. The risk of disease progression or death was reduced by 73% in patients with a gBRCA mutation, 55% in patients without a gBRCA mutation, and 62% in the homologous recombination deficiency (HRD)-positive subgroup of patients without a gBRCA mutation [START_REF] Mirza | Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[END_REF]. Exploratory analyses also indicated a significant increase in PFS with niraparib versus placebo in subgroups of patients with HRD-positive/BRCA wild-type tumors, those with HRD-positive/somatic BRCA-mutant tumors, and in those with HRD-negative tumors. In ARIEL3, rucaparib maintenance treatment significantly improved median investigator-assessed PFS versus placebo in all primary analysis groups of patients with recurrent ovarian cancer who responded to platinum-based chemotherapy [START_REF] Coleman | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF].

There was a 77% reduction in the risk of disease progression or death in the BRCAmutant cohort (deleterious germline or somatic BRCA mutation), a 68% decrease in the HRD cohort (BRCA-mutant or BRCA wild-type and high loss of heterozygosity [LOH]) and a 64% reduction in the intent-to-treat (ITT) population. Investigator-assessed PFS was also significantly longer with rucaparib versus placebo in subgroups of patients with BRCA wild-type and high LOH or low LOH. Significant increases in BICR-assessed PFS were observed across all analysis cohorts with rucaparib versus placebo.

Reduction in tumor burden. Maintenance treatments that lead to a further reduction in tumor burden-or deepening of response-in patients with measurable disease following platinum-based chemotherapy will clearly be beneficial to patients with recurrent ovarian cancer. Data from SOLO2 showed that olaparib was associated with antitumor activity in patients with measurable target tumors at baseline with an objective response rate (ORR) of 41.1% in the olaparib arm versus 17.1% in the placebo arm; in the olaparib arm, 17/113 (15.0%) of patients with measurable disease at baseline achieved a CR versus 5/55 (9.1%) in the placebo arm [START_REF] Oza | Evaluation of tumour responses and olaparib efficacy in platinum-sensitive relapsed ovarian cancer patients with or without measurable disease in the SOLO2 trial (ENGOT Ov-21)[END_REF]. Similarly, in a pre-specified exploratory analysis of ARIEL3, a reduction in carcinoma burden was observed in patients with measurable residual disease at study entry who were treated with rucaparib maintenance treatment (investigator-assessed ORR for rucaparib vs placebo: BRCA-mutant cohort, 37.5% vs 8.7%; HRD cohort, 27.1% vs 7.3%; ITT population, 18.4% vs 7.6%) [START_REF] Coleman | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF]. CRs were observed with rucaparib in 7/40 (17.5%) patients with measurable disease at baseline in the BRCA-mutant cohort, 10/85 (11.8%) in the HRD cohort, and 10/141 (7.1%) in the ITT population. Only one CR (1/66 [1.5%]) was observed in a patient who received placebo in the ITT population.

Improvement in postprogression outcomes. Maintenance treatments for recurrent ovarian cancer should ideally be associated with durable clinical benefits that delay the need for subsequent therapies and persist throughout the course of subsequent treatments without affecting their efficacy [START_REF] Disilvestro | Maintenance treatment of recurrent ovarian cancer: Is it ready for prime time?[END_REF][START_REF] Matulonis | Intermediate clinical endpoints: A bridge between progression-free survival and overall survival in ovarian cancer trials[END_REF]. These properties can be assessed through postprogression outcomes including chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent line therapy or death (PFS2), and time to start of second subsequent therapy (TSST) [START_REF] Matulonis | Intermediate clinical endpoints: A bridge between progression-free survival and overall survival in ovarian cancer trials[END_REF][START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF]. CFI and TFST evaluate the duration of time that patients avoid the need for subsequent treatments such as chemotherapy, which may be associated with more frequent and severe side effects than targeted therapies and, consequently, a more negative impact on patient QoL [START_REF] Matulonis | Intermediate clinical endpoints: A bridge between progression-free survival and overall survival in ovarian cancer trials[END_REF][START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF]. Evaluation of OS in clinical trials of ovarian cancer may be confounded by a long duration of postprogression survival and crossover to highly effective subsequent treatments. Postprogression endpoints such as PFS2 and TSST can serve as surrogates for OS and provide insight into the impact of maintenance treatment on the efficacy of subsequent therapies [START_REF] Matulonis | Intermediate clinical endpoints: A bridge between progression-free survival and overall survival in ovarian cancer trials[END_REF][START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF].

The pivotal clinical studies of PARP inhibitors as second-line maintenance treatment in patients with recurrent ovarian cancer have demonstrated significant improvements in postprogression efficacy endpoints with these maintenance treatments versus placebo (Table 1 [START_REF] Friedlander | Longterm efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy[END_REF]. Median OS in SOLO2 was also longer with olaparib than placebo (51.7 vs 38.8 months; HR 0.74 [95% CI 0.54-1.00]; P=0.0537) [START_REF] Poveda | Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation[END_REF]. OS data for NOVA and ARIEL3 are not yet mature.

