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Maintenance Treatment of Newly Diagnosed Advanced Ovarian Cancer: Time for a Paradigm Shift?

ABSTRACT: Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a BRCA1 and/or BRCA2 mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.

SUBMITTER: DiSilvestro P

PROVIDER: S-EPMC8616471 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The incidence and mortality rates of ovarian cancer are increasing globally. Ovarian cancer is diagnosed at an advanced stage in 80% of women. After standard, platinum-based, front-line chemotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors and antiangiogenic agents are successfully employed as maintenance strategies for newly diagnosed, advanced ovarian cancer patients. Landmark clinical studies, including SOLO-1, PAOLA-1, PRIMA, and VELIA, have provided crucial insights on optimizing first-line maintenance treatment using PARP inhibitors. A group of ovarian cancer experts, primarily from low- and middle-income countries, met in September 2019 to discuss new developments for the first-line treatment of ovarian cancer and its implications. Key implications of the evolving clinical data included: (1) olaparib or niraparib maintenance therapy appears to be the preferred choice for patients with BRCA1/2 mutations; hence, BRCA testing is beneficial in identifying these patients; (2) niraparib monotherapy and olaparib in combination with bevacizumab have demonstrated significant benefit in progression-free survival (PFS) in homologous recombination deficiency (HRD)-positive patients; (3) bevacizumab, niraparib alone, or observation can be an alternative for HRD-negative patients; (4) further data is warranted to explore the role of PARP inhibitors in treating HRD-negative, ovarian cancer patients to confirm findings of the exploratory analysis of PRIMA; (5) PARP inhibitors may be beneficial for stage IV ovarian cancer patients with inoperable disease and patients with prior neoadjuvant chemotherapy; and (6) there is an urgent need to increase awareness in both clinicians and patients on BRCA and HRD testing for optimizing treatment decision-making and improving clinical outcomes in newly diagnosed, advanced ovarian cancer patients. In clinical medicine, the limited availability of family history (FH) information and the complexity of FH criteria has hampered the implementation of BRCA testing. Moreover, many cancer patients with BRCA mutations are not tested because they do not meet the criteria for FH. Consequently, BRCA testing in many high income countries, including the US and Australia, is underused and used inappropriately, which has resulted in the loss of valuable opportunities for better cancer management and cancer prevention.

Project description:ImportanceThe efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease.ObjectiveTo evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted).Design, setting, and participantsThis multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months.InterventionsPatients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/μL [to convert to ×109/μL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy.Main outcomes and measurementsThe primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population.ResultsA total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events.Conclusion and relevanceThis randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting.Trial registrationClinicalTrials.gov Identifier: NCT03709316.

Project description:BackgroundIn patients with newly diagnosed ovarian cancer, bevacizumab and poly(ADP-ribose) polymerase (PARP) inhibitors, alone or in combination, have shown benefit as maintenance treatment following platinum-based chemotherapy. However, no trials have compared a PARP inhibitor plus bevacizumab versus a PARP inhibitor, or a PARP inhibitor versus bevacizumab. We performed an unanchored population-adjusted indirect treatment comparison to estimate the relative efficacy and safety of maintenance treatments for newly diagnosed advanced ovarian cancer.MethodsAnalyses were performed using aggregate data from the PRIMA trial and patient-level data from a subset of patients from the PAOLA-1 trial that met surgery and staging eligibility criteria of PRIMA. Propensity weights were used to match baseline characteristics of the PAOLA-1 subset to those of the PRIMA population. Analysis was performed in overall (biomarker-unselected) and homologous recombination repair deficiency (HRD)-positive populations.ResultsA total of 595/806 (266/387 HRD-positive) PAOLA-1 patients were included. After matching, the effective sample size for PAOLA-1 was 532 (242 HRD-positive). Maintenance olaparib plus bevacizumab reduced the risk of disease progression or death by 43% [hazard ratio (HR) 0.57; 95% confidence interval (CI): 0.47-0.69] versus niraparib and by 40% (HR 0.60; 95% CI: 0.49-0.74) versus bevacizumab in the biomarker-unselected population and by 43% (HR 0.57; 95% CI: 0.41-0.79) and 60% (HR 0.40; 95% CI: 0.29-0.55), respectively, in the HRD-positive population. Progression-free survival (PFS) benefits of maintenance niraparib and bevacizumab arms were comparable in the biomarker-unselected population (HR 1.07; 95% CI: 0.87-1.32); however, niraparib showed a 30% reduced risk compared with bevacizumab (HR 0.70; 95% CI: 0.51-0.97) in the HRD-positive population.ConclusionsIn biomarker-unselected and HRD-positive patients, combination treatment with olaparib plus bevacizumab as maintenance treatment improves PFS for women with newly diagnosed advanced ovarian cancer compared with either bevacizumab or niraparib alone. Results are hypothesis generating and could guide randomised trial design.

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Maintenance Treatment of Newly Diagnosed Advanced Ovarian Cancer: Time for a Paradigm Shift?

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