Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

oing-christoph

The DNA repair machinery is an emerging target for personalised cancer treatment. Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition (PARPi) is one of the most promising approaches, as tumours with DNA repair deficiency have been shown to be sensitive to PARPi in vitro and in vivo, owing to the concept of synthetic lethality [1]. The PARP enzyme family comprises three different subtypes (PARP1-3), which play crucial roles in the repair of single- and double-stranded DNA breaks (DSBs) [2, 3]. DSBs can be repaired by either homologous recombination, or the error-prone non-homologous end-joining.

Unrepaired DSBs lead to genomic instability and cell death by mitotic catastrophe [4]. BRCA1 and BRCA2 mutations cause DNA repair deficiency, and germline mutations in these genes predispose to develop hereditary breast and ovarian cancer (OC). PARPi has been successfully utilized in clinical trials, which commonly selected for germline BRCA mutated (gBRCAm) OC patients (about 10-15% of OC patients).

Recently, phase III ENGOT-OV16/NOVA trial results were published [5]. In this randomised, placebo-controlled, double-blind trial, the PARP1/2-inhibitor niraparib was applied as maintenance therapy in patients suffering cisplatin-sensitive relapse of OC (with or without gBRCAm). 553 patients with predominant high-grade serous cancer of the ovary were enrolled. 203 had gBRCAm, while 350 did not. Patients were randomised at a 2:1 ratio to either niraparib 300mg PO or placebo daily. Treatment was continued until progression or unbearable toxicity. The primary endpoint was progression-free survival (PFS), and cross-over to niraparib after progression was not allowed. The median follow-up at data cut-off was 15 months.

The trial aimed to investigate the therapeutic potential of PARPi in the light of BRCA mutational status and other aberrations resulting in homologous recombination deficiency (HRD). Niraparib significantly prolonged PFS in advanced cisplatin-sensitive OC patients. Interestingly, the beneficial effect was detectable among three distinct subgroups, which were patients with (i) gBRCAm, (ii) HRD with or without somatic BRCA mutations, and (iii) BRCA wild-type without other detectable HRD-associated alterations. These subgroups account for approximately 70% of advanced OC patients, which dramatically expands the OC patient population, who may benefit from PARPi.

As expected, patients with gBRCAm had favourable outcomes with niraparib maintenance (median PFS 21.0 vs. 5.5 months with placebo; hazard ratio (HR) 0.27; P <0.001). But, the cohort of patients lacking gBRCAm did also benefit of PARPi (median PFS 9.3 vs. 3.9 months; HR 0.45; P <0.001). Of particular interest are two facts: (i) patients with somatic BRCA mutations and HRD had comparably favourable outcomes as gBRCAm carrier (median PFS 20.9 vs. 11.0 months; HR 0.27; P = 0.02), and (ii) even patients without somatic BRCA mutations or any other HRD-related aberration experienced almost a doubling of median PFS (6.9 vs. 3.8 months; HR 0.58; P = 0.02).

The safety profile was in line with prior studies of niraparib, with grade 3-4 adverse events occurring in 74.1% of patients (placebo 22.9%), mostly hematologic lab value abnormalities. Toxicity was manageable by protocol-defined dose-reductions. Adverse event-related treatment discontinuation was reported infrequently in 9.3% of patients. Despite increased toxicity, patient reported outcomes were comparable with both treatments.

Overall survival (OS) data are immature, but significant improvements for all other evaluable secondary endpoints were seen among all subgroups, i.e. time to first subsequent treatment, progression-free survival from onset of niraparib to progression following a subsequent treatment (PFS2), and chemotherapy-free interval. These factors are of tremendous importance for OC patients, who usually undergo many courses of cytotoxic treatment in the course of the disease. Moreover, concerns that maintenance PARPi may give rise to more aggressive tumour phenotypes and less effective subsequent treatments, do not seem to be justified. The positive impact on PFS2 rather points at a durable treatment effect of PARPi.

Mutational and HRD analysis may aid in predicting the expected dimension of PFS improvement, but even patients without any such alterations seem to be better off with niraparib maintenance than without. Thus, new predictive biomarkers for patient selection are needed, such as loss of heterozygosity [6].

The NOVA trial results led to FDA approval of niraparib (Zejula®) for maintenance treatment of recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer regardless of BRCA mutational status on 27 March 2017.

Discussion question:

Are we there yet – what other roles may niraparib and other PARPi play in targeted cancer treatment approaches?

References:

  1. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017; 355: 1152-1158.
  2. Sousa FG, Matuo R, Soares DG et al. PARPs and the DNA damage response. Carcinogenesis 2012; 33: 1433-1440.
  3. Patel AG, Sarkaria JN, Kaufmann SH. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A 2011; 108: 3406-3411.
  4. Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer 2016; 115: 1157-1173.
  5. Mirza MR, Monk BJ, Herrstedt J et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016; 375: 2154-2164.
  6. Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18: 75-87.

The author has no actual, potential, real or apparent interest to declare. The author has no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer
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