Safety of maintenance therapy for recurrent ovarian cancer

Patients with recurrent ovarian cancer may receive maintenance treatment for an extended duration of time. Consequently, maintenance treatments should have a manageable tolerability profile to ensure that patients are able to remain on therapy to derive optimal clinical benefit.

Bevacizumab has a well-known and manageable safety profile. Adverse event (AE) profiles were generally similar between the bevacizumab-treated and chemotherapy-only arms across bevacizumab maintenance studies for recurrent ovarian cancer (Figure 3A-B). However, some AEs were observed more frequently in the bevacizumab-treated arms than in chemotherapy-only arms including epistaxis (OCEANS, 55% vs 14%), hypertension (OCEANS, 42% vs 9%; GOG-0213, 42% vs 3%), and pulmonary hemorrhage (GOG-0213, 34% vs 2%) [START_REF] Coleman | Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial[END_REF][START_REF] Aghajanian | Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer[END_REF]. Bevacizumab may also increase the risk of gastrointestinal perforations and arterial or venous thromboembolic events [8,[START_REF]Avastin (bevacizumab) injection, for intravenous use [summary of product characteristics[END_REF].

The AE profiles of PARP inhibitors as maintenance treatment in the recurrent setting are similar to each other, with most AEs being low grade (grade 1 or 2) and manageable with supportive care and/or dose modification [18-21, 35, 38, 44, 45]. The non-hematologic AEs most frequently associated with PARP inhibitors are gastrointestinal side-effects, including nausea (any grade: 71-76%; grade ≥3: 2-4%), vomiting (any grade: 34-37%; grade ≥3: 2-4%), constipation (any grade: 21-40%; grade ≥3: 0-2%), and diarrhea (any grade: 19-33%; grade ≥3: <1-2%) (Figure 3C-F).

Fatigue is also commonly observed (any grade: 52-71%; grade ≥3: 4-8%).

Hematologic AEs may be considered a class effect of PARP inhibitors, with anemia being the most common (any grade: 21-50%; grade ≥3: 5-25%), followed by thrombocytopenia (any grade: <10-61%; grade ≥3: <3-34%), and neutropenia (any grade: 5-30%; grade ≥3: 4-20%). The incidence of myelodysplastic syndrome or acute myeloid leukemia observed with all three PARP inhibitors is low (1-2%) [START_REF] Mirza | Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[END_REF][START_REF] Pujade-Lauraine | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial[END_REF][START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF]; however, in the final OS analysis of SOLO2, the incidence was 8% with olaparib (mean treatment duration: 29.1 months) versus 4% with placebo (mean treatment duration: 18.6 months) [START_REF] Poveda | Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation[END_REF].

There are noteworthy differences in the AE profiles of the individual PARP inhibitors. Pneumonitis is a rare, sometimes fatal AE that has been reported with olaparib (<1%) [START_REF]Lynparza (olaparib) tablets [prescribing information[END_REF] and niraparib (incidence not reported) [START_REF]Zejula (niraparib) capsules[END_REF] but not rucaparib [START_REF]Rubraca (rucaparib) tablets [prescribing information[END_REF][START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF]. Niraparib is associated with a higher incidence of any-grade (61%) and grade ≥3 (34%) thrombocytopenia versus olaparib (any grade: <10-14%; grade ≥3: <3-1%) and rucaparib (any grade: 29%; grade ≥3: 5%) [START_REF] Ledermann | Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial[END_REF][START_REF] Mirza | Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[END_REF][START_REF] Pujade-Lauraine | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial[END_REF][START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF]. More niraparib-treated patients (35%) with a baseline body weight <77 kg or platelet count <150,000 cells/mL had grade ≥3 thrombocytopenia during the first month versus patients with baseline levels over these values (12%). These patients may benefit from a lower starting dose of niraparib of 200 mg/day [START_REF] Berek | Safety and dose modification for patients receiving niraparib[END_REF], with an analysis of data from PRIMA suggesting that an individualized starting dose of niraparib 200-or 300-mg/day may have similar efficacy to a fixed starting dose of niraparib 300 mg/day [START_REF] Mirza | Evaluation of an individualized starting-dose of niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study[END_REF]. Hypertension has also been more frequently reported with niraparib (any grade: 19%; grade ≥3: 8%) [START_REF] Mirza | Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[END_REF] than olaparib (incidence not reported) [START_REF] Ledermann | Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial[END_REF][START_REF] Pujade-Lauraine | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial[END_REF] or rucaparib (any grade: 10%; grade ≥3: 2%) [START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF]. This effect may be mediated via inhibition of the dopamine, norepinephrine, and serotonin transporters by niraparib [START_REF]Zejula (niraparib) capsules[END_REF]. Rucaparib is associated with a higher incidence of elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (any grade: 35%; grade ≥3: 10%) than olaparib (incidence not reported) or niraparib (any grade: 10%; grade ≥3: 4%) [START_REF]Zejula (niraparib) capsules[END_REF][START_REF] Ledermann | Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial[END_REF][START_REF] Pujade-Lauraine | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial[END_REF][START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF]. These ALT/AST elevations are generally transient, self-limiting, and not associated with other signs of liver injury [START_REF] Coleman | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF].

