PARP Inhibitors in Ovarian Cancer

Evidence for Maintenance and Treatment Strategies

Antonio Bahena-González; Alfredo Toledo-Leyva; Dolores Gallardo-Rincón

Disclosures

Chin Clin Oncol. 2020;9(4):51 

In This Article

Combination With Angiogenesis Inhibitors

Since the introduction of bevacizumab, angiogenesis inhibitors represent a treatment option for epithelial ovarian cancer. Data from phase III trials confirming bevacizumab and cediranib benefit in ovarian cancer have been published.[35–38] Moreover, hypoxia has been shown to be associated with impaired homologous recombination, and repression of BRCA expression by hypoxia is a mechanism of BRCA inactivation in the absence of a genetic mutation.[39] In light of these observations, one can hypothesize that PARP inhibitors may be particularly effective against hypoxic cancer cells in which BRCA expression is down-regulated by anti-angiogenic drugs.

Molecular therapy combination of olaparib and cediranib was evaluated in a randomized, phase II trial that assessed efficacy and safety in women with platinum-sensitive ovarian cancer.[40,41] This trial included 90 patients who were randomly assigned to olaparib or olaparib with cediranib. The addition of cediranib led to a more than 8 months PFS improvement (17.7 and 9 months; HR, 0.42), and a greater frequency of serious fatigue, diarrhea and hypertension. A post-hoc analysis stratified patients by their germline BRCA status and suggested that women who were wild-type or not known to have a BRCA mutation derived a greater PFS benefit (16.5 vs. 5.7 months; HR, 0.32; P=0.008) compared to those with a BRCA mutation (19.4 vs. 16.5 months; HR, 0.55; P=0.16), although the latter group was small. A greater synergism with the combination in the setting of more HR-proficient tumours or hypoxia could explain this difference.

The AVANOVA2 phase II study was designed to investigate the effect and safety of the chemotherapy-free combination treatment with niraparib and bevacizumab.[42] This trial randomized 97 patients to receive oral niraparib 300 mg daily plus bevacizumab 15 mg/kg every 3 weeks or single-agent niraparib. Eligible patients had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. BRCA mutation was not mandatory and patients were stratified by HR-deficiency status. As part of the subgroup analyses, the combination therapy also improved PFS in patients with and without HR-deficiency. The safety analysis was consistent with the known profiles of both drugs combined.

The phase III trial PAOLA-1 evaluated maintenance therapy with the combination of olaparib and bevacizumab compared with bevacizumab and placebo after frontline treatment of patients who were receiving chemotherapy plus bevacizumab, regardless of BRCA mutation status.[43] A total of 806 patients were enrolled. The median PFS was longer in the olaparib group (22.1 vs. 16.6 months; HR 0.59; P<0.001), with a greater benefit in patients with a BRCA mutation and with HR-deficient tumors. The addition of olaparib did not increase the known toxic effects of bevacizumab and there was no difference in health-related quality of life between the studied groups. The combination improved PFS compared with olaparib (median 11.9 vs. 5.5 months; HR, 0.35; P<0.0001).

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