Advanced ovarian cancer is considered incurable with chemotherapy alone. A new randomized, controlled, phase 3 study has demonstrated significantly increased progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer treated with niraparib maintenance therapy.1,2 The PFS benefit was observed regardless of homologous recombination deficiency (HRD) status. The study results were presented at the European Society for Medical Oncology (ESMO) Congress 2019 at Barcelona, Spain and simultaneously published in the New England Journal of Medicine.1,2
Ovarian cancer: The “silent killer”
Ovarian cancer is the third most common gynecological cancer in the world and has the highest mortality rate, which has been reported as three times higher than breast cancer.3,4 Most importantly, the burden of ovarian cancer is predicted to rise significantly by year 2040.5 The unfavorable prognosis of ovarian cancer is caused by asymptomatic growth of the tumor, delayed onset of symptoms and a lack of proper screening, that results in late identification.3
The standard of care for front-line therapy is a combination of surgical debulking and platinum-based chemotherapy.6 In some settings, bevacizumab is also used following chemotherapy.6 Although most patients with advanced ovarian cancer initially respond to therapy, 70% of them will eventually experience recurrence.7 There are various factors affecting the treatment approaches, such as duration of response to previous chemotherapy, number of lines of chemotherapy, molecular signature, histological subtype, and residual toxic effects from previous therapies.8 Treatment decisions in subsequent lines of therapy are thus challenging.
Positive survival benefits in recurrent ovarian cancer with niraparib maintenance therapy
Clinical studies have evaluated poly adenosine diphosphate polymerase (PARP) inhibitors in patients with recurrent ovarian cancer, including those with germline BRCA mutations, platinum-sensitive disease, or both. Niraparib is a highly selective inhibitor of PARP and inhibits the DNA damage repair pathway, preventing the repair of single stranded breaks.
Niraparib was evaluated in ENGOT-OV16/NOVA for its efficacy and safety as the maintenance therapy in a broad population of patients with platinum-sensitive, recurrent ovarian cancer.9 A significantly longer median PFS among those receiving niraparib than those receiving placebo, regardless of the presence or absence of germline BRCA mutations or HRD status, was reported.9
Platinum-sensitive disease is observed in 70% to 80% of patients with ovarian cancer after first-line platinum-based chemotherapy.10 It is defined as having a complete or partial response to platinum-based chemotherapy and no progression of disease within 6 months of the final dose of chemotherapy.11 However, in most cases, successive lines of platinum-based therapy lead to the development of platinum resistance, resulting in progression of the cancer despite complete or partial response to chemotherapy.10,11 An updated analysis of ENGOTOV16/ NOVA trial found a significant increase in PFS with niraparib maintenance therapy regardless of response to the last platinum-based therapy.12
On the basis of niraparib’s efficacy demonstrated in the maintenance setting, QUADRA trial was designed to evaluate the anti-tumor activity and safety of niraparib monotherapy as the fourth or later line of therapy in recurrent ovarian cancer.13 Niraparib showed significant overall survival and PFS among women with heavily pretreated ovarian cancer, particularly in HRD-positive platinum-sensitive disease.13 The benefit extended to patients with a BRCA mutation, as well as to the population with BRCA wild-type disease. This data supported the expansion of treatment indication for niraparib to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations.13
Niraparib in newly diagnosed advanced ovarian cancer
At the ESMO 2019 conference, emerging results from the PRIMA trial, a randomized phase 3 trial on advanced ovarian cancer, were presented.2 The study evaluated the efficacy and safety of niraparib maintenance therapy after platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer at high risk for relapse.1 The study population comprised of 733 patients who were randomized to receive either niraparib once daily or placebo for 36 months.1 The eligible patients were at least 18 years of age and had newly diagnosed, histologically confirmed advanced cancer of the ovary, peritoneum, or fallopian tube (collectively defined as ovarian cancer).1 All the participants had undergone surgery and received 6 to 9 cycles of first-line platinum-based chemotherapy, which had resulted in a complete or partial response.1 Tumor samples were tested to identify those with HRD, which was defined as the presence of a BRCA deleterious mutation or a score of at least 42 on the my-Choice test.1 HRD positivity was identified in 50.9% of the study population.1