Educating patients on the AEs to expect and how they can be monitored and managed may improve treatment adherence. Guidance for the management of AEs with bevacizumab, olaparib, niraparib, or rucaparib is provided in their respective prescribing information and summary of product characteristics [8-15], and has also been published [START_REF] Drew | Real-world delivery of rucaparib to patients with ovarian cancer: recommendations based on an integrated safety analysis of ARIEL2 and Study 10[END_REF][START_REF] Lafargue | Exploring and comparing adverse events between PARP inhibitors[END_REF][START_REF] Plummer | Expert recommendations on the management of hypertension in patients with ovarian and cervical cancer receiving bevacizumab in the UK[END_REF][START_REF] Randall | Bevacizumab toxicities and their management in ovarian cancer[END_REF][START_REF] Tookman | Practical guidance for the management of side effects during rucaparib therapy in a multidisciplinary UK setting[END_REF][START_REF] Lorusso | Management of adverse events during rucaparib treatment for relapsed ovarian cancer: a review of published studies and practical guidance[END_REF]. Supportive care measures for AEs include the use of amlodipine for hypertension, antiemetics for nausea/vomiting, loperamide for diarrhea, exercise programs and cognitive behavioral therapy for fatigue, and blood transfusions for anemia [START_REF] Drew | Real-world delivery of rucaparib to patients with ovarian cancer: recommendations based on an integrated safety analysis of ARIEL2 and Study 10[END_REF][START_REF] Lafargue | Exploring and comparing adverse events between PARP inhibitors[END_REF][START_REF] Plummer | Expert recommendations on the management of hypertension in patients with ovarian and cervical cancer receiving bevacizumab in the UK[END_REF][START_REF] Randall | Bevacizumab toxicities and their management in ovarian cancer[END_REF]. Blood pressure should be monitored regularly in patients receiving bevacizumab. Monthly complete differential blood counts are required to monitor for hematologic toxicities in patients treated with a PARP inhibitor, and patients should be provided with information regarding the risk for myelodysplastic syndrome or acute myeloid leukemia. Across therapies, dose interruptions, and/or reductions may be required for moderate/severe AEs; treatment may need to be discontinued for more severe/prolonged AEs.

Impact of maintenance therapy for recurrent ovarian cancer on QoL and patientcentered outcomes

Another goal of maintenance treatment is to maintain patient QoL. Assessment of the impact of maintenance treatment on patient QoL is important given that eligible patients will be largely asymptomatic after responding to chemotherapy. Since these patients do not have disease-related symptoms, it is unlikely that maintenance treatment could improve patient QoL. However, AEs associated with these treatments could negatively impact QoL and offset the clinical benefits associated with a longer PFS.

Traditional QoL measures have shown that patients with recurrent ovarian cancer treated with bevacizumab or PARP inhibitors as maintenance therapy had no detrimental loss in QoL versus controls. In GOG-0213, the overall difference in mean Functional Assessment of Cancer Therapy Ovarian Symptom (FACT-O) Trial Outcome Index (TOI) score between the chemotherapy arm and the bevacizumab plus chemotherapy arm was -0.37 (95% CI -1.80 to 1.06; P=0.62). FACT-O scores decreased in both arms during therapy and returned to baseline by 6 months after the first treatment cycle [START_REF] Coleman | Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial[END_REF]. No QoL data for OCEANS have been reported to date.

In Study 19,there [START_REF] Ledermann | Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer[END_REF]. In SOLO2, the adjusted average mean change from baseline over the first 12 months in the FACT-O TOI score was -2.90 (95% CI -4.13 to -1.67) with olaparib and -2.87 (-4.64 to -1.10) with placebo (estimated difference:

-0.03 [95% CI -2.19 to -2.13]; P=0.98) [START_REF] Friedlander | Healthrelated quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial[END_REF]. The NOVA study used EQ-5D-5L to assess QoL; mean preprogression EQ-5D-5L scores (average of all postbaseline preprogression scores among all patients with disease progression) were similar between the niraparib and placebo arms in the gBRCA (0.838 vs 0.834) and non-gBRCA (0.833 vs 0.815) cohorts [START_REF] Oza | Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial[END_REF]. In ARIEL3, there was no significant difference in time to worsening in the FOSI-18, disease-related symptoms-physical (DRS-P) subscale score between the rucaparib and placebo arms in patients with a BRCAmutant tumor (HR 1.24 [95% CI 0.82-1.86]; P=0.30) [START_REF] Coleman | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF].

Beyond traditional QoL measures, patient-centered outcomes have been developed to evaluate the benefits of a therapy while adjusting for the negative impacts of side effects. No patient-centered outcomes have been reported for OCEANS or GOG-0213. However, data from SOLO2, NOVA, and ARIEL3 have demonstrated that PARP inhibitor maintenance treatment provides significant benefits to patient health status even when accounting for the side effects that patients with recurrent ovarian cancer may experience.

Quality-adjusted PFS (QA-PFS) is a patient-centered outcome that represents the duration of survival without disease progression, adjusted for the value the patient places on their health status. Mean QA-PFS was significantly longer with olaparib versus placebo (13.96 vs 7.28 months; mean difference 6.68 months [95% CI 4.98-8.54]) in SOLO2, (Figure 4A) [START_REF] Friedlander | Healthrelated quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial[END_REF]. In the ITT population of ARIEL3, mean QA-PFS was significantly longer in the rucaparib versus the placebo arm (12.02 vs 5.74 months; mean difference 6.28 months [95% CI 4.85-7.47]) (Figure 4B) [START_REF] Oza | Patientcentered outcomes in ARIEL3, a phase 3, randomized, placebo-controlled trial of rucaparib maintenance treatment in patients with recurrent ovarian carcinoma[END_REF]. QA-PFS was also significantly longer with rucaparib in the BRCA-mutant and HRD cohorts [START_REF] Oza | Patientcentered outcomes in ARIEL3, a phase 3, randomized, placebo-controlled trial of rucaparib maintenance treatment in patients with recurrent ovarian carcinoma[END_REF].

Time without symptoms or toxicity (TWiST), another patient-centered outcome, can be calculated by subtracting all of the time in which patients experience treatment toxicity or disease symptoms from PFS. In SOLO2, the mean duration of TWiST was significantly longer with olaparib versus placebo (15.03 vs 7.70 months; difference 7.33 [95% CI 4.70-8.96]) with toxicity defined as the mean duration of grade ≥2 nausea, vomiting, and fatigue (Figure 4C) [START_REF] Friedlander | Healthrelated quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial[END_REF]. In NOVA, mean TWiST was longer with niraparib than placebo in patients with a gBRCA mutation (3.83 vs 0.88 years; difference 2.95 years) and patients without a gBRCA mutation (2.46 vs 1.12 years; difference 1.34 years) (Figure 4D) with toxicity defined as the mean duration of symptomatic grade ≥2 nausea, vomiting, and fatigue [START_REF] Matulonis | Niraparib maintenance treatment improves time without symptoms or toxicity (TWiST) versus routine surveillance in recurrent ovarian cancer: a TWiST analysis of the ENGOT-OV16/NOVA trial[END_REF]. Rather than using actual on-study PFS values, the NOVA analysis calculated mean PFS with extrapolated survival curves under the assumption that patients could remain progression free for up to 20 years.

For ARIEL3, quality-adjusted TWiST (Q-TWiST), a variation of TWiST that takes into consideration patients' perceptions of the impact of toxicity on PFS, was evaluated.

In the ITT population, mean Q-TWIST was longer in the rucaparib versus the placebo arm (13.16 vs 6.40 months; mean difference 6.77 months [95% CI 5.64-8.14]) with toxicity defined as the mean duration of grade ≥2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was also longer with rucaparib in the BRCA-mutant and HRD cohorts (Figure 4E) [START_REF] Oza | Patientcentered outcomes in ARIEL3, a phase 3, randomized, placebo-controlled trial of rucaparib maintenance treatment in patients with recurrent ovarian carcinoma[END_REF].

Identification of candidates for targeted maintenance treatment in the second-line setting

Selection of second-line maintenance treatment for patients with recurrent ovarian cancer will be influenced by the maintenance treatment that patients received following first-line platinum-based chemotherapy. Bevacizumab is approved in Europe and the US in combination with initial chemotherapy and as continuation maintenance treatment for patients with ovarian cancer following initial surgical resection [8,[START_REF]Avastin (bevacizumab) injection, for intravenous use [summary of product characteristics[END_REF]. GOG-0218 and ICON7 both reported a significant reduction in the risk of disease progression or death with bevacizumab in this setting versus standard frontline chemotherapy alone (28% and 19% reduction, respectively) [START_REF] Burger | Incorporation of bevacizumab in the primary treatment of ovarian cancer[END_REF][START_REF] Perren | A phase 3 trial of bevacizumab in ovarian cancer[END_REF]. Although bevacizumab has demonstrated efficacy as second-line maintenance in patients with recurrent ovarian cancer who received bevacizumab as part of a first-line treatment [START_REF] Pignata | Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first line treatment: The randomized phase 3 trial MITO16B-MaNGO OV2B-ENGOT OV17[END_REF], the use of bevacizumab after prior bevacizumab exposure is not currently approved in Europe [START_REF]Avastin (bevacizumab) injection, for intravenous use [summary of product characteristics[END_REF].