During a press interview, the lead investigator of the study, Dr. Antonio González-Martín, co-director, Department of Medical Oncology, Clinica Universidad de Navarra, Madrid, Spain outlined the results, “In this study, we evaluated the benefits of using niraparib after standard treatment of ovarian cancer and with this new therapeutic approach, we have observed a significant improvement in PFS and a 40% reduction of risk of relapse.”14
In the overall population, the median PFS was 13.8 months for the niraparib group and 8.2 months for placebo (HR=0.62; 95% CI: 0.50-0.76; p<0.001) (Figure 1).1 In the HRD subgroup, the median PFS improvement was twice that of the placebo group (21.9 vs. 10.4 months).1
High risk patients with advanced ovarian cancer included in this trial were generally considered to have incurable disease with chemotherapy alone. Niraparib extended treatment beyond chemotherapy and provided a sustained PFS benefit for those at risk for early relapse, including patients with a partial response to platinum-based chemotherapy.1
At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (HR=0.70; 95% CI: 0.44-1.11).1 Similar to PFS, the benefit from niraparib was greater in the subgroup of patients with HRD (Figure 2).2
Most importantly, at 18 months after randomization and 2 years after the diagnosis of advanced ovarian cancer, in the niraparib group, 59% of patients with HRD were alive without disease progression, as compared to 35% in the placebo group. This clinical observation supports the hypothesis that niraparib has mechanisms of action other than those involved in the repair of DNA damage, such as PARP-regulated gene transcription, ribosome biogenesis and immune activation.15
When discussing the safety profile of niraparib, Dr. González-Martín commented, “The adverse events in the trial were similar to what has been previously reported for niraparib.” Treatment discontinuation due to adverse events was observed in 12% of patients on niraparib and 2.5% on placebo.1 However, according to the patient-reported outcomes, niraparib treatment did not affect the patients’ quality of life.1
In light of these findings, Dr. González-Martín emphasized, “Niraparib monotherapy after first-line platinum chemotherapy should be considered a new standard of care.”14
Currently available therapies together with active surveillance do not address the unmet need in patients with newly diagnosed advanced ovarian cancer after platinum-based chemotherapy. Late-line niraparib therapy in patients with advanced ovarian cancer provided clinically meaningful improvement in PFS. Furthermore, niraparib extended its benefits even to the subgroup of patients at the highest risk of early disease progression. Therefore, clinicians should consider including niraparib monotherapy in the treatment of advanced ovarian cancer after first-line platinum-based chemotherapy.
1. González-Martín A et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. September 2019.
2. Fizazi K et al. LBA15_PRA phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04). Annals of Oncology. 2019;30(Supplement_5):mdz394.
3. Momenimovahed Z et al. Ovarian cancer in the world: epidemiology and risk factors. Int J Womens Health. 2019;11:287-299.
4. Yoneda A et al. Breast and ovarian cancers: a survey and possible roles for the cell surface heparan sulfate proteoglycans. J Histochem Cytochem. 2012;60(1):9-21.
5. Bray F et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
6. Morgan RJ et al. Ovarian Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14(9):1134-1163.
7. McMeekin DS et al. Timing isn’t everything: an analysis of when to start salvage chemotherapy in ovarian cancer. Gynecol Oncol. 2004;95(1):157-164.
8. Alvarez RD et al. Moving beyond the platinum sensitive/resistant paradigm for patients with recurrent ovarian cancer. Gynecol Oncol. 2016;141(3):405-409.
9. Mirza MR et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016;375(22):2154-2164.
10. Hanker LC et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012;23(10):2605-2612.
11. Damia G, Broggini M. Platinum Resistance in Ovarian Cancer: Role of DNA Repair. Cancers (Basel). 2019;11(1).
12. Del Campo JM et al. Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial. J Clin Oncol. June 2019:JCO1802238.
13. Moore KN et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):636-648.
14. PARP Inhibitors Move Into First-Line for Ovarian Cancer. Medscape. http://www.medscape.com/viewarticle/919162. Accessed October 28, 2019.
15. Kim D-S et al. Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21. Mol Cell. 2019;75(6):1270-1285.e14.