Among PARP inhibitors, olaparib is approved in Europe and the US as first-line maintenance treatment for patients with BRCA-mutated ovarian cancer who had a CR or PR to first-line platinum-based chemotherapy, based on the results of SOLO1 which demonstrated a 70% reduction in the risk of disease progression or death for olaparib versus placebo in this setting [START_REF]Lynparza (olaparib) tablets [prescribing information[END_REF][START_REF]Lynparza (olaparib)[END_REF]. Recently, the combination of olaparib and bevacizumab was approved in the US as first-line maintenance for patients with ovarian cancer with HRD [START_REF]Lynparza (olaparib) tablets [prescribing information[END_REF]. In PAOLA-1, this combination resulted in a reduction in risk of disease progression or death versus bevacizumab alone (41% reduction in the ITT population and 67% reduction in the HRD population) [START_REF] Ray-Coquard | Olaparib plus bevacizumab as first-line maintenance in ovarian cancer[END_REF]. Niraparib is also approved in the US as first-line maintenance treatment for patients with ovarian cancer regardless of BRCA or HRD status, based on a 38% reduction in the risk of disease progression or death for niraparib versus placebo in the overall population of PRIMA [START_REF]Zejula (niraparib) capsules[END_REF][START_REF] Gonzalez-Martin | Niraparib in patients with newly diagnosed advanced ovarian cancer[END_REF].

Although not yet approved, the PARP inhibitor veliparib as continuation maintenance following initial chemotherapy led to a 32% reduction in the risk of disease progression or death in the ITT population versus chemotherapy alone without maintenance treatment [START_REF] Coleman | Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer[END_REF].

Patients who are not treated with a PARP inhibitor or those who are treated with bevacizumab in the first-line setting will be candidates to receive a PARP inhibitor after a response to second-line chemotherapy. Data from PAOLA-1, PRIMA, and VELIA suggest that patients who are homologous recombination proficient may not benefit or may benefit less from PARP inhibitors as first-line maintenance treatments versus HRD patients [START_REF] Ray-Coquard | Olaparib plus bevacizumab as first-line maintenance in ovarian cancer[END_REF][START_REF] Gonzalez-Martin | Niraparib in patients with newly diagnosed advanced ovarian cancer[END_REF][START_REF] Coleman | Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer[END_REF]; this is reflected in the current indication for olaparib plus bevacizumab in the first-line setting [START_REF]Lynparza (olaparib) tablets [prescribing information[END_REF]. In contrast, homologous recombination-proficient patients have been shown to derive clinical benefit from rucaparib and niraparib as second-line maintenance treatment versus placebo [START_REF] Coleman | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF][START_REF] Mirza | Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[END_REF], as described earlier. Consequently, homologous recombination-proficient patients may be more suitable for second-line rather than first-line maintenance treatment with a PARP inhibitor. Studies such as DUETTE and OReO/ENGOT-OV-38 may inform whether patients who receive a PARP inhibitor as first-line maintenance treatment may also be candidates for PARP inhibitors in the second-line maintenance setting [START_REF] Clinicaltrials | A study to examine olaparib maintenance retreatment in patients with epithelial ovarian cancer[END_REF][START_REF] Clinicaltrials | A study to evaluate the effectiveness and tolerability of a second maintenance treatment in participants with ovarian cancer, who have previously received polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerase inhibitor (PARPi) treatment[END_REF].

Analyses of the pivotal clinical studies of targeted maintenance treatments for patients with recurrent ovarian cancer have demonstrated consistent efficacy benefits across a broad range of patient subgroups. Improvements in PFS have been observed irrespective of characteristics such as age, BRCA mutation status, disease burden at baseline, ECOG performance status, prior therapies, or response to last platinum-based regimen [START_REF] Coleman | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF][START_REF] Mirza | Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[END_REF][START_REF] Aghajanian | OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer[END_REF][START_REF] Ledermann | Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer[END_REF]. Maintenance treatment with olaparib, niraparib, or rucaparib, significantly improved PFS versus placebo in patients with recurrent ovarian cancer who had a CR or a PR to their last platinum-based chemotherapy [START_REF] Coleman | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF][START_REF] Mirza | Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[END_REF][START_REF] Ledermann | Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer[END_REF]. The extension of PFS in patients with a CR is particularly noteworthy, since some physicians may not consider these patients suitable for maintenance treatment. The safety of targeted maintenance treatments in these patient subgroups is also generally consistent with the overall safety profile of these agents [START_REF] Friedlander | Longterm efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy[END_REF][START_REF] Fabbro | Efficacy and safety of niraparib as maintenance treatment in older patients (≥ 70 years) with recurrent ovarian cancer: Results from the ENGOT-OV16/NOVA trial[END_REF][START_REF] Colombo | The effect of age on efficacy, safety and patient-centered outcomes with rucaparib: a post hoc exploratory analysis of ARIEL3, a phase 3, randomized, maintenance study in patients with recurrent ovarian carcinoma[END_REF][START_REF] Ledermann | Effect of response to last platinum-based chemotherapy in patients (pts) with platinum-sensitive, recurrent ovarian carcinoma in the phase III study ARIEL3 of rucaparib maintenance treatment[END_REF]. Overall, these analyses suggest that a range of patient characteristics do not need to be taken into account when selecting a targeted maintenance treatment for an individual patient with recurrent ovarian cancer.

One factor which may influence the choice of maintenance treatment in the recurrent setting is cancer histology since the use of PARP inhibitors in Europe is limited to patients with high-grade ovarian cancer, whereas bevacizumab is not and so may be an option for patients with non-high-grade ovarian cancer [START_REF]Avastin (bevacizumab) injection, for intravenous use [summary of product characteristics[END_REF][START_REF]Lynparza (olaparib)[END_REF][START_REF]Zejula (niraparib) capsules [summary of product characteristics[END_REF][START_REF]Rubraca (rucaparib) tablets [summary of product characteristics[END_REF].

Patient preference for second-line maintenance treatment or active surveillance must also be taken into consideration, and physicians must clearly explain the benefits and risks of both strategies. Fear of cancer recurrence, particularly when anticipating follow-up appointments, is an important concern for patients in remission, and patients' anxiety levels may increase when undergoing CA-125 level assessments [START_REF] Matulonis | Long-term adjustment of early-stage ovarian cancer survivors[END_REF][START_REF] Mirabeau-Beale | Comparison of the quality of life of early and advanced stage ovarian cancer survivors[END_REF][START_REF] Kyriacou | Fear of cancer recurrence: a study of the experience of survivors of ovarian cancer[END_REF]. Some patients may prefer active surveillance since they feel that they are not a cancer survivor if they continue treatment beyond remission and may consider toxicities associated with maintenance treatment less tolerable than those occurring in the treatment setting [START_REF]Understanding maintenance therapy[END_REF][START_REF] Coleman | Maintenance therapy in ovarian cancer: what's at stake?[END_REF]. However, a majority of patients who have experienced a relapse value disease stabilization [START_REF] Herzog | Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper[END_REF], and physicians need to make sure that these patients are aware of the clinical benefits of targeted maintenance treatment (e.g., extended PFS without affecting QoL). Patients and physicians should also consider resource utilization such as use and cost of health services during active surveillance or second-line maintenance treatment [START_REF] Harrow | Resource utilization and expenditures during the "watchful waiting" period in patients with recurrent ovarian cancer[END_REF][START_REF] Wu | Budget impact analysis of niraparib and olaparib for maintenance treatment of platinum-sensitive, recurrent ovarian cancer in the US[END_REF][START_REF] Dottino | Food and Drug Administration-approved poly (ADP-ribose) polymerase inhibitor maintenance therapy for recurrent ovarian cancer: a cost-effectiveness analysis[END_REF].

Options for second-line maintenance treatment for women with recurrent ovarian cancer are anticipated to expand and may incorporate new treatment modalities such as immunotherapy. For example, the ongoing ATALANTE study is assessing the combination of platinum-based chemotherapy, bevacizumab, and atezolizumab followed by maintenance treatment with bevacizumab and atezolizumab [START_REF] Clinicaltrials | ATALANTE: atezolizumab vs placebo phase III study in late relapse ovarian cancer treated with chemotherapy+bevacizumab[END_REF], and the ANITA study is assessing the combination of platinum-based chemotherapy and atezolizumab followed by maintenance treatment with atezolizumab and niraparib [START_REF] Clinicaltrials | Platinum-based chemotherapy with atezolizumab and niraparib in patients with recurrent ovarian cancer (ANITA)[END_REF].

These and other studies will provide the opportunity to further understand the mechanisms by which maintenance treatment can delay disease progression (e.g., elimination of residual tumor or enhancement of antitumor immune response).

Conclusions

Before the availability of maintenance treatments, options for patients with recurrent ovarian cancer were limited to active surveillance or awaiting symptomatic relapse. Although active surveillance allows patients to recover from AEs associated with chemotherapy [START_REF] Herzog | Recurrent ovarian cancer: how important is it to treat to disease progression?[END_REF], clinical studies have indicated that maintenance treatment with the angiogenesis inhibitor bevacizumab, as well as the PARP inhibitors, olaparib, niraparib, or rucaparib is of greater clinical benefit in patients with recurrent ovarian cancer [18-21, 33, 41]. Maintenance treatments significantly extend PFS and postprogression efficacy outcomes versus placebo (which effectively represents active surveillance) in this setting. PARP inhibitors increase OS in patients with BRCA-mutant ovarian cancer and are also associated with significant improvements in patient-centered outcomes. Furthermore, these targeted maintenance treatments all have manageable toxicity profiles [18-21, 33, 38, 41, 57].

Evidence suggests that maintenance treatments are currently underutilized in patients with recurrent ovarian cancer [START_REF] Garofalo | Realworld data analysis of ovarian cancer (OC) maintenance utilization among maintenance eligible patients[END_REF], representing a missed opportunity for many patients to extend their PFS and delay the time to their next treatment. Maintenance treatment with PARP inhibitors after the second-or later-line chemotherapy is only available to patients with platinum-sensitive disease; therefore, patients who become platinum resistant may lose the opportunity to use PARP inhibitors as maintenance treatment.

Targeted maintenance treatment represents a new standard of care for patients with ovarian cancer in the second-line setting, with demonstrated clinical benefits versus active surveillance. In this setting, PARP inhibitors have shown the greatest efficacy as maintenance treatment in patients with a BRCA mutation or HRD and so may be used to treat those patients who have not received a PARP inhibitor as first line maintenance; otherwise these patients could receive bevacizumab. PARP inhibitor maintenance treatment has also demonstrated efficacy in patients with BRCA wild-type and homologous recombination-proficient recurrent ovarian cancer, and bevacizumab could also be considered in these patients. Overall, we strongly recommend that targeted maintenance treatment with bevacizumab or a PARP inhibitor be offered to all eligible patients with platinum-sensitive recurrent ovarian cancer.

Contributors

All authors contributed to the concept, design, and writing of this manuscript and provided their final approval of the version to be published.

Table 1

Postprogression efficacy outcomes in clinical studies of PARP inhibitors as second-line maintenance treatments in patients with recurrent ovarian cancer [19, 21, 38-40, 42, 43]. c Germline or unknown. d Data were immature, <50% of events. e Data were immature, <40% of events. f Germline, somatic, or unknown. g BRCA mutation + wild-type BRCA/high loss of heterozygosity.

Abbreviations: BRCAmut, BRCA mutation; CFI, chemotherapy-free interval; CI, confidence interval; HR, hazard ratio; HRD, homologous recombination deficient; ITT, intent to treat; NA, not available; NR, not reached; PARP, poly(ADP-ribose) polymerase; PFS2, progression-free survival on subsequent therapy or death; TSST, time to start of second subsequent therapy; TFST, time to start of first subsequent therapy. *QA-PFS was calculated using the product of the adjusted mean EQ-5D-5L utility from randomization to progression and the area under the Kaplan-Meier curve for time to progression. † QA-PFS was calculated using the product of the investigator-assessed PFS function to EQ-5D-3L index score function. ‡ Mean TWiST was estimated as mean PFS -mean time with toxicity based on select grade ≥2 AEs (fatigue, nausea, and vomiting). The NOVA analysis calculated mean PFS with extrapolated survival curves under the assumption that patients could remain progression free for up to 20 years. § Q-TWiST was calculated as μTOX × TOX + TWiST, with toxicity based on select grade ≥2 TEAEs (nausea, vomiting, fatigue, and asthenia). ǁ Germline, somatic, or unknown. ¶ BRCA mutation + wild-type BRCA/high loss of heterozygosity.

[Note to journal: All figures should be printed in color]

#

The 95% CI data are not available.

Fig. 1 . 32 Fig. 2 .

 1322 Fig. 1. Treatment pathway in ovarian cancer, focusing on the clinical decision following a response to second-line platinum-based chemotherapy. Abbreviations: HRD, homologous recombination deficient; PARP, poly(ADP-ribose) polymerase.

Fig. 3 .

 3 Fig. 3. Frequently occurring nonhematologic TEAEs (≥20%) and hematologic TEAEs associated with maintenance treatment for recurrent ovarian cancer in (A) OCEANS*, (B) GOG-0213, (C) Study 19, (D) SOLO2, (E) NOVA, and (F)ARIEL3[19-21, 33, 38, 41]. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; TEAE, treatment-emergent adverse event.

Fig. 4 .

 4 Fig. 4. Patient-centered outcomes in clinical studies of PARP inhibitors as second-line maintenance treatments in patients with recurrent ovarian cancer (A) SOLO2 QA-PFS*, (B) ARIEL3 QA-PFS † , (C) SOLO2 mean TWiST ‡ , (D) NOVA mean TWiST ‡ , and (E) ARIEL 3 Q-TWiST § [55, 57, 58]. Abbreviations: μTOX, mean utility weight for TOX health state; CI, confidence interval; gBRCA, germline BRCA; HRD, homologous recombination deficient; ITT, intent to treat; QA-PFS quality-adjusted progression-free survival; Q-TWiST, quality-adjusted time without symptoms or toxicity; SD, standard deviation; TEAE, treatment-emergent adverse event; TOX, time with toxicity of treatment; TWiST, time without symptoms or toxicity.

  ). In Study 19, TFST and TSST were significantly longer with olaparib maintenance treatment versus placebo in the overall study population (TFST 13.4 vs 6.7 months; hazard ratio [HR] 0.40 [95% CI 0.30-0.52]; P<0.0001; TSST 19.1 vs 14.8 months; HR 0.53 [95% CI 0.40-0.71]; P<0.0001). These improvements were also independent of BRCA mutation status [19]. Similarly, data from SOLO2 showed that TFST (27.9 vs 7.1 months; HR 0.28 [95% CI 0.21-0.38]; P<0.0001) and TSST (not reached vs 18.2 months; HR 0.37 [95% CI 0.26-0.53]; P<0.0001) were significantly longer with olaparib versus placebo in patients with a BRCA mutation[START_REF] Pujade-Lauraine | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial[END_REF]. In the NOVA study, niraparib significantly extended CFI versus placebo in patients with (22.8 vs 9.4 All four postprogression efficacy endpoints were also significantly longer with rucaparib than placebo in the BRCA-mutant and HRD cohorts[START_REF] Ledermann | Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): postprogression outcomes and updated safety from a randomised, placebo-controlled, phase 3 trial[END_REF].

	alone, no statistically significant survival benefit was observed in OCEANS (33.6 vs 32.9
	months; HR 0.95 [95% CI 0.77-1.18]; P=0.65) or GOG-0213 (42.2 vs 37.3 months; HR
	0.83 [95% CI 0.68-1.01]; P=0.056) [33, 41]. In Study 19, median OS was numerically
	but not significantly longer with olaparib than placebo (29.8 vs 27.8 months; HR 0.73
	[95% CI 0.55-0.95]; P=0.0214 [threshold for significance, P<0.0095])
	months; HR 0.26 [95% CI 0.17-0.41]; P<0.0001) and without a gBRCA mutation (12.7
	vs 8.6 months; HR 0.50 [95% CI 0.37-0.67]; P<0.0001). TFST was also significantly
	longer with niraparib versus placebo in patients with (21.0 vs 8.4 months; HR 0.31 [95%
	CI 0.21-0.48]; P<0.0001) and without a gBRCA mutation (11.8 vs 7.2 months; HR 0.55
	[95% CI 0.41-0.72]; P<0.0001) [39, 40]. In a prespecified exploratory analysis of
	ARIEL3, rucaparib significantly extended CFI (14.3 vs 8.8 months; HR 0.43 [95% CI
	0.35-0.53]; P<0.0001), TFST (12.4 vs 7.2 months; HR 0.43 [95% CI 0.35-0.52];
	P<0.0001), PFS2 (21.0 vs 16.5 months; HR 0.66 [95% CI 0.53-0.82]; P=0.0002) and
	TSST (22.4 vs 17.3 months; HR 0.68 [95% CI 0.54-0.85]; P=0.0007) versus placebo in
	the ITT population. Overall survival. OS data are currently available for bevacizumab and olaparib
	maintenance treatments in the recurrent setting. Although OS was numerically longer
	with the addition of bevacizumab maintenance to chemotherapy versus chemotherapy
	10

  were no significant differences between the olaparib and placebo arms in FACT-O TOI score (odds ratio [OR] 1.14; 95% CI 0.58-2.24; P=0.7),

	FACT-O total score (OR 1.17; 95% CI 0.60-2.27; P=0.65), and Functional Assessment
	of Cancer Therapy/National Comprehensive Cancer Network Ovarian Symptom Index
	(FOSI) (OR 1.22; 95% CI 0.60-2.51; P=0.59) in the overall population or in the
	subgroup of patients with a BRCA mutation (FACT-O TOI: OR 1.37; 95% CI 0.56-3.46;
	P=0.5; FACT-O total score: OR 1.38; 95% CI 0.58-3.39; P=0.47; FOSI: OR 1.41; 95%
	CI 0.56-3.70, P=0.47)

Acknowledgements

Medical writing and editorial support funded by Clovis Oncology were provided by Jeremy Kennard, PhD, Nathan Yardley, PhD, and Frederique H. Evans, MBS, of Ashfield Healthcare Communications.

Declarations of competing interest

A du Bois has served on advisory boards for Clovis Oncology, AstraZeneca, Genmab/Seattle Genetics, MSD, Pfizer, PharmaMar, Roche, and Tesaro/GSK.